Difference between revisions of "Chronic lymphocytic leukemia"
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− | ''' | + | <span id="BackToTop"></span> |
− | + | <div class="noprint" style="background-color:LightGray; position:fixed; bottom:2%; right:0.25%; padding-left:5px; padding-right:5px; margin: 15px; opacity:0.8; border-style: solid; border-color:DarkGray; border-width: 1px"> | |
− | + | [[#top|Back to Top]] | |
− | + | </div> | |
+ | {{#lst:Editorial board transclusions|cll}} | ||
+ | ''Are you looking for a regimen but can't find it here? It is possible that we've moved it to the [[Chronic_lymphocytic_leukemia_-_historical|historical regimens page]]. For placebo or observational studies in this condition, other than watchful waiting, please visit [[Chronic lymphocytic leukemia - null regimens|this page]]. If you still can't find it, please let us know so we can add it!'' | ||
+ | <br>'''Note: there are several regimens on this page that are specific to small lymphocytic lymphoma (SLL). The vast majority of the regimens here were evaluated in patients with CLL or in mixed populations of patients with CLL and SLL.''' | ||
+ | *''We have moved [[How I Treat]] articles to a dedicated page.'' | ||
{| class="wikitable" style="float:right; margin-right: 5px;" | {| class="wikitable" style="float:right; margin-right: 5px;" | ||
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− | |<div style="background-color: # | + | |<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div> |
− | <div style="background-color: # | + | <div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div> |
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{{TOC limit|limit=3}} | {{TOC limit|limit=3}} | ||
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=Guidelines= | =Guidelines= | ||
− | == | + | '''Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.''' |
− | *[ | + | ==ASBMT== |
− | *[ | + | *'''2016:''' Kharfan-Dabaja et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5116249/ Clinical practice recommendations for use of allogeneic hematopoietic cell transplantation in chronic lymphocytic leukemia on behalf of the guidelines committee of the American Society for Blood and Marrow Transplantation] [https://pubmed.ncbi.nlm.nih.gov/27660167/ PubMed] |
− | *[ | + | ==[https://www.esmo.org/ ESMO]== |
− | + | *'''2021:''' Eichhorst et al. [https://doi.org/10.1016/j.annonc.2020.09.019 Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/33091559/ PubMed] | |
+ | **'''2015:''' Eichhorst et al. [https://doi.org/10.1093/annonc/mdv303 Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/26314781/ PubMed] | ||
+ | **'''2011:''' Eichhorst et al. [https://doi.org/10.1093/annonc/mdr377 Chronic lymphocytic leukemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/21908504/ PubMed] | ||
+ | **'''2010:''' Eichhorst et al. [https://doi.org/10.1093/annonc/mdq180 Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/20555070/ PubMed] | ||
+ | **'''2009:''' Eichhorst et al. [https://doi.org/10.1093/annonc/mdp142 Chronic lymphocytic leukemia: ESMO minimum clinical recommendations for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/19454423/ PubMed] | ||
+ | **'''2008:''' Eichhorst et al. [https://doi.org/10.1093/annonc/mdn090 Chronic lymphocytic leukemia: ESMO clinical recommendations for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/18456771/ PubMed] | ||
+ | **'''2007:''' Hallek. [https://doi.org/10.1093/annonc/mdm034 Chronic lymphocytic leukemia: ESMO clinical recommendations for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/17491044/ PubMed] | ||
+ | **'''2005:''' Hallek et al. [https://doi.org/10.1093/annonc/mdi806 ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of chronic lymphocytic leukemia] [https://pubmed.ncbi.nlm.nih.gov/15888753/ PubMed] | ||
+ | *'''2016:''' Ladetto et al. [https://doi.org/10.1093/annonc/mdw419 ESMO consensus conference on malignant lymphoma: general perspectives and recommendations for prognostic tools in mature B-cell lymphomas and chronic lymphocytic leukaemia] [https://pubmed.ncbi.nlm.nih.gov/27701070/ PubMed] | ||
+ | *'''2013:''' Ghielmini et al. [https://doi.org/10.1093/annonc/mds517 ESMO Guidelines consensus conference on malignant lymphoma 2011 part 1: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL)] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6267877/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23175624/ PubMed] | ||
+ | ==International Workshop on Chronic Lymphocytic Leukemia (iwCLL)== | ||
+ | *'''2018:''' Hallek et al. [https://doi.org/10.1182/blood-2017-09-806398 iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL] [https://pubmed.ncbi.nlm.nih.gov/29540348/ PubMed] | ||
+ | *'''2008:''' Hallek et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2972576/ Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines] [https://pubmed.ncbi.nlm.nih.gov/18216293 PubMed] | ||
+ | *'''1996:''' Cheson et al. [https://doi.org/10.1182/blood.V87.12.4990.bloodjournal87124990 National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment] [https://pubmed.ncbi.nlm.nih.gov/8652811/ PubMed] | ||
==NCCN== | ==NCCN== | ||
− | *[https://www.nccn.org/ | + | *[https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1478 NCCN Guidelines - Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma] |
+ | **'''2020:''' Wierda et al. [https://doi.org/10.6004/Jnccn.2020.0006 Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 4.2020, NCCN Clinical Practice Guidelines in Oncology.] [https://pubmed.ncbi.nlm.nih.gov/32023533/ PubMed] | ||
+ | **'''2015:''' Zelenetz et al. [https://doi.org/10.6004/jnccn.2015.0045 Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 1.2015] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4841457/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25736010/ PubMed] | ||
− | = | + | =First-line therapy, randomized data= |
+ | ==Acalabrutinib monotherapy {{#subobject:85jgb3|Regimen=1}}== | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen {{#subobject:cjbu87|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8670015/ Byrd et al. 2021 (ACE-CL-001 untreated)] | ||
+ | |2014-2015 | ||
+ | |style="background-color:#91cf61"|Phase 1/2 | ||
+ | |style="background-color:#d3d3d3"| | ||
+ | |style="background-color:#d3d3d3"| | ||
+ | |- | ||
+ | |rowspan=2|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8151619/ Sharman et al. 2020 (ELEVATE TN)] | ||
+ | |rowspan=2|2015-2017 | ||
+ | |rowspan=2 style="background-color:#1a9851"|Phase 3 (E-RT-switch-ooc) | ||
+ | |1. [[#Acalabrutinib_.26_Obinutuzumab|Acalabrutinib & Obinutuzumab]] | ||
+ | |style="background-color:#d3d3d3"|Not reported | ||
+ | |- | ||
+ | |2. [[#Chlorambucil_.26_Obinutuzumab_.28GClb.29|Chlorambucil & Obinutuzumab]] | ||
+ | |style="background-color:#1a9850"|Superior PFS (primary endpoint)<br>Median PFS: NYR vs 22.6 mo<br>(HR 0.20, 95% CI 0.13-0.30) | ||
+ | |- | ||
+ | |} | ||
+ | ''Note: Byrd et al. 2021 reports on a treatment-naive cohort from a trial that mostly enrolled patients in relapse.'' | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
+ | ====Targeted therapy==== | ||
+ | *[[Acalabrutinib (Calquence)]] 100 mg PO twice per day or 200 mg PO once per day | ||
+ | '''Continued indefinitely''' | ||
+ | </div></div> | ||
+ | ===References=== | ||
+ | # '''ELEVATE TN:''' Sharman JP, Egyed M, Jurczak W, Skarbnik A, Pagel JM, Flinn IW, Kamdar M, Munir T, Walewska R, Corbett G, Fogliatto LM, Herishanu Y, Banerji V, Coutre S, Follows G, Walker P, Karlsson K, Ghia P, Janssens A, Cymbalista F, Woyach JA, Salles G, Wierda WG, Izumi R, Munugalavadla V, Patel P, Wang MH, Wong S, Byrd JC. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020 Apr 18;395(10232):1278-1291. [https://doi.org/10.1016/s0140-6736(20)30262-2 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8151619/ link to PMC article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/32305093/ PubMed] [https://clinicaltrials.gov/study/NCT02475681 NCT02475681] | ||
+ | # '''ACE-CL-001 untreated:''' Byrd JC, Woyach JA, Furman RR, Martin P, O'Brien S, Brown JR, Stephens DM, Barrientos JC, Devereux S, Hillmen P, Pagel JM, Hamdy A, Izumi R, Patel P, Wang MH, Jain N, Wierda WG. Acalabrutinib in treatment-naive chronic lymphocytic leukemia. Blood. 2021 Jun 17;137(24):3327-3338. [https://doi.org/10.1182/blood.2020009617 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8670015/ link to PMC article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/33786588/ PubMed] [https://clinicaltrials.gov/study/NCT02029443 NCT02029443] | ||
− | == | + | ==Acalabrutinib & Obinutuzumab {{#subobject:85jajb|Regimen=1}}== |
− | {| class="wikitable" style=" | + | <div class="toccolours" style="background-color:#eeeeee"> |
+ | ===Regimen {{#subobject:cjb857|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
+ | |- | ||
+ | |rowspan=2|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8151619/ Sharman et al. 2020 (ELEVATE TN)] | ||
+ | |rowspan=2|2015-2017 | ||
+ | |rowspan=2 style="background-color:#1a9851"|Phase 3 (E-RT-switch-ooc) | ||
+ | |1. [[#Acalabrutinib_monotherapy|Acalabrutinib]] | ||
+ | |style="background-color:#d3d3d3"|Not reported | ||
+ | |- | ||
+ | |2. [[#Chlorambucil_.26_Obinutuzumab_.28GClb.29|Chlorambucil & Obinutuzumab]] | ||
+ | |style="background-color:#1a9850"|Superior PFS (primary endpoint)<br>Median PFS: NYR vs 22.6 mo<br>(HR 0.10, 95% CI 0.06-0.17) | ||
|- | |- | ||
− | |||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
+ | ====Targeted therapy==== | ||
+ | *[[Acalabrutinib (Calquence)]] 100 mg PO twice per day | ||
+ | *[[Obinutuzumab (Gazyva)]] as follows: | ||
+ | **Cycle 2: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15 | ||
+ | **Cycles 3 to 7: 1000 mg IV once on day 1 | ||
+ | '''28-day cycles''' | ||
+ | </div></div> | ||
+ | ===References=== | ||
+ | # '''ELEVATE TN:''' Sharman JP, Egyed M, Jurczak W, Skarbnik A, Pagel JM, Flinn IW, Kamdar M, Munir T, Walewska R, Corbett G, Fogliatto LM, Herishanu Y, Banerji V, Coutre S, Follows G, Walker P, Karlsson K, Ghia P, Janssens A, Cymbalista F, Woyach JA, Salles G, Wierda WG, Izumi R, Munugalavadla V, Patel P, Wang MH, Wong S, Byrd JC. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020 Apr 18;395(10232):1278-1291. [https://doi.org/10.1016/s0140-6736(20)30262-2 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8151619/ link to PMC article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/32305093/ PubMed] [https://clinicaltrials.gov/study/NCT02475681 NCT02475681] | ||
+ | ==Alemtuzumab monotherapy {{#subobject:9ca7b3|Regimen=1}}== | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
===Regimen {{#subobject:54cc87|Variant=1}}=== | ===Regimen {{#subobject:54cc87|Variant=1}}=== | ||
− | {| | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | | | + | !style="width: 20%"|Study |
− | |[[Levels_of_Evidence#Evidence| | + | !style="width: 20%"|Dates of enrollment |
− | | | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | |[[Levels_of_Evidence# | + | !style="width: 20%"|Comparator |
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.2007.12.9098 Hillmen et al. 2007 (CAM 307)] |
− | |style="background-color:# | + | |2001-2004 |
− | |[[# | + | |style="background-color:#1a9851"|Phase 3 (E-RT-switch-ooc) |
− | |style="background-color:# | + | |[[Chronic_lymphocytic_leukemia_-_historical#Chlorambucil_monotherapy|Chlorambucil]] |
+ | |style="background-color:#1a9850"|Superior PFS<sup>1</sup> (primary endpoint)<br>Median PFS: 15 vs 12 mo<br>(aHR 0.58, 95% CI 0.43-0.77) | ||
|- | |- | ||
|} | |} | ||
− | ''This regimen was intended for patients who were at least 18 years old with flow cytometry–confirmed diagnosis of B-cell CLL, Rai stage I through IV with evidence of progression according to the [[#NCI_Sponsored_International_Working_Group_Criteria_.281999.29|National Cancer Institute Working Group (NCI-WG) 1996 criteria]], no previous chemotherapy for CLL, a life expectancy of at least 12 weeks, [[Performance_status#ECOG_performance_status_.28WHO.2FZubrod_score.29|WHO performance status]] of 0 to 2, and adequate renal and liver function.'' | + | ''<sup>1</sup>Median PFS is not reported in the manuscript and is estimated from the K-M curve (Figure 1A)''<br> |
− | ==== | + | <div class="toccolours" style="background-color:#fdcdac"> |
+ | ====Eligibility criteria==== | ||
+ | *This regimen was intended for patients who were at least 18 years old with flow cytometry–confirmed diagnosis of B-cell CLL, Rai stage I through IV with evidence of progression according to the [[#NCI_Sponsored_International_Working_Group_Criteria_.281999.29|National Cancer Institute Working Group (NCI-WG) 1996 criteria]], no previous chemotherapy for CLL, a life expectancy of at least 12 weeks, [[Performance_status#ECOG_performance_status_.28WHO.2FZubrod_score.29|WHO performance status]] of 0 to 2, and adequate renal and liver function.'' | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
+ | ====Targeted therapy==== | ||
*[[Alemtuzumab (Campath)]] as follows: | *[[Alemtuzumab (Campath)]] as follows: | ||
− | **3 mg IV once per day | + | **Starting dose: 3 mg IV once per day |
+ | **Once tolerated in terms of infusion reactions: 10 mg IV once per day | ||
+ | **Once tolerated in terms of infusion reactions: 30 mg IV once per day | ||
**Once 30 mg dose is tolerated: 30 mg IV over 2 hours, 3 times per week | **Once 30 mg dose is tolerated: 30 mg IV over 2 hours, 3 times per week | ||
− | ====Supportive | + | ====Supportive therapy==== |
*''See references for details, as they differ by paper.'' | *''See references for details, as they differ by paper.'' | ||
− | *[[Diphenhydramine (Benadryl)]] 50 mg PO once 30 minutes prior to | + | *[[Diphenhydramine (Benadryl)]] 50 mg PO once per infusion, 30 minutes prior to alemtuzumab |
− | *[[Acetaminophen (Tylenol)]] 650 mg PO once 30 minutes prior to | + | *[[Acetaminophen (Tylenol)]] 650 mg PO once per infusion, 30 minutes prior to alemtuzumab |
− | *[[Trimethoprim | + | *[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] 160/800 mg PO 3 times per week, starting on day 8, continuing at a minimum until 2 months after treatment is complete |
− | *[[Famciclovir (Famvir)]] 250 mg PO | + | *[[Famciclovir (Famvir)]] 250 mg PO twice per day, starting on day 8, continuing at a minimum until 2 months after treatment is complete |
− | + | '''12- to 16-week course; total course varies depending on reference''' | |
− | ''' | + | </div></div> |
− | |||
− | |||
− | |||
===References=== | ===References=== | ||
− | # Hillmen P, Skotnicki AB, Robak T, Jaksic B, Dmoszynska A, Wu J, Sirard C, Mayer J. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol. 2007 Dec 10;25(35):5616-23. Epub 2007 Nov 5. [ | + | # '''CAM 307:''' Hillmen P, Skotnicki AB, Robak T, Jaksic B, Dmoszynska A, Wu J, Sirard C, Mayer J. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol. 2007 Dec 10;25(35):5616-23. Epub 2007 Nov 5. [https://doi.org/10.1200/jco.2007.12.9098 link to original article] '''dosing details in abstract have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/17984186/ PubMed] [https://clinicaltrials.gov/study/NCT00046683 NCT00046683] |
− | + | ==Bendamustine monotherapy {{#subobject:694d2f|Regimen=1}}== | |
− | ==Bendamustine {{#subobject:694d2f|Regimen=1}}== | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | {| class="wikitable" style=" | + | ===Regimen {{#subobject:a166c6|Variant=1}}=== |
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.2008.20.8389 Knauf et al. 2009] |
− | | | + | |2002-2006 |
− | + | |style="background-color:#1a9851"|Phase 3 (E-RT-switch-ic) | |
− | + | |[[Chronic_lymphocytic_leukemia_-_historical#Chlorambucil_monotherapy|Chlorambucil]] | |
− | | | + | |style="background-color:#1a9850"|Superior PFS (co-primary endpoint)<br>Median PFS: 21.6 vs 8.3 mo |
− | |[[ | ||
− | | | ||
− | |||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1007/s10637-021-01206-2 Zhou et al. 2022 (SIM-79-001)] |
− | |style="background-color:# | + | |2009-2016 |
− | |[[# | + | |style="background-color:#1a9851"|Phase 3 (E-switch-ic) |
− | |style="background-color:# | + | |[[Chronic_lymphocytic_leukemia_-_historical#Chlorambucil_monotherapy|Chlorambucil]] |
+ | |style="background-color:#1a9850"|Superior PFS (secondary endpoint)<br>Median PFS: 16.5 vs 9.6 mo<br><br>Superior ORR (primary endpoint) | ||
|- | |- | ||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#fdcdac"> | |
− | + | ====Eligibility criteria==== | |
+ | *This regimen was intended for previously untreated CLL patients up to 75 years old with [[#Binet_staging_.281981.29|Binet stage]] B or C disease in need for treatment per the [[#NCI_Sponsored_Working_Group_Criteria_.281996.29|NCI-WG guidelines]] or [[#International_Workshop_on_Chronic_Lymphocytic_Leukemia_guidelines_.282008.29|IWCLL guidelines]].'' | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | + | *[[Bendamustine]] 100 mg/m<sup>2</sup> IV once per day on days 1 & 2 | |
− | *[[Bendamustine]] 100 mg/m<sup>2</sup> IV | ||
− | |||
'''28-day cycle for 6 cycles''' | '''28-day cycle for 6 cycles''' | ||
− | + | </div></div> | |
===References=== | ===References=== | ||
<!-- Presented in part at the Annual Meeting of the American Society of Hematology, Atlanta, GA, December 6-9, 2008, and San Francisco, CA, December 8-11, 2007. --> | <!-- Presented in part at the Annual Meeting of the American Society of Hematology, Atlanta, GA, December 6-9, 2008, and San Francisco, CA, December 8-11, 2007. --> | ||
− | # Knauf WU, Lissichkov T, Aldaoud A, Liberati A, Loscertales J, Herbrecht R, Juliusson G, Postner G, Gercheva L, Goranov S, Becker M, Fricke HJ, Huguet F, Del Giudice I, Klein P, Tremmel L, Merkle K, Montillo M. Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009 Sep 10;27(26):4378-84. Epub 2009 Aug 3. [ | + | # Knauf WU, Lissichkov T, Aldaoud A, Liberati A, Loscertales J, Herbrecht R, Juliusson G, Postner G, Gercheva L, Goranov S, Becker M, Fricke HJ, Huguet F, Del Giudice I, Klein P, Tremmel L, Merkle K, Montillo M. Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009 Sep 10;27(26):4378-84. Epub 2009 Aug 3. [https://doi.org/10.1200/jco.2008.20.8389 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/19652068/ PubMed] |
− | ## '''Update:''' Knauf WU, Lissitchkov T, Aldaoud A, Liberati AM, Loscertales J, Herbrecht R, Juliusson G, Postner G, Gercheva L, Goranov S, Becker M, Fricke HJ, Huguet F, Del Giudice I, Klein P, Merkle K, Montillo M. Bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukaemia: updated results of a randomized phase III trial. Br J Haematol. 2012 Oct;159(1):67-77. Epub 2012 Aug 4. [ | + | ## '''Update:''' Knauf WU, Lissitchkov T, Aldaoud A, Liberati AM, Loscertales J, Herbrecht R, Juliusson G, Postner G, Gercheva L, Goranov S, Becker M, Fricke HJ, Huguet F, Del Giudice I, Klein P, Merkle K, Montillo M. Bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukaemia: updated results of a randomized phase III trial. Br J Haematol. 2012 Oct;159(1):67-77. Epub 2012 Aug 4. [https://doi.org/10.1111/bjh.12000 link to original article] [https://pubmed.ncbi.nlm.nih.gov/22861163/ PubMed] |
− | # '''Retrospective:''' Kolibaba KS, Sterchele JA, Joshi AD, Forsyth M, Alwon E, Beygi H, Kennealey GT. Demographics, treatment patterns, safety, and real-world effectiveness in patients aged 70 years and over with chronic lymphocytic leukemia receiving bendamustine with or without rituximab: a retrospective study. Ther Adv Hematol. 2013 Jun;4(3):157-71. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3666446/ link to PMC article] [https:// | + | # '''Retrospective:''' Kolibaba KS, Sterchele JA, Joshi AD, Forsyth M, Alwon E, Beygi H, Kennealey GT. Demographics, treatment patterns, safety, and real-world effectiveness in patients aged 70 years and over with chronic lymphocytic leukemia receiving bendamustine with or without rituximab: a retrospective study. Ther Adv Hematol. 2013 Jun;4(3):157-71. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3666446/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23730494/ PubMed] |
+ | #'''SIM-79-001:''' Zhou D, Xu W, Ma H, Zhao C, Hu Y, Zhao Y, Wu D, Zhao X, He Y, Yan J, Wang C, Meng F, Jin J, Zhang X, Yu K, Hu J, Lv Y. Bendamustine versus chlorambucil in treatment of chronic lymphocytic leukaemia in China: a randomized, open-label, parallel-controlled, phase III clinical trial. Invest New Drugs. 2022 Apr;40(2):349-360. Epub 2022 Jan 15. [https://doi.org/10.1007/s10637-021-01206-2 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/35031896/ PubMed] [https://clinicaltrials.gov/study/NCT01109264 NCT01109264] | ||
− | ==BR {{#subobject:7542a2|Regimen=1}}== | + | ==Bendamustine & Rituximab (BR) {{#subobject:7542a2|Regimen=1}}== |
− | {| class="wikitable" style=" | + | BR: '''<u>B</u>'''endamustine & '''<u>R</u>'''ituximab |
+ | <br>R-B: '''<u>R</u>'''ituximab & '''<u>B</u>'''endamustine | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #1, 6 cycles {{#subobject:da5692|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.2011.39.2688 Fischer et al. 2012 (GCLLSG CLL2M untreated)] |
− | + | |2007-2008 | |
− | + | |style="background-color:#91cf61"|Phase 2 | |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |style="background-color:# | ||
|style="background-color:#d3d3d3"| | |style="background-color:#d3d3d3"| | ||
|style="background-color:#d3d3d3"| | |style="background-color:#d3d3d3"| | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1016/S1470-2045(16)30051-1 Eichhorst et al. 2016 (GCLLSG CLL10)] |
− | |style="background-color:# | + | |2008-2011 |
+ | |style="background-color:#1a9851"|Phase 3 (E-switch-ic) | ||
|[[#FCR|FCR]] | |[[#FCR|FCR]] | ||
− | |style="background-color:# | + | | style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS (primary endpoint)<br>Median PFS: 41.7 vs 55.2 mo<br>(HR 1.64, 90.4% CI 1.31-2.06) |
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865431/ Michallet et al. 2018 (MABLE)] | ||
+ | |2010-2014 | ||
+ | | style="background-color:#1a9851"|Phase 3b (E-switch-ic) | ||
+ | |[[#Chlorambucil_.26_Rituximab_.28RClb.29|R-Clb]] | ||
+ | | style="background-color:#1a9850" |Superior PFS (secondary endpoint)<br>Median PFS: 39.6 vs 29.9 mo<br>(HR 0.52, 95% CI 0.34-0.81) | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6325637/ Woyach et al. 2018 (Alliance A041202)] | ||
+ | |2013-2016 | ||
+ | | style="background-color:#1a9851"|Phase 3 (C) | ||
+ | |1. [[#Ibrutinib_monotherapy|Ibrutinib]]<br>2. [[#Ibrutinib_.26_Rituximab|Ibrutinib & Rituximab]] | ||
+ | | style="background-color:#d73027" |Inferior PFS | ||
+ | |- | ||
+ | |rowspan=2|[https://doi.org/10.1056/nejmoa2213093 Eichhorst et al. 2023 (GAIA)] | ||
+ | |rowspan=2|2016-12-13 to 2019-10-13 | ||
+ | |rowspan=2 style="background-color:#1a9851" |Phase 3 (C) | ||
+ | |1. [[#Venetoclax_.26_Obinutuzumab|Venetoclax & Obinutuzumab]]<br>2. [[#Ibrutinib.2C_Venetoclax.2C_Obinutuzumab|Ibrutinib, Venetoclax, Obinutuzumab]] | ||
+ | | style="background-color:#d73027" |Inferior PFS | ||
+ | |- | ||
+ | |3. [[#Venetoclax_.26_Rituximab_999|Venetoclax & Rituximab]] | ||
+ | | style="background-color:#ffffbf" |Did not meet primary endpoint of PFS | ||
+ | |- | ||
+ | |[https://doi.org/10.1016/s1470-2045(22)00293-5 Tam et al. 2022 (SEQUOIA<sub>CLL</sub>)] | ||
+ | |2017-2019 | ||
+ | |style="background-color:#1a9851"|Phase 3 (C) | ||
+ | |[[#Zanubrutinib_monotherapy|Zanubrutinib]] | ||
+ | | style="background-color:#d73027" |Inferior PFS | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#fdcdac"> | ||
+ | ====Eligibility criteria==== | ||
+ | *GAIA: Older than 65 years old | ||
+ | ====Biomarker eligibility criteria==== | ||
+ | *SEQUOIA<sub>CLL</sub>: No 17p deletion | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Bendamustine]] 90 mg/m<sup>2</sup> IV once per day on days 1 & 2 | *[[Bendamustine]] 90 mg/m<sup>2</sup> IV once per day on days 1 & 2 | ||
+ | ====Targeted therapy==== | ||
*[[Rituximab (Rituxan)]] as follows: | *[[Rituximab (Rituxan)]] as follows: | ||
− | **Cycle 1: 375 mg/m<sup>2</sup> IV once on day 0 | + | **Cycle 1: 375 mg/m<sup>2</sup> IV once on day 0 or 1 |
− | ** | + | **Cycle 2 up to 6: 500 mg/m<sup>2</sup> IV once on day 1 |
− | + | '''28-day cycle for up to 6 cycles''' | |
− | '''28-day cycle for up to 6 cycles | + | </div></div><br> |
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | === | + | ===Regimen variant #2, 6 cycles with escalation {{#subobject:da70c2|Variant=1}}=== |
− | # | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | + | !style="width: 20%"|Study | |
− | + | !style="width: 20%"|Dates of enrollment | |
− | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | |
− | + | !style="width: 20%"|Comparator | |
− | + | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | |
− | + | |- | |
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6325637/ Woyach et al. 2018 (Alliance A041202)] | ||
+ | |2013-2016 | ||
+ | | style="background-color:#1a9851"|Phase 3 (C) | ||
+ | |1. [[#Ibrutinib_monotherapy|Ibrutinib]]<br>2. [[#Ibrutinib_.26_Rituximab|Ibrutinib & Rituximab]] | ||
+ | | style="background-color:#d73027" |Inferior PFS | ||
|- | |- | ||
− | |||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#f2f3f4"> | |
− | + | ====Chemotherapy==== | |
− | ===Regimen {{#subobject: | + | *[[Bendamustine]] as follows: |
− | {| | + | **Cycle 1: 70 mg/m<sup>2</sup> IV once per day on days 1 & 2 |
− | | | + | **Cycles 2 to 6: 90 mg/m<sup>2</sup> IV once per day on days 1 & 2 |
− | |[[Levels_of_Evidence#Evidence| | + | ====Targeted therapy==== |
− | | | + | *[[Rituximab (Rituxan)]] as follows: |
− | + | **Cycle 1: 375 mg/m<sup>2</sup> IV once on day 0 | |
− | + | **Cycle 2 up to 6: 500 mg/m<sup>2</sup> IV once on day 1 | |
− | + | '''28-day cycle for 6 cycles''' | |
− | + | </div></div><br> | |
− | |[[# | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | + | ===Regimen variant #3, 6 cycles with maintenance rituximab {{#subobject:da5ii2|Variant=1}}=== | |
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[[# | + | |[https://doi.org/10.1056/nejmoa2201817 Wang et al. 2022 (SHINE)] |
− | |style="background-color:# | + | |2013-05 to 2014-11 |
+ | |style="background-color:#1a9851"|Phase 3 (C) | ||
+ | |[[#Bendamustine_.26_Rituximab_.28BR.29_.26_Ibrutinib|BR & Ibrutinib]] | ||
+ | | style="background-color:#fc8d59" |Seems to have inferior PFS | ||
|- | |- | ||
|} | |} | ||
+ | ''Note: the cycle timing changes during rituximab maintenance; the dosing does not change.'' | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[ | + | *[[Bendamustine]] as follows: |
− | *[[ | + | **Cycles 1 to 6: 90 mg/m<sup>2</sup> IV once per day on days 1 & 2 |
− | * | + | ====Targeted therapy==== |
− | + | *[[Rituximab (Rituxan)]] as follows: | |
− | ''' | + | **Cycles 1 to 6: 375 mg/m<sup>2</sup> IV once on day 1 |
+ | **Cycles 7 to 18: 375 mg/m<sup>2</sup> IV once on day 1 | ||
+ | '''28-day cycle for 6 cycles, then 8-week cycle for 12 cycles''' | ||
+ | </div></div> | ||
===References=== | ===References=== | ||
− | # | + | # '''GCLLSG CLL2M untreated:''' Fischer K, Cramer P, Busch R, Böttcher S, Bahlo J, Schubert J, Pflüger KH, Schott S, Goede V, Isfort S, von Tresckow J, Fink AM, Bühler A, Winkler D, Kreuzer KA, Staib P, Ritgen M, Kneba M, Döhner H, Eichhorst BF, Hallek M, Stilgenbauer S, Wendtner CM. Bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. 2012 Sep 10;30(26):3209-16. Epub 2012 Aug 6. [https://doi.org/10.1200/jco.2011.39.2688 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/22869884/ PubMed] [https://clinicaltrials.gov/study/NCT00274989 NCT00274989] |
+ | # '''Retrospective:''' Kolibaba KS, Sterchele JA, Joshi AD, Forsyth M, Alwon E, Beygi H, Kennealey GT. Demographics, treatment patterns, safety, and real-world effectiveness in patients aged 70 years and over with chronic lymphocytic leukemia receiving bendamustine with or without rituximab: a retrospective study. Ther Adv Hematol. 2013 Jun;4(3):157-71. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3666446/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23730494/ PubMed] | ||
+ | <!-- # '''Abstract:''' Barbara Eichhorst, MD, Anna-Maria Fink, MD, Raymonde Busch, PhD, Elisabeth Lange, MD, Hubert Köppler, Prof. Dr., Michael Kiehl, MD, Martin Sökler, MD, Rudolf Schlag, MD, Ursula Vehling-Kaiser, MD, Georg Köchling, MD, Christoph Plöger, MD, Michael Gregor, MD, Torben Plesner, MD, Marek Trneny, MD, Ph.D., Prof, Kirsten Fischer, MD, Hartmut Döhner, MD, Michael Kneba, MD, Clemens Wendtner, MD, Wolfram Klapper, Karl-Anton Kreuzer, Dr. med., Stephan Stilgenbauer, MD, Sebastian Böttcher, MD, and Michael Hallek, MD. Chemoimmunotherapy With Fludarabine (F), Cyclophosphamide (C), and Rituximab (R) (FCR) Versus Bendamustine and Rituximab (BR) In Previously Untreated and Physically Fit Patients (pts) With Advanced Chronic Lymphocytic Leukemia (CLL): Results Of a Planned Interim Analysis Of The CLL10 Trial, An International, Randomized Study Of The German CLL Study Group (GCLLSG). 2013 ASH Annual Symposium abstract 526 [https://doi.org/10.1182/blood.V122.21.526.526 link to abstract] --> | ||
+ | # '''GCLLSG CLL10:''' Eichhorst B, Fink AM, Bahlo J, Busch R, Kovacs G, Maurer C, Lange E, Köppler H, Kiehl M, Sökler M, Schlag R, Vehling-Kaiser U, Köchling G, Plöger C, Gregor M, Plesner T, Trneny M, Fischer K, Döhner H, Kneba M, Wendtner CM, Klapper W, Kreuzer KA, Stilgenbauer S, Böttcher S, Hallek M; International Group of Investigators; GCLLSG. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016 Jul;17(7):928-42. Epub 2016 May 20. [https://doi.org/10.1016/S1470-2045(16)30051-1 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/27216274/ PubMed] [https://clinicaltrials.gov/study/NCT00769522 NCT00769522] | ||
+ | # '''MABLE:''' Michallet AS, Aktan M, Hiddemann W, Ilhan O, Johansson P, Laribi K, Meddeb B, Moreno C, Raposo J, Schuh A, Ünal A, Widenius T, Bernhardt A, Kellershohn K, Messeri D, Osborne S, Leblond V. Rituximab plus bendamustine or chlorambucil for chronic lymphocytic leukemia: primary analysis of the randomized, open-label MABLE study. Haematologica. 2018 Apr;103(4):698-706. Epub 2018 Feb 1. [https://doi.org/10.3324/haematol.2017.170480 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865431/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29419437/ PubMed] [https://clinicaltrials.gov/study/NCT01056510 NCT01056510] | ||
+ | # '''Alliance A041202:''' Woyach JA, Ruppert AS, Heerema NA, Zhao W, Booth AM, Ding W, Bartlett NL, Brander DM, Barr PM, Rogers KA, Parikh SA, Coutre S, Hurria A, Brown JR, Lozanski G, Blachly JS, Ozer HG, Major-Elechi B, Fruth B, Nattam S, Larson RA, Erba H, Litzow M, Owen C, Kuzma C, Abramson JS, Little RF, Smith SE, Stone RM, Mandrekar SJ, Byrd JC. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018 Dec 27;379(26):2517-2528. Epub 2018 Dec 1. [https://doi.org/10.1056/NEJMoa1812836 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6325637/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30501481/ PubMed] [https://clinicaltrials.gov/study/NCT01886872 NCT01886872] | ||
+ | ##'''Update:''' Woyach JA, Perez Burbano G, Ruppert AS, Miller C, Heerema NA, Zhao W, Wall A, Ding W, Bartlett NL, Brander DM, Barr PM, Rogers KA, Parikh SA, Stephens DM, Brown JR, Lozanski G, Blachly J, Nattam S, Larson RA, Erba H, Litzow M, Luger S, Owen C, Kuzma C, Abramson JS, Little RF, Dinner S, Stone RM, Uy G, Stock W, Mandrekar SJ, Byrd JC. Follow-up from the A041202 study shows continued efficacy of ibrutinib regimens for older adults with CLL. Blood. 2024 Apr 18;143(16):1616-1627. [https://doi.org/10.1182/blood.2023021959 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11103091/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/38215395/ PubMed] | ||
+ | # '''SHINE:''' Wang ML, Jurczak W, Jerkeman M, Trotman J, Zinzani PL, Belada D, Boccomini C, Flinn IW, Giri P, Goy A, Hamlin PA, Hermine O, Hernández-Rivas JÁ, Hong X, Kim SJ, Lewis D, Mishima Y, Özcan M, Perini GF, Pocock C, Song Y, Spurgeon SE, Storring JM, Walewski J, Zhu J, Qin R, Henninger T, Deshpande S, Howes A, Le Gouill S, Dreyling M; SHINE Investigators. Ibrutinib plus Bendamustine and Rituximab in Untreated Mantle-Cell Lymphoma. N Engl J Med. 2022 Jun 30;386(26):2482-2494. Epub 2022 Jun 3. [https://doi.org/10.1056/nejmoa2201817 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/35657079/ PubMed] [https://clinicaltrials.gov/study/NCT01776840 NCT01776840] | ||
+ | # '''SEQUOIA<sub>CLL</sub>:''' Tam CS, Brown JR, Kahl BS, Ghia P, Giannopoulos K, Jurczak W, Šimkovič M, Shadman M, Österborg A, Laurenti L, Walker P, Opat S, Chan H, Ciepluch H, Greil R, Tani M, Trněný M, Brander DM, Flinn IW, Grosicki S, Verner E, Tedeschi A, Li J, Tian T, Zhou L, Marimpietri C, Paik JC, Cohen A, Huang J, Robak T, Hillmen P. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022 Aug;23(8):1031-1043. Epub 2022 Jul 7. [https://doi.org/10.1016/s1470-2045(22)00293-5 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/35810754/ PubMed] [https://clinicaltrials.gov/study/NCT03336333 NCT03336333] | ||
+ | ##'''HRQoL analysis:''' Ghia P, Barnes G, Yang K, Tam CS, Robak T, Brown JR, Kahl BS, Tian T, Szeto A, Paik JC, Shadman M. Health-related quality-of-life in treatment-naive CLL/SLL patients treated with zanubrutinib versus bendamustine plus rituximab. Curr Med Res Opin. 2023 Nov;39(11):1505-1511. Epub 2023 Oct 12. [https://doi.org/10.1080/03007995.2023.2262381 link to original article] [https://pubmed.ncbi.nlm.nih.gov/37752878/ PubMed] | ||
+ | #'''GAIA:''' Eichhorst B, Niemann CU, Kater AP, Fürstenau M, von Tresckow J, Zhang C, Robrecht S, Gregor M, Juliusson G, Thornton P, Staber PB, Tadmor T, Lindström V, da Cunha-Bang C, Schneider C, Poulsen CB, Illmer T, Schöttker B, Nösslinger T, Janssens A, Christiansen I, Baumann M, Frederiksen H, van der Klift M, Jäger U, Leys MBL, Hoogendoorn M, Lotfi K, Hebart H, Gaska T, Koene H, Enggaard L, Goede J, Regelink JC, Widmer A, Simon F, De Silva N, Fink AM, Bahlo J, Fischer K, Wendtner CM, Kreuzer KA, Ritgen M, Brüggemann M, Tausch E, Levin MD, van Oers M, Geisler C, Stilgenbauer S, Hallek M; GCLLSG, the HOVON and Nordic CLL Study Groups, the SAKK, the Israeli CLL Association, and Cancer Trials Ireland. First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia. N Engl J Med. 2023 May 11;388(19):1739-1754. [https://doi.org/10.1056/nejmoa2213093 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/37163621/ PubMed] [https://clinicaltrials.gov/study/NCT02950051 NCT02950051] | ||
+ | ##'''Update:''' Fürstenau M, Kater AP, Robrecht S, von Tresckow J, Zhang C, Gregor M, Thornton P, Staber PB, Tadmor T, Lindström V, Juliusson G, Janssens A, Levin MD, da Cunha-Bang C, Schneider C, Goldschmidt N, Vandenberghe E, Rossi D, Benz R, Nösslinger T, Heintel D, Poulsen CB, Christiansen I, Frederiksen H, Enggaard L, Posthuma EFM, Issa DE, Visser HPJ, Bellido M, Kutsch N, Dürig J, Stehle A, Vöhringer M, Böttcher S, Schulte C, Simon F, Fink AM, Fischer K, Holmes EE, Kreuzer KA, Ritgen M, Brüggemann M, Tausch E, Stilgenbauer S, Hallek M, Niemann CU, Eichhorst B. First-line venetoclax combinations versus chemoimmunotherapy in fit patients with chronic lymphocytic leukaemia (GAIA/CLL13): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2024 Jun;25(6):744-759. Erratum in: Lancet Oncol. 2024 Jul;25(7):e284. [https://doi.org/10.1016/s1470-2045(24)00196-7 link to original article] [https://pubmed.ncbi.nlm.nih.gov/38821083/ PubMed] | ||
+ | # '''ACE-CL-311:''' [https://clinicaltrials.gov/study/NCT03836261 NCT03836261] | ||
+ | # '''BRUIN CLL-313:''' [https://clinicaltrials.gov/study/NCT05023980 NCT05023980] | ||
+ | # '''CRISTALLO:''' [https://clinicaltrials.gov/study/NCT04285567 NCT04285567] | ||
− | == | + | ==Bendamustine & Rituximab (BR) & Ibrutinib {{#subobject:98jg89|Regimen=1}}== |
− | {| class="wikitable" style=" | + | BR & Ibrutinib: '''<u>B</u>'''endamustine, '''<u>R</u>'''ituximab, Ibrutinib |
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen {{#subobject:adhgg4|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1056/nejmoa2201817 Wang et al. 2022 (SHINE)] |
− | + | |2013-05 to 2014-11 | |
− | + | |style="background-color:#1a9851"|Phase 3 (E-esc) | |
− | + | |[[#Bendamustine_.26_Rituximab_.28BR.29|BR]] | |
− | + | | style="background-color:#91cf60" |Seems to have superior PFS (primary endpoint)<br>Median PFS: 80.6 vs 52.9 mo<br>(HR 0.75, 95% CI 0.59-0.96) | |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |style="background-color:# | ||
− | |[[# | ||
− | |style="background-color:# | ||
|- | |- | ||
|} | |} | ||
+ | ''Note: the cycle timing changes during rituximab maintenance; the dosing does not change.'' | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[ | + | *[[Bendamustine]] as follows: |
− | *[[ | + | **Cycles 1 to 6: 90 mg/m<sup>2</sup> IV once per day on days 1 & 2 |
+ | ====Targeted therapy==== | ||
+ | *[[Rituximab (Rituxan)]] as follows: | ||
+ | **Cycles 1 to 6: 375 mg/m<sup>2</sup> IV once on day 1 | ||
+ | **Cycles 7 to 18: 375 mg/m<sup>2</sup> IV once on day 1 | ||
+ | *[[Ibrutinib (Imbruvica)]] as follows: | ||
+ | **Cycles 1 to 6: 560 mg PO once per day on days 1 to 28 | ||
+ | **Cycle 7 onwards: 560 mg PO once per day on days 1 to 56 | ||
+ | '''28-day cycle for 6 cycles, then 8-week cycles''' | ||
+ | </div></div> | ||
+ | ===References=== | ||
+ | # '''SHINE:''' Wang ML, Jurczak W, Jerkeman M, Trotman J, Zinzani PL, Belada D, Boccomini C, Flinn IW, Giri P, Goy A, Hamlin PA, Hermine O, Hernández-Rivas JÁ, Hong X, Kim SJ, Lewis D, Mishima Y, Özcan M, Perini GF, Pocock C, Song Y, Spurgeon SE, Storring JM, Walewski J, Zhu J, Qin R, Henninger T, Deshpande S, Howes A, Le Gouill S, Dreyling M; SHINE Investigators. Ibrutinib plus Bendamustine and Rituximab in Untreated Mantle-Cell Lymphoma. N Engl J Med. 2022 Jun 30;386(26):2482-2494. Epub 2022 Jun 3. [https://doi.org/10.1056/nejmoa2201817 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/35657079/ PubMed] [https://clinicaltrials.gov/study/NCT01776840 NCT01776840] | ||
− | === | + | ==Cladribine & Cyclophosphamide (CC) {{#subobject:719404|Regimen=1}}== |
− | + | CC: '''<u>C</u>'''ladribine, '''<u>C</u>'''yclophosphamide | |
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | ''' | + | ===Regimen variant #1, 0.36/650 {{#subobject:add51b|Variant=1}}=== |
− | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" | |
− | ===Regimen # | + | !style="width: 20%"|Study |
− | {| | + | !style="width: 20%"|Dates of enrollment |
− | | | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | |[[Levels_of_Evidence#Evidence| | + | !style="width: 20%"|Comparator |
− | | | + | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] |
− | |[[Levels_of_Evidence# | ||
|- | |- | ||
− | |rowspan=2|[ | + | |rowspan=2|[https://doi.org/10.1182/blood-2005-12-4828 Robak et al. 2006 (PALG CLL2)] |
− | |rowspan=2 style="background-color:# | + | |rowspan=2|1998-2003 |
− | |[[# | + | |rowspan=2 style="background-color:#1a9851"|Phase 3 (E-esc) |
− | |style="background-color:# | + | |1. [[#Cladribine_monotherapy|Cladribine]] |
+ | |style="background-color:#d9ef8b"|Might have superior CR rate (primary endpoint) | ||
|- | |- | ||
− | |CMC | + | |2. [[Chronic_lymphocytic_leukemia_-_historical#CMC|CMC]] |
− | |style="background-color:# | + | |style="background-color:#fc8d59"|Seems to have inferior CR rate (primary endpoint) |
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Cladribine (Leustatin)]] 0.12 mg/kg IV over 2 hours once per day on days 1 to 3 | *[[Cladribine (Leustatin)]] 0.12 mg/kg IV over 2 hours once per day on days 1 to 3 | ||
*[[Cyclophosphamide (Cytoxan)]] 650 mg/m<sup>2</sup> IV once on day 1 | *[[Cyclophosphamide (Cytoxan)]] 650 mg/m<sup>2</sup> IV once on day 1 | ||
− | + | ====Supportive therapy==== | |
− | ====Supportive | ||
*No routine prophylactic antibiotics, antiviral agents, or growth factor administration was planned. | *No routine prophylactic antibiotics, antiviral agents, or growth factor administration was planned. | ||
− | |||
'''28-day cycle for up to 6 cycles''' | '''28-day cycle for up to 6 cycles''' | ||
− | + | </div></div><br> | |
− | == | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | + | ===Regimen variant #2, 0.36/750 {{#subobject:99a67c|Variant=1}}=== | |
− | # | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | + | !style="width: 20%"|Study | |
− | # | + | !style="width: 20%"|Dates of enrollment |
− | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | |
− | + | !style="width: 20%"|Comparator | |
− | {| class="wikitable" style=" | + | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] |
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.2009.25.9630 Robak et al. 2010 (PALG-CLL3)] |
− | + | |2004-2007 | |
− | + | |style="background-color:#1a9851"|Phase 3 (E-switch-ic) | |
− | + | |[[Chronic_lymphocytic_leukemia_-_historical#Cyclophosphamide_.26_Fludarabine_.28FC.29|FC]] | |
− | + | |style="background-color:#ffffbf"|Did not meet primary endpoint of CR rate | |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | | | ||
− | |||
− | |style="background-color:# | ||
− | |||
− | |[[# | ||
− | |style="background-color:# | ||
− | |||
− | |||
− | |||
− | |||
− | |||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[ | + | *[[Cladribine (Leustatin)]] 0.12 mg/kg IV over 30 minutes once per day on days 1 to 3 |
− | + | *[[Cyclophosphamide (Cytoxan)]] 250 mg/m<sup>2</sup> IV over 30 to 60 minutes once per day on days 1 to 3 | |
− | ====Supportive | + | ====Supportive therapy==== |
− | * | + | *"No routine prophylaxis with antibiotics, antiviral agents, or growth factors." |
− | + | '''28-day cycle for up to 6 cycles''' | |
− | ''' | + | </div></div> |
− | + | ===References=== | |
− | ===Regimen # | + | # '''PALG CLL2:''' Robak T, Blonski JZ, Gora-Tybor J, Jamroziak K, Dwilewicz-Trojaczek J, Tomaszewska A, Konopka L, Ceglarek B, Dmoszynska A, Kowal M, Kloczko J, Stella-Holowiecka B, Sulek K, Calbecka M, Zawilska K, Kuliczkowski K, Skotnicki AB, Warzocha K, Kasznicki M; PALG. Cladribine alone and in combination with cyclophosphamide or cyclophosphamide plus mitoxantrone in the treatment of progressive chronic lymphocytic leukemia: report of a prospective, multicenter, randomized trial of the Polish Adult Leukemia Group (PALG CLL2). Blood. 2006 Jul 15;108(2):473-9. Epub 2006 Mar 21. [https://doi.org/10.1182/blood-2005-12-4828 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/16551966/ PubMed] |
− | {| | + | ## '''Update:''' Robak T, Blonski JZ, Gora-Tybor J, Calbecka M, Dwilewicz-Trojaczek J, Boguradzki P, Dmoszynska A, Kowal M, Kloczko J, Piszcz J, Stella-Holowiecka B, Sulek K, Kuliczkowski K, Potoczek S, Warzocha K, Lech-Maranda E, Skotnicki AB, Piotrowska M, Moskwa A, Zawilska K, Jamroziak K. Long-term results of the Polish Adult Leukemia Group PALG-CLL2 phase III randomized study comparing cladribine-based combinations in chronic lymphocytic leukemia. Leuk Lymphoma. 2014 Mar;55(3):606-10. Epub 2013 Nov 14. [https://doi.org/10.3109/10428194.2013.809073 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23721512/ PubMed] |
− | | | + | <!-- Presented at the 48th Annual Meeting of the American Society of Hematology, December 9-12, 2006, Orlando, FL; the 12th Congress of the European Hematology Association, June 7-10, 2007, Vienna, Austria; the XII International Workshop on Chronic Lymphocytic Leukemia, September 14-16, 2007, London, United Kingdom; the 49th Annual Meeting of the American Society of Hematology, December 8-11, 2007, Atlanta, GA; the 13th Congress of the European Hematology Association, June 12-15, 2008, Copenhagen, Denmark; and the 50th Annual Meeting of the American Society of Hematology, December 6-9, 2008, San Francisco, CA. --> |
− | |[[Levels_of_Evidence#Evidence| | + | # '''PALG-CLL3:''' Robak T, Jamroziak K, Gora-Tybor J, Stella-Holowiecka B, Konopka L, Ceglarek B, Warzocha K, Seferynska I, Piszcz J, Calbecka M, Kostyra A, Dwilewicz-Trojaczek J, Dmoszyñska A, Zawilska K, Hellmann A, Zdunczyk A, Potoczek S, Piotrowska M, Lewandowski K, Blonski JZ. Comparison of cladribine plus cyclophosphamide with fludarabine plus cyclophosphamide as first-line therapy for chronic lymphocytic leukemia: a phase III randomized study by the Polish Adult Leukemia Group (PALG-CLL3 Study). J Clin Oncol. 2010 Apr 10;28(11):1863-9. Epub 2010 Mar 8. [https://doi.org/10.1200/jco.2009.25.9630 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/20212251/ PubMed] |
− | | | + | ==Chlorambucil & Obinutuzumab (GClb) {{#subobject:50878e|Regimen=1}}== |
− | |[[Levels_of_Evidence# | + | GClb: '''<u>G</u>'''A101 (Obinutuzumab) & '''<u>C</u>'''h'''<u>l</u>'''oram'''<u>b</u>'''ucil |
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #1, 6 cycles {{#subobject:9c3473|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |rowspan = "2" |[ | + | |rowspan = "2" |[https://doi.org/10.1056/NEJMoa1313984 Goede et al. 2014 (GCLLSG CLL11)] |
− | |rowspan = "2" style="background-color:# | + | |rowspan=2|2010-2012 |
− | |[[# | + | |rowspan = "2" style="background-color:#1a9851"|Phase 3 (E-RT-esc) |
− | |style="background-color:# | + | |1. [[Chronic_lymphocytic_leukemia_-_historical#Chlorambucil_monotherapy|Chlorambucil]] |
+ | |style="background-color:#1a9850"|Superior OS (secondary endpoint)<br>Median OS: NYR vs NYR<br>(HR 0.41, 95% CI 0.23-0.74)<br><br>Superior PFS (primary endpoint)<br>Median PFS: 26.7 vs 11.1 mo<br>(HR 0.18, 95% CI 0.13-0.24) | ||
|- | |- | ||
− | |[[#Chlorambucil_.26_Rituximab_.28RClb | + | |2. [[#Chlorambucil_.26_Rituximab_.28RClb.29|Chlorambucil & Rituximab]] |
− | |style="background-color:# | + | |style="background-color:#1a9850"|Superior PFS (primary endpoint)<br>(HR 0.39, 95% CI 0.31-0.49) |
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1016/S1470-2045(18)30788-5 Moreno et al. 2018 (iLLUMINATE)] |
− | |style="background-color:# | + | |2014-10-06 to 2015-10-12 |
− | |[[#Ibrutinib_. | + | | style="background-color:#1a9851" |Phase 3 (C) |
− | |style="background-color:# | + | |[[#Ibrutinib_.26_Obinutuzumab|Ibrutinib & Obinutuzumab]] |
+ | | style="background-color:#d73027" |Inferior PFS | ||
|- | |- | ||
− | | | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8151619/ Sharman et al. 2020 (ELEVATE TN)] |
− | + | |2015-2017 | |
− | + | | style="background-color:#1a9851"|Phase 3 (C) | |
− | + | |1. [[#Acalabrutinib_monotherapy|Acalabrutinib]]<br>2. [[#Acalabrutinib_.26_Obinutuzumab|Acalabrutinib & Obinutuzumab]] | |
− | + | | style="background-color:#d73027" |Inferior PFS | |
− | |||
− | |||
− | |||
− | |||
− | |||
− | | | ||
− | |[[ | ||
− | |||
− | |||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1056/EVIDoa2200006 Kater et al. 2022 (GLOW)] |
− | |style="background-color:# | + | |2018-05 to 2019-04 |
− | |[[# | + | | style="background-color:#1a9851" |Phase 3 (C) |
− | |style="background-color:# | + | |[[#Ibrutinib_.26_Venetoclax|Ibrutinib & Venetoclax]] |
+ | | style="background-color:#d73027" |Inferior PFS | ||
|- | |- | ||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#fdcdac"> | |
+ | ====Eligibility criteria==== | ||
+ | *GLOW: At least 65 years old or 18 to 64 years old with a Cumulative Illness Rating Scale (CIRS) score greater than 6 | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[Chlorambucil (Leukeran)]] 0. | + | *[[Chlorambucil (Leukeran)]] 0.5 mg/kg PO once per day on days 1 & 15 |
− | ** | + | ====Targeted therapy==== |
− | + | *[[Obinutuzumab (Gazyva)]] as follows: | |
− | '''28-day cycle for | + | **Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15 |
− | + | **Cycles 2 to 6: 1000 mg IV once on day 1 | |
− | ===Regimen # | + | '''28-day cycle for 6 cycles''' |
− | {| | + | </div></div><br> |
− | | | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | |[[Levels_of_Evidence#Evidence| | + | ===Regimen variant #2, 12 cycles {{#subobject:9c6233|Variant=1}}=== |
− | | | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | |[[Levels_of_Evidence# | + | !style="width: 20%"|Study |
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1056/NEJMoa1815281 Fischer et al. 2019 (GCLLSG CLL14)] |
− | |style="background-color:# | + | |2015-08-07 to 2016-08-04 |
− | |[[# | + | |style="background-color:#1a9851"|Phase 3 (C) |
− | |style="background-color:# | + | |[[#Venetoclax_.26_Obinutuzumab|Venetoclax & Obinutuzumab]] |
+ | | style="background-color:#d73027" |Inferior PFS | ||
|- | |- | ||
|} | |} | ||
− | '' | + | ''Note: Obinutuzumab is only given for the first six cycles.'' |
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[Chlorambucil (Leukeran)]] as follows: | + | *[[Chlorambucil (Leukeran)]] 0.5 mg/kg PO once per day on days 1 & 15 |
− | **Cycle 1: | + | ====Targeted therapy==== |
− | ** | + | *[[Obinutuzumab (Gazyva)]] as follows: |
+ | **Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15 | ||
+ | **Cycles 2 to 6: 1000 mg IV once on day 1 | ||
+ | '''28-day cycle for 12 cycles''' | ||
+ | </div></div> | ||
+ | ===References=== | ||
+ | <!-- # '''Abstract:''' Valentin Goede, Kirsten Fischer, Kathryn Humphrey, Elina Asikanius, Raymonde Busch, Anja Engelke, Clemens M. Wendtner, Olga Samoylova, Tatiana Chagorova, Marie-Sarah Dilhuydy, Javier De La Serna Torroba, Thomas Illmer, Stephen Opat, Carolyn Owen, Karl A Kreuzer, Anton W Langerak, Matthias Ritgen, Stephan Stilgenbauer, Michael Wenger, Michael Hallek; German CLL Study Group. Obinutuzumab (GA101) plus chlorambucil (Clb) or rituximab (R) plus Clb versus Clb alone in patients with chronic lymphocytic leukemia (CLL) and preexisting medical conditions (comorbidities): Final stage 1 results of the CLL11 (BO21004) phase III trial. J Clin Oncol 31, 2013 (suppl; abstr 7004) [https://doi.org/10.1200/jco.2013.31.15_suppl.7004 link to abstract] --> | ||
+ | # '''GCLLSG CLL11:''' Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, Chagorova T, de la Serna J, Dilhuydy MS, Illmer T, Opat S, Owen CJ, Samoylova O, Kreuzer KA, Stilgenbauer S, Döhner H, Langerak AW, Ritgen M, Kneba M, Asikanius E, Humphrey K, Wenger M, Hallek M. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014 Mar 20;370(12):1101-10. Epub 2014 Jan 8. [https://doi.org/10.1056/NEJMoa1313984 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/24401022/ PubMed] [https://clinicaltrials.gov/study/NCT01010061 NCT01010061] | ||
+ | ## '''Update:''' Goede V, Fischer K, Engelke A, Schlag R, Lepretre S, Casado Montero LF, Montillo M, Fegan C, Asikanius E, Humphrey K, Fingerle-Rowson G, Hallek M. Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study. Leukemia. 2015 Jul;29(7):1602-4. Epub 2015 Jan 30. [https://doi.org/10.1038/leu.2015.14 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25634683/ PubMed] | ||
+ | # '''iLLUMINATE:''' Moreno C, Greil R, Demirkan F, Tedeschi A, Anz B, Larratt L, Simkovic M, Samoilova O, Novak J, Ben-Yehuda D, Strugov V, Gill D, Gribben JG, Hsu E, Lih CJ, Zhou C, Clow F, James DF, Styles L, Flinn IW. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019 Jan;20(1):43-56. Epub 2018 Nov 30. [https://doi.org/10.1016/S1470-2045(18)30788-5 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/30522969/ PubMed] [https://clinicaltrials.gov/study/NCT02264574 NCT02264574] | ||
+ | # '''GCLLSG CLL14:''' Fischer K, Al-Sawaf O, Bahlo J, Fink AM, Tandon M, Dixon M, Robrecht S, Warburton S, Humphrey K, Samoylova O, Liberati AM, Pinilla-Ibarz J, Opat S, Sivcheva L, Le Dû K, Fogliatto LM, Niemann CU, Weinkove R, Robinson S, Kipps TJ, Boettcher S, Tausch E, Humerickhouse R, Eichhorst B, Wendtner CM, Langerak AW, Kreuzer KA, Ritgen M, Goede V, Stilgenbauer S, Mobasher M, Hallek M. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019 Jun 6;380(23):2225-2236. Epub 2019 Jun 4. [https://doi.org/10.1056/NEJMoa1815281 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/31166681/ PubMed] [https://clinicaltrials.gov/study/NCT02242942 NCT02242942] | ||
+ | ## '''Update:''' Al-Sawaf O, Zhang C, Tandon M, Sinha A, Fink AM, Robrecht S, Samoylova O, Liberati AM, Pinilla-Ibarz J, Opat S, Sivcheva L, Le Dû K, Fogliatto LM, Niemann CU, Weinkove R, Robinson S, Kipps TJ, Tausch E, Schary W, Ritgen M, Wendtner CM, Kreuzer KA, Eichhorst B, Stilgenbauer S, Hallek M, Fischer K. Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2020 Sep;21(9):1188-1200. [https://doi.org/10.1016/s1470-2045(20)30443-5 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32888452/ PubMed] | ||
+ | ## '''Update:''' Al-Sawaf O, Zhang C, Lu T, Liao MZ, Panchal A, Robrecht S, Ching T, Tandon M, Fink AM, Tausch E, Schneider C, Ritgen M, Böttcher S, Kreuzer KA, Chyla B, Miles D, Wendtner CM, Eichhorst B, Stilgenbauer S, Jiang Y, Hallek M, Fischer K. Minimal Residual Disease Dynamics after Venetoclax-Obinutuzumab Treatment: Extended Off-Treatment Follow-up From the Randomized CLL14 Study. J Clin Oncol. 2021 Dec 20;39(36):4049-4060. Epub 2021 Oct 28. [https://doi.org/10.1200/jco.21.01181 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8678026/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34709929/ PubMed] | ||
+ | # '''ELEVATE TN:''' Sharman JP, Egyed M, Jurczak W, Skarbnik A, Pagel JM, Flinn IW, Kamdar M, Munir T, Walewska R, Corbett G, Fogliatto LM, Herishanu Y, Banerji V, Coutre S, Follows G, Walker P, Karlsson K, Ghia P, Janssens A, Cymbalista F, Woyach JA, Salles G, Wierda WG, Izumi R, Munugalavadla V, Patel P, Wang MH, Wong S, Byrd JC. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020 Apr 18;395(10232):1278-1291. [https://doi.org/10.1016/s0140-6736(20)30262-2 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8151619/ link to PMC article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/32305093/ PubMed] [https://clinicaltrials.gov/study/NCT02475681 NCT02475681] | ||
+ | # '''GLOW:''' Kater AP, Owen C, Moreno C, Follows G, Munir T, Levin MD, Benjamini O, Janssens A, Osterborg A, Robak T, Simkovic M, Stevens D, Voloshin S, Vorobyev V, Ysebaert L, Qin R, Steele AJ, Schuier N, Baeten K, Caces DB, Niemann CU. Fixed-Duration Ibrutinib-Venetoclax in Patients with Chronic Lymphocytic Leukemia and Comorbidities. NEJM Evid. 2022 Jul;1(7):EVIDoa2200006. Epub 2022 May 13. [https://doi.org/10.1056/EVIDoa2200006 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/38319255/ PubMed] [https://clinicaltrials.gov/study/NCT03462719 NCT03462719] | ||
+ | ##'''Update:''' Niemann CU, Munir T, Moreno C, Owen C, Follows GA, Benjamini O, Janssens A, Levin MD, Robak T, Simkovic M, Voloshin S, Vorobyev V, Yagci M, Ysebaert L, Qi K, Qi Q, Sinet P, Parisi L, Srinivasan S, Schuier N, Baeten K, Howes A, Caces DB, Kater AP. Fixed-duration ibrutinib-venetoclax versus chlorambucil-obinutuzumab in previously untreated chronic lymphocytic leukaemia (GLOW): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2023 Dec;24(12):1423-1433. Epub 2023 Nov 6. [https://doi.org/10.1016/s1470-2045(23)00452-7 link to original article] [https://pubmed.ncbi.nlm.nih.gov/37944541/ PubMed] | ||
+ | # '''UNITY-CLL:''' [https://clinicaltrials.gov/study/NCT02612311 NCT02612311] | ||
− | ''' | + | ==Chlorambucil & Ofatumumab {{#subobject:c168f0|Regimen=1}}== |
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen {{#subobject:c88f0b|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
+ | |- | ||
+ | |[https://doi.org/10.1016/S0140-6736(15)60027-7 Hillmen et al. 2015 (COMPLEMENT 1)] | ||
+ | |2008-2011 | ||
+ | |style="background-color:#1a9851"|Phase 3 (E-RT-esc) | ||
+ | |[[Chronic_lymphocytic_leukemia_-_historical#Chlorambucil_monotherapy|Chlorambucil]] | ||
+ | |style="background-color:#1a9850"|Superior PFS (primary endpoint)<br>Median PFS: 22.4 vs 13.1 mo<br>(HR 0.57, 95% CI 0.45-0.72) | ||
+ | |- | ||
+ | |} | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
+ | ====Chemotherapy==== | ||
+ | *[[Chlorambucil (Leukeran)]] 10 mg/m<sup>2</sup> PO once per day on days 1 to 7 | ||
+ | ====Targeted therapy==== | ||
+ | *[[Ofatumumab (Arzerra)]] as follows: | ||
+ | **Cycle 1: 300 mg IV once on day 1, then 1000 mg IV once on day 8 | ||
+ | **Cycles 2 to 3 up to 12: 1000 mg IV once on day 1 | ||
+ | ====Supportive therapy==== | ||
+ | *Premedication for ofatumumab included [[Acetaminophen (Tylenol)]], [[:Category:Antihistamines|antihistamines]], and [[:Category:Steroids|glucocorticoids]] (no doses or further information provided) | ||
+ | '''28-day cycle for a minimum of 3 cycles, and then given until best response up to a maximum of 12 cycles''' | ||
+ | </div></div> | ||
+ | |||
+ | ===References=== | ||
+ | <!-- # '''Abstract:''' Hillmen P, Tadeusz R, Janssens A, Govindbabu K, Grosicki S, Mayer J, Panagiotidis P, Kimby E, Schuh A, Boyd T, Montillo M, McKeown A, Carey J, Gupta I, Chang C, Lisby S, Offner F. Ofatumumab + Chlorambucil Versus Chlorambucil Alone In Patients With Untreated Chronic Lymphocytic Leukemia (CLL): Results Of The Phase III Study Complement 1 (OMB110911). ASH 2013 Annual Meeting abstract 528.--> | ||
+ | # '''COMPLEMENT 1:''' Hillmen P, Robak T, Janssens A, Babu KG, Kloczko J, Grosicki S, Doubek M, Panagiotidis P, Kimby E, Schuh A, Pettitt AR, Boyd T, Montillo M, Gupta IV, Wright O, Dixon I, Carey JL, Chang CN, Lisby S, McKeown A, Offner F; COMPLEMENT 1 Study Investigators. Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial. Lancet. 2015 May 9;385(9980):1873-83. Epub 2015 Apr 13. [https://doi.org/10.1016/S0140-6736(15)60027-7 link to original article] '''dosing details in abstract have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/25882396/ PubMed] [https://clinicaltrials.gov/study/NCT00748189 NCT00748189] | ||
+ | ## '''Update:''' Offner F, Robak T, Janssens A, Govind Babu K, Kloczko J, Grosicki S, Mayer J, Panagiotidis P, Schuh A, Pettitt A, Montillo M, Werner O, Vincent G, Khanna S, Hillmen P. A five-year follow-up of untreated patients with chronic lymphocytic leukaemia treated with ofatumumab and chlorambucil: final analysis of the Complement 1 phase 3 trial. Br J Haematol. 2020 Sep;190(5):736-740. Epub 2020 Mar 31. [https://doi.org/10.1111/bjh.16625 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32236950/ PubMed] | ||
− | ===Regimen #5 {{#subobject: | + | ==Chlorambucil & Rituximab (RClb) {{#subobject:af2f90|Regimen=1}}== |
− | {| | + | RClb: '''<u>R</u>'''ituximab & '''<u>C</u>'''h'''<u>l</u>'''oram'''<u>b</u>'''ucil |
− | | | + | <br>CLB-R: '''<u>C</u>'''h'''<u>L</u>'''oram'''<u>B</u>'''ucil & '''<u>R</u>'''ituximab |
− | |[[Levels_of_Evidence#Evidence| | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | | | + | ===Regimen variant #1, Clb 0.5 mg/kg q2wk {{#subobject:bdacc9|Variant=1}}=== |
− | |[[Levels_of_Evidence# | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |rowspan=2|[ | + | |rowspan = "2" |[https://doi.org/10.1056/NEJMoa1313984 Goede et al. 2014 (GCLLSG CLL11)] |
− | |rowspan=2 style="background-color:# | + | |rowspan=2|2010-2012 |
− | |Chlorambucil | + | |rowspan = "2" style="background-color:#1a9851"|Phase 3 (E-esc) |
− | |style="background-color:# | + | |1. [[Chronic_lymphocytic_leukemia_-_historical#Chlorambucil_monotherapy|Chlorambucil]] |
+ | |style="background-color:#1a9850"|Superior PFS (primary endpoint)<br>Median PFS: 16.3 vs 11.1 mo<br>(HR 0.44, 95% CI 0.34-0.57) | ||
|- | |- | ||
− | |[[# | + | |2. [[#Chlorambucil_.26_Obinutuzumab_.28GClb.29|Chlorambucil & Obinutuzumab]] |
− | |style="background-color:# | + | |style="background-color:#d73027"|Inferior PFS (primary endpoint) |
|- | |- | ||
− | |[ | + | |[https://www.clinicaltrials.gov/study/NCT04075292 Awaiting publication (D822BC00001)] |
− | |style="background-color:# | + | |2020-2024 |
− | |[[# | + | |style="background-color:#1a9851"|Phase 3 (C) |
− | |style="background-color:# | + | |[[#Acalabrutinib_monotherapy|Acalabrutinib]] |
+ | |style="background-color:#d3d3d3"|TBD if different primary endpoint of PFS | ||
|- | |- | ||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#f2f3f4"> | |
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[Chlorambucil (Leukeran)]] | + | *[[Chlorambucil (Leukeran)]] 0.5 mg/kg PO once per day on days 1 & 15 |
− | + | ====Targeted therapy==== | |
− | '''28-day cycle for | + | *[[Rituximab (Rituxan)]] as follows: |
− | + | **Cycle 1: 375 mg/m<sup>2</sup> IV once on day 1 | |
− | ===Regimen # | + | **Cycles 2 to 6: 500 mg/m<sup>2</sup> IV once on day 1 |
− | {| | + | '''28-day cycle for 6 cycles''' |
− | | | + | </div></div><br> |
− | |[[Levels_of_Evidence#Evidence| | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | + | ===Regimen variant #2, Clb 8 mg/m<sup>2</sup>/d, 1 week out of 4 {{#subobject:ab165a|Variant=1}}=== | |
− | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" | |
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1002/ajh.23668 Foà et al. 2014 (ML21445)] |
− | | | + | |2008-2013 |
− | + | |style="background-color:#91cf61"|Non-randomized part of phase 2 RCT | |
− | |style="background-color:# | ||
|- | |- | ||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#f2f3f4"> | |
− | |||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[Chlorambucil (Leukeran)]] | + | *[[Chlorambucil (Leukeran)]] 8 mg/m<sup>2</sup> PO once per day on days 1 to 7 |
− | + | ====Targeted therapy==== | |
− | + | *[[Rituximab (Rituxan)]] as follows: | |
− | === | + | **Cycle 3: 375 mg/m<sup>2</sup> IV once on day 1 |
− | + | **Cycles 4 to 8: 500 mg/m<sup>2</sup> IV once on day 1 | |
− | + | '''28-day cycle for up to 8 cycles''' | |
− | + | </div> | |
− | + | <div class="toccolours" style="background-color:#cbd5e7"> | |
− | |||
− | |||
− | |||
− | |||
− | < | ||
− | |||
− | < | ||
− | |||
− | |||
− | < | ||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | ===Regimen {{#subobject: | + | ====Subsequent treatment==== |
− | {| | + | *ML21445, PR or better: [[Chronic_lymphocytic_leukemia_-_null_regimens#Observation|Observation]] versus [[#Rituximab_monotherapy_2|Rituximab]] maintenance |
− | | | + | </div></div><br> |
− | |[[Levels_of_Evidence#Evidence| | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | | | + | ===Regimen variant #3, Clb 10 mg/m<sup>2</sup>/d, 1 week out of 4 {{#subobject:8723f7|Variant=1}}=== |
− | |[[Levels_of_Evidence# | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4876343/ Hillmen et al. 2014 (NCRI CLL208)] | |
− | | | + | |2007-2009 |
− | | | + | |style="background-color:#91cf61"|Phase 2 |
− | |style="background-color:# | + | | style="background-color:#d3d3d3" | |
+ | | style="background-color:#d3d3d3" | | ||
|- | |- | ||
− | |[[# | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865431/ Michallet et al. 2018 (MABLE)] |
− | |style="background-color:# | + | |2010-2014 |
+ | | style="background-color:#1a9851"|Phase 3b (E-switch-ic) | ||
+ | |[[#Bendamustine_.26_Rituximab_.28BR.29|BR]] | ||
+ | | style="background-color:#d73027" |Inferior PFS (secondary endpoint) | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[ | + | *[[Chlorambucil (Leukeran)]] 10 mg/m<sup>2</sup> PO once per day on days 1 to 7 |
− | **Cycle 1: | + | ====Targeted therapy==== |
− | **Cycles 2 to 6: | + | *[[Rituximab (Rituxan)]] as follows: |
− | + | **Cycle 1: 375 mg/m<sup>2</sup> IV once on day 1 | |
− | + | **Cycles 2 to 6: 500 mg/m<sup>2</sup> IV once on day 1 | |
'''28-day cycle for 6 cycles''' | '''28-day cycle for 6 cycles''' | ||
− | + | </div> | |
+ | <div class="toccolours" style="background-color:#cbd5e7"> | ||
+ | ====Subsequent treatment==== | ||
+ | *NCRI CLL208, patients not achieving CR: Optional [[Chronic_lymphocytic_leukemia_-_historical#Chlorambucil_monotherapy|chlorambucil]] consolidation x up to 6 cycles | ||
+ | *MABLE, patients not achieving CR: Optional [[Chronic_lymphocytic_leukemia_-_historical#Chlorambucil_monotherapy|chlorambucil]] consolidation x up to 6 cycles or until CR | ||
+ | </div></div> | ||
===References=== | ===References=== | ||
− | <!-- # '''Abstract:''' Valentin Goede, Kirsten Fischer, Kathryn Humphrey, Elina Asikanius, Raymonde Busch, Anja Engelke, Clemens M. Wendtner, Olga Samoylova, Tatiana Chagorova, Marie-Sarah Dilhuydy, Javier De La Serna Torroba, Thomas Illmer, Stephen Opat, Carolyn Owen, Karl A Kreuzer, Anton W Langerak, Matthias Ritgen, Stephan Stilgenbauer, Michael Wenger, Michael Hallek; German CLL Study Group. Obinutuzumab (GA101) plus chlorambucil (Clb) or rituximab (R) plus Clb versus Clb alone in patients with chronic lymphocytic leukemia (CLL) and preexisting medical conditions (comorbidities): Final stage 1 results of the CLL11 (BO21004) phase III trial. J Clin Oncol 31, 2013 (suppl; abstr 7004) [ | + | <!-- # '''Abstract:''' Valentin Goede, Kirsten Fischer, Kathryn Humphrey, Elina Asikanius, Raymonde Busch, Anja Engelke, Clemens M. Wendtner, Olga Samoylova, Tatiana Chagorova, Marie-Sarah Dilhuydy, Javier De La Serna Torroba, Thomas Illmer, Stephen Opat, Carolyn Owen, Karl A Kreuzer, Anton W Langerak, Matthias Ritgen, Stephan Stilgenbauer, Michael Wenger, Michael Hallek; German CLL Study Group. Obinutuzumab (GA101) plus chlorambucil (Clb) or rituximab (R) plus Clb versus Clb alone in patients with chronic lymphocytic leukemia (CLL) and preexisting medical conditions (comorbidities): Final stage 1 results of the CLL11 (BO21004) phase III trial. J Clin Oncol 31, 2013 (suppl; abstr 7004) [https://doi.org/10.1200/jco.2013.31.15_suppl.7004 link to abstract] --> |
− | # Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, Chagorova T, de la Serna J, Dilhuydy MS, Illmer T, Opat S, Owen CJ, Samoylova O, Kreuzer KA, Stilgenbauer S, Döhner H, Langerak AW, Ritgen M, Kneba M, Asikanius E, Humphrey K, Wenger M, Hallek M. Obinutuzumab plus | + | # '''GCLLSG CLL11:''' Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, Chagorova T, de la Serna J, Dilhuydy MS, Illmer T, Opat S, Owen CJ, Samoylova O, Kreuzer KA, Stilgenbauer S, Döhner H, Langerak AW, Ritgen M, Kneba M, Asikanius E, Humphrey K, Wenger M, Hallek M. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014 Mar 20;370(12):1101-10. Epub 2014 Jan 8. [https://doi.org/10.1056/NEJMoa1313984 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/24401022/ PubMed] [https://clinicaltrials.gov/study/NCT01010061 NCT01010061] |
− | ## '''Update:''' Goede V, Fischer K, Engelke A, Schlag R, Lepretre S, Montero LF, Montillo M, Fegan C, Asikanius E, Humphrey K, Fingerle-Rowson G, Hallek M. Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study. Leukemia. 2015 Jul;29(7):1602-4. Epub 2015 Jan 30. [ | + | ## '''Update:''' Goede V, Fischer K, Engelke A, Schlag R, Lepretre S, Casado Montero LF, Montillo M, Fegan C, Asikanius E, Humphrey K, Fingerle-Rowson G, Hallek M. Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study. Leukemia. 2015 Jul;29(7):1602-4. Epub 2015 Jan 30. [https://doi.org/10.1038/leu.2015.14 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25634683/ PubMed] |
− | + | <!-- # '''Abstract:''' R Foa, A Alietti, A Guarini, S Ciolli, F Di Raimondo, G Del Poeta, F Lauria, F Forconi, A Cuneo, A Cortellezzi, F Nobile, V Callea, M Brugiatelli, M Massaia, S Molica, L Trentin, R Rizzi, G Specchia, L Orsucci, A Ambrosetti, M Montillo, L Zinzani, F Ferrara, F Morabito, M Mura, S Soriani, S Santangelo, M Marinelli, M De Propris, A Alietti, J Runggaldier. A PHASE II STUDY OF CHLORAMBUCIL+RITUXIMAB (CLB-R) FOLLOWED BY R MAINTENANCE VS OBSERVATION IN ELDERLY PATIENTS WITH PREVIOUSLY UNTREATED CHRONIC LYMPHOCYTIC LEUKEMIA (CLL): INDUCTION PHASE RESULTS. EHA Annual Meeting 2011, Abstract 0532--> | |
− | == | + | # '''ML21445:''' Foà R, Del Giudice I, Cuneo A, Del Poeta G, Ciolli S, Di Raimondo F, Lauria F, Cencini E, Rigolin GM, Cortelezzi A, Nobile F, Callea V, Brugiatelli M, Massaia M, Molica S, Trentin L, Rizzi R, Specchia G, Di Serio F, Orsucci L, Ambrosetti A, Montillo M, Zinzani PL, Ferrara F, Morabito F, Mura MA, Soriani S, Peragine N, Tavolaro S, Bonina S, Marinelli M, De Propris MS, Starza ID, Piciocchi A, Alietti A, Runggaldier EJ, Gamba E, Mauro FR, Chiaretti S, Guarini A. Chlorambucil plus rituximab with or without maintenance rituximab as first-line treatment for elderly chronic lymphocytic leukemia patients. Am J Hematol. 2014 May;89(5):480-6. Epub 2014 Feb 18. [https://doi.org/10.1002/ajh.23668 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/24415640/ PubMed] EudraCT 2008-001612-20 |
− | {| class="wikitable" style=" | + | # '''NCRI CLL08:''' Hillmen P, Gribben JG, Follows GA, Milligan D, Sayala HA, Moreton P, Oscier DG, Dearden CE, Kennedy DB, Pettitt AR, Nathwani A, Varghese A, Cohen D, Rawstron A, Oertel S, Pocock CF. Rituximab plus chlorambucil as first-line treatment for chronic lymphocytic leukemia: Final analysis of an open-label phase II study. J Clin Oncol. 2014 Apr 20;32(12):1236-41. Epub 2014 Mar 17. [https://doi.org/10.1200/jco.2013.49.6547 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4876343/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24638012/ PubMed] [https://clinicaltrials.gov/study/NCT00532129 NCT00532129] |
+ | # '''MABLE:''' Michallet AS, Aktan M, Hiddemann W, Ilhan O, Johansson P, Laribi K, Meddeb B, Moreno C, Raposo J, Schuh A, Ünal A, Widenius T, Bernhardt A, Kellershohn K, Messeri D, Osborne S, Leblond V. Rituximab plus bendamustine or chlorambucil for chronic lymphocytic leukemia: primary analysis of the randomized, open-label MABLE study. Haematologica. 2018 Apr;103(4):698-706. Epub 2018 Feb 1. [https://doi.org/10.3324/haematol.2017.170480 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865431/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29419437/ PubMed] [https://clinicaltrials.gov/study/NCT01056510 NCT01056510] | ||
+ | #'''D822BC00001:''' '''contains dosing details on CT.gov''' [https://clinicaltrials.gov/study/NCT04075292 NCT04075292] | ||
+ | ==Cladribine monotherapy {{#subobject:3ae1a1|Regimen=1}}== | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #1, 0.6 mg/kg {{#subobject:8cab02|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |rowspan=2|[https://doi.org/10.1182/blood-2005-12-4828 Robak et al. 2006 (PALG CLL2)] |
− | | | + | |rowspan=2|1998-2003 |
− | + | |rowspan=2 style="background-color:#1a9851"|Phase 3 (C) | |
− | + | |1. [[#Cladribine_.26_Cyclophosphamide_.28CC.29|CC]] | |
− | + | |style="background-color:#fee08b"|Might have inferior CR rate | |
− | | | ||
− | |[[ | ||
− | | | ||
− | |||
|- | |- | ||
− | | | + | |2. [[Chronic_lymphocytic_leukemia_-_historical#CMC|CMC]] |
− | + | |style="background-color:#d73027"|Inferior CR rate | |
− | |||
− | |style="background-color:# | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[ | + | *[[Cladribine (Leustatin)]] 0.12 mg/kg IV over 2 hours once per day on days 1 to 5 |
− | + | ====Supportive therapy==== | |
− | + | *No routine prophylactic antibiotics, antiviral agents, or growth factor administration was planned. | |
− | + | '''28-day cycle for up to 6 cycles''' | |
− | + | </div></div><br> | |
− | ====Supportive | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | * | + | ===Regimen variant #2, 0.7 mg/m<sup>2</sup> {{#subobject:57becf|Variant=1}}=== |
− | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" | |
− | '''28-day cycle for | + | !style="width: 33%"|Study |
− | + | !style="width: 33%"|Dates of enrollment | |
− | == | + | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | + | |- | |
− | # | + | |[https://doi.org/10.1200/jco.1995.13.3.570 Saven et al. 1995] |
− | + | |1988-1993 | |
− | + | |style="background-color:#91cf61"|Phase 2 | |
− | {| class="wikitable" style=" | ||
|- | |- | ||
− | |||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
+ | ====Chemotherapy==== | ||
+ | *[[Cladribine (Leustatin)]] 0.1 mg/m<sup>2</sup>/day IV continuous infusion over 7 days, started on day 1 (total dose per cycle: 0.7 mg/m<sup>2</sup>) | ||
+ | '''28- to 35-day cycles, repeated until maximum response or limiting toxicity''' | ||
+ | </div></div><br> | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
− | ===Regimen # | + | ===Regimen variant #3, 5 mg/m<sup>2</sup> {{#subobject:8yr302|Variant=1}}=== |
− | {| | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | | | + | !style="width: 20%"|Study |
− | |[[Levels_of_Evidence#Evidence| | + | !style="width: 20%"|Dates of enrollment |
− | | | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | |[[Levels_of_Evidence# | + | !style="width: 20%"|Comparator |
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.3109/10428194.2014.893306 Mulligan et al. 2014] |
− | |style="background-color:# | + | |1997-2004 |
− | |[[# | + | |style="background-color:#1a9851"|Phase 3 (E-switch-ic) |
− | |style="background-color:# | + | |1. [[Chronic_lymphocytic_leukemia_-_historical#Chlorambucil_monotherapy|Chlorambucil]]<br>2. [[Chronic_lymphocytic_leukemia_-_historical#Fludarabine_monotherapy|Fludarabine]] |
+ | | style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br><br>Superior PFS (secondary endpoint) | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[ | + | *[[Cladribine (Leustatin)]] 5 mg/m<sup>2</sup> SC or IV over 2 hours once per day on days 1 to 5 |
− | + | '''28-day cycle for up to 6 cycles''' | |
− | + | </div></div><br> | |
− | ''' | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | + | ===Regimen variant #4, 10 mg/m<sup>2</sup> {{#subobject:r4r302|Variant=1}}=== | |
− | ===Regimen #2 {{#subobject: | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | {| | + | !style="width: 20%"|Study |
− | | | + | !style="width: 20%"|Dates of enrollment |
− | |[[Levels_of_Evidence#Evidence| | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | | | + | !style="width: 20%"|Comparator |
− | |[[Levels_of_Evidence# | + | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] |
|- | |- | ||
− | |[ | + | |[https://doi.org/10.3109/10428194.2014.893306 Mulligan et al. 2014] |
− | |style="background-color:# | + | |1997-2004 |
− | |[[# | + | |style="background-color:#1a9851"|Phase 3 (E-switch-ic) |
− | |style="background-color:# | + | |1. [[Chronic_lymphocytic_leukemia_-_historical#Chlorambucil_monotherapy|Chlorambucil]]<br>2. [[Chronic_lymphocytic_leukemia_-_historical#Fludarabine_monotherapy|Fludarabine]] |
+ | | style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<br><br>Superior PFS (secondary endpoint) | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[ | + | *[[Cladribine (Leustatin)]] 10 mg/m<sup>2</sup> PO once per day on days 1 to 5 |
− | + | '''28-day cycle for up to 6 cycles''' | |
− | + | </div></div> | |
− | ''' | ||
− | |||
===References=== | ===References=== | ||
− | + | # Saven A, Lemon RH, Kosty M, Beutler E, Piro LD. 2-Chlorodeoxyadenosine activity in patients with untreated chronic lymphocytic leukemia. J Clin Oncol. 1995 Mar;13(3):570-4. [https://doi.org/10.1200/jco.1995.13.3.570 link to original article] '''dosing details in abstract have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/7884417/ PubMed] | |
− | + | # '''PALG CLL2:''' Robak T, Blonski JZ, Gora-Tybor J, Jamroziak K, Dwilewicz-Trojaczek J, Tomaszewska A, Konopka L, Ceglarek B, Dmoszynska A, Kowal M, Kloczko J, Stella-Holowiecka B, Sulek K, Calbecka M, Zawilska K, Kuliczkowski K, Skotnicki AB, Warzocha K, Kasznicki M; Polish Adult Leukemia Group. Cladribine alone and in combination with cyclophosphamide or cyclophosphamide plus mitoxantrone in the treatment of progressive chronic lymphocytic leukemia: report of a prospective, multicenter, randomized trial of the Polish Adult Leukemia Group (PALG CLL2). Blood. 2006 Jul 15;108(2):473-9. Epub 2006 Mar 21. [https://doi.org/10.1182/blood-2005-12-4828 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/16551966/ PubMed] | |
− | # | + | ## '''Update:''' Robak T, Blonski JZ, Gora-Tybor J, Calbecka M, Dwilewicz-Trojaczek J, Boguradzki P, Dmoszynska A, Kowal M, Kloczko J, Piszcz J, Stella-Holowiecka B, Sulek K, Kuliczkowski K, Potoczek S, Warzocha K, Lech-Maranda E, Skotnicki AB, Piotrowska M, Moskwa A, Zawilska K, Jamroziak K. Long-term results of the Polish Adult Leukemia Group PALG-CLL2 phase III randomized study comparing cladribine-based combinations in chronic lymphocytic leukemia. Leuk Lymphoma. 2014 Mar;55(3):606-10. Epub 2013 Nov 14. [https://doi.org/10.3109/10428194.2013.809073 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23721512/ PubMed] |
+ | # Mulligan SP, Karlsson K, Strömberg M, Jønsson V, Gill D, Hammerström J, Hertzberg M, McLennan R, Uggla B, Norman J, Wallvik J, Sundström G, Johansson H, Brandberg Y, Liliemark J, Juliusson G; Scandinavian Lymphoma Group; ALLG. Cladribine prolongs progression-free survival and time to second treatment compared to fludarabine and high-dose chlorambucil in chronic lymphocytic leukemia. Leuk Lymphoma. 2014 Dec;55(12):2769-77. Epub 2014 Apr 16. [https://doi.org/10.3109/10428194.2014.893306 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/24524339/ PubMed] | ||
− | == | + | ==FCA {{#subobject:68d031|Regimen=1}}== |
− | {| class="wikitable" style=" | + | FCA: '''<u>F</u>'''ludarabine, '''<u>C</u>'''yclophosphamide, '''<u>A</u>'''lemtuzumab |
+ | <br>FCCam: '''<u>F</u>'''ludarabine, '''<u>C</u>'''yclophosphamide, '''<u>Cam</u>'''path (Alemtuzumab) | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #1 {{#subobject:218cde|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1182/blood-2014-01-547737 Geisler et al. 2014 (HOVON-68)] |
− | + | |2006-2010 | |
− | + | |style="background-color:#1a9851"|Phase 3 (E-esc) | |
− | + | |[[Chronic_lymphocytic_leukemia_-_historical#Cyclophosphamide_.26_Fludarabine_.28FC.29|FC]] | |
− | + | |style="background-color:#1a9850"|Superior PFS (primary endpoint)<br>PFS36: 53% vs 37% | |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | | | ||
− | |||
− | |style="background-color:# | ||
− | |||
− | |[[# | ||
− | |style="background-color:# | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#fdcdac"> | ||
+ | ====Eligibility criteria==== | ||
+ | *HOVON-68: This regimen was intended for patients with previously untreated CLL diagnosed and in need of treatment according to the [[#NCI_Sponsored_Working_Group_Criteria_.281996.29|National Cancer Institute guidelines]], 18 to 75 years old, with [[Performance_status#ECOG_performance_status_.28WHO.2FZubrod_score.29|WHO performance status]] less than 3 and no severe comorbidities, with high-risk CLL as defined by the presence of either unmutated IGHV, [[#Risk_by_FISH_.282000.29|17p deletion, 11q deletion, or trisomy 12 by FISH]]. | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[ | + | *[[Fludarabine (Fludara)]] 40 mg/m<sup>2</sup> PO once per day on days 1 to 3 |
− | *[[ | + | *[[Cyclophosphamide (Cytoxan)]] 250 mg/m<sup>2</sup> PO once per day on days 1 to 3 |
− | + | ====Targeted therapy==== | |
− | **Cycles 2 to 6: | + | *[[Alemtuzumab (Campath)]] as follows: |
− | + | **Cycle 1: 30 mg SC once per day on days -1, 0, and 1 | |
+ | **Cycles 2 to 6: 30 mg SC once on day 1 | ||
+ | ====Supportive therapy==== | ||
+ | *[[Trimethoprim-Sulfamethoxazole (Bactrim DS) | Cotrimoxazole]] 400/80 mg PO once per day until 6 months after end of treatment | ||
+ | *One of the following: | ||
+ | **[[Acyclovir (Zovirax)]] 400 mg PO three times per day until 3 months after end of treatment | ||
+ | **[[Valacyclovir (Valtrex)]] 500 mg PO twice per day until 3 months after end of treatment | ||
'''28-day cycle for 6 cycles''' | '''28-day cycle for 6 cycles''' | ||
− | + | </div></div><br> | |
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | < | + | ===Regimen variant #2 {{#subobject:21came|Variant=1}}=== |
− | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" | |
− | # | + | !style="width: 20%"|Study |
− | + | !style="width: 20%"|Dates of enrollment | |
− | == | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | {| class="wikitable" style=" | + | !style="width: 20%"|Comparator |
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1182/blood-2011-07-365437 Lepretre et al. 2012 (GOELAMS CLL2007FMP)] |
− | + | |2007-2009 | |
− | + | |style="background-color:#1a9851"|Phase 3 (E-switch-ic) | |
− | + | |[[#FCR|FCR]] | |
− | + | |style="background-color:#ffffbf"|Did not meet primary endpoint of PFS36 | |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | | | ||
− | |||
− | |style="background-color:# | ||
− | |||
− | |[[# | ||
− | |style="background-color:# | ||
|- | |- | ||
|} | |} | ||
+ | ''Note: GOELAMS CLL2007FMP was halted prematurely due to excess mortality.'' | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[ | + | *[[Fludarabine (Fludara)]] 40 mg/m<sup>2</sup> PO once per day on days 1 to 3 |
− | *[[ | + | *[[Cyclophosphamide (Cytoxan)]] 250 mg/m<sup>2</sup> PO once per day on days 1 to 3 |
− | + | ====Targeted therapy==== | |
− | *[[ | + | *[[Alemtuzumab (Campath)]] 30 mg SC once per day on day 1 to 3 |
− | |||
'''28-day cycle for 6 cycles''' | '''28-day cycle for 6 cycles''' | ||
− | + | </div></div> | |
===References=== | ===References=== | ||
− | # | + | <!-- # '''Abstract:''' Lepretre S, Aurran T, Mahe B, Cazin B, Tournihlac O, Maisonneuve H, et al. Immunochemotherapy with fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) versus fludarabine (F), cyclophosphamide (C) and MabCampath (Cam) (FCCam) in previously untreated patients (pts) with advanced B-chronic lymphocytic leukemia (B-CLL): experience on safety and efficacy within a randomised multicenter phase III trial of the French Cooperative Group on CLL and WM (FCGCLL/MW) and the "Groupe Ouest-Est d'Etudes Des Leucemies Aigues Et Autres Maladies Du Sang" (GOELAMS) : CLL2007FMP (for fit medically patients). Blood 2009;114:538. [https://doi.org/10.1182/blood.V114.22.538.538 link to abstract] --> |
− | + | # '''GOELAMS CLL2007FMP:''' Lepretre S, Aurran T, Mahé B, Cazin B, Tournilhac O, Maisonneuve H, Casasnovas O, Delmer A, Leblond V, Royer B, Corront B, Chevret S, Delépine R, Vaudaux S, Van Den Neste E, Béné MC, Letestu R, Cymbalista F, Feugier P. Excess mortality after treatment with fludarabine and cyclophosphamide in combination with alemtuzumab in previously untreated patients with chronic lymphocytic leukemia in a randomized phase 3 trial. Blood. 2012 May 31;119(22):5104-10. Epub 2012 Feb 14. [https://doi.org/10.1182/blood-2011-07-365437 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/22337714/ PubMed] [https://clinicaltrials.gov/study/NCT00564512 NCT00564512] | |
− | == | + | <!-- Presented in abstract form at the 53rd annual meeting of the American Society of Hematology, San Diego, CA, December 10-13, 2011, and the XV International Workshop on CLL, Cologne, Germany, September 8-11, 2013. --> |
− | {| class="wikitable" style=" | + | # '''HOVON-68:''' Geisler CH, van T' Veer MB, Jurlander J, Walewski J, Tjønnfjord G, Itälä Remes M, Kimby E, Kozak T, Polliack A, Wu KL, Wittebol S, Abrahamse-Testroote MC, Doorduijn J, Ghidey Alemayehu W, van Oers MH. Frontline low-dose alemtuzumab with fludarabine and cyclophosphamide prolongs progression-free survival in high-risk CLL. Blood. 2014 May 22;123(21):3255-62. Epub 2014 Apr 15. [https://doi.org/10.1182/blood-2014-01-547737 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/24735962/ PubMed] NTR529 |
+ | ==FCR {{#subobject:1dc12c|Regimen=1}}== | ||
+ | FCR: '''<u>F</u>'''ludarabine, '''<u>C</u>'''yclophosphamide, '''<u>R</u>'''ituximab | ||
+ | <br>R-FC: '''<u>R</u>'''ituximab, '''<u>F</u>'''ludarabine, '''<u>C</u>'''yclophosphamide | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #1, 20/150/375-500 ("FCR-Lite") {{#subobject:44cd18|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | |- | ||
+ | |[https://doi.org/10.1200/jco.2008.17.2619 Foon et al. 2009] | ||
+ | |2003-2007 | ||
+ | |style="background-color:#91cf61"|Phase 2 | ||
|- | |- | ||
− | |||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#f2f3f4"> | |
− | ===Regimen {{#subobject: | + | ====Chemotherapy==== |
− | {| | + | *[[Fludarabine (Fludara)]] as follows: |
− | | | + | **Cycle 1: 20 mg/m<sup>2</sup> IV over 30 minutes once per day on days 2 to 4 |
− | |[[Levels_of_Evidence#Evidence| | + | **Cycles 2 to 6: 20 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 3 |
− | | | + | *[[Cyclophosphamide (Cytoxan)]] as follows: |
− | |[[Levels_of_Evidence# | + | **Cycle 1: 150 mg/m<sup>2</sup> IV over 60 minutes once per day on days 2 to 4 |
+ | **Cycles 2 to 6: 150 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 3 | ||
+ | ====Targeted therapy==== | ||
+ | *[[Rituximab (Rituxan)]] as follows: | ||
+ | **Cycle 1: 375 mg/m<sup>2</sup> IV once on day 1, then 500 mg/m<sup>2</sup> IV once on day 14 | ||
+ | **Cycles 2 to 6: 500 mg/m<sup>2</sup> IV once per day on days 1 & 14 | ||
+ | ====Supportive therapy==== | ||
+ | *[[Diphenhydramine (Benadryl)]] 25 mg PO once per day on days 1 & 14, prior to rituximab | ||
+ | *[[Acetaminophen (Tylenol)]] 650 mg PO once per day on days 1 & 14, prior to rituximab | ||
+ | *[[Dexamethasone (Decadron)]] 10 mg IV or PO once per day on days 1 & 14, prior to rituximab | ||
+ | *Cycle 1: [[Allopurinol (Zyloprim)]] 300 mg PO once per day on days 1 to 10 | ||
+ | *[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] 160/800 mg PO twice per day three times per week, for 6 months past last dose of chemotherapy | ||
+ | *[[Acyclovir (Zovirax)]] 400 mg PO three times per day, for 6 months past last dose of chemotherapy | ||
+ | *One of the following: | ||
+ | **[[Filgrastim (Neupogen)]] (dose not specified), starting 24 hours after chemotherapy | ||
+ | **[[Pegfilgrastim (Neulasta)]] (dose not specified), given 24 hours after chemotherapy | ||
+ | '''28-day cycle for 6 cycles''' | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#cbd5e7"> | ||
+ | ====Subsequent treatment==== | ||
+ | *[[#Rituximab_monotherapy_2|Indefinite rituximab]] maintenance | ||
+ | </div></div><br> | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #2, 24/150/375-500, oral FC {{#subobject:df045c|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | + | |[https://doi.org/10.1038/leu.2017.65 Munir et al. 2017 (ADMIRE)] | |
− | | | + | |2009-2012 |
− | |[[# | + | |style="background-color:#1a9851"|Randomized phase 2b (C) |
− | |style="background-color:# | + | |[[Chronic_lymphocytic_leukemia_-_historical#R-FCM|FCM-R]] |
+ | | style="background-color:#ffffbf" |Did not meet primary endpoint of CR rate | ||
|- | |- | ||
− | | | + | |[https://doi.org/10.1038/leu.2017.96 Howard et al. 2017 (ARCTIC<sub>CLL</sub>)] |
− | |style="background-color:# | + | |2009-2012 |
+ | |style="background-color:#1a9851"|Randomized phase 2b (C) | ||
+ | |[[Chronic_lymphocytic_leukemia_-_historical#R-FCM|FCM-miniR]] | ||
+ | | style="background-color:#1a9850" |Superior CR rate (primary endpoint) | ||
|- | |- | ||
− | | | + | |[https://doi.org/10.1016/s1470-2045(23)00144-4 Hillmen et al. 2023 (FLAIR)] |
− | + | |2014-09-19 to 2018-07-19 | |
− | + | | style="background-color:#1a9851" |Phase 3 (C) | |
− | + | |[[#Ibrutinib_.26_Rituximab|Ibrutinib & Rituximab]] | |
− | + | | style="background-color:#d73027" |Inferior PFS | |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
|- | |- | ||
− | |[ | + | |rowspan=2|[https://doi.org/10.1016/s1470-2045(23)00144-4 Hillmen et al. 2023 (FLAIR part 2)] |
− | + | |rowspan=2|2017-07-20 to 2021-03-24 | |
− | + | |rowspan=2 style="background-color:#1a9851" |Phase 3 (C) | |
− | + | |1. [[#Ibrutinib_.26_Venetoclax|Ibrutinib & Venetoclax]] | |
− | = | + | | style="background-color:#d73027" |Inferior PFS/OS |
− | |||
− | | | ||
− | |[[ | ||
− | | | ||
− | |||
|- | |- | ||
− | | | + | |2. [[#Ibrutinib_monotherapy|Ibrutinib]] |
− | + | | style="background-color:#d3d3d3" |Not reported | |
− | |||
− | |style="background-color:# | ||
|- | |- | ||
|} | |} | ||
+ | ''Note: in contrast to other variants, FC was given over 5 days not 3. ARCTIC should not be confused with the trial by the same name in NSCLC. FLAIR was a platform trial with distinct enrollments, such that Hillmen et al. 2023 is labeled as FLAIR part 2.'' | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[ | + | *[[Fludarabine (Fludara)]] 24 mg/m<sup>2</sup> PO once per day on days 1 to 5 |
− | *[[ | + | *[[Cyclophosphamide (Cytoxan)]] 150 mg/m<sup>2</sup>/day PO on days 1 to 5 |
− | *[[ | + | ====Targeted therapy==== |
− | + | *[[Rituximab (Rituxan)]] as follows: | |
− | ''' | + | **Cycle 1: 375 mg/m<sup>2</sup> IV once on day 1 |
+ | **Cycles 2 to 6: 500 mg/m<sup>2</sup> IV once on day 1 | ||
+ | '''28-day cycle for 6 cycles''' | ||
+ | </div></div><br> | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
− | === | + | ===Regimen variant #3, 25/250/375 {{#subobject:6dc0af|Variant=1}}=== |
− | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" | |
− | + | !style="width: 33%"|Study | |
− | + | !style="width: 33%"|Dates of enrollment | |
− | + | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | |
− | + | |- | |
+ | |[https://doi.org/10.1002/cncr.21882 Tam et al. 2006] | ||
+ | |2000-2005 | ||
+ | |style="background-color:#91cf61"|Phase 2 | ||
|- | |- | ||
− | |||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#f2f3f4"> | |
− | + | ====Chemotherapy==== | |
− | ===Regimen # | + | *[[Fludarabine (Fludara)]] 25 mg/m<sup>2</sup> IV over 15 to 30 minutes once per day on days 1 to 3 |
− | {| | + | *[[Cyclophosphamide (Cytoxan)]] 250 mg/m<sup>2</sup> IV over 15 to 30 minutes once per day on days 1 to 3 |
− | | | + | ====Targeted therapy==== |
− | |[[Levels_of_Evidence#Evidence| | + | *[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1 |
− | | | + | '''28-day cycle for up to 6 cycles or "attainment of maximum response"''' |
− | |[[Levels_of_Evidence#Efficacy| | + | </div></div><br> |
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #4, 25/250/375-500, IV FC {{#subobject:17f90c|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 17%"|Study | ||
+ | !style="width: 15%"|Dates of enrollment | ||
+ | !style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 17%"|Comparator | ||
+ | !style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
+ | !style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]] | ||
+ | |- | ||
+ | |[https://doi.org/10.1200/jco.2005.12.051 Keating et al. 2005] | ||
+ | |1999-2001 | ||
+ | |style="background-color:#91cf61"|Phase 2 | ||
+ | | style="background-color:#d3d3d3" | | ||
+ | | style="background-color:#d3d3d3" | | ||
+ | | style="background-color:#d3d3d3" | | ||
+ | |- | ||
+ | |[https://doi.org/10.1016/S0140-6736(10)61381-5 Hallek et al. 2010 (GCLLSG CLL8)] | ||
+ | |2003-2006 | ||
+ | |style="background-color:#1a9851"|Phase 3 (E-RT-esc) | ||
+ | |[[Chronic_lymphocytic_leukemia_-_historical#Cyclophosphamide_.26_Fludarabine_.28FC.29|FC]] | ||
+ | |style="background-color:#1a9850"|Superior PFS (primary endpoint)<br>PFS36: 65% vs 45%<br>(HR 0.56, 95% CI 0.46-0.69)<br><br>Superior OS<sup>1</sup> (secondary endpoint)<br>Median OS: NYR vs 86 mo<br>(HR 0.68, 95% CI 0.54-0.89) | ||
+ | |style="background-color:#eeee01"|Equivalent HRQoL | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7387319/ Herling et al. 2020 (GCLLSG CLL7)] | ||
+ | |2005-2010 | ||
+ | |style="background-color:#1a9851"|Phase 3 (E-esc) | ||
+ | |[[#Watchful_waiting|Watchful waiting]] | ||
+ | |style="background-color:#1a9850"|Superior EFS (primary endpoint)<br>Median EFS: NYR vs 18.5 mo<br>(HR 0.22, 95% CI 0.15-0.33) | ||
+ | | | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1182/blood-2011-07-365437 Lepretre et al. 2012 (GOELAMS CLL2007FMP)] |
− | |style="background-color:# | + | |2007-2009 |
− | |[[#FCA | + | |style="background-color:#1a9851"|Phase 3 (C) |
− | |style="background-color:# | + | |[[#FCA|FCCam]] |
+ | |style="background-color:#ffffbf"|Did not meet primary endpoint of PFS36 | ||
+ | | | ||
|- | |- | ||
− | | | + | |[https://doi.org/10.1016/S1470-2045(16)30051-1 Eichhorst et al. 2016 (GCLLSG CLL10)] |
− | + | |2008-2011 | |
− | + | |style="background-color:#1a9851"|Phase 3 (C) | |
− | + | |[[#Bendamustine_.26_Rituximab_.28BR.29|BR]] | |
− | + | |style="background-color:#ffffbf"|Inconclusive whether non-inferior PFS | |
− | + | | | |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | | | ||
− | |[[ | ||
− | | | ||
− | | | ||
|- | |- | ||
− | + | |[https://doi.org/10.1016/S2352-3026(16)00004-1 Assouline et al. 2016 (SAWYER)] | |
− | | | + | |2012-08-20 to 2013-06-17 |
− | |[[# | + | |style="background-color:#1a9851"|Randomized Phase 1b (C) |
− | |style="background-color:# | + | |[[#FCR_.28SC_Rituximab.29|FCR (SC Rituximab)]] |
+ | |style="background-color:#d3d3d3"|Not reported | ||
+ | | | ||
|- | |- | ||
− | |[[# | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6908306/ Shanafelt et al. 2019 (ECOG E1912)] |
− | |style="background-color:# | + | |2014-2016 |
+ | |style="background-color:#1a9851"|Phase 3 (C) | ||
+ | |[[#Ibrutinib_.26_Rituximab|Ibrutinib & Rituximab]] | ||
+ | | style="background-color:#d73027" |Inferior OS | ||
+ | | | ||
|- | |- | ||
− | |[ | + | |rowspan=2|[https://doi.org/10.1056/nejmoa2213093 Eichhorst et al. 2023 (GAIA)] |
− | |style="background-color:# | + | |rowspan=2|2016-12-13 to 2019-10-13 |
− | |[[# | + | |rowspan=2 style="background-color:#1a9851" |Phase 3 (C) |
− | |style="background-color:# | + | |1. [[#Venetoclax_.26_Obinutuzumab|Venetoclax & Obinutuzumab]]<br>2. [[#Ibrutinib.2C_Venetoclax.2C_Obinutuzumab|Ibrutinib, Venetoclax, Obinutuzumab]] |
+ | | style="background-color:#d73027" |Inferior PFS | ||
+ | | | ||
|- | |- | ||
− | | | + | |3. [[#Venetoclax_.26_Rituximab_999|Venetoclax & Rituximab]] |
− | + | | style="background-color:#ffffbf" |Did not meet primary endpoint of PFS | |
− | + | | | |
− | |style="background-color:# | ||
|- | |- | ||
|} | |} | ||
− | '' | + | ''<sup>1</sup>Reported efficacy for GCLLSG CLL8 is based on the 2016 update.''<br> |
+ | ''Note: ECOG E1912 used alternate rituximab dosing in cycle 1: 50 mg/m<sup>2</sup> IV once on day 1, then 325 mg/m<sup>2</sup> IV once on day 2.'' | ||
+ | <div class="toccolours" style="background-color:#fdcdac"> | ||
+ | ====Eligibility criteria==== | ||
+ | *GAIA: 65 years old or younger | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
*[[Fludarabine (Fludara)]] 25 mg/m<sup>2</sup> IV once per day on days 1 to 3 | *[[Fludarabine (Fludara)]] 25 mg/m<sup>2</sup> IV once per day on days 1 to 3 | ||
− | *[[Cyclophosphamide (Cytoxan)]] 250 mg/m<sup>2</sup> IV | + | *[[Cyclophosphamide (Cytoxan)]] 250 mg/m<sup>2</sup> IV once per day on days 1 to 3 |
− | + | ====Targeted therapy==== | |
− | ====Supportive | + | *[[Rituximab (Rituxan)]] as follows: |
− | * | + | **Cycle 1: 375 mg/m<sup>2</sup> IV once on day 0 |
− | + | **Cycles 2 to 6: 500 mg/m<sup>2</sup> IV once on day 1 | |
− | '''28-day cycle for | + | ====Supportive therapy==== |
− | + | *''Note: these vary according to reference.'' | |
− | ===Regimen # | + | *[[Diphenhydramine (Benadryl)]] 25 mg IV once per infusion, 30 minutes prior to rituximab |
− | {| | + | *[[Acetaminophen (Tylenol)]] 650 mg PO once per infusion, 30 minutes prior to rituximab |
− | | | + | *Cycle 1: [[Allopurinol (Zyloprim)]] 300 mg PO once per day on days 1 to 7 |
− | |[[Levels_of_Evidence#Evidence| | + | *Some patients received: |
− | | | + | **[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] 160/800 mg PO twice per week |
− | |[[Levels_of_Evidence# | + | **[[Valacyclovir (Valtrex)]] 500 mg PO once per day |
+ | *[[:Category:PCP_prophylaxis|PCP (Pneumocystis jirovecii pneumonia) prophylaxis]] recommended for severe leukopenia greater than 7 days | ||
+ | *No routine prophylaxis with antiviral medications or G-CSF | ||
+ | '''28-day cycle for 6 cycles''' | ||
+ | </div></div><br> | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #5, 25/250/375-500, PO FC {{#subobject:1po90c|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1182/blood-2011-07-365437 Lepretre et al. 2012 (GOELAMS CLL2007FMP)] |
− | |style="background-color:# | + | |2007-2009 |
− | |[[# | + | |style="background-color:#1a9851"|Phase 3 (C) |
− | |style="background-color:# | + | |[[#FCA|FCCam]] |
+ | |style="background-color:#ffffbf"|Did not meet primary endpoint of PFS36 | ||
|- | |- | ||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#f2f3f4"> | |
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[Fludarabine (Fludara)]] | + | *[[Fludarabine (Fludara)]] 25 mg/m<sup>2</sup> PO once per day on days 1 to 3 |
− | *[[Cyclophosphamide (Cytoxan)]] | + | *[[Cyclophosphamide (Cytoxan)]] 250 mg/m<sup>2</sup> PO once per day on days 1 to 3 |
− | + | ====Targeted therapy==== | |
− | '''28-day cycle for | + | *[[Rituximab (Rituxan)]] as follows: |
− | + | **Cycle 1: 375 mg/m<sup>2</sup> IV once on day 0 | |
− | ===Regimen # | + | **Cycles 2 to 6: 500 mg/m<sup>2</sup> IV once on day 1 |
− | {| | + | '''28-day cycle for 6 cycles''' |
− | | | + | </div></div><br> |
− | |[[Levels_of_Evidence#Evidence| | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | | | + | ===Regimen variant #6, 25/250/500 {{#subobject:dg134c|Variant=1}}=== |
− | |[[Levels_of_Evidence# | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | + | |[https://doi.org/10.1111/bjh.13061 Awan et al. 2014 (LUCID)] | |
− | | | + | |2006 to not reported |
− | + | |style="background-color:#1a9851"|Phase 3 (C) | |
− | |style="background-color:# | + | |[[#FCR_.26_Lumiliximab_999|FCR+L]] |
− | + | |style="background-color:#ffffbf"|Did not meet primary endpoint of CR rate | |
− | |[[# | ||
− | |style="background-color:# | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[Fludarabine (Fludara)]] | + | *[[Fludarabine (Fludara)]] as follows: |
− | *[[Cyclophosphamide (Cytoxan)]] | + | **Cycle 1: 25 mg/m<sup>2</sup> IV over at least 10 to 30 minutes once per day on days 2 to 4 |
− | + | **Cycles 2 to 6: 25 mg/m<sup>2</sup> IV over at least 10 to 30 minutes once per day on days 1 to 3 | |
− | '''28-day cycle for | + | *[[Cyclophosphamide (Cytoxan)]] as follows: |
+ | **Cycle 1: 250 mg/m<sup>2</sup> IV over at least 10 to 30 minutes once per day on days 2 to 4 | ||
+ | **Cycles 2 to 6: 250 mg/m<sup>2</sup> IV over at least 10 to 30 minutes once per day on days 1 to 3 | ||
+ | ====Targeted therapy==== | ||
+ | *[[Rituximab (Rituxan)]] as follows: | ||
+ | **Cycle 1: 50 mg/m<sup>2</sup> IV over 4 hours once on day 1, then 450 mg/m<sup>2</sup> IV once on day 3 | ||
+ | **Cycles 2 to 6: 500 mg/m<sup>2</sup> IV once on day 1 | ||
+ | ====Supportive therapy==== | ||
+ | *[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Cotrimoxazole]] or [[:Category:PCP_prophylaxis|equivalent]] | ||
+ | *[[Acyclovir (Zovirax)]] 400 mg PO twice per day or [[:Category:Antivirals|equivalent]] | ||
+ | *[[:Category:Hematopoietic_growth_factors|Growth factors]] at physician discretion | ||
+ | '''28-day cycle for 6 cycles''' | ||
+ | </div></div><br> | ||
− | ===Regimen # | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | {| | + | ===Regimen variant #7, 40/250/375-500, oral FC {{#subobject:e5ab00|Variant=1}}=== |
− | | | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | |[[Levels_of_Evidence#Evidence| | + | !style="width: 33%"|Study |
− | + | !style="width: 33%"|Dates of enrollment | |
− | + | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | |
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1016/S2352-3026(17)30235-1 Dartigeas et al. 2017 (CLL 2007 SA)] |
− | | | + | |2007-2014 |
− | + | |style="background-color:#91cf61"|Non-randomized part of phase 3 RCT | |
− | |style="background-color:# | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[Fludarabine (Fludara)]] | + | *[[Fludarabine (Fludara)]] 40 mg/m<sup>2</sup> PO once per day on days 1 to 3 |
− | *[[Cyclophosphamide (Cytoxan)]] 250 mg/m<sup>2</sup> | + | *[[Cyclophosphamide (Cytoxan)]] 250 mg/m<sup>2</sup> PO once per day on days 1 to 3 |
− | + | ====Targeted therapy==== | |
− | ==== | + | *[[Rituximab (Rituxan)]] as follows: |
− | * | + | **Cycle 1: 375 mg/m<sup>2</sup> IV once on day 1, then 500 mg/m<sup>2</sup> IV once on day 14 |
− | + | **Cycle 2: 500 mg/m<sup>2</sup> IV once per day on days 1 & 14 | |
− | ''' | + | **Cycles 3 & 4: 500 mg/m<sup>2</sup> IV once on day 1 |
− | + | '''1-month cycle for 4 cycles''' | |
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#cbd5e7"> | ||
+ | ====Subsequent treatment==== | ||
+ | *[[#Rituximab_monotherapy_2|Rituximab]] maintenance versus [[Chronic_lymphocytic_leukemia_-_null_regimens#Observation|observation]] | ||
+ | </div></div> | ||
===References=== | ===References=== | ||
− | # | + | # Keating MJ, O'Brien S, Albitar M, Lerner S, Plunkett W, Giles F, Andreeff M, Cortes J, Faderl S, Thomas D, Koller C, Wierda W, Detry MA, Lynn A, Kantarjian H. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol. 2005 Jun 20;23(18):4079-88. Epub 2005 Mar 14. [https://doi.org/10.1200/jco.2005.12.051 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/15767648/ PubMed] |
− | + | ## '''Update:''' Tam CS, O'Brien S, Wierda W, Kantarjian H, Wen S, Do KA, Thomas DA, Cortes J, Lerner S, Keating MJ. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood. 2008 Aug 15;112(4):975-80. Epub 2008 Apr 14. [https://doi.org/10.1182/blood-2008-02-140582 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3952498/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18411418/ PubMed] | |
− | + | ## '''Update:''' Thompson PA, Tam CS, O'Brien SM, Wierda WG, Stingo F, Plunkett W, Smith SC, Kantarjian HM, Freireich EJ, Keating MJ. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood. 2016 Jan 21;127(3):303-9. Epub 2015 Oct 22. [https://doi.org/10.1182/blood-2015-09-667675 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4760129/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26492934/ PubMed] | |
− | + | ##'''Update:''' Thompson PA, Bazinet A, Wierda WG, Tam CS, O'Brien SM, Saha S, Peterson CB, Plunkett W, Keating MJ. Sustained remissions in CLL after frontline FCR treatment with very-long-term follow-up. Blood. 2023 Nov 23;142(21):1784-1788. [https://doi.org/10.1182/blood.2023020158 link to original article] [https://pubmed.ncbi.nlm.nih.gov/37595283/ PubMed] | |
− | + | # Tam CS, Wolf M, Prince HM, Januszewicz EH, Westerman D, Lin KI, Carney D, Seymour JF. Fludarabine, cyclophosphamide, and rituximab for the treatment of patients with chronic lymphocytic leukemia or indolent non-Hodgkin lymphoma. Cancer. 2006 Jun 1;106(11):2412-20. [https://doi.org/10.1002/cncr.21882 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/16649223/ PubMed] | |
− | + | # Foon KA, Boyiadzis M, Land SR, Marks S, Raptis A, Pietragallo L, Meisner D, Laman A, Sulecki M, Butchko A, Schaefer P, Lenzer D, Tarhini A. Chemoimmunotherapy with low-dose fludarabine and cyclophosphamide and high dose rituximab in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009 Feb 1;27(4):498-503. Epub 2008 Dec 15. [https://doi.org/10.1200/jco.2008.17.2619 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/19075274/ PubMed] | |
− | + | ## '''Update:''' Foon KA, Mehta D, Lentzsch S, Kropf P, Marks S, Lenzner D, Pietragallo L, Sulecki M, Tarhini A, Boyiadzis M. Long-term results of chemoimmunotherapy with low-dose fludarabine, cyclophosphamide and high-dose rituximab as initial treatment for patients with chronic lymphocytic leukemia. Blood. 2012 Mar 29;119(13):3184-5. [https://doi.org/10.1182/blood-2012-01-408047 link to original article] [https://pubmed.ncbi.nlm.nih.gov/22461474/ PubMed] | |
− | # | + | <!-- # '''Abstract:''' Hallek, Michael, Fingerle-Rowson, Guenter, Fink, Anna-Maria, Busch, Raymonde, Mayer, Jiri, Hensel, Manfred, Hopfinger, Georg, Hess, Georg, von Gruenhagen, Ulrich, Bergmann, Manuela A., Catalano, John, Zinzano, Pier Luigi, Cappio, Federico Caligaris, Seymour, John F, Berrebi, Alain, Jaeger, Ulrich, Cazin, Bruno, Trneny, Marek, Westermann, Anne, Wendtner, Clemens-Martin, Eichhorst, Barbara F., Staib, Peter, Boettcher, Sebastian, Ritgen, Matthias, Mendila, Myriam, Kneba, Michael, Doehner, Hartmut, Stilgenbauer, Stephan, Fischer, Kirsten |
− | # Hallek | + | First-Line Treatment with Fludarabine (F), Cyclophosphamide (C), and Rituximab (R) (FCR) Improves Overall Survival (OS) in Previously Untreated Patients (pts) with Advanced Chronic Lymphocytic Leukemia (CLL): Results of a Randomized Phase III Trial On Behalf of An International Group of Investigators and the German CLL Study Group. |
− | + | ASH Annual Meeting Abstracts 2009 114: 535 [https://doi.org/10.1182/blood.V114.22.535.535 link to abstract] --> | |
− | + | # '''GCLLSG CLL8:''' Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J, Hensel M, Hopfinger G, Hess G, von Grünhagen U, Bergmann M, Catalano J, Zinzani PL, Caligaris-Cappio F, Seymour JF, Berrebi A, Jäger U, Cazin B, Trneny M, Westermann A, Wendtner CM, Eichhorst BF, Staib P, Bühler A, Winkler D, Zenz T, Böttcher S, Ritgen M, Mendila M, Kneba M, Döhner H, Stilgenbauer S; International Group of Investigators; German Chronic Lymphocytic Leukaemia Study Group. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010 Oct 2;376(9747):1164-74. [https://doi.org/10.1016/S0140-6736(10)61381-5 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/20888994/ PubMed] [https://clinicaltrials.gov/study/NCT00281918 NCT00281918] | |
− | + | ## '''Update:''' Fischer K, Bahlo J, Fink AM, Goede V, Herling CD, Cramer P, Langerbeins P, von Tresckow J, Engelke A, Maurer C, Kovacs G, Herling M, Tausch E, Kreuzer KA, Eichhorst B, Böttcher S, Seymour JF, Ghia P, Marlton P, Kneba M, Wendtner CM, Döhner H, Stilgenbauer S, Hallek M. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016 Jan 14;127(2):208-15. Epub 2015 Oct 20. [https://doi.org/10.1182/blood-2015-06-651125 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26486789/ PubMed] | |
+ | ## '''HRQoL analysis:''' Kutsch N, Busch R, Bahlo J, Mayer J, Hensel M, Hopfinger G, Hess G, von Grünhagen U, Wendtner CM, Maria Fink A, Fischer K, Hallek M, Eichhorst B. FCR front-line therapy and quality of life in patients with chronic lymphocytic leukemia. Leuk Lymphoma. 2017 Feb;58(2):399-407. Epub 2016 Jun 29. [https://doi.org/10.1080/10428194.2016.1190966 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27357445/ PubMed] | ||
+ | <!-- # '''Abstract:''' Lepretre S, Aurran T, Mahe B, Cazin B, Tournihlac O, Maisonneuve H, et al. Immunochemotherapy with fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) versus fludarabine (F), cyclophosphamide (C) and MabCampath (Cam) (FCCam) in previously untreated patients (pts) with advanced B-chronic lymphocytic leukemia (B-CLL): experience on safety and efficacy within a randomised multicenter phase III trial of the French Cooperative Group on CLL and WM (FCGCLL/MW) and the "Groupe Ouest-Est d'Etudes Des Leucemies Aigues Et Autres Maladies Du Sang" (GOELAMS) : CLL2007FMP (for fit medically patients). Blood 2009;114:538. [https://doi.org/10.1182/blood.V114.22.538.538 link to abstract] --> | ||
+ | # '''GOELAMS CLL2007FMP:''' Lepretre S, Aurran T, Mahé B, Cazin B, Tournilhac O, Maisonneuve H, Casasnovas O, Delmer A, Leblond V, Royer B, Corront B, Chevret S, Delépine R, Vaudaux S, Van Den Neste E, Béné MC, Letestu R, Cymbalista F, Feugier P. Excess mortality after treatment with fludarabine and cyclophosphamide in combination with alemtuzumab in previously untreated patients with chronic lymphocytic leukemia in a randomized phase 3 trial. Blood. 2012 May 31;119(22):5104-10. Epub 2012 Feb 14. [https://doi.org/10.1182/blood-2011-07-365437 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/22337714/ PubMed] [https://clinicaltrials.gov/study/NCT00564512 NCT00564512] | ||
+ | <!-- # '''Abstract:''' Carmen D Schweighofer, MD, Florence Cymbalista, MD, Carolin Müller, MD, Raymonde Busch, PhD, Raphael Porcher, PhD, Petra Langerbeins, MD, Bruno Cazin, MD, Anna-Maria Fink, MD, Brigitte Dreyfus, MD, Stefan Ibach, Stéphane Leprêtre, MD, Kirsten Fischer, MD, Ursula Vehling-Kaiser, MD, Barbara Eichhorst, MD, Manuela A. Bergmann, MD, Stephan Stilgenbauer, MD, Hartmut Döhner, MD, Veronique Leblond, MD, Michael Hallek, MD, and Vincent Levy, MD, PhD. Early Versus Deferred Treatment With Combined Fludarabine, Cyclophosphamide and Rituximab (FCR) Improves Event-Free Survival In Patients With High-Risk Binet Stage A Chronic Lymphocytic Leukemia – First Results Of a Randomized German-French Cooperative Phase III Trial. 2013 ASH Annual Symposium abstract 524 [https://doi.org/10.1182/blood.V122.21.524.524 link to abstract] --> | ||
+ | # '''GCLLSG CLL7:''' Herling CD, Cymbalista F, Groß-Ophoff-Müller C, Bahlo J, Robrecht S, Langerbeins P, Fink AM, Al-Sawaf O, Busch R, Porcher R, Cazin B, Dreyfus B, Ibach S, Leprêtre S, Fischer K, Kaiser F, Eichhorst B, Wentner CM, Hoechstetter MA, Döhner H, Leblond V, Kneba M, Letestu R, Böttcher S, Stilgenbauer S, Hallek M, Levy V. Early treatment with FCR versus watch and wait in patients with stage Binet A high-risk chronic lymphocytic leukemia (CLL): a randomized phase 3 trial. Leukemia. 2020 Aug;34(8):2038-2050. Epub 2020 Feb 18. [https://doi.org/10.1038/s41375-020-0747-7 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7387319/ link to PMC article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/32071431/ PubMed] [https://clinicaltrials.gov/study/NCT00275054 NCT00275054] | ||
+ | # '''LUCID:''' Awan FT, Hillmen P, Hellmann A, Robak T, Hughes SG, Trone D, Shannon M, Flinn IW, Byrd JC; LUCID trial investigators. A randomized, open-label, multicentre, phase 2/3 study to evaluate the safety and efficacy of lumiliximab in combination with fludarabine, cyclophosphamide and rituximab versus fludarabine, cyclophosphamide and rituximab alone in subjects with relapsed chronic lymphocytic leukaemia. Br J Haematol. 2014 Nov;167(4):466-77. Epub 2014 Aug 8. [https://doi.org/10.1111/bjh.13061 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/25130401/ PubMed] [https://clinicaltrials.gov/study/NCT00391066 NCT00391066] | ||
+ | # '''SAWYER:''' Assouline S, Buccheri V, Delmer A, Gaidano G, Trneny M, Berthillon N, Brewster M, Catalani O, Li S, McIntyre C, Sayyed P, Badoux X. Pharmacokinetics, safety, and efficacy of subcutaneous versus intravenous rituximab plus chemotherapy as treatment for chronic lymphocytic leukaemia (SAWYER): a phase 1b, open-label, randomised controlled non-inferiority trial. Lancet Haematol. 2016 Mar;3(3):e128-38. [https://doi.org/10.1016/S2352-3026(16)00004-1 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/26947201/ PubMed] [https://clinicaltrials.gov/study/NCT01292603 NCT01292603] | ||
+ | <!-- # '''Abstract:''' Barbara Eichhorst, MD, Anna-Maria Fink, MD, Raymonde Busch, PhD, Elisabeth Lange, MD, Hubert Köppler, Prof. Dr., Michael Kiehl, MD, Martin Sökler, MD, Rudolf Schlag, MD, Ursula Vehling-Kaiser, MD, Georg Köchling, MD, Christoph Plöger, MD, Michael Gregor, MD, Torben Plesner, MD, Marek Trneny, MD, Ph.D., Prof, Kirsten Fischer, MD, Hartmut Döhner, MD, Michael Kneba, MD, Clemens Wendtner, MD, Wolfram Klapper, Karl-Anton Kreuzer, Dr. med., Stephan Stilgenbauer, MD, Sebastian Böttcher, MD, and Michael Hallek, MD. Chemoimmunotherapy With Fludarabine (F), Cyclophosphamide (C), and Rituximab (R) (FCR) Versus Bendamustine and Rituximab (BR) In Previously Untreated and Physically Fit Patients (pts) With Advanced Chronic Lymphocytic Leukemia (CLL): Results Of a Planned Interim Analysis Of The CLL10 Trial, An International, Randomized Study Of The German CLL Study Group (GCLLSG). 2013 ASH Annual Symposium abstract 526 [https://doi.org/10.1182/blood.V122.21.526.526 link to abstract] --> | ||
+ | # '''GCLLSG CLL10:''' Eichhorst B, Fink AM, Bahlo J, Busch R, Kovacs G, Maurer C, Lange E, Köppler H, Kiehl M, Sökler M, Schlag R, Vehling-Kaiser U, Köchling G, Plöger C, Gregor M, Plesner T, Trneny M, Fischer K, Döhner H, Kneba M, Wendtner CM, Klapper W, Kreuzer KA, Stilgenbauer S, Böttcher S, Hallek M; International Group of Investigators; German CLL Study Group. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016 Jul;17(7):928-42. Epub 2016 May 20. [https://doi.org/10.1016/S1470-2045(16)30051-1 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/27216274/ PubMed] [https://clinicaltrials.gov/study/NCT00769522 NCT00769522] | ||
+ | # '''ADMIRE:''' Munir T, Howard DR, McParland L, Pocock C, Rawstron AC, Hockaday A, Varghese A, Hamblin M, Bloor A, Pettitt A, Fegan C, Blundell J, Gribben JG, Phillips D, Hillmen P. Results of the randomized phase IIB ADMIRE trial of FCR with or without mitoxantrone in previously untreated CLL. Leukemia. 2017 Oct;31(10):2085-2093. Epub 2017 Apr 20. [https://doi.org/10.1038/leu.2017.65 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/28216660/ PubMed] ISRCTN42165735 | ||
+ | # '''ARCTIC:''' Howard DR, Munir T, McParland L, Rawstron AC, Milligan D, Schuh A, Hockaday A, Allsup DJ, Marshall S, Duncombe AS, O'Dwyer JL, Smith AF, Longo R, Varghese A, Hillmen P. Results of the randomized phase IIB ARCTIC trial of low-dose rituximab in previously untreated CLL. Leukemia. 2017 Nov;31(11):2416-2425. Epub 2017 Mar 24. [https://doi.org/10.1038/leu.2017.96 link to original article] '''dosing details in supplement have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/28336937/ PubMed] ISRCTN16544962 | ||
+ | # '''CLL 2007 SA:''' Dartigeas C, Van Den Neste E, Léger J, Maisonneuve H, Berthou C, Dilhuydy MS, De Guibert S, Leprêtre S, Béné MC, Nguyen-Khac F, Letestu R, Cymbalista F, Rodon P, Aurran-Schleinitz T, Vilque JP, Tournilhac O, Mahé B, Laribi K, Michallet AS, Delmer A, Feugier P, Lévy V, Delépine R, Colombat P, Leblond V; CLL 2007 SA investigators; FILO. Rituximab maintenance versus observation following abbreviated induction with chemoimmunotherapy in elderly patients with previously untreated chronic lymphocytic leukaemia (CLL 2007 SA): an open-label, randomised phase 3 study. Lancet Haematol. 2018 Feb;5(2):e82-e94. Epub 2017 Dec 20. [https://doi.org/10.1016/S2352-3026(17)30235-1 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/29275118/ PubMed] [https://clinicaltrials.gov/study/NCT00645606 NCT00645606] | ||
+ | # '''ECOG E1912:''' Shanafelt TD, Wang XV, Kay NE, Hanson CA, O'Brien S, Barrientos J, Jelinek DF, Braggio E, Leis JF, Zhang CC, Coutre SE, Barr PM, Cashen AF, Mato AR, Singh AK, Mullane MP, Little RF, Erba H, Stone RM, Litzow M, Tallman M. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019 Aug 1;381(5):432-443. [https://doi.org/10.1056/NEJMoa1817073 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6908306/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31365801/ PubMed] [https://clinicaltrials.gov/study/NCT02048813 NCT02048813] | ||
+ | ##'''Update:''' Shanafelt TD, Wang XV, Hanson CA, Paietta EM, O'Brien S, Barrientos J, Jelinek DF, Braggio E, Leis JF, Zhang CC, Coutre SE, Barr PM, Cashen AF, Mato AR, Singh AK, Mullane MP, Little RF, Erba H, Stone RM, Litzow M, Tallman M, Kay NE. Long-term outcomes for ibrutinib-rituximab and chemoimmunotherapy in CLL: updated results of the E1912 trial. Blood. 2022 Jul 14;140(2):112-120. [https://doi.org/10.1182/blood.2021014960 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9283968/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35427411/ PubMed] | ||
+ | #'''FLAIR:''' Hillmen P, Pitchford A, Bloor A, Broom A, Young M, Kennedy B, Walewska R, Furtado M, Preston G, Neilson JR, Pemberton N, Sidra G, Morley N, Cwynarski K, Schuh A, Forconi F, Elmusharaf N, Paneesha S, Fox CP, Howard DR, Hockaday A, Brown JM, Cairns DA, Jackson S, Greatorex N, Webster N, Shingles J, Dalal S, Patten PEM, Allsup D, Rawstron A, Munir T. Ibrutinib and rituximab versus fludarabine, cyclophosphamide, and rituximab for patients with previously untreated chronic lymphocytic leukaemia (FLAIR): interim analysis of a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2023 May;24(5):535-552. [https://doi.org/10.1016/s1470-2045(23)00144-4 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/37142374/ PubMed] ISRCTN01844152 | ||
+ | #'''GAIA:''' Eichhorst B, Niemann CU, Kater AP, Fürstenau M, von Tresckow J, Zhang C, Robrecht S, Gregor M, Juliusson G, Thornton P, Staber PB, Tadmor T, Lindström V, da Cunha-Bang C, Schneider C, Poulsen CB, Illmer T, Schöttker B, Nösslinger T, Janssens A, Christiansen I, Baumann M, Frederiksen H, van der Klift M, Jäger U, Leys MBL, Hoogendoorn M, Lotfi K, Hebart H, Gaska T, Koene H, Enggaard L, Goede J, Regelink JC, Widmer A, Simon F, De Silva N, Fink AM, Bahlo J, Fischer K, Wendtner CM, Kreuzer KA, Ritgen M, Brüggemann M, Tausch E, Levin MD, van Oers M, Geisler C, Stilgenbauer S, Hallek M; GCLLSG, the HOVON and Nordic CLL Study Groups, the SAKK, the Israeli CLL Association, and Cancer Trials Ireland. First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia. N Engl J Med. 2023 May 11;388(19):1739-1754. [https://doi.org/10.1056/nejmoa2213093 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/37163621/ PubMed] [https://clinicaltrials.gov/study/NCT02950051 NCT02950051] | ||
+ | ##'''Update:''' Fürstenau M, Kater AP, Robrecht S, von Tresckow J, Zhang C, Gregor M, Thornton P, Staber PB, Tadmor T, Lindström V, Juliusson G, Janssens A, Levin MD, da Cunha-Bang C, Schneider C, Goldschmidt N, Vandenberghe E, Rossi D, Benz R, Nösslinger T, Heintel D, Poulsen CB, Christiansen I, Frederiksen H, Enggaard L, Posthuma EFM, Issa DE, Visser HPJ, Bellido M, Kutsch N, Dürig J, Stehle A, Vöhringer M, Böttcher S, Schulte C, Simon F, Fink AM, Fischer K, Holmes EE, Kreuzer KA, Ritgen M, Brüggemann M, Tausch E, Stilgenbauer S, Hallek M, Niemann CU, Eichhorst B. First-line venetoclax combinations versus chemoimmunotherapy in fit patients with chronic lymphocytic leukaemia (GAIA/CLL13): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2024 Jun;25(6):744-759. Erratum in: Lancet Oncol. 2024 Jul;25(7):e284. [https://doi.org/10.1016/s1470-2045(24)00196-7 link to original article] [https://pubmed.ncbi.nlm.nih.gov/38821083/ PubMed] | ||
+ | #'''FLAIR part 2:''' Munir T, Cairns DA, Bloor A, Allsup D, Cwynarski K, Pettitt A, Paneesha S, Fox CP, Eyre TA, Forconi F, Elmusharaf N, Kennedy B, Gribben J, Pemberton N, Sheehy O, Preston G, Schuh A, Walewska R, Duley L, Howard D, Hockaday A, Jackson S, Greatorex N, Girvan S, Bell S, Brown JM, Webster N, Dalal S, de Tute R, Rawstron A, Patten PEM, Hillmen P; National Cancer Research Institute Chronic Lymphocytic Leukemia Subgroup. Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease. N Engl J Med. 2024 Jan 25;390(4):326-337. Epub 2023 Dec 10. [https://doi.org/10.1056/nejmoa2310063 link to original article] '''dosing details in supplement have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/38078508/ PubMed] ISRCTN01844152 | ||
+ | # '''ACE-CL-311:''' [https://clinicaltrials.gov/study/NCT03836261 NCT03836261] | ||
+ | # '''CRISTALLO:''' [https://clinicaltrials.gov/study/NCT04285567 NCT04285567] | ||
− | == | + | ==FCR (SC Rituximab) {{#subobject:1dc25c|Regimen=1}}== |
− | {| class="wikitable" style=" | + | FCR: '''<u>F</u>'''ludarabine, '''<u>C</u>'''yclophosphamide, '''<u>R</u>'''ituximab hyaluronidase |
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen {{#subobject:dcbn4c|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1016/S2352-3026(16)00004-1 Assouline et al. 2016 (SAWYER)] |
− | + | |2012-08-20 to 2013-06-17 | |
− | + | |style="background-color:#1a9851"|Randomized Phase 1b (E-RT-switch-ic) | |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |style="background-color:# | ||
|[[#FCR|FCR]] | |[[#FCR|FCR]] | ||
− | |style="background-color:# | + | |style="background-color:#d3d3d3"|Not reported |
− | |||
− | |||
− | |||
− | |||
− | |||
|- | |- | ||
|} | |} | ||
− | '' | + | ''Note: other variants include oral fludarabine and/or cyclophosphamide; to be completed.'' |
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[Fludarabine (Fludara)]] | + | *[[Fludarabine (Fludara)]] 25 mg/m<sup>2</sup> IV once per day on days 1 to 3 |
− | *[[Cyclophosphamide (Cytoxan)]] 250 mg/m<sup>2</sup> | + | *[[Cyclophosphamide (Cytoxan)]] 250 mg/m<sup>2</sup> IV once per day on days 1 to 3 |
− | *[[ | + | ====Targeted therapy==== |
− | **Cycle 1: | + | *[[Rituximab (Rituxan)]] as follows: |
− | + | **Cycle 1: 375 mg/m<sup>2</sup> IV once on day 0 | |
− | + | *[[Rituximab and hyaluronidase human (Rituxan Hycela)]] as follows: | |
− | + | **Cycles 2 to 6: 1600 mg SC once on day 1 | |
− | *[[ | + | '''28-day cycle for up to 6 cycles''' |
− | * | + | </div></div> |
− | |||
− | * | ||
− | |||
− | '''28-day cycle for 6 cycles''' | ||
− | |||
===References=== | ===References=== | ||
− | + | # '''SAWYER:''' Assouline S, Buccheri V, Delmer A, Gaidano G, Trneny M, Berthillon N, Brewster M, Catalani O, Li S, McIntyre C, Sayyed P, Badoux X. Pharmacokinetics, safety, and efficacy of subcutaneous versus intravenous rituximab plus chemotherapy as treatment for chronic lymphocytic leukaemia (SAWYER): a phase 1b, open-label, randomised controlled non-inferiority trial. Lancet Haematol. 2016 Mar;3(3):e128-38. [https://doi.org/10.1016/S2352-3026(16)00004-1 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/26947201/ PubMed] [https://clinicaltrials.gov/study/NCT01292603 NCT01292603] | |
− | |||
− | |||
− | |||
− | == | + | ==Fludarabine & Alemtuzumab {{#subobject:29bf48|Regimen=1}}== |
− | {| class="wikitable" style=" | + | <div class="toccolours" style="background-color:#eeeeee"> |
+ | ===Regimen {{#subobject:201b46|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1016/S1470-2045(11)70242-X Elter et al. 2011 (CAM 314)] |
− | + | |2004-2008 | |
− | + | |style="background-color:#1a9851"|Phase 3 (E-esc) | |
− | + | |[[Chronic_lymphocytic_leukemia_-_historical#Fludarabine_monotherapy|Fludarabine]] | |
− | + | | style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 23.7 vs 16.5 mo<br>(HR 0.61, 95% CI 0.47-0.80)<br><br>Superior OS (secondary endpoint)<br>Median OS: NYR vs 52.9 mo<br>(HR 0.65, 95% CI 0.45-0.94) | |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |style="background-color:# | ||
− | |[[# | ||
− | |style="background-color:# | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[Fludarabine (Fludara)]] | + | *[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV once per day on days 1 to 3 |
− | *[[ | + | ====Targeted therapy==== |
− | + | *[[Alemtuzumab (Campath)]] 30 mg IV once per day on days 1 to 3 | |
− | + | '''28-day cycle for up to 6 cycles''' | |
− | '''28-day cycle for 6 cycles''' | + | </div></div> |
− | |||
===References=== | ===References=== | ||
− | + | # '''CAM 314:''' Elter T, Gercheva-Kyuchukova L, Pylylpenko H, Robak T, Jaksic B, Rekhtman G, Kyrcz-Krzemień S, Vatutin M, Wu J, Sirard C, Hallek M, Engert A. Fludarabine plus alemtuzumab versus fludarabine alone in patients with previously treated chronic lymphocytic leukaemia: a randomised phase 3 trial. Lancet Oncol. 2011 Dec;12(13):1204-13. Epub 2011 Oct 10. [https://doi.org/10.1016/S1470-2045(11)70242-X link to original article] '''dosing details in abstract have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/21992852/ PubMed] [https://clinicaltrials.gov/study/NCT00086580 NCT00086580] | |
− | # | + | ==Ibrutinib monotherapy {{#subobject:8c370d|Regimen=1}}== |
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | - | + | ===Regimen {{#subobject:9887c1|Variant=1}}=== |
− | + | {| class="wikitable" style="color:white; background-color:#404040" | |
− | + | |<small>'''FDA-recommended dose'''</small> | |
− | == | ||
− | {| class="wikitable" style=" | ||
|- | |- | ||
− | |||
|} | |} | ||
− | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" | |
− | + | !style="width: 20%"|Study | |
− | + | !style="width: 20%"|Dates of enrollment | |
− | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | |
− | + | !style="width: 20%"|Comparator | |
− | | | + | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] |
− | |[[Levels_of_Evidence#Evidence| | ||
− | | | ||
− | |[[Levels_of_Evidence# | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1016/S1470-2045(13)70513-8 O'Brien et al. 2013 (PCYC-1102 untreated)] |
− | |style="background-color:# | + | |2010-2012 |
− | |[[# | + | |style="background-color:#91cf61"|Phase 1b/2 |
− | |style="background-color:# | + | |style="background-color:#d3d3d3"| |
+ | |style="background-color:#d3d3d3"| | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342187/ Farooqui et al. 2014 (NHLBI 12-H-0035)] | ||
+ | |2011-2014 | ||
+ | |style="background-color:#91cf61"|Phase 2 | ||
+ | |style="background-color:#d3d3d3"| | ||
+ | |style="background-color:#d3d3d3"| | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4722809/ Burger et al. 2015 (RESONATE-2)] | ||
+ | |2013 to not reported | ||
+ | |style="background-color:#1a9851"|Phase 3 (E-RT-switch-ooc) | ||
+ | |[[Chronic_lymphocytic_leukemia_-_historical#Chlorambucil_monotherapy|Chlorambucil]] | ||
+ | | style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>PFS18: 90% vs 52%<br>(HR 0.16, 95% CI 0.09-0.28)<br><br>Superior OS<sup>1</sup> (secondary endpoint)<br>OS60: 83% vs 68%<br>(HR 0.45, 95% CI 0.27-0.76) | ||
+ | |- | ||
+ | |rowspan=2|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6325637/ Woyach et al. 2018 (Alliance A041202)] | ||
+ | |rowspan=2|2013-2016 | ||
+ | |rowspan=2 style="background-color:#1a9851"|Phase 3 (E-switch-ooc) | ||
+ | |1. [[#Bendamustine_.26_Rituximab_.28BR.29|BR]] | ||
+ | | style="background-color:#1a9850" |Superior PFS<sup>2</sup> (primary endpoint)<br>Median PFS: NYR vs 44 mo<br>(HR 0.36, 95% CI 0.25-0.51) | ||
|- | |- | ||
− | | | + | |2. [[#Ibrutinib_.26_Rituximab|Ibrutinib & Rituximab]] |
− | + | | style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<sup>2</sup><br>Median PFS: NYR vs NYR<br>(HR 1.01, 95% CI 0.68-1.52) | |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405333/ Burger et al. 2018 (MDACC 2013-0703)] |
− | + | |2013-2017 | |
− | + | |style="background-color:#1a9851"|Phase 3 (C) | |
− | + | |[[#Ibrutinib_.26_Rituximab|Ibrutinib & Rituximab]] | |
− | + | | style="background-color:#ffffbf" |Did not meet primary endpoint of PFS | |
− | |||
− | | | ||
− | |[[ | ||
− | | | ||
− | |||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1182/blood.2021010845 Langerbeins et al. 2022 (CLL12)] |
− | |style="background-color:# | + | |2014-2019 |
− | |[[# | + | |style="background-color:#1a9851"|Phase 3 (E-esc) |
− | |style="background-color:# | + | |[[#Watchful_waiting|Placebo]] |
+ | | style="background-color:#1a9850" |Superior EFS (primary endpoint)<br>Median EFS: NYR vs 47.8 mo<br>(HR 0.25, 95% CI 0.14-0.43) | ||
|- | |- | ||
− | |[ | + | |[https://www.clinicaltrials.gov/study/NCT03112174 Awaiting publication (SYMPATICO)] |
− | |style="background-color:# | + | |2017-2023 |
− | |[[# | + | |style="background-color:#1a9851"|Phase 3 (C) |
− | |style="background-color:# | + | |[[#Ibrutinib_.26_Venetoclax_.28VI.29|VI]] |
+ | | style="background-color:#d3d3d3" |TBD if different primary endpoint of PFS | ||
|- | |- | ||
− | |[ | + | |[https://www.clinicaltrials.gov/study/NCT04608318 Awaiting publication (GCLLSG CLL17)] |
− | |style="background-color:# | + | |2021-2027 |
− | |[[# | + | |style="background-color:#1a9851"|Phase 3 (C) |
− | |style="background-color:# | + | |1. [[#Venetoclax_.26_Obinutuzumab|VG]]<br>2. [[#Ibrutinib_.26_Venetoclax_.28VI.29|VI]] |
+ | | style="background-color:#d3d3d3" |TBD if different primary endpoint of PFS | ||
|- | |- | ||
− | |[ | + | |[https://www.clinicaltrials.gov/study/NCT05254743 Awaiting publication (BRUIN CLL-314)] |
− | |style="background-color:# | + | |2022-2028 |
− | |[[# | + | |style="background-color:#1a9851"|Phase 3 (C) |
− | |style="background-color:# | + | |[[#Pirtobrutinib_monotherapy_666|Pirtobrutinib]] |
+ | | style="background-color:#d3d3d3" |TBD if different primary endpoint of ORR | ||
|- | |- | ||
|} | |} | ||
− | '' | + | ''<sup>1</sup>Reported efficacy for RESONATE-2 is based on the 2019 update.''<br> |
− | ==== | + | ''<sup>2</sup>Reported efficacy for Alliance A041202 is based on the 2024 update.''<br> |
− | *[[ | + | ''Note: PCYC-1102 was intended for elderly patients. Although both 420 mg and 840 mg doses were planned, the 840 mg cohort was closed due to findings of comparable efficacy in other studies. RESONATE-2 was intended for patients older than 65 years. CLL12 was intended for patients with asymptomatic [[#Binet_staging_.281981.29|Binet stage A]] CLL.'' |
− | + | <div class="toccolours" style="background-color:#fdcdac"> | |
− | + | ====Biomarker eligibility criteria==== | |
− | + | *NHLBI 12-H-0035: TP53 aberrations | |
− | + | </div> | |
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
+ | ====Targeted therapy==== | ||
+ | *[[Ibrutinib (Imbruvica)]] 420 mg PO once per day on days 1 to 28 | ||
+ | '''28-day cycles''' | ||
+ | </div></div> | ||
+ | ===References=== | ||
+ | # '''PCYC-1102 untreated:''' O'Brien S, Furman RR, Coutre SE, Sharman JP, Burger JA, Blum KA, Grant B, Richards DA, Coleman M, Wierda WG, Jones JA, Zhao W, Heerema NA, Johnson AJ, Izumi R, Hamdy A, Chang BY, Graef T, Clow F, Buggy JJ, James DF, Byrd JC. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol. 2014 Jan;15(1):48-58. Epub 2013 Dec 10. [https://doi.org/10.1016/S1470-2045(13)70513-8 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4134524/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24332241/ PubMed] [https://clinicaltrials.gov/study/NCT01105247 NCT01105247] | ||
+ | ## '''Update:''' Byrd JC, Furman RR, Coutre SE, Burger JA, Blum KA, Coleman M, Wierda WG, Jones JA, Zhao W, Heerema NA, Johnson AJ, Shaw Y, Bilotti E, Zhou C, James DF, O'Brien S. Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015 Apr 16;125(16):2497-506. Epub 2015 Feb 19. [https://doi.org/10.1182/blood-2014-10-606038 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4400288/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25700432/ PubMed] | ||
+ | ## '''Update:''' O'Brien S, Furman RR, Coutre S, Flinn IW, Burger JA, Blum K, Sharman J, Wierda W, Jones J, Zhao W, Heerema NA, Johnson AJ, Luan Y, James DF, Chu AD, Byrd JC. Single-agent ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. Blood. 2018 Apr 26;131(17):1910-1919. Epub 2018 Feb 2. [https://doi.org/10.1182/blood-2017-10-810044 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5921964/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29437592/ PubMed] | ||
+ | ## '''Update:''' Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum K, Sharman JP, Wierda W, Zhao W, Heerema NA, Luan Y, Liu EA, Dean JP, O'Brien S. Ibrutinib Treatment for First-Line and Relapsed/Refractory Chronic Lymphocytic Leukemia: Final Analysis of the Pivotal Phase Ib/II PCYC-1102 Study. Clin Cancer Res. 2020 Aug 1;26(15):3918-3927. Epub 2020 Mar 24. [https://doi.org/10.1158/1078-0432.ccr-19-2856 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8175012/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32209572/ PubMed] | ||
+ | # '''NHLBI 12-H-0035:''' Farooqui MZ, Valdez J, Martyr S, Aue G, Saba N, Niemann CU, Herman SE, Tian X, Marti G, Soto S, Hughes TE, Jones J, Lipsky A, Pittaluga S, Stetler-Stevenson M, Yuan C, Lee YS, Pedersen LB, Geisler CH, Calvo KR, Arthur DC, Maric I, Childs R, Young NS, Wiestner A. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol. 2015 Feb;16(2):169-76. Epub 2014 Dec 31. [https://doi.org/10.1016/S1470-2045(14)71182-9 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342187/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25555420/ PubMed] [https://clinicaltrials.gov/study/NCT01500733 NCT01500733] | ||
+ | # '''RESONATE-2:''' Burger JA, Tedeschi A, Barr PM, Robak T, Owen C, Ghia P, Bairey O, Hillmen P, Bartlett NL, Li J, Simpson D, Grosicki S, Devereux S, McCarthy H, Coutre S, Quach H, Gaidano G, Maslyak Z, Stevens DA, Janssens A, Offner F, Mayer J, O'Dwyer M, Hellmann A, Schuh A, Siddiqi T, Polliack A, Tam CS, Suri D, Cheng M, Clow F, Styles L, James DF, Kipps TJ; RESONATE-2 Investigators. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015 Dec 17;373(25):2425-37. Epub 2015 Dec 6. [https://doi.org/10.1056/NEJMoa1509388 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4722809/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26639149/ PubMed] [https://clinicaltrials.gov/study/NCT01722487 NCT01722487] | ||
+ | ## '''Update:''' Barr PM, Robak T, Owen C, Tedeschi A, Bairey O, Bartlett NL, Burger JA, Hillmen P, Coutre S, Devereux S, Grosicki S, McCarthy H, Li J, Simpson D, Offner F, Moreno C, Zhou C, Styles L, James D, Kipps TJ, Ghia P. Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: extended phase 3 results from RESONATE-2. Haematologica. 2018 Sep;103(9):1502-1510. Epub 2018 Jun 7. [https://doi.org/10.3324/haematol.2018.192328 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119145/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29880603/ PubMed] | ||
+ | ## '''Update:''' Burger JA, Barr PM, Robak T, Owen C, Ghia P, Tedeschi A, Bairey O, Hillmen P, Coutre SE, Devereux S, Grosicki S, McCarthy H, Simpson D, Offner F, Moreno C, Dai S, Lal I, Dean JP, Kipps TJ. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia. 2020 Mar;34(3):787-798. Epub 2019 Oct 18. [https://doi.org/10.1038/s41375-019-0602-x link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7214263/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31628428/ PubMed] | ||
+ | # '''Alliance A041202:''' Woyach JA, Ruppert AS, Heerema NA, Zhao W, Booth AM, Ding W, Bartlett NL, Brander DM, Barr PM, Rogers KA, Parikh SA, Coutre S, Hurria A, Brown JR, Lozanski G, Blachly JS, Ozer HG, Major-Elechi B, Fruth B, Nattam S, Larson RA, Erba H, Litzow M, Owen C, Kuzma C, Abramson JS, Little RF, Smith SE, Stone RM, Mandrekar SJ, Byrd JC. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018 Dec 27;379(26):2517-2528. Epub 2018 Dec 1. [https://doi.org/10.1056/NEJMoa1812836 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6325637/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30501481/ PubMed] [https://clinicaltrials.gov/study/NCT01886872 NCT01886872] | ||
+ | ##'''Update:''' Woyach JA, Perez Burbano G, Ruppert AS, Miller C, Heerema NA, Zhao W, Wall A, Ding W, Bartlett NL, Brander DM, Barr PM, Rogers KA, Parikh SA, Stephens DM, Brown JR, Lozanski G, Blachly J, Nattam S, Larson RA, Erba H, Litzow M, Luger S, Owen C, Kuzma C, Abramson JS, Little RF, Dinner S, Stone RM, Uy G, Stock W, Mandrekar SJ, Byrd JC. Follow-up from the A041202 study shows continued efficacy of ibrutinib regimens for older adults with CLL. Blood. 2024 Apr 18;143(16):1616-1627. [https://doi.org/10.1182/blood.2023021959 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11103091/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/38215395/ PubMed] | ||
+ | # '''MDACC 2013-0703:''' Burger JA, Sivina M, Jain N, Kim E, Kadia T, Estrov Z, Nogueras-Gonzalez GM, Huang X, Jorgensen J, Li J, Cheng M, Clow F, Ohanian M, Andreeff M, Mathew T, Thompson P, Kantarjian H, O'Brien S, Wierda WG, Ferrajoli A, Keating MJ. Randomized trial of ibrutinib vs ibrutinib plus rituximab in patients with chronic lymphocytic leukemia. Blood. 2019 Mar 7;133(10):1011-1019. Epub 2018 Dec 7. [https://doi.org/10.1182/blood-2018-10-879429 link to original article] '''dosing details in abstract have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405333/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30530801/ PubMed] [https://clinicaltrials.gov/study/NCT02007044 NCT02007044] | ||
+ | <!-- # '''Abstract:''' Petra Langerbeins, MD, Jasmin Bahlo, Christina Rhein, Paula Cramer, MD, Anna-Maria Fink, MD, Natali Pflug, MD, Julia von Tresckow, MD, Stephan Stilgenbauer, MD, Karl-Anton Kreuzer, Michael J. Eckart, MD, Ursula Vehling-Kaiser, MD, Rudolf Schlag, MD, Christina Balser, MD, Lothar Müller, MD, Clemens-Martin Wendtner, MD, Kirsten Fischer, MD, Barbara Eichhorst, MD and Michael Hallek, MD. Ibrutinib in Early Stage CLL: Preliminary Safety Results of a Placebo-Controlled Phase III Study. ASH Annual Meeting 2015 Abstract 2934. [https://doi.org/10.1182/blood.V126.23.2934.2934 link to abstract] --> | ||
+ | #'''CLL12:''' Langerbeins P, Zhang C, Robrecht S, Cramer P, Fürstenau M, Al-Sawaf O, von Tresckow J, Fink AM, Kreuzer KA, Vehling-Kaiser U, Tausch E, Müller L, Eckart MJ, Schlag R, Freier W, Gaska T, Balser C, Reiser M, Stauch M, Wendtner CM, Fischer K, Stilgenbauer S, Eichhorst B, Hallek M. The CLL12 trial: ibrutinib vs placebo in treatment-naïve, early-stage chronic lymphocytic leukemia. Blood. 2022 Jan 13;139(2):177-187. [https://doi.org/10.1182/blood.2021010845 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/34758069/ PubMed] [https://clinicaltrials.gov/study/NCT02863718 NCT02863718] | ||
+ | #'''BRUIN CLL-314:''' [https://clinicaltrials.gov/study/NCT05254743 NCT05254743] | ||
+ | # '''GCLLSG CLL17:''' [https://clinicaltrials.gov/study/NCT04608318 NCT04608318] | ||
+ | # '''SYMPATICO:''' [https://clinicaltrials.gov/study/NCT03112174 NCT03112174] | ||
− | ==== | + | ==Ibrutinib & Obinutuzumab {{#subobject:7bb15f|Regimen=1}}== |
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | * | + | ===Regimen {{#subobject:e7072b|Variant=1}}=== |
− | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" | |
− | '''28-day | + | !style="width: 20%"|Study |
− | + | !style="width: 20%"|Dates of enrollment | |
− | ===Regimen # | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | {| | + | !style="width: 20%"|Comparator |
− | | | + | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] |
− | |[[Levels_of_Evidence#Evidence| | + | |- |
− | | | + | |[https://doi.org/10.1016/S1470-2045(18)30788-5 Moreno et al. 2018 (iLLUMINATE)] |
− | |[[Levels_of_Evidence# | + | |2014-10-06 to 2015-10-12 |
+ | | style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc) | ||
+ | |[[#Chlorambucil_.26_Obinutuzumab_.28GClb.29|G-Clb]] | ||
+ | | style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: NYR vs 19 mo<br>(HR 0.23, 95% CI 0.15-0.37) | ||
+ | |- | ||
+ | |} | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
+ | ====Targeted therapy==== | ||
+ | *[[Ibrutinib (Imbruvica)]] 420 mg PO once per day | ||
+ | *[[Obinutuzumab (Gazyva)]] as follows: | ||
+ | **Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15 | ||
+ | **Cycles 2 to 6: 1000 mg IV once on day 1 | ||
+ | '''28-day cycles''' | ||
+ | </div></div> | ||
+ | ===References=== | ||
+ | # '''iLLUMINATE:''' Moreno C, Greil R, Demirkan F, Tedeschi A, Anz B, Larratt L, Simkovic M, Samoilova O, Novak J, Ben-Yehuda D, Strugov V, Gill D, Gribben JG, Hsu E, Lih CJ, Zhou C, Clow F, James DF, Styles L, Flinn IW. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019 Jan;20(1):43-56. Epub 2018 Nov 30. [https://doi.org/10.1016/S1470-2045(18)30788-5 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/30522969/ PubMed] [https://clinicaltrials.gov/study/NCT02264574 NCT02264574] | ||
+ | # '''ECOG-ACRIN EA9161:''' [https://clinicaltrials.gov/study/NCT03701282 NCT03701282] | ||
+ | # '''Alliance A041702:''' [https://clinicaltrials.gov/study/NCT03737981 NCT03737981] | ||
+ | ==Ibrutinib & Rituximab {{#subobject:7ccq6f|Regimen=1}}== | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #1, limited duration {{#subobject:1y91tb|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1016/s1470-2045(23)00144-4 Hillmen et al. 2023 (FLAIR)] |
− | |style="background-color:# | + | |2014-09-19 to 2018-07-19 |
− | |FCR | + | | style="background-color:#1a9851" |Phase 3 (E-switch-ooc) |
− | |style="background-color:# | + | |[[#FCR|FCR]] |
+ | | style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: NYR vs 67 mo<br>(HR 0.44, 95% CI 0.32-0.60) | ||
|- | |- | ||
|} | |} | ||
− | ==== | + | <div class="toccolours" style="background-color:#f2f3f4"> |
− | *[[ | + | ====Targeted therapy==== |
− | + | *[[Ibrutinib (Imbruvica)]] 420 mg PO once per day on days 1 to 28 | |
− | |||
− | |||
− | |||
− | |||
*[[Rituximab (Rituxan)]] as follows: | *[[Rituximab (Rituxan)]] as follows: | ||
− | **Cycle 1: | + | **Cycle 1: 375 mg/m<sup>2</sup> IV once on day 1 |
**Cycles 2 to 6: 500 mg/m<sup>2</sup> IV once on day 1 | **Cycles 2 to 6: 500 mg/m<sup>2</sup> IV once on day 1 | ||
+ | '''28-day cycle for up to 78 cycles (6 years)''' | ||
+ | </div></div><br> | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
− | ==== | + | ===Regimen variant #2, indefinite {{#subobject:ec91tb|Variant=1}}=== |
− | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" | |
− | *[[ | + | !style="width: 20%"|Study |
− | * | + | !style="width: 20%"|Dates of enrollment |
− | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | |
− | '''28-day | + | !style="width: 20%"|Comparator |
− | + | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | |
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6908306/ Shanafelt et al. 2019 (ECOG E1912)] | ||
+ | |2014-2016 | ||
+ | | style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc) | ||
+ | |[[#FCR|FCR]] | ||
+ | | style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>PFS36: 89.4% vs 72.9%<br>(HR 0.35, 95% CI 0.22-0.56)<br><br>Superior OS<sup>1</sup> (secondary endpoint)<br>OS60: 95% vs 89%<br>(HR 0.47, 95% CI 0.25-0.89) | ||
+ | |- | ||
+ | |} | ||
+ | ''<sup>1</sup>Reported efficacy is based on the 2022 update.'' | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
+ | ====Targeted therapy==== | ||
+ | *[[Ibrutinib (Imbruvica)]] 420 mg PO once per day on days 1 to 28 | ||
+ | *[[Rituximab (Rituxan)]] as follows: | ||
+ | **Cycle 2: 50 mg/m<sup>2</sup> IV once on day 1, then 325 mg/m<sup>2</sup> IV once on day 2 | ||
+ | **Cycles 3 to 7: 500 mg/m<sup>2</sup> IV once on day 1 | ||
+ | '''28-day cycles''' | ||
+ | </div></div> | ||
===References=== | ===References=== | ||
− | + | # '''Alliance A041202:''' Woyach JA, Ruppert AS, Heerema NA, Zhao W, Booth AM, Ding W, Bartlett NL, Brander DM, Barr PM, Rogers KA, Parikh SA, Coutre S, Hurria A, Brown JR, Lozanski G, Blachly JS, Ozer HG, Major-Elechi B, Fruth B, Nattam S, Larson RA, Erba H, Litzow M, Owen C, Kuzma C, Abramson JS, Little RF, Smith SE, Stone RM, Mandrekar SJ, Byrd JC. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018 Dec 27;379(26):2517-2528. Epub 2018 Dec 1. [https://doi.org/10.1056/NEJMoa1812836 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6325637/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30501481/ PubMed] [https://clinicaltrials.gov/study/NCT01886872 NCT01886872] | |
− | + | ##'''Update:''' Woyach JA, Perez Burbano G, Ruppert AS, Miller C, Heerema NA, Zhao W, Wall A, Ding W, Bartlett NL, Brander DM, Barr PM, Rogers KA, Parikh SA, Stephens DM, Brown JR, Lozanski G, Blachly J, Nattam S, Larson RA, Erba H, Litzow M, Luger S, Owen C, Kuzma C, Abramson JS, Little RF, Dinner S, Stone RM, Uy G, Stock W, Mandrekar SJ, Byrd JC. Follow-up from the A041202 study shows continued efficacy of ibrutinib regimens for older adults with CLL. Blood. 2024 Apr 18;143(16):1616-1627. [https://doi.org/10.1182/blood.2023021959 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11103091/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/38215395/ PubMed] | |
− | + | # '''ECOG E1912:''' Shanafelt TD, Wang XV, Kay NE, Hanson CA, O'Brien S, Barrientos J, Jelinek DF, Braggio E, Leis JF, Zhang CC, Coutre SE, Barr PM, Cashen AF, Mato AR, Singh AK, Mullane MP, Little RF, Erba H, Stone RM, Litzow M, Tallman M. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019 Aug 1;381(5):432-443. [https://doi.org/10.1056/NEJMoa1817073 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6908306/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31365801/ PubMed] [https://clinicaltrials.gov/study/NCT02048813 NCT02048813] | |
− | + | ##'''Update:''' Shanafelt TD, Wang XV, Hanson CA, Paietta EM, O'Brien S, Barrientos J, Jelinek DF, Braggio E, Leis JF, Zhang CC, Coutre SE, Barr PM, Cashen AF, Mato AR, Singh AK, Mullane MP, Little RF, Erba H, Stone RM, Litzow M, Tallman M, Kay NE. Long-term outcomes for ibrutinib-rituximab and chemoimmunotherapy in CLL: updated results of the E1912 trial. Blood. 2022 Jul 14;140(2):112-120. [https://doi.org/10.1182/blood.2021014960 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9283968/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35427411/ PubMed] | |
− | ## '''Update:''' | + | #'''FLAIR:''' Hillmen P, Pitchford A, Bloor A, Broom A, Young M, Kennedy B, Walewska R, Furtado M, Preston G, Neilson JR, Pemberton N, Sidra G, Morley N, Cwynarski K, Schuh A, Forconi F, Elmusharaf N, Paneesha S, Fox CP, Howard DR, Hockaday A, Brown JM, Cairns DA, Jackson S, Greatorex N, Webster N, Shingles J, Dalal S, Patten PEM, Allsup D, Rawstron A, Munir T. Ibrutinib and rituximab versus fludarabine, cyclophosphamide, and rituximab for patients with previously untreated chronic lymphocytic leukaemia (FLAIR): interim analysis of a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2023 May;24(5):535-552. [https://doi.org/10.1016/s1470-2045(23)00144-4 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/37142374/ PubMed] ISRCTN01844152 |
− | |||
− | |||
− | # ''' | ||
− | |||
− | |||
− | |||
− | == | + | ==Ibrutinib & Venetoclax {{#subobject:7c8bdd|Regimen=1}}== |
− | {| class="wikitable" style=" | + | VI: '''<u>V</u>'''entoclax & '''<u>I</u>'''brutinib |
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #1, 15 cycles {{#subobject:44u8nv|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
+ | |- | ||
+ | |[https://doi.org/10.1056/EVIDoa2200006 Kater et al. 2022 (GLOW)] | ||
+ | |2018-05 to 2019-04 | ||
+ | | style="background-color:#1a9851" |Phase 3 (E-switch-ooc) | ||
+ | |[[#Chlorambucil_.26_Obinutuzumab_.28GClb.29|GClb]] | ||
+ | | style="background-color:#1a9850" |Superior PFS<sup>1</sup> (primary endpoint)<br>PFS42: 74.6% vs 24.8%<br>(HR 0.21, 95% CI 0.14-0.33) | ||
|- | |- | ||
− | |||
|} | |} | ||
− | ===Regimen # | + | ''<sup>1</sup>Reported efficacy is based on the 2023 update.'' |
− | {| | + | <div class="toccolours" style="background-color:#fdcdac"> |
− | | | + | ====Eligibility criteria==== |
− | |[[Levels_of_Evidence#Evidence| | + | *GLOW: At least 65 years old or 18 to 64 years old with a Cumulative Illness Rating Scale (CIRS) score greater than 6 |
− | + | </div> | |
− | + | <div class="toccolours" style="background-color:#f2f3f4"> | |
+ | ====Targeted therapy==== | ||
+ | *[[Ibrutinib (Imbruvica)]] 420 mg PO once per day on days 1 to 28 | ||
+ | *[[Venetoclax (Venclexta)]] as follows: | ||
+ | **Cycle 4: 20 mg PO once per day on days 1 to 7, then 50 mg PO once per day on days 8 to 14, then 100 mg PO once per day on days 15 to 21, then 200 mg PO once per day on days 22 to 28 | ||
+ | **Cycles 5 to 15: 400 mg PO once per day on days 1 to 28 | ||
+ | '''28-day cycle for 15 cycles''' | ||
+ | </div></div><br> | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #2, 24 cycles {{#subobject:44ddcc|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | + | |[https://doi.org/10.1056/NEJMoa1900574 Jain et al. 2019 (MDACC 2015-0860)] | |
− | | | + | |2016-2018 |
− | + | |style="background-color:#91cf61"|Phase 2 | |
− | |style="background-color:# | ||
|- | |- | ||
− | | | + | |} |
− | + | ''Note: the starting dose and escalation schedule of venetoclax are not clearly specified in the manuscript; the authors were contacted for clarification and informed us that they used the FDA-recommended dosing, which is replicated here.'' | |
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
+ | ====Targeted therapy==== | ||
+ | *[[Ibrutinib (Imbruvica)]] 420 mg PO once per day on days 1 to 28 | ||
+ | *[[Venetoclax (Venclexta)]] as follows: | ||
+ | **Cycle 4: 20 mg PO once per day on days 1 to 7, then 50 mg PO once per day on days 8 to 14, then 100 mg PO once per day on days 15 to 21, then 200 mg PO once per day on days 22 to 28 | ||
+ | **Cycles 5 to 24: 400 mg PO once per day on days 1 to 28 | ||
+ | '''28-day cycle for up to 24 cycles''' | ||
+ | </div></div><br> | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #3, MRD-guided discontinuation {{#subobject:44jcmv|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |rowspan=2|[ | + | |rowspan=2|[https://doi.org/10.1016/s1470-2045(23)00144-4 Hillmen et al. 2023 (FLAIR part 2)] |
− | |rowspan=2 style="background-color:# | + | |rowspan=2|2017-07-20 to 2021-03-24 |
− | |[[# | + | |rowspan=2 style="background-color:#1a9851" |Phase 3 (E-switch-ooc) |
− | |style="background-color:# | + | |1. [[#FCR|FCR]] |
+ | | style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>PFS36: 97.2% vs 76.8%%<br>(HR 0.13, 95% CI 0.07-0.24)<br><br>Superior OS (secondary endpoint)<br>OS36: 98% vs 93%<br>(HR 0.31, 95% CI 0.15-0.67) | ||
|- | |- | ||
− | |[[# | + | |2. [[#Ibrutinib_monotherapy|Ibrutinib]] |
− | |style="background-color:# | + | | style="background-color:#d3d3d3" |Not reported |
|- | |- | ||
− | |[ | + | |} |
− | |style="background-color:# | + | ''Note: See paper for details regarding MRD-guided discontinuation.'' |
− | |[[# | + | <div class="toccolours" style="background-color:#f2f3f4"> |
− | |style=" | + | ====Targeted therapy==== |
+ | *[[Ibrutinib (Imbruvica)]] 420 mg PO once per day on days 1 to 28 | ||
+ | *[[Venetoclax (Venclexta)]] as follows: | ||
+ | **Cycle 3: 20 mg PO once per day on days 1 to 7, then 50 mg PO once per day on days 8 to 14, then 100 mg PO once per day on days 15 to 21, then 200 mg PO once per day on days 22 to 28 | ||
+ | **Cycles 4 up to 78: 400 mg PO once per day on days 1 to 28 | ||
+ | '''28-day cycle for up to 78 cycles''' | ||
+ | </div></div> | ||
+ | |||
+ | ===References=== | ||
+ | # '''MDACC 2015-0860:''' Jain N, Keating M, Thompson P, Ferrajoli A, Burger J, Borthakur G, Takahashi K, Estrov Z, Fowler N, Kadia T, Konopleva M, Alvarado Y, Yilmaz M, DiNardo C, Bose P, Ohanian M, Pemmaraju N, Jabbour E, Sasaki K, Kanagal-Shamanna R, Patel K, Jorgensen J, Garg N, Wang X, Sondermann K, Cruz N, Wei C, Ayala A, Plunkett W, Kantarjian H, Gandhi V, Wierda W. Ibrutinib and venetoclax for first-line treatment of CLL. N Engl J Med. 2019 May 30;380(22):2095-2103. [https://doi.org/10.1056/NEJMoa1900574 link to original article] '''dosing details in abstract have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/31141631/ PubMed] [https://clinicaltrials.gov/study/NCT02756897 NCT02756897] | ||
+ | # '''GLOW:''' Kater AP, Owen C, Moreno C, Follows G, Munir T, Levin MD, Benjamini O, Janssens A, Osterborg A, Robak T, Simkovic M, Stevens D, Voloshin S, Vorobyev V, Ysebaert L, Qin R, Steele AJ, Schuier N, Baeten K, Caces DB, Niemann CU. Fixed-Duration Ibrutinib-Venetoclax in Patients with Chronic Lymphocytic Leukemia and Comorbidities. NEJM Evid. 2022 Jul;1(7):EVIDoa2200006. Epub 2022 May 13. [https://doi.org/10.1056/EVIDoa2200006 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/38319255/ PubMed] [https://clinicaltrials.gov/study/NCT03462719 NCT03462719] | ||
+ | ##'''Update:''' Niemann CU, Munir T, Moreno C, Owen C, Follows GA, Benjamini O, Janssens A, Levin MD, Robak T, Simkovic M, Voloshin S, Vorobyev V, Yagci M, Ysebaert L, Qi K, Qi Q, Sinet P, Parisi L, Srinivasan S, Schuier N, Baeten K, Howes A, Caces DB, Kater AP. Fixed-duration ibrutinib-venetoclax versus chlorambucil-obinutuzumab in previously untreated chronic lymphocytic leukaemia (GLOW): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2023 Dec;24(12):1423-1433. Epub 2023 Nov 6. [https://doi.org/10.1016/s1470-2045(23)00452-7 link to original article] [https://pubmed.ncbi.nlm.nih.gov/37944541/ PubMed] | ||
+ | #'''FLAIR part 2:''' Munir T, Cairns DA, Bloor A, Allsup D, Cwynarski K, Pettitt A, Paneesha S, Fox CP, Eyre TA, Forconi F, Elmusharaf N, Kennedy B, Gribben J, Pemberton N, Sheehy O, Preston G, Schuh A, Walewska R, Duley L, Howard D, Hockaday A, Jackson S, Greatorex N, Girvan S, Bell S, Brown JM, Webster N, Dalal S, de Tute R, Rawstron A, Patten PEM, Hillmen P; National Cancer Research Institute Chronic Lymphocytic Leukemia Subgroup. Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease. N Engl J Med. 2024 Jan 25;390(4):326-337. Epub 2023 Dec 10. [https://doi.org/10.1056/nejmoa2310063 link to original article] '''dosing details in supplement have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/38078508/ PubMed] ISRCTN01844152 | ||
+ | |||
+ | ==Ibrutinib, Venetoclax, Obinutuzumab {{#subobject:78gu1g|Regimen=1}}== | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #1 {{#subobject:9c134a|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |rowspan=3|[https://doi.org/10.1056/nejmoa2213093 Eichhorst et al. 2023 (GAIA)] |
− | |style="background-color:# | + | |rowspan=3|2016-12-13 to 2019-10-13 |
− | |[[# | + | |rowspan=3 style="background-color:#1a9851" |Phase 3 (E-switch-ooc) |
− | |style="background-color:# | + | |1a. [[#Bendamustine_.26_Rituximab_.28BR.29|BR]]<br>1b. [[#FCR|FCR]] |
+ | | style="background-color:#1a9850" |Superior PFS<sup>2</sup> (co-primary endpoint)<br>PFS48: 85.5% vs 62%<br>(HR 0.30, 97.5% CI 0.19-0.47) | ||
|- | |- | ||
− | | | + | |2. [[#Venetoclax_.26_Obinutuzumab|Venetoclax & Obinutuzumab]] |
− | + | | style="background-color:#d9ef8b" |Might have superior PFS<sup>2</sup> (co-primary endpoint)<br>PFS48: 85.5% vs 81.8%<br>(HR 0.63, 97.5% CI 0.39-1.02) | |
− | |||
− | |style="background-color:# | ||
|- | |- | ||
− | |[[# | + | |3. [[#Venetoclax_.26_Rituximab_999|Venetoclax & Rituximab]] |
− | |style="background-color:# | + | | style="background-color:#1a9850" |Superior PFS<sup>2</sup> (co-primary endpoint)<br>PFS48: 85.5% vs 70.1%<br>(HR 0.38, 97.5% CI 0.24-0.59) |
|- | |- | ||
− | | | + | |} |
− | + | ''<sup>1</sup>Reported efficacy is based on the 2021 update.''<br> | |
− | + | ''Note: Obinutuzumab is only given for the first six cycles.'' | |
− | + | <div class="toccolours" style="background-color:#f2f3f4"> | |
+ | ====Targeted therapy==== | ||
+ | *[[Ibrutinib (Imbruvica)]] 420 mg PO once per day on days 1 to 28 | ||
+ | *[[Venetoclax (Venclexta)]] as follows: | ||
+ | **Cycle 1: 20 mg PO once per day on days 22 to 28 | ||
+ | **Cycle 2: 50 mg PO once per day on days 1 to 7, then 100 mg PO once per day on days 8 to 14, then 200 mg PO once per day on days 15 to 21, then 400 mg PO once per day on days 22 to 28 | ||
+ | **Cycles 3 to 12: 400 mg PO once per day | ||
+ | *[[Obinutuzumab (Gazyva)]] as follows: | ||
+ | **Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15 | ||
+ | **Cycles 2 to 6: 1000 mg IV once on day 1 | ||
+ | '''28-day cycle for up to 36 cycles''' | ||
+ | </div></div><br> | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #2 {{#subobject:52rgcc|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7605394/ Rogers et al. 2020 (OSU-14266)] |
− | | | + | |2015-2017 |
− | + | |style="background-color:#91cf61"|Phase 2 | |
− | |style="background-color:# | ||
|- | |- | ||
|} | |} | ||
− | '' | + | <div class="toccolours" style="background-color:#f2f3f4"> |
− | + | ====Targeted therapy==== | |
− | + | *[[Ibrutinib (Imbruvica)]] as follows: | |
− | + | **Cycle 2 onwards: 420 mg PO once per day on days 1 to 28 | |
− | + | *[[Venetoclax (Venclexta)]] as follows: | |
− | + | **Cycle 3: 20 mg PO once per day on days 1 to 7, then 50 mg PO once per day on days 8 to 14, then 100 mg PO once per day on days 15 to 21, then 200 mg PO once per day on days 22 to 28 | |
− | + | **Cycles 4 to 14: 400 mg PO once per day | |
− | + | *[[Obinutuzumab (Gazyva)]] as follows: | |
+ | **Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15 | ||
+ | **Cycles 2 to 8: 1000 mg IV once on day 1 | ||
+ | '''28-day cycles''' | ||
+ | </div></div> | ||
+ | ===References=== | ||
+ | # '''OSU-14266:''' Rogers KA, Huang Y, Ruppert AS, Abruzzo LV, Andersen BL, Awan FT, Bhat SA, Dean A, Lucas M, Banks C, Grantier C, Heerema NA, Lozanski G, Maddocks KJ, Valentine TR, Weiss DM, Jones JA, Woyach JA, Byrd JC. Phase II Study of Combination Obinutuzumab, Ibrutinib, and Venetoclax in Treatment-Naïve and Relapsed or Refractory Chronic Lymphocytic Leukemia. J Clin Oncol. 2020 Nov 1;38(31):3626-3637. Epub 2020 Aug 14. [https://doi.org/10.1200/jco.20.00491 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7605394/ link to PMC article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/32795224/ PubMed] [https://clinicaltrials.gov/study/NCT02427451 NCT02427451] | ||
+ | #'''GAIA:''' Eichhorst B, Niemann CU, Kater AP, Fürstenau M, von Tresckow J, Zhang C, Robrecht S, Gregor M, Juliusson G, Thornton P, Staber PB, Tadmor T, Lindström V, da Cunha-Bang C, Schneider C, Poulsen CB, Illmer T, Schöttker B, Nösslinger T, Janssens A, Christiansen I, Baumann M, Frederiksen H, van der Klift M, Jäger U, Leys MBL, Hoogendoorn M, Lotfi K, Hebart H, Gaska T, Koene H, Enggaard L, Goede J, Regelink JC, Widmer A, Simon F, De Silva N, Fink AM, Bahlo J, Fischer K, Wendtner CM, Kreuzer KA, Ritgen M, Brüggemann M, Tausch E, Levin MD, van Oers M, Geisler C, Stilgenbauer S, Hallek M; GCLLSG, the HOVON and Nordic CLL Study Groups, the SAKK, the Israeli CLL Association, and Cancer Trials Ireland. First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia. N Engl J Med. 2023 May 11;388(19):1739-1754. [https://doi.org/10.1056/nejmoa2213093 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/37163621/ PubMed] [https://clinicaltrials.gov/study/NCT02950051 NCT02950051] | ||
+ | ##'''Update:''' Fürstenau M, Kater AP, Robrecht S, von Tresckow J, Zhang C, Gregor M, Thornton P, Staber PB, Tadmor T, Lindström V, Juliusson G, Janssens A, Levin MD, da Cunha-Bang C, Schneider C, Goldschmidt N, Vandenberghe E, Rossi D, Benz R, Nösslinger T, Heintel D, Poulsen CB, Christiansen I, Frederiksen H, Enggaard L, Posthuma EFM, Issa DE, Visser HPJ, Bellido M, Kutsch N, Dürig J, Stehle A, Vöhringer M, Böttcher S, Schulte C, Simon F, Fink AM, Fischer K, Holmes EE, Kreuzer KA, Ritgen M, Brüggemann M, Tausch E, Stilgenbauer S, Hallek M, Niemann CU, Eichhorst B. First-line venetoclax combinations versus chemoimmunotherapy in fit patients with chronic lymphocytic leukaemia (GAIA/CLL13): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2024 Jun;25(6):744-759. Erratum in: Lancet Oncol. 2024 Jul;25(7):e284. [https://doi.org/10.1016/s1470-2045(24)00196-7 link to original article] [https://pubmed.ncbi.nlm.nih.gov/38821083/ PubMed] | ||
− | ===Regimen # | + | ==Obinutuzumab monotherapy {{#subobject:f0a8d4|Regimen=1}}== |
− | {| | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | | | + | ===Regimen variant #1, standard-dose (1000 mg) {{#subobject:f89f3a|Variant=1}}=== |
− | |[[Levels_of_Evidence#Evidence| | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | | | + | !style="width: 20%"|Study |
− | |[[Levels_of_Evidence# | + | !style="width: 20%"|Dates of enrollment |
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4705612/ Byrd et al. 2015 (GAGE)] | |
− | | | + | |2011 to not reported |
− | |[[# | + | |style="background-color:#1a9851"|Randomized Phase 2 (C) |
− | |style="background-color:# | + | |[[#Obinutuzumab_monotherapy|Obinutuzumab]]; high-dose |
+ | |style="background-color:#fee08b"|Might have inferior ORR | ||
|- | |- | ||
− | |[[ | + | |} |
− | + | <div class="toccolours" style="background-color:#f2f3f4"> | |
+ | ====Targeted therapy==== | ||
+ | *[[Obinutuzumab (Gazyva)]] as follows: | ||
+ | **Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15 | ||
+ | **Cycles 2 up to 8: 1000 mg IV once on day 1 | ||
+ | ====Supportive therapy==== | ||
+ | *[[Acetaminophen (Tylenol)]] 650 to 1000 mg PO once per infusion, 30 to 60 minutes prior to obinutuzumab | ||
+ | *[[:Category:Antihistamines|Antihistamine]] "such as" [[Diphenhydramine (Benadryl)]] 50 to 100 mg PO once per infusion, 30 to 60 minutes prior to obinutuzumab | ||
+ | *[[Prednisolone (Millipred)]] (or equivalent) 100 mg IV once per infusion, prior to each of the first three doses of obinutuzumab, afterwards at the discretion of treating physician | ||
+ | '''21-day cycle for up to 8 cycles''' | ||
+ | </div></div><br> | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #2, high-dose (2000 mg), option A {{#subobject:6ca538|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | | | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4705612/ Byrd et al. 2015 (GAGE)] |
− | + | |2011 to not reported | |
− | + | |style="background-color:#1a9851"|Randomized Phase 2 (E-esc) | |
− | + | |[[#Obinutuzumab_monotherapy|Obinutuzumab]]; standard-dose | |
− | + | |style="background-color:#d9ef8b"|Might have superior ORR (primary endpoint) | |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | # | ||
− | |||
− | # | ||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
|- | |- | ||
− | |||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#f2f3f4"> | |
− | + | ====Targeted therapy==== | |
− | ===Regimen {{#subobject: | + | *[[Obinutuzumab (Gazyva)]] as follows: |
− | {| | + | **Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once on day 3, then 2000 mg IV once per day on days 8 & 15 |
− | | | + | **Cycles 2 up to 8: 2000 mg IV once on day 1 |
− | |[[Levels_of_Evidence#Evidence| | + | ====Supportive therapy==== |
− | | | + | *[[Acetaminophen (Tylenol)]] 650 to 1000 mg PO once per infusion, 30 to 60 minutes prior to obinutuzumab |
− | |[[Levels_of_Evidence# | + | *[[:Category:Antihistamines|Antihistamine]] "such as" [[Diphenhydramine (Benadryl)]] 50 to 100 mg PO once per infusion, 30 to 60 minutes prior to obinutuzumab |
+ | *[[Prednisolone (Millipred)]] (or equivalent) 100 mg IV once per infusion, prior to each of the first three doses of obinutuzumab, afterwards at the discretion of treating physician | ||
+ | '''21-day cycle for up to 8 cycles''' | ||
+ | </div></div><br> | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #3, high-dose (2000 mg), option B {{#subobject:6cb538|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4705612/ Byrd et al. 2015 (GAGE)] |
− | |style="background-color:# | + | |2011 to not reported |
− | | | + | |style="background-color:#1a9851"|Randomized Phase 2 (E-esc) |
− | |style="background-color:# | + | |[[#Obinutuzumab_monotherapy|Obinutuzumab]]; standard-dose |
+ | |style="background-color:#d9ef8b"|Might have superior ORR (primary endpoint) | ||
|- | |- | ||
|} | |} | ||
− | ==== | + | <div class="toccolours" style="background-color:#f2f3f4"> |
− | *[[ | + | ====Targeted therapy==== |
− | + | *[[Obinutuzumab (Gazyva)]] as follows: | |
− | **Cycle 1: | + | **Cycle 1: 100 mg IV once on day 1, then 1900 mg IV once on day 2, then 2000 mg IV once per day on days 8 & 15 |
− | **Cycles 2 to | + | **Cycles 2 up to 8: 2000 mg IV once on day 1 |
− | + | ====Supportive therapy==== | |
− | ====Supportive | + | *[[Acetaminophen (Tylenol)]] 650 to 1000 mg PO once per infusion, 30 to 60 minutes prior to obinutuzumab |
− | *[[ | + | *[[:Category:Antihistamines|Antihistamine]] "such as" [[Diphenhydramine (Benadryl)]] 50 to 100 mg PO once per infusion, 30 to 60 minutes prior to obinutuzumab |
− | *[[Diphenhydramine (Benadryl)]] 50 mg | + | *[[Prednisolone (Millipred)]] (or equivalent) 100 mg IV once per infusion, prior to each of the first three doses of obinutuzumab, afterwards at the discretion of treating physician |
− | + | '''21-day cycle for up to 8 cycles''' | |
− | + | </div></div> | |
− | ''' | ||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
===References=== | ===References=== | ||
− | + | # '''GAGE:''' Byrd JC, Flynn JM, Kipps TJ, Boxer M, Kolibaba KS, Carlile DJ, Fingerle-Rowson G, Tyson N, Hirata J, Sharman JP. Randomized phase 2 study of obinutuzumab monotherapy in symptomatic, previously untreated chronic lymphocytic leukemia. Blood. 2016 Jan 7;127(1):79-86. Epub 2015 Oct 15. [https://doi.org/10.1182/blood-2015-03-634394 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4705612/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26472752/ PubMed] [https://clinicaltrials.gov/study/NCT01414205 NCT01414205] | |
− | + | ==Venetoclax & Obinutuzumab {{#subobject:62ac8e|Regimen=1}}== | |
− | + | VG: '''<u>V</u>'''enetoclax & '''<u>G</u>'''azyva (Obinutuzumab) | |
− | + | <br>VO: '''<u>V</u>'''enetoclax & '''<u>O</u>'''binutuzumab | |
− | # | + | <br>GVE: '''<u>G</u>'''azyva (Obinutuzumab) & '''<u>VE</u>'''netoclax |
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | == | + | ===Regimen {{#subobject:9c134a|Variant=1}}=== |
− | {| class="wikitable" style=" | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[[# | + | |[https://doi.org/10.1056/NEJMoa1815281 Fischer et al. 2019 (GCLLSG CLL14)] |
− | | | + | |2015-08-07 to 2016-08-04 |
− | + | |style="background-color:#1a9851"|Phase 3 (E-RT-switch-ooc) | |
− | = | + | |[[#Chlorambucil_.26_Obinutuzumab_.28GClb.29|Chlorambucil & Obinutuzumab]] |
− | + | |style="background-color:#1a9850"|Superior PFS<sup>1</sup> (primary endpoint)<br>Median PFS: NYR vs 36.4 mo<br>(HR 0.33, 95% CI 0.25-0.45) | |
− | | | + | |- |
− | |[[ | + | |rowspan=3|[https://doi.org/10.1056/nejmoa2213093 Eichhorst et al. 2023 (GAIA)] |
− | + | |rowspan=3|2016-12-13 to 2019-10-13 | |
− | + | |rowspan=3 style="background-color:#1a9851" |Phase 3 (E-switch-ooc) | |
+ | |1a. [[#Bendamustine_.26_Rituximab_.28BR.29|BR]]<br>1b. [[#FCR|FCR]] | ||
+ | | style="background-color:#1a9850" |Superior PFS<sup>2</sup> (co-primary endpoint)<br>PFS48: 81.8% vs 62%<br>(HR 0.47, 97.5% CI 0.32-0.69) | ||
|- | |- | ||
− | |[ | + | |2. [[#Ibrutinib.2C_Venetoclax.2C_Obinutuzumab|Ibrutinib, Venetoclax, Obinutuzumab]] |
− | |style="background-color:# | + | | style="background-color:#fee08b" |Might have inferior PFS<sup>2</sup> |
− | |||
− | |||
|- | |- | ||
− | |[ | + | |3. [[#Venetoclax_.26_Rituximab_999|Venetoclax & Rituximab]] |
− | |style="background-color:# | + | | style="background-color:#1a9850" |Superior PFS<sup>2</sup> (co-primary endpoint)<br>PFS48: 81.8% vs 70.1%<br>(HR 0.57, 97.5% CI 0.38-0.84) |
− | |||
− | |||
|- | |- | ||
− | |[ | + | |[https://www.clinicaltrials.gov/study/NCT05197192 Awaiting publication (GCLLSG CLL16)] |
− | |style="background-color:# | + | |2022-2026 |
− | |[[# | + | |style="background-color:#1a9851"|Phase 3 (C) |
− | |style="background-color:# | + | |[[#GAVE_666|GAVE]] |
+ | |style="background-color:#d3d3d3"|TBD if different primary endpoint of PFS | ||
|- | |- | ||
− | |[https:// | + | |[https://www.clinicaltrials.gov/study/NCT05057494 Awaiting publication (MAJIC)] |
− | |style="background-color:# | + | |2022-2029 |
− | |[[# | + | |style="background-color:#1a9851"|Phase 3 (C) |
− | |TBD | + | |[[#Acalabrutinib_.26_Venetoclax_666|Acalabrutinib & Venetoclax]] |
+ | |style="background-color:#d3d3d3"|TBD if different primary endpoint of PFS | ||
|- | |- | ||
|} | |} | ||
− | + | ''<sup>1</sup>Reported efficacy is based on the 2021 update.''<br> | |
− | ''''' | + | ''<sup>2</sup>Reported efficacy is based on the 2024 update.''<br> |
− | ==== | + | ''Note: Obinutuzumab is only given for the first six cycles.'' |
− | *[[ | + | <div class="toccolours" style="background-color:#f2f3f4"> |
− | + | ====Targeted therapy==== | |
− | '''28-day cycles | + | *[[Venetoclax (Venclexta)]] as follows: |
− | + | **Cycle 1: 20 mg PO once per day on days 22 to 28 | |
+ | **Cycle 2: 50 mg PO once per day on days 1 to 7, then 100 mg PO once per day on days 8 to 14, then 200 mg PO once per day on days 15 to 21, then 400 mg PO once per day on days 22 to 28 | ||
+ | **Cycles 3 to 12: 400 mg PO once per day | ||
+ | *[[Obinutuzumab (Gazyva)]] as follows: | ||
+ | **Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15 | ||
+ | **Cycles 2 to 6: 1000 mg IV once on day 1 | ||
+ | '''28-day cycle for 12 cycles''' | ||
+ | </div></div> | ||
===References=== | ===References=== | ||
− | # O | + | # '''GCLLSG CLL14:''' Fischer K, Al-Sawaf O, Bahlo J, Fink AM, Tandon M, Dixon M, Robrecht S, Warburton S, Humphrey K, Samoylova O, Liberati AM, Pinilla-Ibarz J, Opat S, Sivcheva L, Le Dû K, Fogliatto LM, Niemann CU, Weinkove R, Robinson S, Kipps TJ, Boettcher S, Tausch E, Humerickhouse R, Eichhorst B, Wendtner CM, Langerak AW, Kreuzer KA, Ritgen M, Goede V, Stilgenbauer S, Mobasher M, Hallek M. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019 Jun 6;380(23):2225-2236. Epub 2019 Jun 4. [https://doi.org/10.1056/NEJMoa1815281 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/31166681/ PubMed] [https://clinicaltrials.gov/study/NCT02242942 NCT02242942] |
− | ## '''Update:''' | + | ## '''Update:''' Al-Sawaf O, Zhang C, Tandon M, Sinha A, Fink AM, Robrecht S, Samoylova O, Liberati AM, Pinilla-Ibarz J, Opat S, Sivcheva L, Le Dû K, Fogliatto LM, Niemann CU, Weinkove R, Robinson S, Kipps TJ, Tausch E, Schary W, Ritgen M, Wendtner CM, Kreuzer KA, Eichhorst B, Stilgenbauer S, Hallek M, Fischer K. Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2020 Sep;21(9):1188-1200. [https://doi.org/10.1016/s1470-2045(20)30443-5 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32888452/ PubMed] |
− | # | + | ## '''Update:''' Al-Sawaf O, Zhang C, Lu T, Liao MZ, Panchal A, Robrecht S, Ching T, Tandon M, Fink AM, Tausch E, Schneider C, Ritgen M, Böttcher S, Kreuzer KA, Chyla B, Miles D, Wendtner CM, Eichhorst B, Stilgenbauer S, Jiang Y, Hallek M, Fischer K. Minimal Residual Disease Dynamics after Venetoclax-Obinutuzumab Treatment: Extended Off-Treatment Follow-up From the Randomized CLL14 Study. J Clin Oncol. 2021 Dec 20;39(36):4049-4060. Epub 2021 Oct 28. [https://doi.org/10.1200/jco.21.01181 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8678026/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34709929/ PubMed] |
− | # | + | #'''GAIA:''' Eichhorst B, Niemann CU, Kater AP, Fürstenau M, von Tresckow J, Zhang C, Robrecht S, Gregor M, Juliusson G, Thornton P, Staber PB, Tadmor T, Lindström V, da Cunha-Bang C, Schneider C, Poulsen CB, Illmer T, Schöttker B, Nösslinger T, Janssens A, Christiansen I, Baumann M, Frederiksen H, van der Klift M, Jäger U, Leys MBL, Hoogendoorn M, Lotfi K, Hebart H, Gaska T, Koene H, Enggaard L, Goede J, Regelink JC, Widmer A, Simon F, De Silva N, Fink AM, Bahlo J, Fischer K, Wendtner CM, Kreuzer KA, Ritgen M, Brüggemann M, Tausch E, Levin MD, van Oers M, Geisler C, Stilgenbauer S, Hallek M; GCLLSG, the HOVON and Nordic CLL Study Groups, the SAKK, the Israeli CLL Association, and Cancer Trials Ireland. First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia. N Engl J Med. 2023 May 11;388(19):1739-1754. [https://doi.org/10.1056/nejmoa2213093 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/37163621/ PubMed] [https://clinicaltrials.gov/study/NCT02950051 NCT02950051] |
− | # ''' | + | ##'''Update:''' Fürstenau M, Kater AP, Robrecht S, von Tresckow J, Zhang C, Gregor M, Thornton P, Staber PB, Tadmor T, Lindström V, Juliusson G, Janssens A, Levin MD, da Cunha-Bang C, Schneider C, Goldschmidt N, Vandenberghe E, Rossi D, Benz R, Nösslinger T, Heintel D, Poulsen CB, Christiansen I, Frederiksen H, Enggaard L, Posthuma EFM, Issa DE, Visser HPJ, Bellido M, Kutsch N, Dürig J, Stehle A, Vöhringer M, Böttcher S, Schulte C, Simon F, Fink AM, Fischer K, Holmes EE, Kreuzer KA, Ritgen M, Brüggemann M, Tausch E, Stilgenbauer S, Hallek M, Niemann CU, Eichhorst B. First-line venetoclax combinations versus chemoimmunotherapy in fit patients with chronic lymphocytic leukaemia (GAIA/CLL13): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2024 Jun;25(6):744-759. Erratum in: Lancet Oncol. 2024 Jul;25(7):e284. [https://doi.org/10.1016/s1470-2045(24)00196-7 link to original article] [https://pubmed.ncbi.nlm.nih.gov/38821083/ PubMed] |
− | + | #'''EVOLVE CLL/SLL:''' [https://clinicaltrials.gov/study/NCT04269902 NCT04269902] | |
− | == | + | #'''GCLLSG CLL16:''' [https://clinicaltrials.gov/study/NCT05197192 NCT05197192] |
− | {| class="wikitable" style=" | + | #'''MAJIC:''' [https://clinicaltrials.gov/study/NCT05057494 NCT05057494] |
+ | ==Watchful waiting== | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
+ | |- | ||
+ | |[https://doi.org/10.1056/NEJM199805213382104 Dighiero et al. 1998 (FRE-CLL-85)] | ||
+ | |1980-1985 | ||
+ | |style="background-color:#1a9851"|Phase 3 (C) | ||
+ | |[[Chronic_lymphocytic_leukemia_-_historical#Chlorambucil_monotherapy|Chlorambucil]] | ||
+ | |style="background-color:#fc8d59"|Seems to have inferior PFS | ||
+ | |- | ||
+ | |[https://doi.org/10.1056/NEJM199805213382104 Dighiero et al. 1998 (FRE-CLL-90)] | ||
+ | |1985-1990 | ||
+ | |style="background-color:#1a9851"|Phase 3 (C) | ||
+ | |[[Chronic_lymphocytic_leukemia_-_historical#Chlorambucil_.26_Prednisone|Chlorambucil & Prednisone]] | ||
+ | |style="background-color:#d73027"|Inferior PFS | ||
+ | |- | ||
+ | |[https://doi.org/10.1038/leu.2017.246 Hoechstetter et al. 2017 (GCLLSG CLL1)] | ||
+ | |1997-2004 | ||
+ | |style="background-color:#1a9851"|Phase 3 (C) | ||
+ | |[[Chronic_lymphocytic_leukemia_-_historical#Fludarabine_monotherapy|Fludarabine]] | ||
+ | |style="background-color:#d73027"|Inferior PFS | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7387319/ Herling et al. 2020 (GCLLSG CLL7)] | ||
+ | |2005-2010 | ||
+ | |style="background-color:#1a9851"|Phase 3 (C) | ||
+ | |[[#FCR|FCR]] | ||
+ | |style="background-color:#d73027"|Inferior EFS | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1182/blood.2021010845 Langerbeins et al. 2022 (CLL12)] |
− | | | + | |2014-2019 |
− | + | |style="background-color:#1a9851"|Phase 3 (C) | |
− | + | |[[#Ibrutinib_monotherapy|Ibrutinib]] | |
− | + | | style="background-color:#d73027" |Inferior EFS | |
− | | | ||
− | |[[ | ||
− | | | ||
− | |||
|- | |- | ||
− | |[ | + | |[https://www.clinicaltrials.gov/study/NCT04178798 Awaiting publication (GLLC-EARLY)] |
− | |style="background-color:# | + | |2019-2024 |
− | | | + | |style="background-color:#1a9851"|Phase 3 (C) |
− | |style="background-color:# | + | |[[#Acalabrutinib_monotherapy|Acalabrutinib]] |
+ | | style="background-color:#d3d3d3" |TBD if different primary endpoint of EFS | ||
|- | |- | ||
|} | |} | ||
− | ==== | + | </div></div> |
− | + | ===References=== | |
− | ** | + | # '''FRE-CLL-85:''' Dighiero G, Maloum K, Desablens B, Cazin B, Navarro M, Leblay R, Leporrier M, Jaubert J, Lepeu G, Dreyfus B, Binet JL, Travade P; French Cooperative Group on Chronic Lymphocytic Leukemia. Chlorambucil in indolent chronic lymphocytic leukemia. N Engl J Med. 1998 May 21;338(21):1506-14. [https://doi.org/10.1056/NEJM199805213382104 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9593789/ PubMed] |
− | + | # '''FRE-CLL-90:''' Dighiero G, Maloum K, Desablens B, Cazin B, Navarro M, Leblay R, Leporrier M, Jaubert J, Lepeu G, Dreyfus B, Binet JL, Travade P; French Cooperative Group on Chronic Lymphocytic Leukemia. Chlorambucil in indolent chronic lymphocytic leukemia. N Engl J Med. 1998 May 21;338(21):1506-14. [https://doi.org/10.1056/NEJM199805213382104 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9593789/ PubMed] | |
+ | <!-- # '''Abstract:''' Carmen D Schweighofer, MD, Florence Cymbalista, MD, Carolin Müller, MD, Raymonde Busch, PhD, Raphael Porcher, PhD, Petra Langerbeins, MD, Bruno Cazin, MD, Anna-Maria Fink, MD, Brigitte Dreyfus, MD, Stefan Ibach, Stéphane Leprêtre, MD, Kirsten Fischer, MD, Ursula Vehling-Kaiser, MD, Barbara Eichhorst, MD, Manuela A. Bergmann, MD, Stephan Stilgenbauer, MD, Hartmut Döhner, MD, Veronique Leblond, MD, Michael Hallek, MD, and Vincent Levy, MD, PhD. Early Versus Deferred Treatment With Combined Fludarabine, Cyclophosphamide and Rituximab (FCR) Improves Event-Free Survival In Patients With High-Risk Binet Stage A Chronic Lymphocytic Leukemia – First Results Of a Randomized German-French Cooperative Phase III Trial. 2013 ASH Annual Symposium abstract 524 [https://doi.org/10.1182/blood.V122.21.524.524 link to abstract] --> | ||
+ | # '''GCLLSG CLL7:''' Herling CD, Cymbalista F, Groß-Ophoff-Müller C, Bahlo J, Robrecht S, Langerbeins P, Fink AM, Al-Sawaf O, Busch R, Porcher R, Cazin B, Dreyfus B, Ibach S, Leprêtre S, Fischer K, Kaiser F, Eichhorst B, Wentner CM, Hoechstetter MA, Döhner H, Leblond V, Kneba M, Letestu R, Böttcher S, Stilgenbauer S, Hallek M, Levy V. Early treatment with FCR versus watch and wait in patients with stage Binet A high-risk chronic lymphocytic leukemia (CLL): a randomized phase 3 trial. Leukemia. 2020 Aug;34(8):2038-2050. Epub 2020 Feb 18. [https://doi.org/10.1038/s41375-020-0747-7 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7387319/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32071431/ PubMed] [https://clinicaltrials.gov/study/NCT00275054 NCT00275054] | ||
+ | <!-- # '''Abstract:''' Manuela A. Bergmann, MD, Raymonde Busch, PhD, Barbara Eichhorst, MD, Andreas Buehler, MD, Norbert Fischer, MD, Michael J Eckart, MD, Ursula Vehling-Kaiser, MD, Ulrich Jäger, MD, Georg Hopfinger, MD, Clemens Wendtner, MD, Kirsten Fischer, MD, Bertold Emmerich, MD, Hartmut Döhner, MD, Michael Hallek, M.D. Ph.D. and Stephan Stilgenbauer, MD; German CLL Study Group. Overall Survival In Early Stage Chronic Lymphocytic Leukemia Patients With Treatment Indication Due To Disease Progression: Follow-Up Data Of The CLL1 Trial Of The German CLL Study Group (GCLLSG). Blood 2013 122:4127. [https://doi.org/10.1182/blood.V122.21.4127.4127 link to abstract] --> | ||
+ | #'''GCLLSG CLL1:''' Hoechstetter MA, Busch R, Eichhorst B, Bühler A, Winkler D, Eckart MJ, Vehling-Kaiser U, Schimke H, Jäger U, Hurtz HJ, Hopfinger G, Hartmann F, Fuss H, Abenhardt W, Blau I, Freier W, Müller L, Goebeler M, Wendtner CM, Bahlo J, Fischer K, Bentz M, Emmerich B, Döhner H, Hallek M, Stilgenbauer S. Early, risk-adapted treatment with fludarabine in Binet stage A chronic lymphocytic leukemia patients: results of the CLL1 trial of the German CLL study group. Leukemia. 2017 Dec;31(12):2833-2837. Epub 2017 Aug 14. [https://doi.org/10.1038/leu.2017.246 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28804126/ PubMed] [https://clinicaltrials.gov/study/NCT00262782 NCT00262782] | ||
+ | <!-- # '''Abstract:''' Petra Langerbeins, MD, Jasmin Bahlo, Christina Rhein, Paula Cramer, MD, Anna-Maria Fink, MD, Natali Pflug, MD, Julia von Tresckow, MD, Stephan Stilgenbauer, MD, Karl-Anton Kreuzer, Michael J. Eckart, MD, Ursula Vehling-Kaiser, MD, Rudolf Schlag, MD, Christina Balser, MD, Lothar Müller, MD, Clemens-Martin Wendtner, MD, Kirsten Fischer, MD, Barbara Eichhorst, MD and Michael Hallek, MD. Ibrutinib in Early Stage CLL: Preliminary Safety Results of a Placebo-Controlled Phase III Study. ASH Annual Meeting 2015 Abstract 2934. [https://doi.org/10.1182/blood.V126.23.2934.2934 link to abstract] --> | ||
+ | #'''CLL12:''' Langerbeins P, Zhang C, Robrecht S, Cramer P, Fürstenau M, Al-Sawaf O, von Tresckow J, Fink AM, Kreuzer KA, Vehling-Kaiser U, Tausch E, Müller L, Eckart MJ, Schlag R, Freier W, Gaska T, Balser C, Reiser M, Stauch M, Wendtner CM, Fischer K, Stilgenbauer S, Eichhorst B, Hallek M. The CLL12 trial: ibrutinib vs placebo in treatment-naïve, early-stage chronic lymphocytic leukemia. Blood. 2022 Jan 13;139(2):177-187. [https://doi.org/10.1182/blood.2021010845 link to original article] [https://pubmed.ncbi.nlm.nih.gov/34758069/ PubMed] [https://clinicaltrials.gov/study/NCT02863718 NCT02863718] | ||
+ | #'''GLLC-EARLY:''' [https://clinicaltrials.gov/study/NCT04178798 NCT04178798] | ||
+ | ==Zanubrutinib monotherapy {{#subobject:6cbzze|Regimen=1}}== | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen {{#subobject:5175aa|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
+ | |- | ||
+ | |[https://doi.org/10.1016/s1470-2045(22)00293-5 Tam et al. 2022 (SEQUOIA<sub>CLL</sub>)] | ||
+ | |2017-2019 | ||
+ | |style="background-color:#1a9851"|Phase 3 (E-RT-switch-ooc) | ||
+ | |[[#Bendamustine_.26_Rituximab_.28BR.29|BR]] | ||
+ | | style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: NYR vs NYR<br>(HR 0.42, 95% CI 0.28-0.63) | ||
+ | |- | ||
+ | |} | ||
+ | <div class="toccolours" style="background-color:#fdcdac"> | ||
+ | ====Biomarker eligibility criteria==== | ||
+ | *SEQUOIA<sub>CLL</sub>: No 17p deletion | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
+ | ====Targeted therapy==== | ||
+ | *[[Zanubrutinib (Brukinsa)]] 160 mg PO twice per day on days 1 to 28 | ||
+ | '''28-day cycles''' | ||
+ | </div></div> | ||
+ | ===References=== | ||
+ | # '''SEQUOIA<sub>CLL</sub>:''' Tam CS, Brown JR, Kahl BS, Ghia P, Giannopoulos K, Jurczak W, Šimkovič M, Shadman M, Österborg A, Laurenti L, Walker P, Opat S, Chan H, Ciepluch H, Greil R, Tani M, Trněný M, Brander DM, Flinn IW, Grosicki S, Verner E, Tedeschi A, Li J, Tian T, Zhou L, Marimpietri C, Paik JC, Cohen A, Huang J, Robak T, Hillmen P. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022 Aug;23(8):1031-1043. Epub 2022 Jul 7. [https://doi.org/10.1016/s1470-2045(22)00293-5 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/35810754/ PubMed] [https://clinicaltrials.gov/study/NCT03336333 NCT03336333] | ||
− | ==== | + | =First-line therapy, non-randomized or retrospective data= |
− | + | ==Alemtuzumab & Methylprednisolone {{#subobject:29fd75|Regimen=1}}== | |
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | + | ===Regimen {{#subobject:14ff47|Variant=1}}=== | |
− | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" | |
− | + | !style="width: 33%"|Study | |
− | + | !style="width: 33%"|Dates of enrollment | |
− | ===Regimen | + | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | {| | ||
− | | | ||
− | |[[Levels_of_Evidence#Evidence| | ||
− | |||
− | |||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/JCO.2011.35.9695 Pettitt et al. 2012 (NCRI CLL206)] |
− | | | + | |2006-2008 |
− | + | |style="background-color:#91cf61"|Phase 2 | |
− | |style="background-color:# | ||
|- | |- | ||
|} | |} | ||
− | ==== | + | <div class="toccolours" style="background-color:#fdcdac"> |
− | *[[ | + | ====Biomarker eligibility criteria==== |
− | **Cycle 1: | + | *TP53 deletion |
− | + | </div> | |
− | ** | + | <div class="toccolours" style="background-color:#f2f3f4"> |
− | + | ====Targeted therapy==== | |
− | + | *[[Alemtuzumab (Campath)]] as follows: | |
− | ==== | + | **Cycle 1: 3 mg IV once on day 1, then 10 mg IV once on day 3, then 30 mg IV once per day on days 5, 8, 10, 12, 15, 17, 19, 22, 24, 26 (three times per week; increased as tolerated) |
− | *[[ | + | **Cycles 2 to 4: 30 mg SC once per day on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26 (three times per week) |
− | + | ====Glucocorticoid therapy==== | |
− | + | *[[Methylprednisolone (Solumedrol)]] 1000 mg/m<sup>2</sup>/day (route not specified) on days 1 to 5 | |
− | + | '''28-day cycle for 4 cycles''' | |
− | ''' | + | </div></div> |
− | |||
===References=== | ===References=== | ||
− | # | + | # '''NCRI CLL206:''' Pettitt AR, Jackson R, Carruthers S, Dodd J, Dodd S, Oates M, Johnson GG, Schuh A, Matutes E, Dearden CE, Catovsky D, Radford JA, Bloor A, Follows GA, Devereux S, Kruger A, Blundell J, Agrawal S, Allsup D, Proctor S, Heartin E, Oscier D, Hamblin TJ, Rawstron A, Hillmen P. Alemtuzumab in combination with methylprednisolone is a highly effective induction regimen for patients with chronic lymphocytic leukemia and deletion of TP53: final results of the National Cancer Research Institute CLL206 trial. J Clin Oncol. 2012 May 10;30(14):1647-55. Epub 2012 Apr 9. [https://doi.org/10.1200/JCO.2011.35.9695 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/22493413/ PubMed] [https://clinicaltrials.gov/study/NCT00292760 NCT00292760] |
− | + | ==AVO {{#subobject:78g7gg|Regimen=1}}== | |
− | == | + | AVO: '''<u>A</u>'''calabrutinib, '''<u>V</u>'''enetoclax, '''<u>O</u>'''binutuzumab |
− | {| class="wikitable" style=" | + | <div class="toccolours" style="background-color:#eeeeee"> |
+ | ===Regimen {{#subobject:1hcgcc|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | |- | ||
+ | |[https://doi.org/10.1016/s1470-2045(21)00455-1 Davids et al. 2021 (DFCI 18-226)] | ||
+ | |2018-2019 | ||
+ | |style="background-color:#91cf61"|Phase 2 | ||
|- | |- | ||
− | |||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
+ | ====Targeted therapy==== | ||
+ | *[[Acalabrutinib (Calquence)]] 100 mg PO twice per day on days 1 to 28 | ||
+ | *[[Venetoclax (Venclexta)]] as follows: | ||
+ | **Cycle 4: 20 mg PO once on day 1, then 50 mg PO once per day on days 2 to 7, then 100 mg PO once per day on days 8 to 14, then 200 mg PO once per day on days 15 to 21, then 400 mg PO once per day on days 22 to 28 | ||
+ | **Cycle 5 onwards: 400 mg PO once per day on days 1 to 28 | ||
+ | *[[Obinutuzumab (Gazyva)]] as follows: | ||
+ | **Cycle 2: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15 | ||
+ | **Cycles 3 to 7: 1000 mg IV once on day 1 | ||
+ | '''28-day cycles''' | ||
+ | </div></div> | ||
+ | ===References=== | ||
+ | # '''DFCI 18-226:''' Davids MS, Lampson BL, Tyekucheva S, Wang Z, Lowney JC, Pazienza S, Montegaard J, Patterson V, Weinstock M, Crombie JL, Ng SY, Kim AI, Jacobson CA, LaCasce AS, Armand P, Arnason JE, Fisher DC, Brown JR. Acalabrutinib, venetoclax, and obinutuzumab as frontline treatment for chronic lymphocytic leukaemia: a single-arm, open-label, phase 2 study. Lancet Oncol. 2021 Oct;22(10):1391-1402. Epub 2021 Sep 14. [https://doi.org/10.1016/s1470-2045(21)00455-1 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/34534514/ PubMed] [https://clinicaltrials.gov/study/NCT03580928 NCT03580928] | ||
− | ===Regimen=== | + | ==Bendamustine & Obinutuzumab {{#subobject:e26569|Regimen=1}}== |
− | {| | + | G-B: '''<u>G</u>'''azyva (Obinutuzumab), '''<u>B</u>'''endamustine |
− | | | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | |[[Levels_of_Evidence#Evidence| | + | ===Regimen {{#subobject:c1bbd2|Variant=1}}=== |
− | + | {| class="wikitable sortable" style="width: 80%; text-align:center;" | |
− | |[[Levels_of_Evidence#Efficacy| | + | !style="width: 25%"|Study |
+ | !style="width: 25%"|Dates of enrollment | ||
+ | !style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]] | ||
|- | |- | ||
− | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4416529/ Brown et al. 2015 (GALTON)] | |
− | | | + | |2011 to not reported |
− | + | |style="background-color:#91cf61"|Phase 1b | |
− | |style="background-color:# | + | | style="background-color:#f7fcfd" |ORR: 90% |
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1080/10428194.2020.1850719 Sharman et al. 2020 (GIBB)] |
− | + | |2015-2016 | |
− | + | |style="background-color:#91cf61"|Phase 2 | |
− | + | |CR rate: 50% | |
− | |||
− | |||
− | |||
− | |||
− | |||
− | | | ||
− | |||
− | |style="background-color:# | ||
− | |||
− | |||
− | | | ||
− | |||
− | |||
|- | |- | ||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#f2f3f4"> | |
− | '' | + | ====Chemotherapy==== |
− | + | *[[Bendamustine]] as follows: | |
+ | **Cycle 1: 90 mg/m<sup>2</sup> IV once per day on days 2 & 3 | ||
+ | **Cycles 2 to 6: 90 mg/m<sup>2</sup> IV once per day on days 1 & 2 | ||
+ | ====Targeted therapy==== | ||
+ | *[[Obinutuzumab (Gazyva)]] as follows: | ||
+ | **Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15 | ||
+ | **Cycles 2 to 6: 1000 mg IV once on day 1 | ||
+ | ====Supportive therapy==== | ||
+ | *[[Acetaminophen (Tylenol)]] (dose not specified) once per infusion, prior to obinutuzumab | ||
+ | *[[:Category:Antihistamines|Antihistamine]] e.g. [[Diphenhydramine (Benadryl)]] once per infusion, prior to obinutuzumab | ||
+ | *[[:Category:Steroids|Highly potent corticosteroid]] (e.g. [[Prednisolone (Millipred)]] 100 mg IV) once, prior to first dose of obinutuzumab | ||
+ | *[[Allopurinol (Zyloprim)]] or [[Rasburicase (Elitek)]] recommended for tumor lysis syndrome prophylaxis | ||
+ | *[[:Category:PCP_prophylaxis|PCP prophylaxis]] recommended | ||
+ | *[[:Category:Antivirals|Antiviral prophylaxis]] recommended | ||
+ | '''28-day cycle for 6 cycles''' | ||
+ | </div></div> | ||
===References=== | ===References=== | ||
− | + | <!-- Presented at the 55th annual meeting of the American Society of Hematology, New Orleans, LA, December 9, 2013. --> | |
− | + | # '''GALTON:''' Brown JR, O'Brien S, Kingsley CD, Eradat H, Pagel JM, Lymp J, Hirata J, Kipps TJ. Obinutuzumab plus fludarabine/cyclophosphamide or bendamustine in the initial therapy of CLL patients: the phase 1b GALTON trial. Blood. 2015 Apr 30;125(18):2779-85. Epub 2015 Mar 13. [https://doi.org/10.1182/blood-2014-12-613570 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4416529/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25769620/ PubMed] [https://clinicaltrials.gov/study/NCT01300247 NCT01300247] | |
− | # ''' | + | # '''GIBB:''' Sharman JP, Burke JM, Yimer HA, Boxer MA, Babu S, Li J, Mun Y, Danilov AV; GIBB study investigators. Phase 2, multicenter GIBB study of obinutuzumab plus bendamustine in previously untreated patients with chronic lymphocytic leukemia. Leuk Lymphoma. 2021 Apr;62(4):791-800. Epub 2020 Nov 26. [https://doi.org/10.1080/10428194.2020.1850719 link to original article] '''dosing details in abstract have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/33243049/ PubMed] [https://clinicaltrials.gov/study/NCT02320487 NCT02320487] |
− | + | ==CFAR {{#subobject:30ac6b|Regimen=1}}== | |
− | + | CFAR: '''<u>C</u>'''yclophosphamide, '''<u>F</u>'''ludarabine, '''<u>A</u>'''lemtuzumab, '''<u>R</u>'''ituximab | |
− | = | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | + | ===Regimen {{#subobject:8db0af|Variant=1}}=== | |
− | == | + | {| class="wikitable sortable" style="width: 80%; text-align:center;" |
− | {| class="wikitable" style=" | + | !style="width: 25%"|Study |
+ | !style="width: 25%"|Dates of enrollment | ||
+ | !style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081295/ Parikh et al. 2011] |
− | + | |2005-2008 | |
− | + | |style="background-color:#91cf61"|Phase 2 | |
− | + | | style="background-color:#f7fcfd" |ORR: 92% | |
− | |||
− | |||
− | |||
− | | | ||
− | |||
− | |||
− | |||
− | |style="background-color:# | ||
|- | |- | ||
|} | |} | ||
+ | ''Note: the doses of cyclophosphamide and fludarabine are lower than in the r/r CFAR regimen.'' | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[ | + | *[[Cyclophosphamide (Cytoxan)]] 200 mg/m<sup>2</sup> IV once per day on days 3 to 5 |
+ | *[[Fludarabine (Fludara)]] 20 mg/m<sup>2</sup> IV once per day on days 3 to 5 | ||
+ | ====Targeted therapy==== | ||
+ | *[[Alemtuzumab (Campath)]] 30 mg IV once per day on days 1, 3, 5 | ||
*[[Rituximab (Rituxan)]] as follows: | *[[Rituximab (Rituxan)]] as follows: | ||
− | **Cycle 1: 375 mg/m<sup>2</sup> IV once on day | + | **Cycle 1: 375 mg/m<sup>2</sup> IV once on day 2 |
− | **Cycles 2 to 6: 500 mg/m<sup>2</sup> IV once on day | + | **Cycles 2 to 6: 500 mg/m<sup>2</sup> IV once on day 2 |
− | + | ====Supportive therapy==== | |
− | + | *[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 6 | |
− | + | *[[Acetaminophen (Tylenol)]] 500 mg PO once per day on days 1, 2, 3, 5, prior to rituximab/[[Alemtuzumab (Campath)]] | |
− | + | *[[Diphenhydramine (Benadryl)]] 25 to 50 mg IV or PO once per day on days 1, 2, 3, 5, prior to rituximab/[[Alemtuzumab (Campath)]] | |
− | + | *[[Hydrocortisone (Cortef)]] 100 mg IV once per day on days 1, 2, 3, 5, prior to rituximab/[[Alemtuzumab (Campath)]] | |
− | + | *Cycle 1: [[Allopurinol (Zyloprim)]] 300 mg PO once per day for at least days 1 to 7 | |
− | + | *[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] 160/800 mg PO once per day during treatment and for at least 3 to 6 months after last course | |
− | + | *Antiviral prophylaxis with ONE of the following: | |
− | + | **[[Valacyclovir (Valtrex)]] 500 mg PO once per day during treatment and for at least 3 to 6 months after last course | |
− | + | **OR [[Valganciclovir (Valcyte)]] 450 mg PO twice per day during treatment and for at least 3 to 6 months after last course | |
− | + | '''28-day cycle for 6 cycles''' | |
− | + | </div></div> | |
− | |||
− | |||
− | |||
− | *[[ | ||
− | *[[ | ||
− | |||
− | ** | ||
− | |||
− | '''28-day cycle for | ||
− | |||
− | |||
− | |||
===References=== | ===References=== | ||
− | + | # Parikh SA, Keating MJ, O'Brien S, Wang X, Ferrajoli A, Faderl S, Burger J, Koller C, Estrov Z, Badoux X, Lerner S, Wierda WG. Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, alemtuzumab, and rituximab for high-risk chronic lymphocytic leukemia. Blood. 2011 Aug 25;118(8):2062-8. Epub 2011 Jul 12. [https://doi.org/10.1182/blood-2011-01-329177 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081295/ link to PMC article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/21750315/ PubMed] | |
− | + | ==G-FC {{#subobject:b5592a|Regimen=1}}== | |
− | + | G-FC: '''<u>G</u>'''azyva (Obinutuzumab), '''<u>F</u>'''ludarabine, '''<u>C</u>'''yclophosphamide | |
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | == | + | ===Regimen {{#subobject:8a0232|Variant=1}}=== |
− | {| class="wikitable" style=" | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4416529/ Brown et al. 2015 (GALTON)] |
− | + | |2011 to not reported | |
− | + | |style="background-color:#91cf61"|Phase 1b | |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |style="background-color:# | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
+ | ====Targeted therapy==== | ||
+ | *[[Obinutuzumab (Gazyva)]] as follows: | ||
+ | **Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15 | ||
+ | **Cycles 2 to 6: 1000 mg IV once on day 1 | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[ | + | *[[Fludarabine (Fludara)]] as follows: |
− | + | **Cycle 1: 25 mg/m<sup>2</sup> IV once per day on days 2 to 4 | |
− | '''28 | + | **Cycles 2 to 6: 25 mg/m<sup>2</sup> IV once per day on days 1 to 3 |
− | + | *[[Cyclophosphamide (Cytoxan)]] as follows: | |
+ | **Cycle 1: 250 mg/m<sup>2</sup> IV once per day on days 2 to 4 | ||
+ | **Cycles 2 to 6: 250 mg/m<sup>2</sup> IV once per day on days 1 to 3 | ||
+ | ====Supportive therapy==== | ||
+ | *[[Acetaminophen (Tylenol)]] (dose not specified) once per infusion, prior to obinutuzumab | ||
+ | *[[:Category:Antihistamines|Antihistamine]] e.g. [[Diphenhydramine (Benadryl)]] once per infusion, prior to obinutuzumab | ||
+ | *[[:Category:Steroids|Highly potent corticosteroid]] (e.g. [[Prednisolone (Millipred)]] 100 mg IV) once, prior to first dose of obinutuzumab | ||
+ | *[[Allopurinol (Zyloprim)]] or [[Rasburicase (Elitek)]] recommended for tumor lysis syndrome prophylaxis | ||
+ | *[[:Category:PCP_prophylaxis|PCP prophylaxis]] recommended | ||
+ | *[[:Category:Antivirals|Antiviral prophylaxis]] recommended | ||
+ | '''28-day cycle for 6 cycles''' | ||
+ | </div></div> | ||
===References=== | ===References=== | ||
− | # | + | <!-- Presented at the 55th annual meeting of the American Society of Hematology, New Orleans, LA, December 9, 2013. --> |
− | + | # '''GALTON:''' Brown JR, O'Brien S, Kingsley CD, Eradat H, Pagel JM, Lymp J, Hirata J, Kipps TJ. Obinutuzumab plus fludarabine/cyclophosphamide or bendamustine in the initial therapy of CLL patients: the phase 1b GALTON trial. Blood. 2015 Apr 30;125(18):2779-85. Epub 2015 Mar 13. [https://doi.org/10.1182/blood-2014-12-613570 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4416529/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25769620/ PubMed] [https://clinicaltrials.gov/study/NCT01300247 NCT01300247] | |
− | == | + | ==HDMP-R {{#subobject:1c202|Regimen=1}}== |
− | {| class="wikitable" style=" | + | HDMP-R: '''<u>H</u>'''igh '''<u>D</u>'''ose, '''<u>M</u>'''ethyl'''<u>P</u>'''rednisolone & '''<u>R</u>'''ituximab |
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen {{#subobject:38a97d|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2761991/ Castro et al. 2009] | ||
+ | |Not reported | ||
+ | |style="background-color:#91cf61"|Phase 2 | ||
|- | |- | ||
− | |||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#f2f3f4"> | |
− | + | ====Glucocorticoid therapy==== | |
− | ===Regimen {{#subobject: | + | *[[Methylprednisolone (Solumedrol)]] 1000 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1 to 3 |
− | {| | + | ====Targeted therapy==== |
− | | | + | *[[Rituximab (Rituxan)]] as follows: |
− | |[[Levels_of_Evidence#Evidence| | + | **Cycle 1: 375 mg/m<sup>2</sup> total divided over 2 days IV once on days 1 & 2, then 375 mg/m<sup>2</sup> IV once per day on days 8, 15, 22 |
+ | **Cycles 2 & 3: 375 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22 | ||
+ | ====Supportive therapy==== | ||
+ | *[[Cimetidine (Tagamet)]] as premedication for methylprednisolone | ||
+ | *[[Acetaminophen (Tylenol)]] as premedication for rituximab | ||
+ | *[[Diphenhydramine (Benadryl)]] as premedication for rituximab | ||
+ | *[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] (or equivalent) prophylaxis during therapy and continuing for 2 months after treatment is complete | ||
+ | *[[Acyclovir (Zovirax)]] (or equivalent) prophylaxis during therapy and continuing for 2 months after treatment is complete | ||
+ | *[[Fluconazole (Diflucan)]] (or equivalent) prophylaxis during therapy and continuing for 2 months after treatment is complete | ||
+ | *[[Allopurinol (Zyloprim)]] 300 mg PO once per day, started 3 days before the start of therapy and continued during treatment | ||
+ | *Patients with glucose greater than 200 on days of treatment received regular insulin SC sliding scale on days of treatment | ||
+ | '''28-day cycle for 3 cycles''' | ||
+ | </div></div> | ||
+ | ===References=== | ||
+ | # Castro JE, James DF, Sandoval-Sus JD, Jain S, Bole J, Rassenti L, Kipps TJ. Rituximab in combination with high-dose methylprednisolone for the treatment of chronic lymphocytic leukemia. Leukemia. 2009 Oct;23(10):1779-89. Epub 2009 Aug 20. [https://doi.org/10.1038/leu.2009.133 link to original article] '''dosing details in abstract have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2761991/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19693094/ PubMed] | ||
+ | ==iFCR {{#subobject:7c8bdd|Regimen=1}}== | ||
+ | iFCR: '''<u>i</u>'''brutinib, '''<u>F</u>'''ludarabine, '''<u>C</u>'''yclophosphamide, '''<u>R</u>'''ituximab | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen {{#subobject:44ddcc|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7036668/ Davids et al. 2019 (DFCI 14-296)] |
− | |style="background-color:# | + | |2014-10 to 2018-04 |
+ | |style="background-color:#91cf61"|Phase 2 | ||
|- | |- | ||
|} | |} | ||
− | ==== | + | ''Note: Patients with undetectable minimal residual disease in bone marrow after 2 years were required to discontinue treatment, after a protocol amendment.'' |
− | *[[ | + | <div class="toccolours" style="background-color:#f2f3f4"> |
− | *[[ | + | ====Targeted therapy==== |
− | * | + | *[[Ibrutinib (Imbruvica)]] as follows: |
− | + | **Lead-in: 420 mg PO once per day on days 1 to 7 | |
− | + | **Cycle 1 onwards: 420 mg PO once per day on days 1 to 28 | |
− | + | *[[Rituximab (Rituxan)]] as follows: | |
− | + | **Cycle 1: 375 mg/m<sup>2</sup> IV once on day 1 | |
+ | **Cycles 2 to 6: 500 mg/m<sup>2</sup> IV once on day 1 | ||
+ | ====Chemotherapy==== | ||
+ | *[[Fludarabine (Fludara)]] as follows: | ||
+ | **Cycles 1 to 6: 25 mg/m<sup>2</sup> IV once per day on days 1 to 3 | ||
+ | *[[Cyclophosphamide (Cytoxan)]] as follows: | ||
+ | **Cycles 1 to 6: 250 mg/m<sup>2</sup> IV once per day on days 1 to 3 | ||
+ | '''7-day lead-in, then 28-day cycles (see note)''' | ||
+ | </div></div> | ||
===References=== | ===References=== | ||
− | # | + | #'''DFCI 14-296:''' Davids MS, Brander DM, Kim HT, Tyekucheva S, Bsat J, Savell A, Hellman JM, Bazemore J, Francoeur K, Alencar A, Shune L, Omaira M, Jacobson CA, Armand P, Ng S, Crombie J, LaCasce AS, Arnason J, Hochberg EP, Takvorian RW, Abramson JS, Fisher DC, Brown JR; Blood Cancer Research Partnership of the Leukemia & Lymphoma Society. Ibrutinib plus fludarabine, cyclophosphamide, and rituximab as initial treatment for younger patients with chronic lymphocytic leukaemia: a single-arm, multicentre, phase 2 trial. Lancet Haematol. 2019 Aug;6(8):e419-e428. Epub 2019 Jun 14. [https://doi.org/10.1016/s2352-3026(19)30104-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7036668/ link to PMC article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/31208944/ PubMed] [https://clinicaltrials.gov/study/NCT02251548 NCT02251548] |
− | == | + | ==Lenalidomide & Rituximab (R<sup>2</sup>) {{#subobject:d71dfb|Regimen=1}}== |
− | {| class="wikitable" style=" | + | <div class="toccolours" style="background-color:#eeeeee"> |
+ | ===Regimen variant #1 {{#subobject:5d17e2|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4067945/ James et al. 2014 (CRC014)] | ||
+ | |2008 to not reported | ||
+ | |style="background-color:#91cf61"|Phase 2 | ||
|- | |- | ||
− | |||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#f2f3f4"> | |
− | + | ====Targeted therapy==== | |
− | ===Regimen {{#subobject: | + | *[[Lenalidomide (Revlimid)]] with escalation in the absence of grade 2 or higher toxicities as follows: |
− | {| | + | **Cycle 1: 2.5 mg PO once per day on days 1 to 7, then 5 mg PO once per day on days 8 to 21 |
− | | | + | **Cycle 2: 5 mg PO once per day on days 1 to 21 |
− | |[[Levels_of_Evidence#Evidence| | + | **Cycles 3 up to 7: 10 mg PO once per day on days 1 to 21 |
+ | *[[Rituximab (Rituxan)]] as follows: | ||
+ | **Cycle 1: 375 mg/m<sup>2</sup> IV once per day on days 31 & 33 | ||
+ | **Cycle 2: 375 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22 | ||
+ | **Cycles 3 up to 7: 375 mg/m<sup>2</sup> IV once on day 1 | ||
+ | ====Supportive therapy==== | ||
+ | *[[Allopurinol (Zyloprim)]] prior to starting [[Lenalidomide (Revlimid) | lenalidomide]] and with any dose escalation | ||
+ | *[[Aspirin]] 81 mg PO once per day | ||
+ | '''35-day course, then 28-day cycle for up to 6 cycles''' | ||
+ | </div></div><br> | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #2 {{#subobject:82c08|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1016/S1470-2045(14)70455-3 Fowler et al. 2014 (MDACC 2008-0042)] |
− | |style="background-color:# | + | |2008-2011 |
+ | |style="background-color:#91cf61"|Phase 2 | ||
|- | |- | ||
|} | |} | ||
− | ==== | + | ''Note: This combination was only studied in SLL (as opposed to CLL). Lenalidomide is dose-escalated to avoid tumor flare.'' |
− | *[[ | + | <div class="toccolours" style="background-color:#f2f3f4"> |
− | + | ====Targeted therapy==== | |
− | *[[ | + | *[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21, then escalated by 5 mg/month to goal of 20 mg PO once per day |
− | + | *[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1 | |
− | + | '''28-day cycle for up to 12 cycles''' | |
− | + | </div></div> | |
− | |||
− | |||
− | '''28-day cycle for | ||
− | |||
===References=== | ===References=== | ||
− | # | + | # '''CRC014:''' James DF, Werner L, Brown JR, Wierda WG, Barrientos JC, Castro JE, Greaves A, Johnson AJ, Rassenti LZ, Rai KR, Neuberg D, Kipps TJ. Lenalidomide and rituximab for the initial treatment of patients with chronic lymphocytic leukemia: a multicenter clinical-translational study from the Chronic Lymphocytic Leukemia Research Consortium. J Clin Oncol. 2014 Jul 1;32(19):2067-73. Epub 2014 May 27. [https://doi.org/10.1200/jco.2013.51.5890 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4067945/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24868031/ PubMed] [https://clinicaltrials.gov/study/NCT00628238 NCT00628238] |
+ | <!-- | ||
+ | # '''Abstract:''' N. H. Fowler, P. McLaughlin, F. B. Hagemeister, L. W. Kwak, M. A. Fanale, S. S. Neelapu, L. Fayad, R. Z. Orlowski, M. Wang, F. Samaniego. Complete response rates with lenalidomide plus rituximab for untreated indolent B-cell non-Hodgkin's lymphoma. J Clin Oncol 28:15s, 2010 (suppl; abstr 8036). 2010 ASCO Annual Meeting abstract 8036. [https://doi.org/10.1200/jco.2010.28.15_suppl.8036 link to abstract] | ||
+ | # '''Abstract:''' Nathan H Fowler, MD, Sattva S. Neelapu, MD, Fredrick B Hagemeister, MD, Peter McLaughlin, MD, Larry W. Kwak, MD, PhD, Jorge E Romaguera, MD, Michelle A. Fanale, MD, Luis E Fayad, MD, Robert Z. Orlowski, M.D., Ph.D., Michael Wang, M.D., Francesco Turturro, MD, Yasuhiro Oki, MD, Linda Catherine Lacerte, RN and Felipe Samaniego, MD, MPH. Lenalidomide and Rituximab for Untreated Indolent Lymphoma: Final Results of a Phase II Study. 2012 ASH Annual Meeting abstract 901. [https://doi.org/10.1182/blood.V120.21.901.901 link to abstract] --> | ||
+ | # '''MDACC 2008-0042:''' Fowler NH, Davis RE, Rawal S, Nastoupil L, Hagemeister FB, McLaughlin P, Kwak LW, Romaguera JE, Fanale MA, Fayad LE, Westin JR, Shah J, Orlowski RZ, Wang M, Turturro F, Oki Y, Claret LC, Feng L, Baladandayuthapani V, Muzzafar T, Tsai KY, Samaniego F, Neelapu SS. Safety and activity of lenalidomide and rituximab in untreated indolent lymphoma: an open-label, phase 2 trial. Lancet Oncol. 2014 Nov;15(12):1311-8. Epub 2014 Oct 15. [https://doi.org/10.1016/S1470-2045(14)70455-3 link to original article] '''dosing details in abstract have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4370362/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25439689/ PubMed] [https://clinicaltrials.gov/study/NCT00695786 NCT00695786] | ||
− | == | + | ==O-FC {{#subobject:a1a5f0|Regimen=1}}== |
− | {| class="wikitable" style=" | + | O-FC: '''<u>O</u>'''fatumumab, '''<u>F</u>'''ludarabine, '''<u>C</u>'''yclophosphamide |
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen {{#subobject:e10e20|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916561/ Wierda et al. 2011 (407 Study)] | ||
+ | |2007 to not reported | ||
+ | |style="background-color:#91cf61"|Phase 2 | ||
|- | |- | ||
− | |||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#f2f3f4"> | |
− | + | ====Targeted therapy==== | |
− | + | *[[Ofatumumab (Arzerra)]] as follows: | |
− | ===Regimen | + | **Cycle 1: 300 mg IV once on day 1 |
− | {| | + | **Cycles 2 to 6: 500 mg or 1000 mg IV once on day 1 |
− | | | + | ====Chemotherapy==== |
− | |[[Levels_of_Evidence#Evidence| | + | *[[Fludarabine (Fludara)]] as follows: |
+ | **Cycle 1: 25 mg/m<sup>2</sup> IV once per day on days 2 to 4 | ||
+ | **Cycles 2 to 6: 25 mg/m<sup>2</sup> IV once per day on days 1 to 3 (note: there was ambiguity in Wierda et al. 2011 about whether both fludarabine and cyclophosphamide are given three days per cycle, or whether fludarabine is given once per cycle and only cyclophosphamide is given three days per cycle) | ||
+ | *[[Cyclophosphamide (Cytoxan)]] as follows: | ||
+ | **Cycle 1: 250 mg/m<sup>2</sup> IV once per day on days 2 to 4 | ||
+ | **Cycles 2 to 6: 250 mg/m<sup>2</sup> IV once per day on days 1 to 3 | ||
+ | ====Supportive therapy==== | ||
+ | *[[Acetaminophen (Tylenol)]] 1000 mg PO once on day 1, prior to ofatumumab | ||
+ | *[[Cetirizine (Zyrtec)]] 10 mg (or equivalent) PO once on day 1, prior to ofatumumab | ||
+ | *[[Prednisolone (Millipred)]] 100 mg ([[Steroid conversions|or equivalent]]) PO once on day 1, prior to doses 1 & 2 of ofatumumab, then reduced by physician discretion for later doses | ||
+ | *May be used at physician discretion: | ||
+ | **[[Allopurinol (Zyloprim)]] for tumor lysis syndrome prophylaxis | ||
+ | **[[:Category:Antivirals|Antiviral]] prophylaxis | ||
+ | **[[:Category:PCP_prophylaxis|PCP (Pneumocystis jiroveci pneumonia)]] prophylaxis | ||
+ | **Growth factor support | ||
+ | '''28-day cycle for 6 cycles''' | ||
+ | </div></div> | ||
+ | ===References=== | ||
+ | <!-- Data from this study were presented in part at the American Society of Hematology Annual Meeting, December 5-8, 2009, New Orleans, LA; the American Society of Clinical Oncology Annual Meeting, June 4-8, 2010, Chicago, IL; and the Congress of the European Hematology Association, June 10-13, 2010, Barcelona, Spain. --> | ||
+ | # '''407 Study:''' Wierda WG, Kipps TJ, Dürig J, Griskevicius L, Stilgenbauer S, Mayer J, Smolej L, Hess G, Griniute R, Hernandez-Ilizaliturri FJ, Padmanabhan S, Gorczyca M, Chang CN, Chan G, Gupta I, Nielsen TG, Russell CA; 407 Study Investigators. Chemoimmunotherapy with O-FC in previously untreated patients with chronic lymphocytic leukemia. Blood. 2011 Jun 16;117(24):6450-8. Epub 2011 Apr 15. [https://doi.org/10.1182/blood-2010-12-323980 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916561/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21498674/ PubMed] [https://clinicaltrials.gov/study/NCT00410163 NCT00410163] | ||
+ | ==PCO {{#subobject:4eca93|Regimen=1}}== | ||
+ | PCO: '''<u>P</u>'''entostatin, '''<u>C</u>'''yclophosphamide, '''<u>O</u>'''fatumumab | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen {{#subobject:75a1af|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3894149/ Shanafelt et al. 2013 (MC0983 arm 1)] | ||
+ | |2010-2011 | ||
+ | |style="background-color:#91cf61"|Phase 2 | ||
+ | |- | ||
+ | |[https://doi.org/10.1016/S2352-3026(16)30064-3 Strati et al. 2016 (MC0983 arm 2)] | ||
+ | |2011-2012 | ||
+ | |style="background-color:#91cf61"|Phase 2 | ||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4666341/ Tedeschi et al. 2015] |
− | |style="background-color:# | + | |2011-2013 |
+ | |style="background-color:#91cf61"|Phase 2 | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[ | + | *[[Pentostatin (Nipent)]] 2 mg/m<sup>2</sup> IV once on day 1 |
− | + | *[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1 | |
− | + | ====Targeted therapy==== | |
− | *[[ | + | *[[Ofatumumab (Arzerra)]] as follows: |
− | *[[ | + | **Cycle 1: 300 mg IV once on day 1, then 1000 mg IV once on day 8 |
− | * | + | **Cycles 2 to 6: 1000 mg IV once on day 1 |
− | + | ====Supportive therapy==== | |
− | ====Supportive | + | *Best described in Shanafelt et al. 2013: |
− | *[[ | + | *[[Methylprednisolone (Solumedrol)]] 80 mg IV once, prior to ofatumumab |
− | *[[Allopurinol (Zyloprim)]] 300 mg PO once per day on days 1 to | + | *Cycle 1: [[Allopurinol (Zyloprim)]] 300 mg PO once per day on days 1 to 14 |
− | *[[Trimethoprim | + | *[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 2 |
− | + | *[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] or similar for PJP prophylaxis for one year from start of treatment | |
− | ''' | + | *[[Valacyclovir (Valtrex)]] or similar for HSV prophylaxis for one year from start of treatment |
− | + | '''21-day cycle for 6 cycles''' | |
− | + | </div> | |
− | + | <div class="toccolours" style="background-color:#cbd5e7"> | |
− | + | ====Subsequent treatment==== | |
− | + | *MC0983 arm 2: [[#Ofatumumab_monotherapy|Ofatumumab]] consolidation | |
− | + | </div></div> | |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | ==== | ||
− | * | ||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
===References=== | ===References=== | ||
− | + | # '''MC0983 arm 1:''' Shanafelt T, Lanasa MC, Call TG, Beaven AW, Leis JF, LaPlant B, Bowen D, Conte M, Jelinek DF, Hanson CA, Kay NE, Zent CS. Ofatumumab-based chemoimmunotherapy is effective and well tolerated in patients with previously untreated chronic lymphocytic leukemia (CLL). Cancer. 2013 Nov 1;119(21):3788-96. Epub 2013 Aug 6. Erratum in: Cancer. 2014 Mar 15;120(6):926. Dosage error in article text. [https://doi.org/10.1002/cncr.28292 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3894149/ link to PMC article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/23922059/ PubMed] [https://clinicaltrials.gov/study/NCT01024010 NCT01024010] | |
− | + | # Tedeschi A, Rossi D, Motta M, Quaresmini G, Rossi M, Coscia M, Anastasia A, Rossini F, Cortelezzi A, Nador G, Scarfò L, Cairoli R, Frustaci AM, Dalceggio D, Picardi P, De Paoli L, Orlandi E, Rambaldi A, Massaia M, Gaidano G, Montillo M; Rete Ematologica Lombarda–CLL Workgroup. A phase II multi-center trial of pentostatin plus cyclophosphamide with ofatumumab in older previously untreated chronic lymphocytic leukemia patients. Haematologica. 2015 Dec;100(12):e501-4. Epub 2015 Aug 20. [https://doi.org/10.3324/haematol.2015.132035 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4666341/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26294723/ PubMed] [https://clinicaltrials.gov/study/NCT01681563 NCT01681563] | |
− | # | + | # '''MC0983 arm 2:''' Strati P, Lanasa M, Call TG, Leis JF, Brander DM, LaPlant BR, Pettinger AM, Ding W, Parikh SA, Hanson CA, Chanan-Khan AA, Bowen DA, Conte M, Kay NE, Shanafelt TD. Ofatumumab monotherapy as a consolidation strategy in patients with previously untreated chronic lymphocytic leukaemia: a phase 2 trial. Lancet Haematol. 2016 Sep;3(9):e407-14. Epub 2016 Aug 1. [https://doi.org/10.1016/S2352-3026(16)30064-3 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/27570087/ PubMed] [https://clinicaltrials.gov/study/NCT01024010 NCT01024010] |
− | # | + | ==PCR {{#subobject:6b0b68|Regimen=1}}== |
− | + | PCR: '''<u>P</u>'''entostatin, '''<u>C</u>'''yclophosphamide, '''<u>R</u>'''ituximab | |
− | == | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | {| class="wikitable" style=" | + | ===Regimen variant #1, 2/600/100->375 {{#subobject:90f7f6|Variant=1}}=== |
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1785105/ Kay et al. 2007] |
− | + | |2002-2005 | |
− | + | |style="background-color:#91cf61"|Phase 2 | |
− | |||
− | |||
− | |||
− | |||
− | | | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1002/cncr.22662 Shanafelt et al. 2007] |
− | |style="background-color:# | + | |Not reported |
+ | |style="background-color:#91cf61"|Phase 2 | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[ | + | *[[Pentostatin (Nipent)]] 2 mg/m<sup>2</sup> IV once on day 1 |
− | + | *[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1 | |
− | + | ====Targeted therapy==== | |
− | *[[Cyclophosphamide (Cytoxan)]] | ||
− | |||
− | |||
*[[Rituximab (Rituxan)]] as follows: | *[[Rituximab (Rituxan)]] as follows: | ||
− | **Cycle 1: | + | **Cycle 1: 100 mg/m<sup>2</sup> IV once on day 1, then 375 mg/m<sup>2</sup> IV once per day on days 3 & 5 |
− | **Cycles 2 to 6: | + | **Cycles 2 to 6: 375 mg/m<sup>2</sup> IV once on day 1 |
− | + | ====Supportive therapy==== | |
− | ====Supportive | + | *''Note: see references for details, as they differ by paper.'' |
− | * | + | *[[Filgrastim (Neupogen)]] once per day, starting on day 3 for up to 10 days or until ANC greater than 1000/μL for 2 straight days |
− | *[[ | + | *Cycle 1: [[Allopurinol (Zyloprim)]] 300 mg PO once per day on days 1 to 15 |
− | + | *Prophylactic [[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] for 1 year | |
− | *[[Allopurinol (Zyloprim)]] 300 mg PO once per day on days 1 to | + | *Prophylactic [[Acyclovir (Zovirax)]] for 1 year |
− | *[[Trimethoprim | + | '''28-day cycle for 6 cycles''' |
− | *[[Acyclovir (Zovirax)]] | + | </div></div><br> |
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | + | ===Regimen variant #2, 4/600/375 {{#subobject:90f7f7|Variant=1}}=== | |
− | '''28-day | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | + | !style="width: 33%"|Study | |
− | + | !style="width: 33%"|Dates of enrollment | |
− | + | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | |
− | ===Regimen #2 {{#subobject: | ||
− | {| | ||
− | | | ||
− | |[[Levels_of_Evidence#Evidence| | ||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5278955/ Samaniego et al. 2015 (MDACC 2004-0818)] |
− | |style="background-color:# | + | |2005 to not reported |
+ | |style="background-color:#91cf61"|Phase 2 | ||
|- | |- | ||
|} | |} | ||
+ | ''Note: this regimen was specifically studied in SLL, not CLL.'' | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[ | + | *[[Pentostatin (Nipent)]] 4 mg/m<sup>2</sup> IV once on day 1 |
− | *[[Cyclophosphamide (Cytoxan)]] | + | *[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1 |
+ | ====Targeted therapy==== | ||
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1 | *[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1 | ||
− | + | ====Supportive therapy==== | |
− | ''' | + | *[[Ondansetron (Zofran)]] 8 mg (route not specified) once on day 1, prior to chemotherapy |
− | + | *[[Diphenhydramine (Benadryl)]] 25 mg (route not specified) once on day 1, prior to chemotherapy | |
− | ===Regimen # | + | *500 ml of 5% dextrose/one-half normal saline before and after each pentostatin dose |
− | {| | + | *[[Filgrastim (Neupogen)]] at the discretion of the treating physician |
− | | | + | *Cycle 1: [[Allopurinol (Zyloprim)]] 300 mg PO once per day on days 1 to 15 |
− | |[[Levels_of_Evidence#Evidence| | + | *[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] once per day three days per week during and for 1 month following therapy |
+ | *[[Acyclovir (Zovirax)]] 400 mg PO twice per day during and for 1 month following therapy | ||
+ | '''21-day cycle for 6 cycles''' | ||
+ | </div></div> | ||
+ | ===References=== | ||
+ | # Kay NE, Geyer SM, Call TG, Shanafelt TD, Zent CS, Jelinek DF, Tschumper R, Bone ND, Dewald GW, Lin TS, Heerema NA, Smith L, Grever MR, Byrd JC. Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia. Blood. 2007 Jan 15;109(2):405-11. Epub 2006 Sep 28. [https://doi.org/10.1182/blood-2006-07-033274 link to original article] '''dosing details in abstract have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1785105/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/17008537/ PubMed] | ||
+ | # Shanafelt TD, Lin T, Geyer SM, Zent CS, Leung N, Kabat B, Bowen D, Grever MR, Byrd JC, Kay NE. Pentostatin, cyclophosphamide, and rituximab regimen in older patients with chronic lymphocytic leukemia. Cancer. 2007 Jun 1;109(11):2291-8. [https://doi.org/10.1002/cncr.22662 link to original article] [https://pubmed.ncbi.nlm.nih.gov/17514743/ PubMed] | ||
+ | # '''MDACC 2004-0818:''' Samaniego F, Hagemeister F, Romaguera JE, Fanale MA, Pro B, McLaughlin P, Rodriguez MA, Neelapu SS, Fayad L, Younes A, Feng L, Berkova Z, Khashab T, Sehgal L, Vega-Vasquez F, Kwak LW. Pentostatin, cyclophosphamide and rituximab for previously untreated advanced stage, low-grade B-cell lymphomas. Br J Haematol. 2015 Jun;169(6):814-23. Epub 2015 Mar 31. [https://doi.org/10.1111/bjh.13367 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5278955/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25828695/ PubMed] [https://clinicaltrials.gov/study/NCT00496873 NCT00496873] | ||
+ | ==RCC {{#subobject:7c1b68|Regimen=1}}== | ||
+ | RCC: '''<u>R</u>'''ituximab, '''<u>C</u>'''ladribine, '''<u>C</u>'''yclophosphamide | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen {{#subobject:81c7f7|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1111/ejh.13042 Robak et al. 2018 (PALG CLL4)] |
− | |style="background-color:# | + | |2009-07 to 2011-12 |
+ | |style="background-color:#91cf61"|Non-randomized part of phase 3b RCT | ||
|- | |- | ||
|} | |} | ||
− | ==== | + | <div class="toccolours" style="background-color:#f2f3f4"> |
− | + | ====Targeted therapy==== | |
− | |||
*[[Rituximab (Rituxan)]] as follows: | *[[Rituximab (Rituxan)]] as follows: | ||
**Cycle 1: 375 mg/m<sup>2</sup> IV once on day 1 | **Cycle 1: 375 mg/m<sup>2</sup> IV once on day 1 | ||
**Cycles 2 to 6: 500 mg/m<sup>2</sup> IV once on day 1 | **Cycles 2 to 6: 500 mg/m<sup>2</sup> IV once on day 1 | ||
− | + | ====Chemotherapy==== | |
− | ==== | + | *[[Cladribine (Leustatin)]] 0.12 mg/kg IV once per day on days 2 to 4 |
− | + | *[[Cyclophosphamide (Cytoxan)]] 250 mg/m<sup>2</sup> IV over 15 to 30 minutes once per day on days 2 to 4 | |
− | *[[ | + | '''28-day cycle for 6 cycles''' |
− | *[[ | + | </div> |
− | + | <div class="toccolours" style="background-color:#cbd5e7"> | |
− | + | ====Subsequent treatment==== | |
− | + | *[[Chronic_lymphocytic_leukemia_-_null_regimens#Observation|Observation]] versus [[#Rituximab_monotherapy_2|Rituximab]] maintenance | |
− | + | </div></div> | |
− | |||
− | |||
− | |||
===References=== | ===References=== | ||
− | # | + | # '''PALG CLL4:''' Robak T, Błoński J, Skotnicki AB, Piotrowska M, Wróbel T, Rybka J, Kłoczko J, Bołkun Ł, Budziszewska BK, Walczak U, Uss A, Fidecka M, Smolewski P. Rituximab, cladribine, and cyclophosphamide (RCC) induction with rituximab maintenance in chronic lymphocytic leukemia: PALG - CLL4 (ML21283) trial. Eur J Haematol. 2018 May;100(5):465-474. Epub 2018 Mar 22. [https://doi.org/10.1111/ejh.13042 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/29427355/ PubMed] [https://clinicaltrials.gov/study/NCT00718549 NCT00718549] |
− | |||
− | |||
− | |||
− | |||
− | |||
− | == | + | ==Rituximab monotherapy {{#subobject:9f1176|Regimen=1}}== |
− | {| class="wikitable" style=" | + | <div class="toccolours" style="background-color:#eeeeee"> |
+ | ===Regimen {{#subobject:c47e54|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | |- | ||
+ | |[https://doi.org/10.1200/jco.2003.09.027 Hainsworth et al. 2003] | ||
+ | |2000-2001 | ||
+ | |style="background-color:#91cf61"|Phase 2 | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4900920/ Williams et al. 2016 (RESORT substudy)] | ||
+ | |2003-2008 | ||
+ | |style="background-color:#91cf61"|Non-randomized part of phase 3 RCT | ||
|- | |- | ||
− | |||
|} | |} | ||
− | ===Regimen {{#subobject: | + | <div class="toccolours" style="background-color:#f2f3f4"> |
− | {| | + | ====Targeted therapy==== |
− | | | + | *[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1 |
− | |[[Levels_of_Evidence#Evidence| | + | **In Hainsworth et al. 2003, optional alternate initial dosing for patients with WBC count more than 100 x 10<sup>9</sup>/L: 100 mg IV once on day 1, with remainder of the 375 mg/m<sup>2</sup> dosage given on day 2 |
+ | ====Supportive therapy==== | ||
+ | *[[Acetaminophen (Tylenol)]] 650 mg PO once on day 1; 30 minutes prior to rituximab | ||
+ | *[[Diphenhydramine (Benadryl)]] 50 mg PO or IV once on day 1; 30 minutes prior to rituximab | ||
+ | *In Hainsworth et al. 2003, if WBC count more than 50 x 10<sup>9</sup>/L or massive lymphadenopathy: [[Allopurinol (Zyloprim)]] 300 mg PO once per day, starting 3 days before the first dose of rituximab | ||
+ | *In Hainsworth et al. 2003, one of the following: | ||
+ | **[[Cimetidine (Tagamet)]] 300 mg IV once on day 1; 30 minutes prior to rituximab | ||
+ | **[[Ranitidine (Zantac)]] 50 mg IV once on day 1; 30 minutes prior to rituximab | ||
+ | '''7-day cycle for 4 cycles''' | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#cbd5e7"> | ||
+ | ====Subsequent treatment==== | ||
+ | *Hainsworth et al. 2003, SD or better: [[#Rituximab_monotherapy_2|Rituximab]] maintenance | ||
+ | *RESORT substudy, PR/CR: Indefinite [[#Rituximab_monotherapy_2|rituximab]] continuation versus salvage [[#Rituximab_monotherapy_3|rituximab]] at time of progression | ||
+ | </div></div> | ||
+ | ===References=== | ||
+ | # Hainsworth JD, Litchy S, Barton JH, Houston GA, Hermann RC, Bradof JE, Greco FA; Minnie Pearl Cancer Research Network. Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol. 2003 May 1;21(9):1746-51. [https://doi.org/10.1200/jco.2003.09.027 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/12721250/ PubMed] | ||
+ | <!-- Presented in part at the American Society of Clinical Oncology 2012 Annual Meeting, Chicago, IL, USA. --> | ||
+ | # '''RESORT substudy:''' Williams ME, Hong F, Gascoyne RD, Wagner LI, Krauss JC, Habermann TM, Swinnen LJ, Schuster SJ, Peterson CG, Sborov MD, Martin SE, Weiss M, Ehmann WC, Horning SJ, Kahl BS; Eastern Cooperative Oncology Group. Rituximab extended schedule or retreatment trial for low tumour burden non-follicular indolent B-cell non-Hodgkin lymphomas: Eastern Cooperative Oncology Group Protocol E4402. Br J Haematol. 2016 Jun;173(6):867-75. Epub 2016 Mar 11. [https://doi.org/10.1111/bjh.14007 link to original article] '''dosing details in abstract have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4900920/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26970533/ PubMed] [https://clinicaltrials.gov/study/NCT01406782 NCT01406782] | ||
+ | ==Ruxolitinib monotherapy {{#subobject:a99c0d |Regimen=1}}== | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen {{#subobject:bc61db |Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356368/ Jain et al. 2017 (MDACC 2013-0044)] |
− | |style="background-color:# | + | |2014-2015 |
+ | |style="background-color:#91cf61"|Phase 2 | ||
|- | |- | ||
|} | |} | ||
− | ==== | + | ''Note: this was a trial focused on symptom control, not efficacy.'' |
− | *[[ | + | <div class="toccolours" style="background-color:#f2f3f4"> |
− | + | ====Targeted therapy==== | |
− | + | *[[Ruxolitinib (Jakafi)]] 10 mg PO twice per day | |
− | ''' | + | '''Continued indefinitely''' |
− | + | </div></div> | |
===References=== | ===References=== | ||
− | # | + | # '''MDACC 2013-0044:''' Jain P, Keating M, Renner S, Cleeland C, Xuelin H, Gonzalez GN, Harris D, Li P, Liu Z, Veletic I, Rozovski U, Jain N, Thompson P, Bose P, DiNardo C, Ferrajoli A, O'Brien S, Burger J, Wierda W, Verstovsek S, Kantarjian H, Estrov Z. Ruxolitinib for symptom control in patients with chronic lymphocytic leukaemia: a single-group, phase 2 trial. Lancet Haematol. 2017 Feb;4(2):e67-e74. Epub 2017 Jan 11. [https://doi.org/10.1016/S2352-3026(16)30194-6 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356368/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28089238/ PubMed] [https://clinicaltrials.gov/study/NCT02131584 NCT02131584] |
− | + | ==Zanubrutinib & Obinutuzumab {{#subobject:7ygqqd |Regimen=1}}== | |
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | == | + | ===Regimen {{#subobject:it81db |Variant=1}}=== |
− | {| class="wikitable" style=" | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7556127/ Tam et al. 2020] | ||
+ | |2016 to not reported | ||
+ | |style="background-color:#91cf61"|Phase 1b, >20 pts in this subgroup | ||
|- | |- | ||
− | |||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#f2f3f4"> | |
− | + | ====Targeted therapy==== | |
− | + | *[[Zanubrutinib (Brukinsa)]] 160 mg PO twice per day or 320 mg PO once per day | |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | ==== | ||
*[[Obinutuzumab (Gazyva)]] as follows: | *[[Obinutuzumab (Gazyva)]] as follows: | ||
− | **Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once on days 8 & 15 | + | **Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15 |
**Cycles 2 to 6: 1000 mg IV once on day 1 | **Cycles 2 to 6: 1000 mg IV once on day 1 | ||
− | + | '''28-day cycles''' | |
− | + | </div></div> | |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | '''28-day | ||
− | |||
===References=== | ===References=== | ||
− | + | #Tam CS, Quach H, Nicol A, Badoux X, Rose H, Prince HM, Leahy MF, Eek R, Wickham N, Patil SS, Huang J, Prathikanti R, Cohen A, Elstrom R, Reed W, Schneider J, Flinn IW. Zanubrutinib (BGB-3111) plus obinutuzumab in patients with chronic lymphocytic leukemia and follicular lymphoma. Blood Adv. 2020 Oct 13;4(19):4802-4811. [https://doi.org/10.1182/bloodadvances.2020002183 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7556127/ link to PMC article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/33022066/ PubMed] [https://clinicaltrials.gov/study/NCT02569476 NCT02569476] | |
− | |||
− | == | + | =Consolidation and/or maintenance after first-line therapy= |
− | {| class="wikitable" style=" | + | ==Alemtuzumab monotherapy {{#subobject:004de9|Regimen=1}}== |
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #1, 6-week course {{#subobject:831bd9|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | |- | ||
+ | |[https://doi.org/10.1111/bjh.14342 Varghese et al. 2017 (NCRN CLL 207)] | ||
+ | |2006-2010 | ||
+ | |style="background-color:#91cf61"|Phase 2 | ||
|- | |- | ||
− | |||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#cbd5e8"> | |
− | + | ====Preceding treatment==== | |
− | + | *First-line [[Regimen_classes#Chemotherapy-based_regimen|Chemotherapy]] (details not specified) | |
− | ===Regimen {{#subobject: | + | </div> |
− | {| | + | <div class="toccolours" style="background-color:#f2f3f4"> |
− | | | + | ====Targeted therapy==== |
− | |[[Levels_of_Evidence#Evidence| | + | *[[Alemtuzumab (Campath)]] 30 mg SC once per day on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26, 29, 31, 33, 36, 38, 40 (three times per week) |
+ | '''6-week course''' | ||
+ | </div></div><br> | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #2, 12-week course {{#subobject:36b1c2|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1038/sj.leu.2403354 Wendtner et al. 2004 (GCLLSG CLL4B)] |
− | |style="background-color:# | + | |Not reported |
+ | |style="background-color:#1a9851"|Phase 3 (E-esc) | ||
+ | |[[Chronic_lymphocytic_leukemia_-_null_regimens#Observation|Observation]] | ||
+ | | style="background-color:#1a9850" |Superior PFS<sup>1</sup> (primary endpoint) | ||
|- | |- | ||
|} | |} | ||
− | ==== | + | ''<sup>1</sup>Reported efficacy is based on the 2009 update.''<br> |
− | *[[ | + | ''Note: this study closed early due to high rates of infections in the experimental arm. Alemtuzumab dose is increased only if tolerated.'' |
− | + | <div class="toccolours" style="background-color:#cbd5e8"> | |
− | + | ====Preceding treatment==== | |
− | + | *First-line [[Chronic_lymphocytic_leukemia_-_historical#Fludarabine_monotherapy|F]] x 6 or [[Chronic_lymphocytic_leukemia_-_historical#Cyclophosphamide_.26_Fludarabine_.28FC.29|FC]] x 6 | |
− | + | </div> | |
− | + | <div class="toccolours" style="background-color:#f2f3f4"> | |
− | *[[ | + | ====Targeted therapy==== |
− | **Cycle 1: | + | *[[Alemtuzumab (Campath)]] as follows: |
− | **Cycles 2 to | + | **Cycle 1: 3 mg SC once on day 1, then 10 mg SC once on day 2, then 30 mg SC once on day 5 |
− | + | **Cycles 2 to 12: 30 mg SC once per day on days 1, 3, 5 (three times per week) | |
− | + | '''7-day cycle for 12 cycles''' | |
− | + | </div></div> | |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | ''' | ||
− | |||
===References=== | ===References=== | ||
− | + | # '''GCLLSG CLL4B:''' Wendtner CM, Ritgen M, Schweighofer CD, Fingerle-Rowson G, Campe H, Jäger G, Eichhorst B, Busch R, Diem H, Engert A, Stilgenbauer S, Döhner H, Kneba M, Emmerich B, Hallek M; German CLL Study Group. Consolidation with alemtuzumab in patients with chronic lymphocytic leukemia (CLL) in first remission--experience on safety and efficacy within a randomized multicenter phase III trial of the German CLL Study Group (GCLLSG). Leukemia. 2004 Jun;18(6):1093-101. [https://doi.org/10.1038/sj.leu.2403354 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/15071604/ PubMed] | |
− | # | + | ## '''Update:''' Schweighofer CD, Ritgen M, Eichhorst BF, Busch R, Abenhardt W, Kneba M, Hallek M, Wendtner CM. Consolidation with alemtuzumab improves progression-free survival in patients with chronic lymphocytic leukaemia (CLL) in first remission: long-term follow-up of a randomized phase III trial of the German CLL Study Group (GCLLSG). Br J Haematol. 2009 Jan;144(1):95-8. Epub 2008 Oct 30. [https://doi.org/10.1111/j.1365-2141.2008.07394.x link to original article] [https://pubmed.ncbi.nlm.nih.gov/19016732/ PubMed] |
− | + | # '''NCRN CLL207:''' Varghese AM, Howard DR, Pocock C, Rawstron AC, Follows G, McCarthy H, Dearden C, Fegan C, Milligan D, Smith AF, Gregory W, Hillmen P; NCRI CLL Sub-Group. Eradication of minimal residual disease improves overall and progression-free survival in patients with chronic lymphocytic leukaemia, evidence from NCRN CLL207: a phase II trial assessing alemtuzumab consolidation. Br J Haematol. 2017 Feb;176(4):573-582. Epub 2016 Dec 29. [https://doi.org/10.1111/bjh.14342 link to original article] '''dosing details in abstract have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/28032335/ PubMed] | |
− | == | + | ==Lenalidomide monotherapy {{#subobject:7210a7|Regimen=1}}== |
− | {| class="wikitable" style=" | + | <div class="toccolours" style="background-color:#eeeeee"> |
+ | ===Regimen {{#subobject:e227a0|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
+ | |- | ||
+ | |[https://doi.org/10.1016/S2352-3026(17)30171-0 Fink et al. 2017 (GCLLSG CLLM1)] | ||
+ | |2012-2016 | ||
+ | |style="background-color:#1a9851"|Phase 3 (E-esc) | ||
+ | |[[Chronic_lymphocytic_leukemia_-_null_regimens#Observation|Observation]] | ||
+ | |style="background-color:#1a9850"|Superior PFS (primary endpoint)<br>Median PFS: NYR vs 13.3 mo<br>(HR 0.17, 95% CI 0.07-0.38) | ||
|- | |- | ||
− | |||
|} | |} | ||
− | + | ''Note that while the [https://clinicaltrials.gov/study/NCT01556776 NCT01556776] NCT record] reports dose increases beyond 15 mg PO once per day, the abstract states that 15 mg PO once per day was the "target dose". Lenalidomide dose is only increased if tolerated.'' | |
− | + | <div class="toccolours" style="background-color:#cbd5e8"> | |
− | ===Regimen {{#subobject: | + | ====Preceding treatment==== |
− | {| | + | *GCLLSG CLLM1: First-line [[Regimen_classes#Multi-agent_regimen|chemoimmunotherapy]] |
− | | | + | </div> |
− | |[[Levels_of_Evidence#Evidence| | + | <div class="toccolours" style="background-color:#f2f3f4"> |
+ | ====Targeted therapy==== | ||
+ | *[[Lenalidomide (Revlimid)]] as follows: | ||
+ | **Cycle 1: 5 mg PO once per day on days 1 to 28 | ||
+ | **Cycles 2 to 6: 10 mg PO once per day on days 1 to 28 | ||
+ | **Cycle 7 onwards: 15 mg PO once per day on days 1 to 28 | ||
+ | '''28-day cycles''' | ||
+ | </div></div> | ||
+ | ===References=== | ||
+ | # '''GCLLSG CLLM1:''' Fink AM, Bahlo J, Robrecht S, Al-Sawaf O, Aldaoud A, Hebart H, Jentsch-Ullrich K, Dörfel S, Fischer K, Wendtner CM, Nösslinger T, Ghia P, Bosch F, Kater AP, Döhner H, Kneba M, Kreuzer KA, Tausch E, Stilgenbauer S, Ritgen M, Böttcher S, Eichhorst B, Hallek M. Lenalidomide maintenance after first-line therapy for high-risk chronic lymphocytic leukaemia (CLLM1): final results from a randomised, double-blind, phase 3 study. Lancet Haematol. 2017 Oct;4(10):e475-e486. Epub 2017 Sep 12. [https://doi.org/10.1016/S2352-3026(17)30171-0 link to original article] '''dosing details in abstract have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/28916311/ PubMed] [https://clinicaltrials.gov/study/NCT01556776 NCT01556776] | ||
+ | ==Ofatumumab monotherapy {{#subobject:4ff470|Regimen=1}}== | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen {{#subobject:245061|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[https:// | + | |[https://doi.org/10.1016/S2352-3026(16)30064-3 Strati et al. 2016 (MC0983 arm 2)] |
− | |style="background-color:# | + | |2011-2012 |
+ | |style="background-color:#91cf61"|Phase 2 | ||
|- | |- | ||
|} | |} | ||
− | ==== | + | <div class="toccolours" style="background-color:#cbd5e8"> |
− | *[[ | + | ====Preceding treatment==== |
− | + | *First-line [[#PCO|PCO]] x 6 | |
− | + | </div> | |
− | + | <div class="toccolours" style="background-color:#f2f3f4"> | |
− | + | ====Targeted therapy==== | |
− | ==== | + | *[[Ofatumumab (Arzerra)]] 1000 mg IV once on day 1 |
− | *[[ | + | '''28-day cycle for 6 cycles''' |
− | + | </div></div> | |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | '''28-day | ||
− | |||
===References=== | ===References=== | ||
− | # | + | # '''MC0983 arm 2:''' Strati P, Lanasa M, Call TG, Leis JF, Brander DM, LaPlant BR, Pettinger AM, Ding W, Parikh SA, Hanson CA, Chanan-Khan AA, Bowen DA, Conte M, Kay NE, Shanafelt TD. Ofatumumab monotherapy as a consolidation strategy in patients with previously untreated chronic lymphocytic leukaemia: a phase 2 trial. Lancet Haematol. 2016 Sep;3(9):e407-14. Epub 2016 Aug 1. [https://doi.org/10.1016/S2352-3026(16)30064-3 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/27570087/ PubMed] [https://clinicaltrials.gov/study/NCT01024010 NCT01024010] |
− | == | + | ==Rituximab monotherapy {{#subobject:726c55|Regimen=1}}== |
− | {| class="wikitable" style=" | + | <div class="toccolours" style="background-color:#eeeeee"> |
+ | ===Regimen variant #1, 1 year {{#subobject:64c1ce|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
+ | |- | ||
+ | |[https://doi.org/10.1002/ajh.23668 Foà et al. 2014 (ML21445)] | ||
+ | |2008-2013 | ||
+ | |style="background-color:#1a9851"|Randomized Phase 2 (E-esc) | ||
+ | |[[Chronic_lymphocytic_leukemia_-_null_regimens#Observation|Observation]] | ||
+ | |style="background-color:#d9ef8b"|Might have superior PFS (secondary endpoint) | ||
|- | |- | ||
− | |||
|} | |} | ||
− | ===Regimen {{#subobject: | + | <div class="toccolours" style="background-color:#cbd5e8"> |
− | {| | + | ====Preceding treatment==== |
− | | | + | *ML21445: First-line [[#Chlorambucil_.26_Rituximab_.28RClb.29|Clb-R]] |
− | |[[Levels_of_Evidence#Evidence| | + | </div> |
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
+ | ====Targeted therapy==== | ||
+ | *[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1 | ||
+ | '''8-week cycle for 6 cycles''' | ||
+ | </div></div><br> | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #2, 2 years, given q3mo {{#subobject:783b2c|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.2009.22.0442 Bosch et al. 2009] |
− | |style="background-color:# | + | |2005-11 to 2007-11 |
+ | |style="background-color:#91cf61"|Phase 2 | ||
+ | |style="background-color:#d3d3d3"| | ||
+ | |style="background-color:#d3d3d3"| | ||
|- | |- | ||
− | | | + | |[https://doi.org/10.1111/ejh.13042 Robak et al. 2018 (PALG CLL4)] |
− | + | |2009-07 to 2011-12 | |
− | + | |style="background-color:#1a9851"|Phase 3b (E-esc) | |
− | + | |[[Chronic_lymphocytic_leukemia_-_null_regimens#Observation|Observation]] | |
− | + | |style="background-color:#91cf60"|Seems to have superior PFS | |
− | + | |- | |
− | + | |[https://doi.org/10.1016/s2352-3026(16)30045-x Greil et al. 2016 (AGMT CLL-8a)] | |
− | + | |2010-2013 | |
− | = | + | |style="background-color:#1a9851"|Phase 3 (E-esc) |
− | + | |[[Chronic_lymphocytic_leukemia_-_null_regimens#Observation|Observation]] | |
− | + | |style="background-color:#1a9850"|Superior PFS (primary endpoint)<br>Median PFS: 47 vs 35.5 mo<br>(HR 0.50, 95% CI 0.33-0.75) | |
− | |||
− | = | ||
− | |||
|- | |- | ||
− | |||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#cbd5e8"> | |
− | ===Regimen # | + | ====Preceding treatment==== |
− | {| | + | *Bosch et al. 2009: First-line [[Chronic_lymphocytic_leukemia_-_historical#R-FCM|R-FCM]] |
− | | | + | *PALG CLL4: First-line [[#RCC|RCC]] x 6 |
− | |[[Levels_of_Evidence#Evidence| | + | *AGMT CLL-8a: First-line [[Regimen_classes#Rituximab-containing_regimen|rituximab-containing chemoimmunotherapy]] |
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
+ | ====Targeted therapy==== | ||
+ | *[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1 | ||
+ | '''3-month cycle for 8 cycles (2 years)''' | ||
+ | </div></div><br> | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #3, 2 years, given q8wk {{#subobject:14014d|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1016/S2352-3026(17)30235-1 Dartigeas et al. 2017 (CLL 2007 SA)] |
− | |style="background-color:# | + | |2007-2014 |
+ | |style="background-color:#1a9851"|Phase 3 (E-esc) | ||
+ | |[[Chronic_lymphocytic_leukemia_-_null_regimens#Observation|Observation]] | ||
+ | |style="background-color:#1a9850"|Superior PFS (primary endpoint)<br>Median PFS: 59.3 vs 49 mo<br>(HR 0.55, 95% CI 0.40-0.75) | ||
|- | |- | ||
|} | |} | ||
− | ==== | + | ''Note the higher dose used here.'' |
− | *[[ | + | <div class="toccolours" style="background-color:#cbd5e8"> |
+ | ====Preceding treatment==== | ||
+ | *First-line [[#FCR|FCR]] x 4 | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
+ | ====Targeted therapy==== | ||
+ | *[[Rituximab (Rituxan)]] 500 mg/m<sup>2</sup> IV once on day 1 | ||
+ | '''8-week cycle for up to 13 cycles (2 years)''' | ||
+ | </div></div><br> | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #4, 2 years, given q6mo {{#subobject:14014d|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
+ | |- | ||
+ | |[https://doi.org/10.1200/jco.2003.09.027 Hainsworth et al. 2003] | ||
+ | |2000-2001 | ||
+ | |style="background-color:#91cf61"|Phase 2 | ||
+ | |style="background-color:#d3d3d3"| | ||
+ | |style="background-color:#d3d3d3"| | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2668968/ Hochster et al. 2009 (ECOG E1496)] | ||
+ | |Not reported | ||
+ | |style="background-color:#1a9851"|Phase 3 (E-esc) | ||
+ | |[[Chronic_lymphocytic_leukemia_-_null_regimens#Observation|Observation]] | ||
+ | |style="background-color:#1a9850"|Superior PFS (primary endpoint)<br>Median PFS: 4.3 vs 1.3 y<br>(HR 0.40, 95% CI 0.30-0.50) | ||
+ | |- | ||
+ | |} | ||
+ | ''ECOG E1496 included patients with SLL, but they were grouped into an "other" non-follicular lymphoma category.'' | ||
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
+ | ====Preceding treatment==== | ||
+ | *Hainsworth et al. 2003: First-line [[#Rituximab_monotherapy|rituximab]] | ||
+ | *ECOG E1496: First-line [[Chronic_lymphocytic_leukemia_-_historical#CVP|CVP]] | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
+ | ====Targeted therapy==== | ||
+ | *[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22 | ||
+ | ====Supportive therapy==== | ||
+ | *[[Acetaminophen (Tylenol)]] 650 mg PO once per day on days 1, 8, 15, 22; 30 minutes prior to rituximab | ||
+ | *[[Diphenhydramine (Benadryl)]] 50 mg IV once per day on days 1, 8, 15, 22; 30 minutes prior to rituximab | ||
+ | *One of the following: | ||
+ | **[[Cimetidine (Tagamet)]] 300 mg IV once per day on days 1, 8, 15, 22; 30 minutes prior to rituximab | ||
+ | **[[Ranitidine (Zantac)]] 50 mg IV once per day on days 1, 8, 15, 22; 30 minutes prior to rituximab | ||
+ | '''6-month cycle for 4 cycles (2 years)''' | ||
+ | </div></div><br> | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
− | ''' | + | ===Regimen variant #5, indefinite 375 mg/m<sup>2</sup> q3mo {{#subobject:d2473c|Variant=1}}=== |
− | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" | |
− | ===Regimen #2 {{#subobject: | + | !style="width: 20%"|Study |
− | {| | + | !style="width: 20%"|Dates of enrollment |
− | | | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | |[[Levels_of_Evidence#Evidence| | + | !style="width: 20%"|Comparator |
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4900920/ Williams et al. 2016 (RESORT substudy)] | ||
+ | |2003-2008 | ||
+ | |style="background-color:#1a9851"|Phase 3 (E-esc) | ||
+ | |[[#Rituximab_monotherapy_3|Rituximab]] salvage | ||
+ | |style="background-color:#91cf60"|Seems to have superior TTTF | ||
+ | |- | ||
+ | |} | ||
+ | ''Intended for patients with SLL.'' | ||
+ | <div class="toccolours" style="background-color:#cbd5e8"> | ||
+ | ====Preceding treatment==== | ||
+ | *First-line [[#Rituximab_monotherapy|Rituximab]] | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
+ | ====Targeted therapy==== | ||
+ | *[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1 | ||
+ | '''13-week cycles''' | ||
+ | </div></div><br> | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #6, indefinite 500 mg/m<sup>2</sup> q3mo {{#subobject:0b3b08|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.2008.17.2619 Foon et al. 2009] |
− | |style="background-color:# | + | |2003-2007 |
+ | |style="background-color:#91cf61"|Phase 2 | ||
|- | |- | ||
|} | |} | ||
− | ==== | + | <div class="toccolours" style="background-color:#cbd5e8"> |
− | *[[ | + | ====Preceding treatment==== |
− | + | *First-line [[#FCR|FCR-Lite]] x 6 | |
− | + | </div> | |
− | + | <div class="toccolours" style="background-color:#f2f3f4"> | |
− | + | ====Targeted therapy==== | |
− | ==== | + | *[[Rituximab (Rituxan)]] 500 mg/m<sup>2</sup> IV once on day 1 |
− | *[[ | + | '''3-month cycles''' |
− | + | </div></div> | |
− | ''' | ||
− | |||
===References=== | ===References=== | ||
− | <!-- Presented in part at the | + | # Hainsworth JD, Litchy S, Barton JH, Houston GA, Hermann RC, Bradof JE, Greco FA; Minnie Pearl Cancer Research Network. Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol. 2003 May 1;21(9):1746-51. [https://doi.org/10.1200/jco.2003.09.027 link to original article] [https://pubmed.ncbi.nlm.nih.gov/12721250/ PubMed] |
− | # | + | # Foon KA, Boyiadzis M, Land SR, Marks S, Raptis A, Pietragallo L, Meisner D, Laman A, Sulecki M, Butchko A, Schaefer P, Lenzer D, Tarhini A. Chemoimmunotherapy with low-dose fludarabine and cyclophosphamide and high dose rituximab in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009 Feb 1;27(4):498-503. Epub 2008 Dec 15. [https://doi.org/10.1200/jco.2008.17.2619 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/19075274/ PubMed] |
− | ## ''' | + | ## '''Update:''' Foon KA, Mehta D, Lentzsch S, Kropf P, Marks S, Lenzner D, Pietragallo L, Sulecki M, Tarhini A, Boyiadzis M. Long-term results of chemoimmunotherapy with low-dose fludarabine, cyclophosphamide and high-dose rituximab as initial treatment for patients with chronic lymphocytic leukemia. Blood. 2012 Mar 29;119(13):3184-5. [https://doi.org/10.1182/blood-2012-01-408047 link to original article] [https://pubmed.ncbi.nlm.nih.gov/22461474/ PubMed] |
− | <!-- Presented in part | + | <!-- Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL, and the Annual Meeting of the American Society of Hematology, December 9-12, 2006, Orlando, FL. --> |
− | # | + | # '''ECOG E1496:''' Hochster H, Weller E, Gascoyne RD, Habermann TM, Gordon LI, Ryan T, Zhang L, Colocci N, Frankel S, Horning SJ. Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG1496 Study. J Clin Oncol. 2009 Apr 1;27(10):1607-14. Epub 2009 Mar 2. [https://doi.org/10.1200/jco.2008.17.1561 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2668968/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19255334/ PubMed] [https://clinicaltrials.gov/study/NCT00003204 NCT00003204] |
− | + | <!-- Presented in part at the 43rd Annual Meeting of the American Society of Hematology, December 8-11, 2007, Atlanta, GA. --> | |
+ | # Bosch F, Abrisqueta P, Villamor N, Terol MJ, González-Barca E, Ferra C, González Diaz M, Abella E, Delgado J, Carbonell F, García Marco JA, Escoda L, Ferrer S, Monzó E, González Y, Estany C, Jarque I, Salamero O, Muntañola A, Montserrat E. Rituximab, fludarabine, cyclophosphamide, and mitoxantrone: a new, highly active chemoimmunotherapy regimen for chronic lymphocytic leukemia. J Clin Oncol. 2009 Sep 20;27(27):4578-84. Epub 2009 Aug 24. [https://doi.org/10.1200/jco.2009.22.0442 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/19704063/ PubMed] EudraCT 2005-001569-33 | ||
+ | ## '''Update:''' Abrisqueta P, Villamor N, Terol MJ, González-Barca E, González M, Ferrà C, Abella E, Delgado J, García-Marco JA, González Y, Carbonell F, Ferrer S, Monzó E, Jarque I, Muntañola A, Constants M, Escoda L, Calvo X, Bobillo S, Montoro JB, Montserrat E, Bosch F. Rituximab maintenance after first-line therapy with rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) for chronic lymphocytic leukemia. Blood. 2013 Dec 5;122(24):3951-9. Epub 2013 Oct 11. [https://doi.org/10.1182/blood-2013-05-502773 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/24124086/ PubMed] | ||
+ | <!-- # '''Abstract:''' R Foa, A Alietti, A Guarini, S Ciolli, F Di Raimondo, G Del Poeta, F Lauria, F Forconi, A Cuneo, A Cortellezzi, F Nobile, V Callea, M Brugiatelli, M Massaia, S Molica, L Trentin, R Rizzi, G Specchia, L Orsucci, A Ambrosetti, M Montillo, L Zinzani, F Ferrara, F Morabito, M Mura, S Soriani, S Santangelo, M Marinelli, M De Propris, A Alietti, J Runggaldier. A PHASE II STUDY OF CHLORAMBUCIL+RITUXIMAB (CLB-R) FOLLOWED BY R MAINTENANCE VS OBSERVATION IN ELDERLY PATIENTS WITH PREVIOUSLY UNTREATED CHRONIC LYMPHOCYTIC LEUKEMIA (CLL): INDUCTION PHASE RESULTS. EHA Annual Meeting 2011, Abstract 0532--> | ||
+ | # '''ML21445:''' Foà R, Del Giudice I, Cuneo A, Del Poeta G, Ciolli S, Di Raimondo F, Lauria F, Cencini E, Rigolin GM, Cortelezzi A, Nobile F, Callea V, Brugiatelli M, Massaia M, Molica S, Trentin L, Rizzi R, Specchia G, Di Serio F, Orsucci L, Ambrosetti A, Montillo M, Zinzani PL, Ferrara F, Morabito F, Mura MA, Soriani S, Peragine N, Tavolaro S, Bonina S, Marinelli M, De Propris MS, Starza ID, Piciocchi A, Alietti A, Runggaldier EJ, Gamba E, Mauro FR, Chiaretti S, Guarini A. Chlorambucil plus rituximab with or without maintenance rituximab as first-line treatment for elderly chronic lymphocytic leukemia patients. Am J Hematol. 2014 May;89(5):480-6. Epub 2014 Feb 18. [https://doi.org/10.1002/ajh.23668 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/24415640/ PubMed] EudraCT 2008-001612-20 | ||
+ | <!-- Presented in part at the American Society of Clinical Oncology 2012 Annual Meeting, Chicago, IL, USA. --> | ||
+ | # '''RESORT substudy:''' Williams ME, Hong F, Gascoyne RD, Wagner LI, Krauss JC, Habermann TM, Swinnen LJ, Schuster SJ, Peterson CG, Sborov MD, Martin SE, Weiss M, Ehmann WC, Horning SJ, Kahl BS; Eastern Cooperative Oncology Group. Rituximab extended schedule or retreatment trial for low tumour burden non-follicular indolent B-cell non-Hodgkin lymphomas: Eastern Cooperative Oncology Group Protocol E4402. Br J Haematol. 2016 Jun;173(6):867-75. Epub 2016 Mar 11. [https://doi.org/10.1111/bjh.14007 link to original article] '''dosing details in abstract have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4900920/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26970533/ PubMed] [https://clinicaltrials.gov/study/NCT01406782 NCT01406782] | ||
+ | # '''AGMT CLL-8a:''' Greil R, Obrtlíková P, Smolej L, Kozák T, Steurer M, Andel J, Burgstaller S, Mikušková E, Gercheva L, Nösslinger T, Papajík T, Ladická M, Girschikofsky M, Hrubiško M, Jäger U, Fridrik M, Pecherstorfer M, Králiková E, Burcoveanu C, Spasov E, Petzer A, Mihaylov G, Raynov J, Oexle H, Zabernigg A, Flochová E, Palášthy S, Stehlíková O, Doubek M, Altenhofer P, Pleyer L, Melchardt T, Klingler A, Mayer J, Egle A. Rituximab maintenance versus observation alone in patients with chronic lymphocytic leukaemia who respond to first-line or second-line rituximab-containing chemoimmunotherapy: final results of the AGMT CLL-8a Mabtenance randomised trial. Lancet Haematol. 2016 Jul;3(7):e317-29. Epub 2016 Jun 16. [https://doi.org/10.1016/s2352-3026(16)30045-x link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/27374465/ PubMed] [https://clinicaltrials.gov/study/NCT01118234 NCT01118234] | ||
+ | # '''CLL 2007 SA:''' Dartigeas C, Van Den Neste E, Léger J, Maisonneuve H, Berthou C, Dilhuydy MS, De Guibert S, Leprêtre S, Béné MC, Nguyen-Khac F, Letestu R, Cymbalista F, Rodon P, Aurran-Schleinitz T, Vilque JP, Tournilhac O, Mahé B, Laribi K, Michallet AS, Delmer A, Feugier P, Lévy V, Delépine R, Colombat P, Leblond V; CLL 2007 SA investigators; FILO. Rituximab maintenance versus observation following abbreviated induction with chemoimmunotherapy in elderly patients with previously untreated chronic lymphocytic leukaemia (CLL 2007 SA): an open-label, randomised phase 3 study. Lancet Haematol. 2018 Feb;5(2):e82-e94. Epub 2017 Dec 20. [https://doi.org/10.1016/S2352-3026(17)30235-1 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/29275118/ PubMed] [https://clinicaltrials.gov/study/NCT00645606 NCT00645606] | ||
+ | # '''PALG CLL4:''' Robak T, Błoński J, Skotnicki AB, Piotrowska M, Wróbel T, Rybka J, Kłoczko J, Bołkun Ł, Budziszewska BK, Walczak U, Uss A, Fidecka M, Smolewski P. Rituximab, cladribine, and cyclophosphamide (RCC) induction with rituximab maintenance in chronic lymphocytic leukemia: PALG - CLL4 (ML21283) trial. Eur J Haematol. 2018 May;100(5):465-474. Epub 2018 Mar 22. [https://doi.org/10.1111/ejh.13042 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/29427355/ PubMed] [https://clinicaltrials.gov/study/NCT00718549 NCT00718549] | ||
− | == | + | =Relapsed or refractory, randomized data= |
− | {| class="wikitable" style=" | + | ==Acalabrutinib monotherapy {{#subobject:68ce71|Regimen=1}}== |
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen {{#subobject:b52ef9|Variant=1}}=== | ||
+ | {| class="wikitable" style="color:white; background-color:#404040" | ||
+ | |<small>'''FDA-recommended dose'''</small> | ||
|- | |- | ||
− | |||
|} | |} | ||
− | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" | |
− | + | !style="width: 20%"|Study | |
− | {| | + | !style="width: 20%"|Dates of enrollment |
− | | | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | |[[Levels_of_Evidence#Evidence| | + | !style="width: 20%"|Comparator |
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4862586/ Byrd et al. 2015 (ACE-CL-001 r/r)] | ||
+ | |2014 to not reported | ||
+ | |style="background-color:#91cf61"|Phase 1/2 | ||
+ | | | ||
+ | |ORR: 95% | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8547923/ Byrd et al. 2021 (ACE-CL-006)] | ||
+ | |2015-2017 | ||
+ | | style="background-color:#1a9851" |Phase 3 (E-switch-ic) | ||
+ | |[[#Ibrutinib_monotherapy_2|Ibrutinib]] | ||
+ | | style="background-color:#eeee01" |Non-inferior PFS (primary endpoint)<br>Median PFS: 38.4 vs 38.4 mo<br>(HR 1.00, 95% CI 0.79-1.27) | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.19.03355 Ghia et al. 2020 (ASCEND)] |
− | |style="background-color:# | + | |2017-02-21 to 2018-01-17 |
+ | | style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc) | ||
+ | |Investigator's choice of:<br>1a. [[#Bendamustine_.26_Rituximab_.28BR.29_2|BR]]<br>1b. [[#Idelalisib_.26_Rituximab|Idelalisib & Rituximab]] | ||
+ | | style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: NYR vs 16.5 mo<br>(HR 0.31, 95% CI 0.20-0.49) | ||
|- | |- | ||
|} | |} | ||
− | ==== | + | <div class="toccolours" style="background-color:#fdcdac"> |
− | * | + | ====Biomarker eligibility criteria==== |
− | * | + | *ACE-CL-006: del(17)(p13.1) or del(11)(q22.3) |
− | + | ====Prior treatment criteria==== | |
− | + | *ACE-CL-006 & ASCEND: At least 1 prior systemic therapy | |
− | *[[ | + | </div> |
− | + | <div class="toccolours" style="background-color:#f2f3f4"> | |
− | + | ====Targeted therapy==== | |
− | + | *[[Acalabrutinib (Calquence)]] 100 mg PO twice per day | |
− | + | '''Continued indefinitely''' | |
− | === | + | </div></div> |
− | + | ===References=== | |
− | + | # '''ACE-CL-001 r/r:''' Byrd JC, Harrington B, O'Brien S, Jones JA, Schuh A, Devereux S, Chaves J, Wierda WG, Awan FT, Brown JR, Hillmen P, Stephens DM, Ghia P, Barrientos JC, Pagel JM, Woyach J, Johnson D, Huang J, Wang X, Kaptein A, Lannutti BJ, Covey T, Fardis M, McGreivy J, Hamdy A, Rothbaum W, Izumi R, Diacovo TG, Johnson AJ, Furman RR. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016 Jan 28;374(4):323-32. Epub 2015 Dec 7. [https://doi.org/10.1056/NEJMoa1509981 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4862586/ link to PMC article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/26641137/ PubMed] [https://clinicaltrials.gov/study/NCT02029443 NCT02029443] | |
− | + | # '''ASCEND:''' Ghia P, Pluta A, Wach M, Lysak D, Kozak T, Simkovic M, Kaplan P, Kraychok I, Illes A, de la Serna J, Dolan S, Campbell P, Musuraca G, Jacob A, Avery E, Lee JH, Liang W, Patel P, Quah C, Jurczak W. ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. J Clin Oncol. 2020 Sep 1;38(25):2849-2861. Epub 2020 May 27. [https://doi.org/10.1200/jco.19.03355 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/32459600/ PubMed] [https://clinicaltrials.gov/study/NCT02970318 NCT02970318] | |
− | ''' | + | # '''ACE-CL-006:''' Byrd JC, Hillmen P, Ghia P, Kater AP, Chanan-Khan A, Furman RR, O'Brien S, Yenerel MN, Illés A, Kay N, Garcia-Marco JA, Mato A, Pinilla-Ibarz J, Seymour JF, Lepretre S, Stilgenbauer S, Robak T, Rothbaum W, Izumi R, Hamdy A, Patel P, Higgins K, Sohoni S, Jurczak W. Acalabrutinib Versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia: Results of the First Randomized Phase III Trial. J Clin Oncol. 2021 Nov 1;39(31):3441-3452. Epub 2021 Jul 26. [https://doi.org/10.1200/jco.21.01210 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8547923/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34310172/ PubMed] [https://clinicaltrials.gov/study/NCT02477696 NCT02477696] |
− | ===Regimen #2 {{#subobject: | + | ==Bendamustine monotherapy {{#subobject:8973e4|Regimen=1}}== |
− | {| | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | | | + | ===Regimen variant #1, 70 mg/m<sup>2</sup> {{#subobject:faab75|Variant=1}}=== |
− | |[[Levels_of_Evidence#Evidence| | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5324531/ Robak et al. 2016 (Aptevo 16201)] |
− | |style="background-color:# | + | |2011-2013 |
+ | |style="background-color:#1a9851"|Randomized Phase 2 (C) | ||
+ | |[[#Bendamustine_.26_Otlertuzumab_777|Bendamustine & Otlertuzumab]] | ||
+ | |style="background-color:#fc8d59"|Seems to have inferior PFS | ||
|- | |- | ||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#f2f3f4"> | |
− | |||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[ | + | *[[Bendamustine]] 70 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 2 |
− | + | '''28-day cycle for 6 cycles''' | |
− | + | </div></div><br> | |
− | '''28-day cycle for | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | + | ===Regimen variant #2, 100 mg/m<sup>2</sup> {{#subobject:b1e65|Variant=1}}=== | |
− | === | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | # | + | !style="width: 20%"|Study |
− | + | !style="width: 20%"|Dates of enrollment | |
− | # | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | + | !style="width: 20%"|Comparator | |
− | + | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | |
− | + | |- | |
− | = | + | |[https://doi.org/10.1007/s00277-012-1660-6 Niederle et al. 2013 (WiSP RI05)] |
− | + | |2001-2006 | |
+ | |style="background-color:#1a9851"|Phase 3 (E-switch-ic) | ||
+ | |[[#Fludarabine_monotherapy|Fludarabine]] | ||
+ | |style="background-color:#eeee01"|Seems to have non-inferior PFS (primary endpoint)<br>Median PFS: 20.1 vs 14.8 mo<br>(HR 0.87, 90% CI 0.60-1.27) | ||
|- | |- | ||
− | |||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#f2f3f4"> | |
− | ===Regimen {{#subobject: | + | ====Chemotherapy==== |
− | {| | + | *[[Bendamustine]] 100 mg/m<sup>2</sup> IV once per day on days 1 & 2 |
− | | | + | '''28-day cycle for up to 8 cycles''' |
− | |[[Levels_of_Evidence#Evidence| | + | </div></div><br> |
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #3, 120 mg/m<sup>2</sup> {{#subobject:3f29c2|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | |- | ||
+ | |[https://doi.org/10.1200/jco.2007.12.5070 Friedberg et al. 2008] | ||
+ | |2003-09 to 2005-02 | ||
+ | |style="background-color:#91cf61"|Phase 2 | ||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2916680/ Kahl et al. 2010 (SDX-105-01 part 2)] |
− | |style="background-color:# | + | |2005-2007 |
+ | |style="background-color:#91cf61"|Phase 3b | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[ | + | *[[Bendamustine]] 120 mg/m<sup>2</sup> IV once per day on days 1 & 2 |
− | + | '''21-day cycle for 6 to 8 (SDX-105-01 part 2) or up to 12 (Friedberg et al. 2008) cycles''' | |
− | + | </div></div> | |
− | + | ===References=== | |
− | + | <!-- Presented in part at the 48th Annual Meeting of the American Society of Hematology, December 9-12, 2006, Orlando, Florida --> | |
− | + | # Friedberg JW, Cohen P, Chen L, Robinson KS, Forero-Torres A, La Casce AS, Fayad LE, Bessudo A, Camacho ES, Williams ME, van der Jagt RH, Oliver JW, Cheson BD. Bendamustine in patients with rituximab-refractory indolent and transformed non-Hodgkin's lymphoma: results from a phase II multicenter, single-agent study. J Clin Oncol. 2008 Jan 10;26(2):204-10. Erratum in: J Clin Oncol. 2008 Apr 10;26(11) 1911. [https://doi.org/10.1200/jco.2007.12.5070 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/18182663/ PubMed] | |
− | + | <!-- Preliminary research findings from this study were presented at the 2007 American Society of Hematology Annual Meeting and Exposition, Atlanta, Georgia, December 8-11, 2007. --> | |
− | + | # '''SDX-105-01 part 2:''' Kahl BS, Bartlett NL, Leonard JP, Chen L, Ganjoo K, Williams ME, Czuczman MS, Robinson KS, Joyce R, van der Jagt RH, Cheson BD. Bendamustine is effective therapy in patients with rituximab-refractory, indolent B-cell non-Hodgkin lymphoma: results from a multicenter study. Cancer. 2010 Jan 1;116(1):106-14. [https://doi.org/10.1002/cncr.24714 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2916680/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19890959/ PubMed] [https://clinicaltrials.gov/study/NCT00069758 NCT00069758] | |
− | + | # '''Retrospective:''' Kolibaba KS, Sterchele JA, Joshi AD, Forsyth M, Alwon E, Beygi H, Kennealey GT. Demographics, treatment patterns, safety, and real-world effectiveness in patients aged 70 years and over with chronic lymphocytic leukemia receiving bendamustine with or without rituximab: a retrospective study. Ther Adv Hematol. 2013 Jun;4(3):157-71. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3666446/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23730494/ PubMed] | |
+ | # '''WiSP RI05:''' Niederle N, Megdenberg D, Balleisen L, Heit W, Knauf W, Weiß J, Freier W, Hinke A, Ibach S, Eimermacher H. Bendamustine compared to fludarabine as second-line treatment in chronic lymphocytic leukemia. Ann Hematol. 2013 May;92(5):653-60. Epub 2013 Jan 23. [https://doi.org/10.1007/s00277-012-1660-6 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/23340738/ PubMed] [https://clinicaltrials.gov/study/NCT01423032 NCT01423032] | ||
+ | # '''Aptevo 16201:''' Robak T, Hellmann A, Kloczko J, Loscertales J, Lech-Maranda E, Pagel JM, Mato A, Byrd JC, Awan FT, Hebart H, Garcia-Marco JA, Hill BT, Hallek M, Eisenfeld AJ, Stromatt SC, Jaeger U. Randomized phase 2 study of otlertuzumab and bendamustine versus bendamustine in patients with relapsed chronic lymphocytic leukaemia. Br J Haematol. 2017 Feb;176(4):618-628. Epub 2016 Dec 15. [https://doi.org/10.1111/bjh.14464 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5324531/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27977057/ PubMed] [https://clinicaltrials.gov/study/NCT01188681 NCT01188681] | ||
− | === | + | ==Bendamustine & Rituximab (BR) {{#subobject:4d7261|Regimen=1}}== |
− | + | BR: '''<u>B</u>'''endamustine & '''<u>R</u>'''ituximab | |
− | + | <br>R-B: '''<u>R</u>'''ituximab & '''<u>B</u>'''endamustine | |
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | + | ===Regimen {{#subobject:39f839|Variant=1}}=== | |
− | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" | |
− | + | !style="width: 20%"|Study | |
− | + | !style="width: 20%"|Dates of enrollment | |
− | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | |
− | ''' | + | !style="width: 20%"|Comparator |
− | + | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | |
− | === | + | |- |
− | + | |[https://doi.org/10.1200/jco.2010.33.8061 Fischer et al. 2011 (GCLLSG CLL2M r/r)] | |
− | # | + | |2006-2007 |
− | + | |style="background-color:#91cf61"|Phase 2 | |
− | = | + | |style="background-color:#d3d3d3"| |
− | + | |style="background-color:#d3d3d3"| | |
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865431/ Michallet et al. 2018 (MABLE)] |
− | + | |2010-2014 | |
− | + | | style="background-color:#1a9851"|Phase 3b (E-switch-ic) | |
− | + | |[[#Chlorambucil_.26_Rituximab_.28RClb.29_999|R-Clb]] | |
− | + | | style="background-color:#1a9850" |Superior CR rate<sup>1</sup> (primary endpoint) | |
− | |||
− | | | ||
− | |[[ | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1016/S1470-2045(15)00465-9 Chanan-Khan et al. 2015 (HELIOS)] |
− | |style="background-color:# | + | |2012-2014 |
+ | |style="background-color:#1a9851"|Phase 3 (C) | ||
+ | |[[#Bendamustine_.26_Rituximab_.28BR.29_.26_Ibrutinib_2|BR & Ibrutinib]] | ||
+ | |style="background-color:#d73027"|Inferior OS<sup>2</sup> | ||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5589180/ Zelenetz et al. 2017 (Tugela)] |
− | |style="background-color:# | + | |2012-2014 |
+ | |style="background-color:#1a9851"|Phase 3 (C) | ||
+ | |[[#Bendamustine_.26_Rituximab_.28BR.29_.26_Idelalisib|BR & Idelalisib]] | ||
+ | |style="background-color:#d73027"|Inferior PFS | ||
+ | |- | ||
+ | |[https://doi.org/10.1056/NEJMoa1713976 Seymour et al. 2018 (MURANO)] | ||
+ | |2014-03-31 to 2015-09-23 | ||
+ | |style="background-color:#1a9851"|Phase 3 (C) | ||
+ | |[[#Venetoclax_.26_Rituximab|Venetoclax & Rituximab]] | ||
+ | |style="background-color:#d73027"|Inferior OS | ||
+ | |- | ||
+ | |[https://doi.org/10.1200/jco.19.03355 Ghia et al. 2020 (ASCEND)] | ||
+ | |2017-02-21 to 2018-01-17 | ||
+ | | style="background-color:#1a9851" |Phase 3 (C) | ||
+ | |[[#Acalabrutinib_monotherapy_2|Acalabrutinib]] | ||
+ | |style="background-color:#d73027"|Inferior PFS | ||
+ | |- | ||
+ | |[https://www.clinicaltrials.gov/study/NCT04666038 Awaiting publication (BRUIN CLL-321)] | ||
+ | |2021-2024 | ||
+ | | style="background-color:#1a9851" |Phase 3 (C) | ||
+ | |[[#Pirtobrutinib_monotherapy_666|Pirtobrutinib]] | ||
+ | |style="background-color:#d3d3d3"|TBD if different primary endpoint of PFS | ||
|- | |- | ||
|} | |} | ||
+ | ''<sup>1</sup>Reported efficacy for MABLE is for 2L patients only.''<br> | ||
+ | ''<sup>2</sup>Reported efficacy for HELIOS is based on the 2020 update.'' | ||
+ | <div class="toccolours" style="background-color:#fdcdac"> | ||
+ | ====Prior treatment criteria==== | ||
+ | *ASCEND: At least 1 prior systemic therapy | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[ | + | *[[Bendamustine]] 70 mg/m<sup>2</sup> IV once per day on days 1 & 2 |
− | *[[ | + | **HELIOS gave 1st cycle on days 2 & 3 |
− | * | + | ====Targeted therapy==== |
− | ** | + | *[[Rituximab (Rituxan)]] as follows: |
− | **Cycles 2 to 6: | + | **Cycle 1: 375 mg/m<sup>2</sup> IV once on day 0 |
− | + | ***HELIOS gave on day 1 | |
− | ''' | + | **Cycles 2 to 6: 500 mg/m<sup>2</sup> IV once on day 1 |
− | + | '''28-day cycle for up to 6 cycles''' | |
− | + | </div></div> | |
===References=== | ===References=== | ||
− | # | + | <!-- Presented in part at the 49th Annual Meeting of the American Society of Hematology, December 8-10, 2007, Atlanta, GA; and at the 50th Annual Meeting of the American Society of Hematology, December 6-9, 2008, San Francisco, CA. --> |
− | # | + | # '''GCLLSG CLL2M r/r:''' Fischer K, Cramer P, Busch R, Stilgenbauer S, Bahlo J, Schweighofer CD, Böttcher S, Staib P, Kiehl M, Eckart MJ, Kranz G, Goede V, Elter T, Bühler A, Winkler D, Kneba M, Döhner H, Eichhorst BF, Hallek M, Wendtner CM; GCLLSG. Bendamustine combined with rituximab in patients with relapsed and/or refractory chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. 2011 Sep 10;29(26):3559-66. Epub 2011 Aug 15. [https://doi.org/10.1200/jco.2010.33.8061 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/21844497/ PubMed] [https://clinicaltrials.gov/study/NCT00274989 NCT00274989] |
+ | # '''Retrospective:''' Kolibaba KS, Sterchele JA, Joshi AD, Forsyth M, Alwon E, Beygi H, Kennealey GT. Demographics, treatment patterns, safety, and real-world effectiveness in patients aged 70 years and over with chronic lymphocytic leukemia receiving bendamustine with or without rituximab: a retrospective study. Ther Adv Hematol. 2013 Jun;4(3):157-71. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3666446/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23730494/ PubMed] | ||
+ | # '''HELIOS:''' Chanan-Khan A, Cramer P, Demirkan F, Fraser G, Silva RS, Grosicki S, Pristupa A, Janssens A, Mayer J, Bartlett NL, Dilhuydy MS, Pylypenko H, Loscertales J, Avigdor A, Rule S, Villa D, Samoilova O, Panagiotidis P, Goy A, Mato A, Pavlovsky MA, Karlsson C, Mahler M, Salman M, Sun S, Phelps C, Balasubramanian S, Howes A, Hallek M; HELIOS investigators. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol. 2016 Feb;17(2):200-11. Epub 2015 Dec 5. [https://doi.org/10.1016/S1470-2045(15)00465-9 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/26655421/ PubMed] [https://clinicaltrials.gov/study/NCT01611090 NCT01611090] | ||
+ | ## '''Update:''' Fraser G, Cramer P, Demirkan F, Silva RS, Grosicki S, Pristupa A, Janssens A, Mayer J, Bartlett NL, Dilhuydy MS, Pylypenko H, Loscertales J, Avigdor A, Rule S, Villa D, Samoilova O, Panagiotidis P, Goy A, Pavlovsky MA, Karlsson C, Hallek M, Mahler M, Salman M, Sun S, Phelps C, Balasubramanian S, Howes A, Chanan-Khan A. Updated results from the phase 3 HELIOS study of ibrutinib, bendamustine, and rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma. Leukemia. 2019 Apr;33(4):969-980. Epub 2018 Oct 12. [https://doi.org/10.1038/s41375-018-0276-9 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6484712/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30315239/ PubMed] | ||
+ | ## '''Update:''' Fraser GAM, Chanan-Khan A, Demirkan F, Santucci Silva R, Grosicki S, Janssens A, Mayer J, Bartlett NL, Dilhuydy MS, Loscertales J, Avigdor A, Rule S, Samoilova O, Pavlovsky MA, Goy A, Mato A, Hallek M, Salman M, Tamegnon M, Sun S, Connor A, Nottage K, Schuier N, Balasubramanian S, Howes A, Cramer P. Final 5-year findings from the phase 3 HELIOS study of ibrutinib plus bendamustine and rituximab in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Leuk Lymphoma. 2020 Dec;61(13):3188-3197. Epub 2020 Aug 6. [https://doi.org/10.1080/10428194.2020.1795159 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9094431/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32762271/ PubMed] | ||
+ | <!-- | ||
+ | # '''Abstract:''' Andrew D Zelenetz, MD, PhD et al. Idelalisib Plus Bendamustine and Rituximab (BR) Is Superior to BR Alone in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia: Results of a Phase 3 Randomized Double-Blind Placebo-Controlled Study. ASH 2015 Abstract LBA5 --> | ||
+ | # '''Tugela:''' Zelenetz AD, Barrientos JC, Brown JR, Coiffier B, Delgado J, Egyed M, Ghia P, Illés Á, Jurczak W, Marlton P, Montillo M, Morschhauser F, Pristupa AS, Robak T, Sharman JP, Simpson D, Smolej L, Tausch E, Adewoye AH, Dreiling LK, Kim Y, Stilgenbauer S, Hillmen P. Idelalisib or placebo in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia: interim results from a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2017 Mar;18(3):297-311. Epub 2017 Jan 28. [https://doi.org/10.1016/S1470-2045(16)30671-4 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5589180/ link to PMC article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/28139405/ PubMed] [https://clinicaltrials.gov/study/NCT01569295 NCT01569295] | ||
+ | # '''MABLE:''' Michallet AS, Aktan M, Hiddemann W, Ilhan O, Johansson P, Laribi K, Meddeb B, Moreno C, Raposo J, Schuh A, Ünal A, Widenius T, Bernhardt A, Kellershohn K, Messeri D, Osborne S, Leblond V. Rituximab plus bendamustine or chlorambucil for chronic lymphocytic leukemia: primary analysis of the randomized, open-label MABLE study. Haematologica. 2018 Apr;103(4):698-706. Epub 2018 Feb 1. [https://doi.org/10.3324/haematol.2017.170480 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865431/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29419437/ PubMed] [https://clinicaltrials.gov/study/NCT01056510 NCT01056510] | ||
+ | # '''MURANO:''' Seymour JF, Kipps TJ, Eichhorst B, Hillmen P, D'Rozario J, Assouline S, Owen C, Gerecitano J, Robak T, De la Serna J, Jaeger U, Cartron G, Montillo M, Humerickhouse R, Punnoose EA, Li Y, Boyer M, Humphrey K, Mobasher M, Kater AP. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018 Mar 22;378(12):1107-1120. [https://doi.org/10.1056/NEJMoa1713976 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/29562156/ PubMed] [https://clinicaltrials.gov/study/NCT02005471 NCT02005471] | ||
+ | ## '''Update:''' Kater AP, Seymour JF, Hillmen P, Eichhorst B, Langerak AW, Owen C, Verdugo M, Wu J, Punnoose EA, Jiang Y, Wang J, Boyer M, Humphrey K, Mobasher M, Kipps TJ. Fixed duration of venetoclax-rituximab in relapsed/refractory chronic lymphocytic leukemia eradicates minimal residual disease and prolongs survival: post-treatment follow-up of the MURANO phase III study. J Clin Oncol. 2019 Feb 1;37(4):269-277. Epub 2018 Dec 3. [https://doi.org/10.1200/JCO.18.01580 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30523712/ PubMed] | ||
+ | ## '''Update:''' Kater AP, Wu JQ, Kipps T, Eichhorst B, Hillmen P, D'Rozario J, Assouline S, Owen C, Robak T, de la Serna J, Jaeger U, Cartron G, Montillo M, Dubois J, Eldering E, Mellink C, Van Der Kevie-Kersemaekers AM, Kim SY, Chyla B, Punnoose E, Bolen CR, Assaf ZJ, Jiang Y, Wang J, Lefebure M, Boyer M, Humphrey K, Seymour JF. Venetoclax Plus Rituximab in Relapsed Chronic Lymphocytic Leukemia: 4-Year Results and Evaluation of Impact of Genomic Complexity and Gene Mutations From the MURANO Phase III Study. J Clin Oncol. 2020 Dec 1;38(34):4042-4054. Epub 2020 Sep 28. [https://doi.org/10.1200/jco.20.00948 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768340/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32986498/ PubMed] | ||
+ | ## '''Update:''' Seymour JF, Kipps TJ, Eichhorst BF, D'Rozario J, Owen CJ, Assouline S, Lamanna N, Robak T, de la Serna J, Jaeger U, Cartron G, Montillo M, Mellink C, Chyla B, Panchal A, Lu T, Wu JQ, Jiang Y, Lefebure M, Boyer M, Kater AP. Enduring undetectable MRD and updated outcomes in relapsed/refractory CLL after fixed-duration venetoclax-rituximab. Blood. 2022 Aug 25;140(8):839-850. [https://doi.org/10.1182/blood.2021015014 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9412011/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35605176/ PubMed] | ||
+ | # '''ASCEND:''' Ghia P, Pluta A, Wach M, Lysak D, Kozak T, Simkovic M, Kaplan P, Kraychok I, Illes A, de la Serna J, Dolan S, Campbell P, Musuraca G, Jacob A, Avery E, Lee JH, Liang W, Patel P, Quah C, Jurczak W. ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. J Clin Oncol. 2020 Sep 1;38(25):2849-2861. Epub 2020 May 27. [https://doi.org/10.1200/jco.19.03355 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/32459600/ PubMed] [https://clinicaltrials.gov/study/NCT02970318 NCT02970318] | ||
+ | #'''BRUIN CLL-321:''' [https://clinicaltrials.gov/study/NCT04666038 NCT04666038] | ||
− | == | + | ==Bendamustine & Rituximab (BR) & Ibrutinib {{#subobject:9861f9|Regimen=1}}== |
− | {| class="wikitable" style=" | + | BR & Ibrutinib: '''<u>B</u>'''endamustine, '''<u>R</u>'''ituximab, Ibrutinib |
+ | <br>IBR: '''<u>I</u>'''brutinib, '''<u>B</u>'''endamustine, '''<u>R</u>'''ituximab | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen {{#subobject:ad1034|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4424415/ Brown et al. 2015 (PCYC-1108)] |
− | + | |2011 to not reported | |
− | + | |style="background-color:#91cf61"|Phase 2 | |
− | + | |style="background-color:#d3d3d3"| | |
− | + | |style="background-color:#d3d3d3"| | |
− | | | ||
− | | | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1016/S1470-2045(15)00465-9 Chanan-Khan et al. 2015 (HELIOS)] |
− | |style="background-color:# | + | |2012-2014 |
+ | |style="background-color:#1a9851"|Phase 3 (E-RT-esc) | ||
+ | |[[#Bendamustine_.26_Rituximab_.28BR.29_2|BR]] | ||
+ | | style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: NYR vs 13.3 mo<br>(HR 0.20, 95% CI 0.15-0.28)<br><br>Superior OS<sup>1</sup> (secondary endpoint)<br>Median OS: NYR vs NYR<br>(HR 0.61, 95% CI 0.455-0.82) | ||
|- | |- | ||
|} | |} | ||
− | '' | + | ''<sup>1</sup>Reported efficacy for HELIOS is based on the 2020 update.''<br> |
+ | ''Note: PCYC-1108 also evaluated FCR-ibrutinib (non-randomized) but accrual to that arm was extremely low and it was prematurely discontinued.'' | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[ | + | *[[Bendamustine]] as follows: |
− | *[[ | + | **Cycles 1 to 6: 70 mg/m<sup>2</sup> IV once per day on days 1 & 2 |
− | * | + | ***HELIOS gave 1st cycle on days 2 & 3 |
− | + | ====Targeted therapy==== | |
− | === | + | *[[Rituximab (Rituxan)]] as follows: |
− | + | **Cycle 1: 375 mg/m<sup>2</sup> IV once on day 1 | |
− | + | ***PCYC-1108 gave the option of splitting the dose between days 1 & 2 | |
− | + | **Cycles 2 to 6: 500 mg/m<sup>2</sup> IV once on day 1 | |
− | + | *[[Ibrutinib (Imbruvica)]] 420 mg PO once per day on days 1 to 28 | |
− | + | '''28-day cycles''' | |
− | + | </div></div> | |
− | + | ===References=== | |
− | + | # '''PCYC-1108:''' Brown JR, Barrientos JC, Barr PM, Flinn IW, Burger JA, Tran A, Clow F, James DF, Graef T, Friedberg JW, Rai K, O'Brien S. The Bruton tyrosine kinase inhibitor ibrutinib with chemoimmunotherapy in patients with chronic lymphocytic leukemia. Blood. 2015 May 7;125(19):2915-22. Epub 2015 Mar 9. [https://doi.org/10.1182/blood-2014-09-585869 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4424415/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25755291/ PubMed] [https://clinicaltrials.gov/study/NCT01292135 NCT01292135] | |
− | ''' | + | # '''HELIOS:''' Chanan-Khan A, Cramer P, Demirkan F, Fraser G, Silva RS, Grosicki S, Pristupa A, Janssens A, Mayer J, Bartlett NL, Dilhuydy MS, Pylypenko H, Loscertales J, Avigdor A, Rule S, Villa D, Samoilova O, Panagiotidis P, Goy A, Mato A, Pavlovsky MA, Karlsson C, Mahler M, Salman M, Sun S, Phelps C, Balasubramanian S, Howes A, Hallek M; HELIOS investigators. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol. 2016 Feb;17(2):200-11. Epub 2015 Dec 5. [https://doi.org/10.1016/S1470-2045(15)00465-9 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/26655421/ PubMed] [https://clinicaltrials.gov/study/NCT01611090 NCT01611090] |
− | + | ## '''Update:''' Fraser G, Cramer P, Demirkan F, Silva RS, Grosicki S, Pristupa A, Janssens A, Mayer J, Bartlett NL, Dilhuydy MS, Pylypenko H, Loscertales J, Avigdor A, Rule S, Villa D, Samoilova O, Panagiotidis P, Goy A, Pavlovsky MA, Karlsson C, Hallek M, Mahler M, Salman M, Sun S, Phelps C, Balasubramanian S, Howes A, Chanan-Khan A. Updated results from the phase 3 HELIOS study of ibrutinib, bendamustine, and rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma. Leukemia. 2019 Apr;33(4):969-980. Epub 2018 Oct 12. [https://doi.org/10.1038/s41375-018-0276-9 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6484712/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30315239/ PubMed] | |
− | ===Regimen | + | ## '''Update:''' Fraser GAM, Chanan-Khan A, Demirkan F, Santucci Silva R, Grosicki S, Janssens A, Mayer J, Bartlett NL, Dilhuydy MS, Loscertales J, Avigdor A, Rule S, Samoilova O, Pavlovsky MA, Goy A, Mato A, Hallek M, Salman M, Tamegnon M, Sun S, Connor A, Nottage K, Schuier N, Balasubramanian S, Howes A, Cramer P. Final 5-year findings from the phase 3 HELIOS study of ibrutinib plus bendamustine and rituximab in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Leuk Lymphoma. 2020 Dec;61(13):3188-3197. Epub 2020 Aug 6. [https://doi.org/10.1080/10428194.2020.1795159 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9094431/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32762271/ PubMed] |
− | {| | + | ==Bendamustine & Rituximab (BR) & Idelalisib {{#subobject:025828|Regimen=1}}== |
− | | | + | BR & Idelalisib: '''<u>B</u>'''endamustine, '''<u>R</u>'''ituximab, Idelalisib |
− | |[[Levels_of_Evidence#Evidence| | + | <div class="toccolours" style="background-color:#eeeeee"> |
+ | ===Regimen {{#subobject:5c2b6f|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5589180/ Zelenetz et al. 2017 (Tugela)] |
− | |style="background-color:# | + | |2012-2014 |
− | + | |style="background-color:#1a9851"|Phase 3 (E-esc) | |
− | |[ | + | |[[#Bendamustine_.26_Rituximab_.28BR.29_2|BR]] |
− | |style="background-color:# | + | |style="background-color:#1a9850"|Superior PFS (primary endpoint)<br>Median PFS: 20.8 vs 11.1 mo<br>(HR 0.33, 95% CI 0.25-0.44) |
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[ | + | *[[Bendamustine]] as follows: |
− | * | + | **Cycles 1 to 6: 70 mg/m<sup>2</sup> IV once per day on days 1 & 2 |
+ | ====Targeted therapy==== | ||
*[[Rituximab (Rituxan)]] as follows: | *[[Rituximab (Rituxan)]] as follows: | ||
− | **Cycle 1: | + | **Cycle 1: 375 mg/m<sup>2</sup> IV once on day 0 |
− | **Cycles 2 to 6: | + | **Cycles 2 to 6: 500 mg/m<sup>2</sup> IV once on day 1 |
− | + | *[[Idelalisib (Zydelig)]] 150 mg PO twice per day on days 1 to 28 | |
− | + | '''28-day cycles''' | |
− | + | </div></div> | |
− | |||
− | *[[ | ||
− | |||
− | |||
− | |||
− | '''28-day | ||
− | |||
===References=== | ===References=== | ||
− | # | + | <!-- |
− | + | # '''Abstract:''' Andrew D Zelenetz, MD, PhD et al. Idelalisib Plus Bendamustine and Rituximab (BR) Is Superior to BR Alone in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia: Results of a Phase 3 Randomized Double-Blind Placebo-Controlled Study. ASH 2015 Abstract LBA5 --> | |
− | + | # '''Tugela:''' Zelenetz AD, Barrientos JC, Brown JR, Coiffier B, Delgado J, Egyed M, Ghia P, Illés Á, Jurczak W, Marlton P, Montillo M, Morschhauser F, Pristupa AS, Robak T, Sharman JP, Simpson D, Smolej L, Tausch E, Adewoye AH, Dreiling LK, Kim Y, Stilgenbauer S, Hillmen P. Idelalisib or placebo in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia: interim results from a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2017 Mar;18(3):297-311. Epub 2017 Jan 28. [https://doi.org/10.1016/S1470-2045(16)30671-4 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5589180/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28139405/ PubMed] [https://clinicaltrials.gov/study/NCT01569295 NCT01569295] | |
− | + | ==Duvelisib monotherapy {{#subobject:4a9cdb|Regimen=1}}== | |
− | == | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | {| class="wikitable" style=" | + | ===Regimen {{#subobject:8e168d|Variant=1}}=== |
+ | {| class="wikitable" style="color:white; background-color:#404040" | ||
+ | |<small>'''FDA-recommended dose'''</small> | ||
|- | |- | ||
− | |||
|} | |} | ||
− | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" | |
− | + | !style="width: 20%"|Study | |
− | + | !style="width: 20%"|Dates of enrollment | |
− | | | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | |[[Levels_of_Evidence#Evidence| | + | !style="width: 20%"|Comparator |
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284216/ Flinn et al. 2018 (DUO)] |
− | |style="background-color:# | + | |2014-01-21 to 2015-12-09 |
+ | |style="background-color:#1a9851"|Phase 3 (E-RT-switch-ooc) | ||
+ | |[[#Ofatumumab_monotherapy_2|Ofatumumab]] | ||
+ | |style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 13.3 vs 9.9 mo<br>(HR 0.52) | ||
|- | |- | ||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#f2f3f4"> | |
− | ==== | + | ====Targeted therapy==== |
− | *[[ | + | *[[Duvelisib (Copiktra)]] 25 mg PO twice per day on days 1 to 28 |
− | + | '''28-day cycles''' | |
− | === | + | </div></div> |
− | + | ===References=== | |
− | + | # '''DUO:''' Flinn IW, Hillmen P, Montillo M, Nagy Z, Illés Á, Etienne G, Delgado J, Kuss BJ, Tam CS, Gasztonyi Z, Offner F, Lunin S, Bosch F, Davids MS, Lamanna N, Jaeger U, Ghia P, Cymbalista F, Portell CA, Skarbnik AP, Cashen AF, Weaver DT, Kelly VM, Turnbull B, Stilgenbauer S. The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL. Blood. 2018 Dec 6;132(23):2446-2455. Epub 2018 Oct 4. [https://doi.org/10.1182/blood-2018-05-850461 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284216/ link to PMC article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/30287523/ PubMed] [https://clinicaltrials.gov/study/NCT02004522 NCT02004522] | |
− | + | ==FCR {{#subobject:b079e8|Regimen=1}}== | |
− | ''' | + | FCR: '''<u>F</u>'''ludarabine, '''<u>C</u>'''yclophosphamide, '''<u>R</u>'''ituximab |
− | + | <br>R-FC: '''<u>R</u>'''ituximab, '''<u>F</u>'''ludarabine, '''<u>C</u>'''yclophosphamide | |
− | '' | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | + | ===Regimen variant #1 {{#subobject:b7f6d5|Variant=1}}=== | |
− | ===Regimen # | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | {| | + | !style="width: 20%"|Study |
− | | | + | !style="width: 20%"|Dates of enrollment |
− | |[[Levels_of_Evidence#Evidence| | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1111/bjh.13061 Awan et al. 2014 (LUCID)] |
− | |style="background-color:# | + | |2006 to not reported |
+ | |style="background-color:#1a9851"|Phase 3 (C) | ||
+ | |[[#FCR_.26_Lumiliximab_999|FCR+L]] | ||
+ | |style="background-color:#ffffbf"|Did not meet primary endpoint of CR rate | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[ | + | *[[Fludarabine (Fludara)]] as follows: |
− | ** | + | **Cycle 1: 25 mg/m<sup>2</sup> IV over at least 10 to 30 minutes once per day on days 2 to 4 |
− | ** | + | **Cycles 2 to 6: 25 mg/m<sup>2</sup> IV over at least 10 to 30 minutes once per day on days 1 to 3 |
− | + | *[[Cyclophosphamide (Cytoxan)]] as follows: | |
− | ==== | + | **Cycle 1: 250 mg/m<sup>2</sup> IV over at least 10 to 30 minutes once per day on days 2 to 4 |
− | * | + | **Cycles 2 to 6: 250 mg/m<sup>2</sup> IV over at least 10 to 30 minutes once per day on days 1 to 3 |
− | * | + | ====Targeted therapy==== |
− | * | + | *[[Rituximab (Rituxan)]] as follows: |
− | *[[ | + | **Cycle 1: 50 mg/m<sup>2</sup> IV over 4 hours once on day 1, then 450 mg/m<sup>2</sup> IV once on day 3 |
− | + | **Cycles 2 to 6: 500 mg/m<sup>2</sup> IV once on day 1 | |
+ | ====Supportive therapy==== | ||
+ | *[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Cotrimoxazole]] or an equivalent | ||
+ | *[[Acyclovir (Zovirax)]] 400 mg PO twice per day or [[:Category:Antivirals|equivalent]] | ||
'''28-day cycle for 6 cycles''' | '''28-day cycle for 6 cycles''' | ||
− | + | </div></div><br> | |
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | + | ===Regimen variant #2 {{#subobject:9882b5|Variant=1}}=== | |
− | === | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
− | + | !style="width: 20%"|Study | |
− | + | !style="width: 20%"|Dates of enrollment | |
− | # | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | + | !style="width: 20%"|Comparator | |
− | == | + | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] |
− | {| class="wikitable" style=" | + | |- |
+ | |[https://doi.org/10.1200/jco.2009.26.4556 Robak et al. 2010 (REACH)] | ||
+ | |2003-2007 | ||
+ | |style="background-color:#1a9851"|Phase 3 (E-RT-esc) | ||
+ | |[[Chronic_lymphocytic_leukemia_-_historical#FC_2|FC]] | ||
+ | |style="background-color:#1a9850"|Superior PFS (primary endpoint)<br>Median PFS: 30.6 vs 20.6 mo<br>(HR 0.65) | ||
+ | |- | ||
+ | |} | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
+ | ====Chemotherapy==== | ||
+ | *[[Fludarabine (Fludara)]] as follows: | ||
+ | **Cycle 1: 25 mg/m<sup>2</sup> IV once per day on days 2 to 4 | ||
+ | **Cycles 2 to 6: 25 mg/m<sup>2</sup> IV once per day on days 1 to 3 | ||
+ | *[[Cyclophosphamide (Cytoxan)]] as follows: | ||
+ | **Cycle 1: 250 mg/m<sup>2</sup> IV once per day on days 2 to 4 | ||
+ | **Cycles 2 to 6: 250 mg/m<sup>2</sup> IV once per day on days 1 to 3 | ||
+ | ====Targeted therapy==== | ||
+ | *[[Rituximab (Rituxan)]] as follows: | ||
+ | **Cycle 1: 375 mg/m<sup>2</sup> IV once on day 1 | ||
+ | **Cycles 2 to 6: 500 mg/m<sup>2</sup> IV once on day 1 | ||
+ | ====Supportive therapy==== | ||
+ | *''Note: varied according to reference.'' | ||
+ | *[[Diphenhydramine (Benadryl)]] 25 mg IV once on day 1; 30 minutes prior to rituximab | ||
+ | *[[Acetaminophen (Tylenol)]] 650 mg PO once on day 1; 30 minutes prior to rituximab | ||
+ | *[[Allopurinol (Zyloprim)]] as follows: | ||
+ | **Cycle 1: 300 mg PO once per day on days 1 to 7 | ||
+ | *Some patients received: | ||
+ | **[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] 160/800 mg PO twice per week | ||
+ | **[[Valacyclovir (Valtrex)]] 500 mg PO once per day | ||
+ | '''28-day cycle for 6 cycles''' | ||
+ | </div></div><br> | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #3 {{#subobject:fb9678|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.2005.12.516 Wierda et al. 2005] |
− | + | |1999-2001 | |
− | + | |style="background-color:#91cf61"|Phase 2 | |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |style="background-color:# | ||
|- | |- | ||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#f2f3f4"> | |
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[ | + | *[[Fludarabine (Fludara)]] as follows: |
− | + | **Cycle 1: 25 mg/m<sup>2</sup> IV once per day on days 2 to 4 | |
+ | **Cycles 2 to 6: 25 mg/m<sup>2</sup> IV once per day on days 1 to 3 | ||
+ | *[[Cyclophosphamide (Cytoxan)]] as follows: | ||
+ | **Cycle 1: 250 mg/m<sup>2</sup> IV once per day on days 2 to 4 | ||
+ | **Cycles 2 to 6: 250 mg/m<sup>2</sup> IV once per day on days 1 to 3 | ||
+ | ====Targeted therapy==== | ||
+ | *[[Rituximab (Rituxan)]] as follows: | ||
+ | **Cycle 1: 375 mg/m<sup>2</sup> IV once on day 1 | ||
+ | **Cycles 2 to 6: 500 mg/m<sup>2</sup> IV once on day 1 | ||
+ | ====Supportive therapy==== | ||
+ | *[[Diphenhydramine (Benadryl)]] 25 to 50 mg PO once on day 1, prior to rituximab | ||
+ | *[[Acetaminophen (Tylenol)]] 650 mg PO once on day 1, prior to rituximab | ||
+ | *[[Ondansetron (Zofran)]] 24 mg IV once, prior to chemotherapy | ||
+ | '''28-day cycle for up to 6 cycles''' | ||
+ | </div></div><br> | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #4 {{#subobject:49da52|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | |- | ||
+ | |[https://doi.org/10.1002/cncr.21882 Tam et al. 2006] | ||
+ | |2000-2005 | ||
+ | |style="background-color:#91cf61"|Phase 2 | ||
+ | |- | ||
+ | |} | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
+ | ====Chemotherapy==== | ||
+ | *[[Fludarabine (Fludara)]] 25 mg/m<sup>2</sup> IV over 15 to 30 minutes once per day on days 1 to 3 | ||
+ | *[[Cyclophosphamide (Cytoxan)]] 250 mg/m<sup>2</sup> IV over 15 to 30 minutes once per day on days 1 to 3 | ||
+ | ====Targeted therapy==== | ||
+ | *[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1 | ||
+ | '''28-day cycle for up to 6 cycles or "attainment of maximum response"''' | ||
+ | </div></div> | ||
===References=== | ===References=== | ||
− | # | + | # Wierda W, O'Brien S, Wen S, Faderl S, Garcia-Manero G, Thomas D, Do KA, Cortes J, Koller C, Beran M, Ferrajoli A, Giles F, Lerner S, Albitar M, Kantarjian H, Keating M. Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. J Clin Oncol. 2005 Jun 20;23(18):4070-8. Epub 2005 Mar 14. [https://doi.org/10.1200/jco.2005.12.516 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/15767647/ PubMed] |
− | + | ## '''Update:''' Badoux XC, Keating MJ, Wang X, O'Brien SM, Ferrajoli A, Faderl S, Burger J, Koller C, Lerner S, Kantarjian H, Wierda WG. Fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy is highly effective treatment for relapsed patients with CLL. Blood. 2011 Mar 17;117(11):3016-24. Epub 2011 Jan 18. [https://doi.org/10.1182/blood-2010-08-304683 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123386/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21245487/ PubMed] | |
− | = | + | # Tam CS, Wolf M, Prince HM, Januszewicz EH, Westerman D, Lin KI, Carney D, Seymour JF. Fludarabine, cyclophosphamide, and rituximab for the treatment of patients with chronic lymphocytic leukemia or indolent non-Hodgkin lymphoma. Cancer. 2006 Jun 1;106(11):2412-20. [https://doi.org/10.1002/cncr.21882 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/16649223/ PubMed] |
− | + | <!-- Presented in part at the 50th Annual Meeting of the American Society of Hematology, December 6-9, 2008, San Francisco, CA. --> | |
− | == | + | # '''REACH:''' Robak T, Dmoszynska A, Solal-Céligny P, Warzocha K, Loscertales J, Catalano J, Afanasiev BV, Larratt L, Geisler CH, Montillo M, Zyuzgin I, Ganly PS, Dartigeas C, Rosta A, Maurer J, Mendila M, Saville MW, Valente N, Wenger MK, Moiseev SI. Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia. J Clin Oncol. 2010 Apr 1;28(10):1756-65. Epub 2010 Mar 1. [https://doi.org/10.1200/jco.2009.26.4556 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/20194844/ PubMed] content property of [https://hemonc.org HemOnc.org] [https://clinicaltrials.gov/study/NCT00090051 NCT00090051] |
− | {| class="wikitable" style=" | + | # '''LUCID:''' Awan FT, Hillmen P, Hellmann A, Robak T, Hughes SG, Trone D, Shannon M, Flinn IW, Byrd JC; LUCID trial investigators. A randomized, open-label, multicentre, phase 2/3 study to evaluate the safety and efficacy of lumiliximab in combination with fludarabine, cyclophosphamide and rituximab versus fludarabine, cyclophosphamide and rituximab alone in subjects with relapsed chronic lymphocytic leukaemia. Br J Haematol. 2014 Nov;167(4):466-77. Epub 2014 Aug 8. [https://doi.org/10.1111/bjh.13061 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/25130401/ PubMed] [https://clinicaltrials.gov/study/NCT00391066 NCT00391066] |
+ | ==Fludarabine monotherapy {{#subobject:1b68a3|Regimen=1}}== | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen {{#subobject:d0644b|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1016/S0140-6736(96)91681-5 Johnson et al. 1996] |
− | | | + | |1990-1992 |
− | + | |style="background-color:#1a9851"|Phase 3 (E-de-esc) | |
− | + | |[[Chronic_lymphocytic_leukemia_-_historical#CAP|CAP]] | |
− | | | + | | style="background-color:#91cf60" |Seems to have superior ORR |
− | |[[ | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1007/s00277-012-1660-6 Niederle et al. 2013 (WiSP RI05)] |
− | |style="background-color:# | + | |2001-2006 |
+ | |style="background-color:#1a9851"|Phase 3 (C) | ||
+ | |[[#Bendamustine_monotherapy_2|Bendamustine]] | ||
+ | |style="background-color:#eeee01"|Seems to have non-inferior PFS | ||
|- | |- | ||
|} | |} | ||
+ | ''Note: This was an experimental arm that did not meet its primary endpoint; included here because it was eventually used to establish this regimen as a standard comparator.'' | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[ | + | *[[Fludarabine (Fludara)]] 25 mg/m<sup>2</sup> IV once per day on days 1 to 5 |
− | + | '''28-day cycle for varying durations: 6 to 10 cycles (Johnson et al. 1996); 8 cycles (WiSP RI05)''' | |
− | '''6 | + | </div></div> |
− | |||
===References=== | ===References=== | ||
− | # | + | # Johnson S, Smith AG, Löffler H, Osby E, Juliusson G, Emmerich B, Wyld PJ, Hiddemann W; FRE-CLL. Multicentre prospective randomised trial of fludarabine versus cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of advanced-stage chronic lymphocytic leukaemia. Lancet. 1996 May 25;347(9013):1432-8. [https://doi.org/10.1016/S0140-6736(96)91681-5 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/8676625/ PubMed] |
+ | <!-- Presented in abstract form at the 15th Congress of the European CanCer Organisation and 34th Congress of the European Society for Medical Oncology, Berlin, Germany, September 20–24, 2009. --> | ||
+ | # '''WiSP RI05:''' Niederle N, Megdenberg D, Balleisen L, Heit W, Knauf W, Weiß J, Freier W, Hinke A, Ibach S, Eimermacher H. Bendamustine compared to fludarabine as second-line treatment in chronic lymphocytic leukemia. Ann Hematol. 2013 May;92(5):653-60. Epub 2013 Jan 23. [https://doi.org/10.1007/s00277-012-1660-6 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/23340738/ PubMed] [https://clinicaltrials.gov/study/NCT01423032 NCT01423032] | ||
− | == | + | ==Ibrutinib monotherapy {{#subobject:29205a|Regimen=1}}== |
− | {| class="wikitable" style=" | + | <div class="toccolours" style="background-color:#eeeeee"> |
+ | ===Regimen {{#subobject:acff1c|Variant=1}}=== | ||
+ | {| class="wikitable" style="color:white; background-color:#404040" | ||
+ | |<small>'''FDA-recommended dose'''</small> | ||
|- | |- | ||
− | |||
|} | |} | ||
− | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" | |
− | {| | + | !style="width: 20%"|Study |
− | | | + | !style="width: 20%"|Dates of enrollment |
− | |[[Levels_of_Evidence#Evidence| | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | | | + | !style="width: 20%"|Comparator |
− | |[[Levels_of_Evidence# | + | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] |
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772525/ Byrd et al. 2013 (PCYC-1102 relapsed)] |
− | |style="background-color:# | + | |2010-2011 |
− | |[[# | + | |style="background-color:#91cf61"|Phase 2 (RT) |
− | |style="background-color:# | + | |style="background-color:#d3d3d3"| |
+ | |style="background-color:#d3d3d3"| | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342187/ Farooqui et al. 2014 (NHLBI 12-H-0035)] | ||
+ | |2011-2014 | ||
+ | |style="background-color:#ffffbe"|Phase 2, fewer than 20 pts | ||
+ | |style="background-color:#d3d3d3"| | ||
+ | |style="background-color:#d3d3d3"| | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4134521/ Byrd et al. 2014 (RESONATE)] | ||
+ | |2012-06 to 2013-04 | ||
+ | |style="background-color:#1a9851"|Phase 3 (E-RT-switch-ooc) | ||
+ | |[[#Ofatumumab_monotherapy_2|Ofatumumab]] | ||
+ | | style="background-color:#1a9850" |Superior PFS<sup>1</sup> (primary endpoint)<br>Median PFS: 44.1 vs 8.1 mo<br>(HR 0.15, 95% CI 0.11-0.20) | ||
+ | |- | ||
+ | |[https://doi.org/10.1016/S1470-2045(16)30212-1 O'Brien et al. 2016 (RESONATE-17)] | ||
+ | |2013 | ||
+ | |style="background-color:#91cf61"|Phase 2 | ||
+ | |style="background-color:#d3d3d3"| | ||
+ | |style="background-color:#d3d3d3"| | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5911578/ Huang et al. 2018 (CR102604)] | ||
+ | |2013-2015 | ||
+ | |style="background-color:#1a9851"|Phase 3 (E-switch-ooc) | ||
+ | |[[#Rituximab_monotherapy_3|Rituximab]] | ||
+ | | style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>PFS18: 74% vs 11.9%<br>(HR 0.18, 95% CI 0.105-0.31)<br><br>Superior OS (secondary endpoint)<br>OS24: 79.8% vs 57.6%<br>(HR 0.45, 95% CI 0.22-0.90) | ||
+ | |- | ||
+ | |[https://doi.org/10.1016/s2352-3026(20)30433-6 Sharman et al. 2021 (GENUINE)] | ||
+ | |2015-02-06 to 2016-12-19 | ||
+ | |style="background-color:#1a9851"|Phase 3 (C) | ||
+ | |[[#Ibrutinib_.26_Ublituximab|Ibrutinib & Ublituximab]] | ||
+ | | style="background-color:#fc8d59" |Seems to have inferior ORR | ||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8547923/ Byrd et al. 2021 (ACE-CL-006)] |
− | |style="background-color:# | + | |2015-2017 |
− | |[[# | + | | style="background-color:#1a9851" |Phase 3 (C) |
− | |style="background-color:# | + | |[[#Acalabrutinib_monotherapy_2|Acalabrutinib]] |
+ | | style="background-color:#eeee01" |Non-inferior PFS | ||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9928683/ Hillmen et al. 2022 (ALPINE)] |
− | |style="background-color:# | + | |2018-2020 |
− | |[[# | + | |style="background-color:#1a9851"|Phase 3 (C) |
− | |style="background-color:# | + | |[[#Zanubrutinib_monotherapy_2|Zanubrutinib]] |
+ | | style="background-color:#d73027" |Inferior PFS<sup>2</sup> | ||
|- | |- | ||
|} | |} | ||
− | '' | + | ''<sup>1</sup>Reported efficacy for RESONATE is based on the second 2019 update.''<br> |
+ | ''<sup>2</sup>Reported efficacy for ALPINE is based on the 2022 update.''<br> | ||
+ | ''Note: Both 420 mg and 840 mg doses were investigated in PCYC-1102: "the similar response in the two dose groups provide support for the use of the 420-mg dose of ibrutinib for relapsed CLL." The others used the 420 mg dose.'' | ||
+ | <div class="toccolours" style="background-color:#fdcdac"> | ||
+ | ====Biomarker eligibility criteria==== | ||
+ | *RESONATE-17: 17p deletion | ||
+ | *GENUINE: 17p deletion, 11q deletion, or TP53 mutation | ||
+ | *ACE-CL-006: del(17)(p13.1) or del(11)(q22.3) | ||
+ | ====Prior treatment criteria==== | ||
+ | *ACE-CL-006 & ALPINE: At least 1 prior systemic therapy | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
+ | ====Targeted therapy==== | ||
+ | *[[Ibrutinib (Imbruvica)]] 420 mg PO once per day on days 1 to 28 | ||
+ | '''28-day cycles''' | ||
+ | </div></div> | ||
===References=== | ===References=== | ||
− | # | + | # '''PCYC-1102 relapsed:''' Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, Grant B, Sharman JP, Coleman M, Wierda WG, Jones JA, Zhao W, Heerema NA, Johnson AJ, Sukbuntherng J, Chang BY, Clow F, Hedrick E, Buggy JJ, James DF, O'Brien S. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013 Jul 4;369(1):32-42. Epub 2013 Jun 19. [https://doi.org/10.1056/NEJMoa1215637 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772525/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23782158/ PubMed] [https://clinicaltrials.gov/study/NCT01105247 NCT01105247] |
− | <!-- # '''Abstract:''' R | + | ## '''Update:''' Byrd JC, Furman RR, Coutre SE, Burger JA, Blum KA, Coleman M, Wierda WG, Jones JA, Zhao W, Heerema NA, Johnson AJ, Shaw Y, Bilotti E, Zhou C, James DF, O'Brien S. Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015 Apr 16;125(16):2497-506. Epub 2015 Feb 19. [https://doi.org/10.1182/blood-2014-10-606038 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4400288/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25700432/ PubMed] |
− | # | + | ## '''Update:''' O'Brien S, Furman RR, Coutre S, Flinn IW, Burger JA, Blum K, Sharman J, Wierda W, Jones J, Zhao W, Heerema NA, Johnson AJ, Luan Y, James DF, Chu AD, Byrd JC. Single-agent ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. Blood. 2018 Apr 26;131(17):1910-1919. Epub 2018 Feb 2. [https://doi.org/10.1182/blood-2017-10-810044 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5921964/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29437592/ PubMed] |
− | # | + | ## '''Update:''' Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum K, Sharman JP, Wierda W, Zhao W, Heerema NA, Luan Y, Liu EA, Dean JP, O'Brien S. Ibrutinib Treatment for First-Line and Relapsed/Refractory Chronic Lymphocytic Leukemia: Final Analysis of the Pivotal Phase Ib/II PCYC-1102 Study. Clin Cancer Res. 2020 Aug 1;26(15):3918-3927. Epub 2020 Mar 24. [https://doi.org/10.1158/1078-0432.ccr-19-2856 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8175012/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32209572/ PubMed] |
+ | <!-- # '''Abstract:''' John C. Byrd, Jennifer R. Brown, Susan Mary O'Brien, Jacqueline Claudia Barrientos, Neil E. Kay, Nishitha M. Reddy, Steven E. Coutre, Constantine Tam, Stephen P. Mulligan, Ulrich Jäger, Steve Devereux, Paul M. Barr, Richard R. Furman, Thomas J. Kipps, Florence Cymbalista, Maria Fardis, Jesse S. McGreivy, Fong Clow, Danelle Frances James, Peter Hillmen. Randomized comparison of ibrutinib versus ofatumumab in relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma: Results from the phase III RESONATE trial. J Clin Oncol 32:5s, 2014 (suppl; abstr LBA7008) [https://doi.org/10.1200/jco.2014.32.18_suppl.lba7008 link to original abstract] --> | ||
+ | # '''RESONATE:''' Byrd JC, Brown JR, O'Brien S, Barrientos JC, Kay NE, Reddy NM, Coutre S, Tam CS, Mulligan SP, Jaeger U, Devereux S, Barr PM, Furman RR, Kipps TJ, Cymbalista F, Pocock C, Thornton P, Caligaris-Cappio F, Robak T, Delgado J, Schuster SJ, Montillo M, Schuh A, de Vos S, Gill D, Bloor A, Dearden C, Moreno C, Jones JJ, Chu AD, Fardis M, McGreivy J, Clow F, James DF, Hillmen P; the RESONATE Investigators. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014 Jul 17;371(3):213-23. Epub 2014 May 31. [https://doi.org/10.1056/NEJMoa1400376 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4134521/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24881631/ PubMed] [https://clinicaltrials.gov/study/NCT01578707 NCT01578707] | ||
+ | <!-- ## '''Update: Abstract:''' John C. Byrd, Peter Hillmen, Susan Mary O'Brien, Jacqueline Claudia Barrientos, Nishitha M. Reddy, Steven Coutre, ... Constantine S. Tam, Stephen P. Mulligan, Ulrich Jäger, Paul M. Barr, Richard R. Furman, Thomas J. Kipps, Patrick Thornton, John M. Pagel, Jan Andreas Burger, Jeffrey Alan Jones, Sandra Dai, Remus N. Vezan, Danelle Frances James, Jennifer R. Brown. Long-term efficacy and safety with ibrutinib (ibr) in previously treated chronic lymphocytic leukemia (CLL): Up to four years follow-up of the RESONATE study. Journal of Clinical Oncology 35, no. 15_suppl (May 2017) 7510-7510. [https://doi.org/10.1200/JCO.2017.35.15_suppl.7510 link to abstract] --> | ||
+ | ## '''Update:''' Brown JR, Hillmen P, O'Brien S, Barrientos JC, Reddy NM, Coutre SE, Tam CS, Mulligan SP, Jaeger U, Barr PM, Furman RR, Kipps TJ, Cymbalista F, Thornton P, Caligaris-Cappio F, Delgado J, Montillo M, De Vos S, Moreno C, Pagel JM, Munir T, Burger JA, Chung D, Lin J, Gau L, Chang B, Cole G, Hsu E, James DF, Byrd JC. Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL. Leukemia. 2018 Jan;32(1):83-91. Epub 2017 Jun 8. [https://doi.org/10.1038/leu.2017.175 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5770586/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28592889/ PubMed] | ||
+ | ## '''Update:''' Byrd JC, Hillmen P, O'Brien S, Barrientos JC, Reddy NM, Coutre S, Tam CS, Mulligan SP, Jaeger U, Barr PM, Furman RR, Kipps TJ, Thornton P, Moreno C, Montillo M, Pagel JM, Burger JA, Woyach JA, Dai S, Vezan R, James DF, Brown JR. Long-term follow-up of the RESONATE phase 3 trial of ibrutinib vs ofatumumab. Blood. 2019 May 9;133(19):2031-2042. Epub 2019 Mar 6. [https://doi.org/10.1182/blood-2018-08-870238 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6509542/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30842083/ PubMed] | ||
+ | ## '''Update:''' Munir T, Brown JR, O'Brien S, Barrientos JC, Barr PM, Reddy NM, Coutre S, Tam CS, Mulligan SP, Jaeger U, Kipps TJ, Moreno C, Montillo M, Burger JA, Byrd JC, Hillmen P, Dai S, Szoke A, Dean JP, Woyach JA. Final analysis from RESONATE: Up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma. Am J Hematol. 2019 Dec;94(12):1353-1363. Epub 2019 Oct 13. [https://doi.org/10.1002/ajh.25638 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6899718/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31512258/ PubMed] | ||
+ | # '''NHLBI 12-H-0035:''' Farooqui MZ, Valdez J, Martyr S, Aue G, Saba N, Niemann CU, Herman SE, Tian X, Marti G, Soto S, Hughes TE, Jones J, Lipsky A, Pittaluga S, Stetler-Stevenson M, Yuan C, Lee YS, Pedersen LB, Geisler CH, Calvo KR, Arthur DC, Maric I, Childs R, Young NS, Wiestner A. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol. 2015 Feb;16(2):169-76. Epub 2014 Dec 31. [https://doi.org/10.1016/S1470-2045(14)71182-9 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342187/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25555420/ PubMed] [https://clinicaltrials.gov/study/NCT01500733 NCT01500733] | ||
+ | # '''RESONATE-17:''' O'Brien S, Jones JA, Coutre SE, Mato AR, Hillmen P, Tam C, Österborg A, Siddiqi T, Thirman MJ, Furman RR, Ilhan O, Keating MJ, Call TG, Brown JR, Stevens-Brogan M, Li Y, Clow F, James DF, Chu AD, Hallek M, Stilgenbauer S. Ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia with 17p deletion (RESONATE-17): a phase 2, open-label, multicentre study. Lancet Oncol. 2016 Oct;17(10):1409-1418. Epub 2016 Sep 13. [https://doi.org/10.1016/S1470-2045(16)30212-1 link to original article] '''dosing details in abstract have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/27637985/ PubMed] [https://clinicaltrials.gov/study/NCT01744691 NCT01744691] | ||
+ | # '''Retrospective:''' Ryan CE, Sahaf B, Logan AC, O'Brien S, Byrd JC, Hillmen P, Brown JR, Dyer MJ, Mato AR, Keating MJ, Jaglowski S, Clow F, Rezvani AR, Styles L, Coutre SE, Miklos DB. Ibrutinib efficacy and tolerability in patients with relapsed chronic lymphocytic leukemia following allogeneic HCT. Blood. 2016 Dec 22;128(25):2899-2908. [https://doi.org/10.1182/blood-2016-06-715284 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5179333/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27802969/ PubMed] | ||
+ | # '''CR102604:''' Huang X, Qiu L, Jin J, Zhou D, Chen X, Hou M, Hu J, Hu Y, Ke X, Li J, Liang Y, Liu T, Lv Y, Ren H, Sun A, Wang J, Zhao C, Salman M, Sun S, Howes A, Wang J, Wu P, Li J. Ibrutinib versus rituximab in relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma: a randomized, open-label phase 3 study. Cancer Med. 2018 Apr;7(4):1043-1055. Epub 2018 Mar 13. [https://doi.org/10.1002/cam4.1337 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5911578/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29533000/ PubMed] [https://clinicaltrials.gov/study/NCT01973387 NCT01973387] | ||
+ | <!-- # '''Abstract:''' Jeff Porter Sharman, Danielle M. Brander, Anthony R. Mato, Suman Kambhampati, John M. Burke, Frederick Lansigan, Marshall T. Schreeder, Scott D. Lunin, Nilanjan Ghosh, Alexander Zweibach, Mikhail Shtivelband, Patrick M. Travis, Jason Claud Chandler, Kathryn S. Kolibaba, Peter Sportelli, Hari P. Miskin, Michael S. Weiss, and Ian Flinn. Ublituximab and ibrutinib for previously treated genetically high-risk chronic lymphocytic leukemia: Results of the GENUINE phase 3 study. Journal of Clinical Oncology 2017 35:15_suppl, 7504-7504 [https://doi.org/10.1200/JCO.2017.35.15_suppl.7504 link to abstract] --> | ||
+ | # '''GENUINE:''' Sharman JP, Brander DM, Mato AR, Ghosh N, Schuster SJ, Kambhampati S, Burke JM, Lansigan F, Schreeder MT, Lunin SD, Zweibach A, Shtivelband M, Travis PM, Chandler JC, Kolibaba KS, Sportelli P, Miskin HP, Weiss MS, Flinn IW. Ublituximab plus ibrutinib versus ibrutinib alone for patients with relapsed or refractory high-risk chronic lymphocytic leukaemia (GENUINE): a phase 3, multicentre, open-label, randomised trial. Lancet Haematol. 2021 Apr;8(4):e254-e266. Epub 2021 Feb 22. [https://doi.org/10.1016/s2352-3026(20)30433-6 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/33631112/ PubMed] [https://clinicaltrials.gov/study/NCT02301156 NCT02301156] | ||
+ | # '''ACE-CL-006:''' Byrd JC, Hillmen P, Ghia P, Kater AP, Chanan-Khan A, Furman RR, O'Brien S, Yenerel MN, Illés A, Kay N, Garcia-Marco JA, Mato A, Pinilla-Ibarz J, Seymour JF, Lepretre S, Stilgenbauer S, Robak T, Rothbaum W, Izumi R, Hamdy A, Patel P, Higgins K, Sohoni S, Jurczak W. Acalabrutinib Versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia: Results of the First Randomized Phase III Trial. J Clin Oncol. 2021 Nov 1;39(31):3441-3452. Epub 2021 Jul 26. [https://doi.org/10.1200/jco.21.01210 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8547923/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34310172/ PubMed] [https://clinicaltrials.gov/study/NCT02477696 NCT02477696] | ||
+ | <!-- #'''ALPINE:''' Brown JR, Hillmen P, Eichhorst B, Lamanna N, O'Brien S, Tam CS, Qiu L, Kazmierczak M, Zhou K, Šimkovič M, Mayer J, Gillespie-Twardy A, Shadman M, Ferrajoli A, Ganly PS, Weinkove R, Salmi T, Wu K, Novotny W, Jurczak W. CLL-115 First Interim Analysis of ALPINE Study: Results of a Phase 3 Randomized Study of Zanubrutinib vs Ibrutinib in Patients With Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL). Clin Lymphoma Myeloma Leuk. 2022 Oct;22 Suppl 2:S266. [https://doi.org/10.1016/s2152-2650(22)01324-6 link to original abstract]--> | ||
+ | #'''ALPINE:''' Hillmen P, Eichhorst B, Brown JR, Lamanna N, O'Brien SM, Tam CS, Qiu L, Kazmierczak M, Zhou K, Šimkovič M, Mayer J, Gillespie-Twardy A, Shadman M, Ferrajoli A, Ganly PS, Weinkove R, Grosicki S, Mital A, Robak T, Österborg A, Yimer HA, Salmi T, Ji M, Yecies J, Idoine A, Wu K, Huang J, Jurczak W. Zanubrutinib Versus Ibrutinib in Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma: Interim Analysis of a Randomized Phase III Trial. J Clin Oncol. 2023 Feb 10;41(5):1035-1045. Epub 2022 Nov 17. [https://doi.org/10.1200/jco.22.00510 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9928683/ link to PMC article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/36395435/ PubMed] [https://clinicaltrials.gov/study/NCT03734016 NCT03734016] | ||
+ | ##'''Update:''' Brown JR, Eichhorst B, Hillmen P, Jurczak W, Kaźmierczak M, Lamanna N, O'Brien SM, Tam CS, Qiu L, Zhou K, Simkovic M, Mayer J, Gillespie-Twardy A, Ferrajoli A, Ganly PS, Weinkove R, Grosicki S, Mital A, Robak T, Osterborg A, Yimer HA, Salmi T, Wang MD, Fu L, Li J, Wu K, Cohen A, Shadman M. Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. N Engl J Med. 2023 Jan 26;388(4):319-332. Epub 2022 Dec 13. [https://doi.org/10.1056/nejmoa2211582 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36511784/ PubMed] | ||
+ | ##'''HRQoL analysis:''' Tam CS, Lamanna N, O'Brien SM, Qiu L, Yang K, Barnes G, Wu K, Salmi T, Brown JR. Health-related quality of life outcomes associated with zanubrutinib versus ibrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma: results from the ALPINE Trial. Curr Med Res Opin. 2023 Nov;39(11):1497-1503. Epub 2023 Oct 27. [https://doi.org/10.1080/03007995.2023.2262378 link to original article] [https://pubmed.ncbi.nlm.nih.gov/37752892/ PubMed] | ||
− | == | + | ==Ibrutinib & Ublituximab {{#subobject:29ub5a|Regimen=1}}== |
− | {| class="wikitable" style=" | + | <div class="toccolours" style="background-color:#eeeeee"> |
+ | ===Regimen {{#subobject:aycr1c|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1016/s2352-3026(20)30433-6 Sharman et al. 2021 (GENUINE)] |
− | | | + | |2015-02-06 to 2016-12-19 |
− | + | |style="background-color:#1a9851"|Phase 3 (E-esc) | |
− | + | |[[#Ibrutinib_monotherapy_2|Ibrutinib]] | |
− | | | + | | style="background-color:#91cf60" |Seems to have superior ORR (primary endpoint) |
− | |[[ | ||
− | |||
− | |||
− | |style="background-color:# | ||
|- | |- | ||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#fdcdac"> | |
− | ==== | + | ====Biomarker eligibility criteria==== |
− | *[[ | + | *17p deletion, 11q deletion, or TP53 mutation |
− | + | </div> | |
− | '''28-day cycle for | + | <div class="toccolours" style="background-color:#f2f3f4"> |
− | + | ====Targeted therapy==== | |
+ | *[[Ibrutinib (Imbruvica)]] 420 mg PO once per day on days 1 to 28 | ||
+ | *[[Ublituximab (Briumvi)]] as follows: | ||
+ | **Cycle 1: 150 mg IV over 4 hours once on day 1, then 750 mg IV over 4 hours once on day 2, then 900 mg IV over 3 hours once per day on days 8 & 15 | ||
+ | **Cycles 2 to 5: 900 mg IV over 90 minutes once on day 1 | ||
+ | **Cycle 6 onwards: 900 mg IV once on day 1 | ||
+ | '''28-day cycle for 5 cycles, then 12-week cycles''' | ||
+ | </div></div> | ||
===References=== | ===References=== | ||
− | # | + | # '''GENUINE:''' Sharman JP, Brander DM, Mato AR, Ghosh N, Schuster SJ, Kambhampati S, Burke JM, Lansigan F, Schreeder MT, Lunin SD, Zweibach A, Shtivelband M, Travis PM, Chandler JC, Kolibaba KS, Sportelli P, Miskin HP, Weiss MS, Flinn IW. Ublituximab plus ibrutinib versus ibrutinib alone for patients with relapsed or refractory high-risk chronic lymphocytic leukaemia (GENUINE): a phase 3, multicentre, open-label, randomised trial. Lancet Haematol. 2021 Apr;8(4):e254-e266. Epub 2021 Feb 22. [https://doi.org/10.1016/s2352-3026(20)30433-6 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/33631112/ PubMed] [https://clinicaltrials.gov/study/NCT02301156 NCT02301156] |
− | == | + | ==Idelalisib & Ofatumumab {{#subobject:c4f11b|Regimen=1}}== |
− | {| class="wikitable" style=" | + | <div class="toccolours" style="background-color:#eeeeee"> |
+ | ===Regimen {{#subobject:7619d2|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1016/S2352-3026(17)30019-4 Jones et al. 2017 (GS-US-312-0119)] |
− | + | |2012-2014 | |
− | + | |style="background-color:#1a9851"|Phase 3 (E-esc) | |
− | + | |[[#Ofatumumab_monotherapy_2|Ofatumumab]] | |
− | + | |style="background-color:#1a9850"|Superior PFS (primary endpoint)<br>Median PFS: 16.3 vs 8 mo<br>(HR 0.27, 95% CI 0.19-0.39) | |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |style="background-color:# | ||
− | |[[# | ||
− | |style="background-color:# | ||
|- | |- | ||
|} | |} | ||
− | '' | + | <div class="toccolours" style="background-color:#f2f3f4"> |
− | === | + | ====Targeted therapy==== |
− | + | *[[Idelalisib (Zydelig)]] 150 mg PO twice per day | |
− | + | *[[Ofatumumab (Arzerra)]] as follows: | |
− | ''' | + | **Cycle 1: 300 mg IV once on day 1, then 1000 mg IV once per day on days 8, 15, 22 |
− | + | **Cycle 2: 1000 mg IV once per day on days 1, 8, 15, 22 | |
− | ===Regimen # | + | **Cycles 3 to 6: 1000 mg IV once on day 1 |
− | {| | + | '''28-day cycle for 6 cycles''' |
− | | | + | </div></div> |
− | |[[Levels_of_Evidence#Evidence| | + | ===References=== |
− | | | + | # '''GS-US-312-0119:''' Jones JA, Robak T, Brown JR, Awan FT, Badoux X, Coutre S, Loscertales J, Taylor K, Vandenberghe E, Wach M, Wagner-Johnston N, Ysebaert L, Dreiling L, Dubowy R, Xing G, Flinn IW, Owen C. Efficacy and safety of idelalisib in combination with ofatumumab for previously treated chronic lymphocytic leukaemia: an open-label, randomised phase 3 trial. Lancet Haematol. 2017 Mar;4(3):e114-e126. [https://doi.org/10.1016/S2352-3026(17)30019-4 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/28257752/ PubMed] [https://clinicaltrials.gov/study/NCT01659021 NCT01659021] |
− | |[[Levels_of_Evidence# | + | ==Idelalisib & Rituximab {{#subobject:353bcd|Regimen=1}}== |
+ | IdelaR: '''<u>Idela</u>'''lisib & '''<u>R</u>'''ituximab | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #1, finite duration {{#subobject:2fb35e|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161365/ Furman et al. 2014 (GS-US-312-0116)] |
− | |style="background-color:# | + | |2012-05 to 2013-08 |
− | |[[# | + | |style="background-color:#1a9851"|Phase 3 (E-RT-esc) |
− | |style="background-color:# | + | |[[#Rituximab_monotherapy_3|Rituximab]] |
+ | | style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>PFS6: 93% vs 46%<br>(aHR 0.15, 95% CI 0.08-0.28) | ||
|- | |- | ||
|} | |} | ||
− | + | ''Note: Upon progression, idelalisib can be increased to 300 mg PO twice per day.'' | |
− | '' | + | <div class="toccolours" style="background-color:#f2f3f4"> |
− | ==== | + | ====Targeted therapy==== |
− | *[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once | + | *[[Idelalisib (Zydelig)]] 150 mg PO twice per day on days 1 to 28 |
− | + | *[[Rituximab (Rituxan)]] as follows: | |
− | ''' | + | **Cycle 1: 375 mg/m<sup>2</sup> IV once on day 1, then 500 mg/m<sup>2</sup> IV once on day 15 |
− | + | **Cycle 2: 500 mg/m<sup>2</sup> IV once per day on days 1 & 15 | |
− | ===Regimen # | + | **Cycles 3 to 6: 500 mg/m<sup>2</sup> IV once on day 1 |
− | {| | + | '''28-day cycle for up to 18 cycles''' |
− | | | + | </div></div><br> |
− | |[[Levels_of_Evidence#Evidence| | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | | | + | ===Regimen variant #2, indefinite {{#subobject:2fu7bz|Variant=1}}=== |
− | |[[Levels_of_Evidence# | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" |
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.19.03355 Ghia et al. 2020 (ASCEND)] |
− | |style="background-color:# | + | |2017-02-21 to 2018-01-17 |
− | |[[# | + | | style="background-color:#1a9851" |Phase 3 (C) |
− | |style="background-color:# | + | |[[#Acalabrutinib_monotherapy_2|Acalabrutinib]] |
+ | |style="background-color:#d73027"|Inferior PFS | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#fdcdac"> | ||
+ | ====Prior treatment criteria==== | ||
+ | *ASCEND: At least 1 prior systemic therapy | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
+ | ====Targeted therapy==== | ||
+ | *[[Idelalisib (Zydelig)]] 150 mg PO twice per day on days 1 to 28 | ||
+ | *[[Rituximab (Rituxan)]] as follows: | ||
+ | **Cycle 1: 375 mg/m<sup>2</sup> IV once on day 15 | ||
+ | **Cycles 2 to 3: 500 mg/m<sup>2</sup> IV once per day on days 1 & 15 | ||
+ | **Cycles 4 to 6: 500 mg/m<sup>2</sup> IV once on day 1 | ||
+ | '''28-day cycles''' | ||
+ | </div></div> | ||
+ | ===References=== | ||
+ | # '''GS-US-312-0116:''' Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, Barrientos JC, Zelenetz AD, Kipps TJ, Flinn I, Ghia P, Eradat H, Ervin T, Lamanna N, Coiffier B, Pettitt AR, Ma S, Stilgenbauer S, Cramer P, Aiello M, Johnson DM, Miller LL, Li D, Jahn TM, Dansey RD, Hallek M, O'Brien SM. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014 Mar 13;370(11):997-1007. Epub 2014 Jan 22. [https://doi.org/10.1056/NEJMoa1315226 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161365/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24450857/ PubMed] [https://clinicaltrials.gov/study/NCT01539512 NCT01539512] | ||
+ | ## '''Update:''' Sharman JP, Coutre SE, Furman RR, Cheson BD, Pagel JM, Hillmen P, Barrientos JC, Zelenetz AD, Kipps TJ, Flinn IW, Ghia P, Eradat H, Ervin T, Lamanna N, Coiffier B, Pettitt AR, Ma S, Tausch E, Cramer P, Huang J, Mitra S, Hallek M, O'Brien SM, Stilgenbauer S. Final results of a randomized, phase III study of rituximab with or without idelalisib followed by open-label idelalisib in patients with relapsed chronic lymphocytic leukemia. J Clin Oncol. 2019 Jun 1;37(16):1391-1402. Epub 2019 Apr 17. [https://doi.org/10.1200/JCO.18.01460 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10448866/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30995176/ PubMed] | ||
+ | # '''ASCEND:''' Ghia P, Pluta A, Wach M, Lysak D, Kozak T, Simkovic M, Kaplan P, Kraychok I, Illes A, de la Serna J, Dolan S, Campbell P, Musuraca G, Jacob A, Avery E, Lee JH, Liang W, Patel P, Quah C, Jurczak W. ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. J Clin Oncol. 2020 Sep 1;38(25):2849-2861. Epub 2020 May 27. [https://doi.org/10.1200/jco.19.03355 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/32459600/ PubMed] [https://clinicaltrials.gov/study/NCT02970318 NCT02970318] | ||
+ | #'''BRUIN CLL-321:''' [https://clinicaltrials.gov/study/NCT04666038 NCT04666038] | ||
− | + | ==Ofatumumab monotherapy {{#subobject:75bd7e|Regimen=1}}== | |
− | ==== | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | + | ===Regimen variant #1, 2 cycles {{#subobject:e4b8d5|Variant=1}}=== | |
− | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" | |
− | + | !style="width: 33%"|Study | |
− | + | !style="width: 33%"|Dates of enrollment | |
− | ===Regimen # | + | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | {| | ||
− | | | ||
− | |[[Levels_of_Evidence#Evidence| | ||
− | |||
− | |||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1111/bjh.13380 Österborg et al. 2015 (GEN416)] |
− | | | + | |2009-2011 |
− | + | |style="background-color:#91cf61"|Phase 2 | |
− | |style="background-color:# | ||
|- | |- | ||
|} | |} | ||
− | + | ''Note: Patients in this trial were fludarabine refractory and had previously received ofatumumab; this is a re-treatment trial.'' | |
− | '' | + | <div class="toccolours" style="background-color:#fdcdac"> |
− | ==== | + | ====Prior treatment criteria==== |
− | *[[ | + | *Fludarabine and ofatumumab exposure, with refractory disease |
− | + | </div> | |
− | ''' | + | <div class="toccolours" style="background-color:#f2f3f4"> |
− | + | ====Targeted therapy==== | |
− | ===Regimen # | + | *[[Ofatumumab (Arzerra)]] as follows: |
− | {| | + | **Cycle 1: 300 mg IV once on day 1, then 2000 mg IV once per day on days 8, 15, 22 |
− | | | + | **Cycle 2: 2000 mg IV once per day on days 1, 8, 15, 22 |
− | |[[Levels_of_Evidence#Evidence| | + | ====Supportive therapy==== |
+ | *[[Acetaminophen (Tylenol)]] 1000 mg PO once per day on days 1, 8, 15, 22, prior to ofatumumab | ||
+ | *[[Cetirizine (Zyrtec)]] (or equivalent) 10 mg PO once per day on days 1, 8, 15, 22, prior to ofatumumab | ||
+ | *[[Prednisolone (Millipred)]] 100 mg (or [[Steroid conversions|equivalent]]) PO once, prior to infusions 1, 2, and 9 (question whether this was a typo), reduced or omitted if initial infusions well-tolerated | ||
+ | '''28-day cycle for 2 cycles''' | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#cbd5e7"> | ||
+ | ====Subsequent treatment==== | ||
+ | *GEN416, patients with SD or better: [[#Ofatumumab_monotherapy_3|ofatumumab]] maintenance | ||
+ | </div></div><br> | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #2, 6 cycles {{#subobject:d30c3f|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
+ | |- | ||
+ | |[https://doi.org/10.1182/blood-2007-09-111781 Coiffier et al. 2007] | ||
+ | |2004-2006 | ||
+ | |style="background-color:#91cf61"|Phase 1/2 | ||
+ | |style="background-color:#d3d3d3"| | ||
+ | |style="background-color:#d3d3d3"| | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979101/ Wierda et al. 2010 (Hx-CD20-406)] | ||
+ | |2006 to not reported | ||
+ | |style="background-color:#91cf61"|Phase 2 (RT) | ||
+ | |style="background-color:#d3d3d3"| | ||
+ | |style="background-color:#d3d3d3"| | ||
+ | |- | ||
+ | |[https://doi.org/10.3109/10428194.2015.1122783 Österborg et al. 2016 (Novartis 114242)] | ||
+ | |2011 to not reported | ||
+ | |style="background-color:#1a9851"|Phase 3 (E-switch) | ||
+ | |Physician's choice | ||
+ | | style="background-color:#ffffbf" |Did not meet primary endpoint of PFS | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4134521/ Byrd et al. 2014 (RESONATE)] | ||
+ | |2012-06 to 2013-04 | ||
+ | |style="background-color:#1a9851"|Phase 3 (C) | ||
+ | |[[#Ibrutinib_monotherapy_2|Ibrutinib]] | ||
+ | | style="background-color:#d73027" |Inferior PFS<sup>1</sup> | ||
+ | |- | ||
+ | |[https://doi.org/10.1016/S2352-3026(17)30019-4 Jones et al. 2017 (GS-US-312-0119)] | ||
+ | |2012-2014 | ||
+ | |style="background-color:#1a9851"|Phase 3 (C) | ||
+ | |[[#Idelalisib_.26_Ofatumumab|Idelalisib & Ofatumumab]] | ||
+ | |style="background-color:#d73027"|Inferior PFS | ||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284216/ Flinn et al. 2018 (DUO)] |
− | |style="background-color:# | + | |2014-01-21 to 2015-12-09 |
+ | |style="background-color:#1a9851"|Phase 3 (C) | ||
+ | |[[#Duvelisib_monotherapy|Duvelisib]] | ||
+ | |style="background-color:#d73027"|Inferior PFS | ||
|- | |- | ||
|} | |} | ||
− | + | ''<sup>1</sup>Reported efficacy for RESONATE is based on the second 2019 update.''<br> | |
− | '' | + | ''Note: this regimen is sometimes described as 300 mg IV once on day 1, then 2000 mg IV once per week for 7 weeks, then 2000 mg IV once every 4 weeks for 16 weeks. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.'' |
− | ==== | + | <div class="toccolours" style="background-color:#fdcdac"> |
− | *[[ | + | ====Prior treatment criteria==== |
− | + | *Hx-CD20-406 & Novartis 114242: Fludarabine exposure, with refractory disease | |
− | ''' | + | </div> |
− | + | <div class="toccolours" style="background-color:#f2f3f4"> | |
− | ===Regimen # | + | ====Targeted therapy==== |
− | {| | + | *[[Ofatumumab (Arzerra)]] as follows: |
− | | | + | **Cycle 1: 300 mg IV once on day 1, then 2000 mg IV once per day on days 8, 15, 22 |
− | |[[Levels_of_Evidence#Evidence| | + | **Cycle 2: 2000 mg IV once per day on days 1, 8, 15, 22 |
+ | **Cycles 3 to 6: 2000 mg IV once on day 1 | ||
+ | ====Supportive therapy==== | ||
+ | *[[Prednisolone (Millipred)]] 100 mg (or [[Steroid conversions|equivalent]]) PO once, prior to infusions 1, 2, and 9 (question whether this was a typo), reduced to lower doses if initial infusions well-tolerated | ||
+ | '''28-day cycle for 6 cycles''' | ||
+ | </div></div><br> | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #3, 12 cycles {{#subobject:72f09e|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1182/blood-2016-10-748210 Ghia et al. 2017 (P07714)] |
− | |style="background-color:# | + | |2012 to not reported |
+ | |style="background-color:#1a9851"|Phase 3 (C) | ||
+ | |[[#Dinaciclib_monotherapy_777|Dinaciclib]] | ||
+ | |style="background-color:#d3d3d3"|Not reported | ||
|- | |- | ||
|} | |} | ||
− | + | ''Note: this trial was terminated early and no statistical tests were performed; note also that cycle 3 is "skipped".'' | |
− | '' | + | <div class="toccolours" style="background-color:#f2f3f4"> |
− | ==== | + | ====Targeted therapy==== |
− | *[[ | + | *[[Ofatumumab (Arzerra)]] as follows: |
− | + | **Cycle 1: 300 mg IV once on day 1, then 2000 mg IV once per day on days 8, 15, 22 | |
− | + | **Cycle 2: 2000 mg IV once per day on days 1, 8, 15, 22 | |
− | * | + | **Cycle 3: no treatment |
− | * | + | **Cycles 4 to 12: 2000 mg IV once on day 1 |
− | + | '''28-day cycle for 12 cycles''' | |
− | + | </div></div> | |
− | ''' | ||
− | |||
===References=== | ===References=== | ||
− | # | + | # Coiffier B, Lepretre S, Pedersen LM, Gadeberg O, Fredriksen H, van Oers MH, Wooldridge J, Kloczko J, Holowiecki J, Hellmann A, Walewski J, Flensburg M, Petersen J, Robak T. Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1-2 study. Blood. 2008 Feb 1;111(3):1094-100. Epub 2007 Nov 14. [https://doi.org/10.1182/blood-2007-09-111781 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18003886/ PubMed] |
− | # | + | <!-- # Wierda, W.G., Kipps, T.J., Mayer, J., Robak, T., Dyer, M.J.S., Furman, R.R., Hillmen, P., Stilgenbauer, S., Williams, C.D., Trneny, M., Cartron, G., Hernandez-Ilizaliturri, F.J., Padmanabhan, S., Chan, G.W., Gupta, I.V., Gorczyca, M.M., Davis, R.L., Losic, N., Lisby, S. & Österborg, A. (2010a) Final analysis from the international trial of single-agent ofatumumab in patients with fludarabine-refractory chronic lymphocytic leukemia. Blood (ASH Annual Meeting Abstracts), 116, Abstract 921. --> |
− | + | # '''Hx-CD20-406:''' Wierda WG, Kipps TJ, Mayer J, Stilgenbauer S, Williams CD, Hellmann A, Robak T, Furman RR, Hillmen P, Trneny M, Dyer MJ, Padmanabhan S, Piotrowska M, Kozak T, Chan G, Davis R, Losic N, Wilms J, Russell CA, Osterborg A; Hx-CD20-406 Study Investigators. Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol. 2010 Apr 1;28(10):1749-55. Epub 2010 Mar 1. [https://doi.org/10.1200/jco.2009.25.3187 link to original article] '''dosing details in abstract have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979101/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20194866/ PubMed] [https://clinicaltrials.gov/study/NCT00349349 NCT00349349] | |
− | + | <!-- Presented in part as an oral presentation at the 52nd Annual Meeting of the American Society of Hematology, December 7, 2010, Orlando, FL; and as a poster presentation at the 15th Annual International Congress on Hematologic Malignancies: Focus on Leukemias, Lymphomas, and Myelomas, February 17-20, 2011, Whistler, BC. --> | |
− | + | ## '''Subgroup analysis:''' Wierda WG, Padmanabhan S, Chan GW, Gupta IV, Lisby S, Osterborg A; Hx-CD20-406 Study Investigators. Ofatumumab is active in patients with fludarabine-refractory CLL irrespective of prior rituximab: results from the phase 2 international study. Blood. 2011 Nov 10;118(19):5126-9. Epub 2011 Aug 19. [https://doi.org/10.1182/blood-2011-04-348656 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916553/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21856867/ PubMed] | |
− | + | ## '''Update:''' Österborg A, Jewell RC, Padmanabhan-Iyer S, Kipps TJ, Mayer J, Stilgenbauer S, Williams CD, Hellmann A, Furman RR, Robak T, Hillmen P, Trnêný M, Dyer MJ, Piotrowska M, Kozak T, Gupta IV, Phillips JL, Goldstein N, Struemper H, Losic N, Lisby S, Wierda WG; Hx-CD20-406 Study Investigators. Ofatumumab monotherapy in fludarabine-refractory chronic lymphocytic leukemia: final results from a pivotal study. Haematologica. 2015 Aug;100(8):e311-4. Epub 2015 Mar 13. [https://doi.org/10.3324/haematol.2014.121459 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004432/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25769539/ PubMed] | |
− | + | <!-- # '''Abstract:''' John C. Byrd, Jennifer R. Brown, Susan Mary O'Brien, Jacqueline Claudia Barrientos, Neil E. Kay, Nishitha M. Reddy, Steven E. Coutre, Constantine Tam, Stephen P. Mulligan, Ulrich Jäger, Steve Devereux, Paul M. Barr, Richard R. Furman, Thomas J. Kipps, Florence Cymbalista, Maria Fardis, Jesse S. McGreivy, Fong Clow, Danelle Frances James, Peter Hillmen. Randomized comparison of ibrutinib versus ofatumumab in relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma: Results from the phase III RESONATE trial. J Clin Oncol 32:5s, 2014 (suppl; abstr LBA7008) [https://doi.org/10.1200/jco.2014.32.18_suppl.lba7008 link to original abstract] --> | |
− | ## '''Update:''' | + | # '''RESONATE:''' Byrd JC, Brown JR, O'Brien S, Barrientos JC, Kay NE, Reddy NM, Coutre S, Tam CS, Mulligan SP, Jaeger U, Devereux S, Barr PM, Furman RR, Kipps TJ, Cymbalista F, Pocock C, Thornton P, Caligaris-Cappio F, Robak T, Delgado J, Schuster SJ, Montillo M, Schuh A, de Vos S, Gill D, Bloor A, Dearden C, Moreno C, Jones JJ, Chu AD, Fardis M, McGreivy J, Clow F, James DF, Hillmen P; the RESONATE Investigators. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014 Jul 17;371(3):213-23. Epub 2014 May 31. [https://doi.org/10.1056/NEJMoa1400376 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4134521/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24881631/ PubMed] [https://clinicaltrials.gov/study/NCT01578707 NCT01578707] |
− | <!-- # '''Abstract:''' R | + | <!-- ## '''Update: Abstract:''' John C. Byrd, Peter Hillmen, Susan Mary O'Brien, Jacqueline Claudia Barrientos, Nishitha M. Reddy, Steven Coutre, ... Constantine S. Tam, Stephen P. Mulligan, Ulrich Jäger, Paul M. Barr, Richard R. Furman, Thomas J. Kipps, Patrick Thornton, John M. Pagel, Jan Andreas Burger, Jeffrey Alan Jones, Sandra Dai, Remus N. Vezan, Danelle Frances James, Jennifer R. Brown. Long-term efficacy and safety with ibrutinib (ibr) in previously treated chronic lymphocytic leukemia (CLL): Up to four years follow-up of the RESONATE study. Journal of Clinical Oncology 35, no. 15_suppl (May 2017) 7510-7510. [https://doi.org/10.1200/JCO.2017.35.15_suppl.7510 link to abstract] --> |
− | + | ## '''Update:''' Brown JR, Hillmen P, O'Brien S, Barrientos JC, Reddy NM, Coutre SE, Tam CS, Mulligan SP, Jaeger U, Barr PM, Furman RR, Kipps TJ, Cymbalista F, Thornton P, Caligaris-Cappio F, Delgado J, Montillo M, De Vos S, Moreno C, Pagel JM, Munir T, Burger JA, Chung D, Lin J, Gau L, Chang B, Cole G, Hsu E, James DF, Byrd JC. Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL. Leukemia. 2018 Jan;32(1):83-91. Epub 2017 Jun 8. [https://doi.org/10.1038/leu.2017.175 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5770586/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28592889/ PubMed] | |
− | <!-- | + | ## '''Update:''' Byrd JC, Hillmen P, O'Brien S, Barrientos JC, Reddy NM, Coutre S, Tam CS, Mulligan SP, Jaeger U, Barr PM, Furman RR, Kipps TJ, Thornton P, Moreno C, Montillo M, Pagel JM, Burger JA, Woyach JA, Dai S, Vezan R, James DF, Brown JR. Long-term follow-up of the RESONATE phase 3 trial of ibrutinib vs ofatumumab. Blood. 2019 May 9;133(19):2031-2042. Epub 2019 Mar 6. [https://doi.org/10.1182/blood-2018-08-870238 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6509542/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30842083/ PubMed] |
− | + | ## '''Update:''' Munir T, Brown JR, O'Brien S, Barrientos JC, Barr PM, Reddy NM, Coutre S, Tam CS, Mulligan SP, Jaeger U, Kipps TJ, Moreno C, Montillo M, Burger JA, Byrd JC, Hillmen P, Dai S, Szoke A, Dean JP, Woyach JA. Final analysis from RESONATE: Up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma. Am J Hematol. 2019 Dec;94(12):1353-1363. Epub 2019 Oct 13. [https://doi.org/10.1002/ajh.25638 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6899718/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31512258/ PubMed] | |
− | + | # '''Retrospective:''' Moreno C, Montillo M, Panayiotidis P, Dimou M, Bloor A, Dupuis J, Schuh A, Norin S, Geisler C, Hillmen P, Doubek M, Trněný M, Obrtlikova P, Laurenti L, Stilgenbauer S, Smolej L, Ghia P, Cymbalista F, Jaeger U, Stamatopoulos K, Stavroyianni N, Carrington P, Zouabi H, Leblond V, Gomez-Garcia JC, Rubio M, Marasca R, Musuraca G, Rigacci L, Farina L, Paolini R, Pospisilova S, Kimby E, Bradley C, Montserrat E. Ofatumumab in poor-prognosis chronic lymphocytic leukemia: a Phase 4, non--interventional, observational study from the European Research Initiative on Chronic Lymphocytic Leukemia. Haematologica. 2015 Apr;100(4):511-6. Epub 2015 Jan 16. [https://doi.org/10.3324/haematol.2014.118158 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380724/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25596264/ PubMed] | |
+ | # '''GEN416:''' Österborg A, Wierda WG, Mayer J, Hess G, Hillmen P, Schetelig J, Schuh A, Smolej L, Beck C, Dreyfus B, Hellman A, Kozlowski P, Pfreundschuh M, Rizzi R, Spacek M, Phillips JL, Gupta IV, Williams V, Jewell RC, Nebot N, Lisby S, Dyer MJ. Ofatumumab retreatment and maintenance in fludarabine-refractory chronic lymphocytic leukaemia patients. Br J Haematol. 2015 Jul;170(1):40-9. Epub 2015 Mar 30. [https://doi.org/10.1111/bjh.13380 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/25825041/ PubMed] [https://clinicaltrials.gov/study/NCT00802737 NCT00802737] | ||
+ | # '''Novartis 114242:''' Österborg A, Udvardy M, Zaritskey A, Andersson PO, Grosicki S, Mazur G, Kaplan P, Steurer M, Schuh A, Montillo M, Kriachok I, Middeke JM, Kulyaba Y, Rekhtman G, Gorczyca M, Daly S, Chang CN, Lisby S, Gupta I. Phase III, randomized study of ofatumumab versus physicians' choice of therapy and standard versus extended-length ofatumumab in patients with bulky fludarabine-refractory chronic lymphocytic leukemia. Leuk Lymphoma. 2016 Sep;57(9):2037-46. Epub 2016 Jan 19. [https://doi.org/10.3109/10428194.2015.1122783 link to original article][https://pubmed.ncbi.nlm.nih.gov/26784000/ PubMed] [https://clinicaltrials.gov/study/NCT01313689 NCT01313689] | ||
+ | ##'''Update:''' Miklos U, Strugov V, Lewerin C, Grosicki S, Mazur G, Steurer M, Montillo M, Kriachok I, Middeke JM, Rekhtman G, Stefanelli T, Vincent G, Govindaraju S, Österborg A. Five-year survival follow-up of a phase III randomised trial comparing ofatumumab versus physicians' choice for bulky fludarabine-refractory chronic lymphocytic leukaemia: a short report. Br J Haematol. 2020 May;189(4):689-693. Epub 2020 Jan 28. [https://doi.org/10.1111/bjh.16429 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31994178/ PubMed] | ||
+ | # '''GS-US-312-0119:''' Jones JA, Robak T, Brown JR, Awan FT, Badoux X, Coutre S, Loscertales J, Taylor K, Vandenberghe E, Wach M, Wagner-Johnston N, Ysebaert L, Dreiling L, Dubowy R, Xing G, Flinn IW, Owen C. Efficacy and safety of idelalisib in combination with ofatumumab for previously treated chronic lymphocytic leukaemia: an open-label, randomised phase 3 trial. Lancet Haematol. 2017 Mar;4(3):e114-e126. [https://doi.org/10.1016/S2352-3026(17)30019-4 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/28257752/ PubMed] [https://clinicaltrials.gov/study/NCT01659021 NCT01659021] | ||
+ | # '''P07714:''' Ghia P, Scarfò L, Perez S, Pathiraja K, Derosier M, Small K, McCrary Sisk C, Patton N. Efficacy and safety of dinaciclib vs ofatumumab in patients with relapsed/refractory chronic lymphocytic leukemia. Blood. 2017 Mar 30;129(13):1876-1878. Epub 2017 Jan 26. [https://doi.org/10.1182/blood-2016-10-748210 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28126927/ PubMed] [https://clinicaltrials.gov/study/NCT01580228 NCT01580228] | ||
+ | # '''DUO:''' Flinn IW, Hillmen P, Montillo M, Nagy Z, Illés Á, Etienne G, Delgado J, Kuss BJ, Tam CS, Gasztonyi Z, Offner F, Lunin S, Bosch F, Davids MS, Lamanna N, Jaeger U, Ghia P, Cymbalista F, Portell CA, Skarbnik AP, Cashen AF, Weaver DT, Kelly VM, Turnbull B, Stilgenbauer S. The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL. Blood. 2018 Dec 6;132(23):2446-2455. Epub 2018 Oct 4. [https://doi.org/10.1182/blood-2018-05-850461 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284216/ link to PMC article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/30287523/ PubMed] [https://clinicaltrials.gov/study/NCT02004522 NCT02004522] | ||
− | = | + | ==O-FC {{#subobject:815d07|Regimen=1}}== |
− | + | O-FC: '''<u>O</u>'''fatumumab, '''<u>F</u>'''ludarabine, '''<u>C</u>'''yclophosphamide | |
− | == | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | {| class="wikitable" style=" | + | ===Regimen {{#subobject:f8f0ee|Variant=1}}=== |
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
+ | |- | ||
+ | |[https://doi.org/10.1080/10428194.2016.1233536 Robak et al. 2016 (COMPLEMENT 2)] | ||
+ | |2008 to not reported | ||
+ | |style="background-color:#1a9851"|Phase 3 (E-RT-esc) | ||
+ | |[[Chronic_lymphocytic_leukemia_-_historical#FC_2|FC]] | ||
+ | |style="background-color:#1a9850"|Superior PFS (primary endpoint)<br>Median PFS: 28.9 vs 18.8 mo<br>(HR 0.67, 95% CI 0.51-0.88) | ||
|- | |- | ||
− | |||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#f2f3f4"> | |
− | ===Regimen {{#subobject: | + | ====Targeted therapy==== |
− | {| | + | *[[Ofatumumab (Arzerra)]] as follows: |
− | | | + | **Cycle 1: 300 mg IV once on day 1, then 1000 mg IV once on day 8 |
− | |[[Levels_of_Evidence#Evidence| | + | **Cycles 2 to 6: 1000 mg IV once on day 1 |
− | | | + | ====Chemotherapy==== |
− | |[[Levels_of_Evidence# | + | *[[Fludarabine (Fludara)]] 25 mg/m<sup>2</sup> IV once per day on days 1 to 3 |
+ | *[[Cyclophosphamide (Cytoxan)]] 250 mg/m<sup>2</sup> IV once per day on days 1 to 3 | ||
+ | ====Supportive therapy==== | ||
+ | *[[Acetaminophen (Tylenol)]] 1000 mg PO once on day 1, prior to ofatumumab | ||
+ | *[[Cetirizine (Zyrtec)]] 10 mg (or equivalent) PO once on day 1, prior to ofatumumab | ||
+ | *[[Prednisolone (Millipred)]] 100 mg ([[Steroid conversions|or equivalent]]) PO once on day 1, prior to doses 1 & 2 of ofatumumab, then reduced by physician discretion for later doses | ||
+ | *May be used at physician discretion: | ||
+ | **[[Allopurinol (Zyloprim)]] for tumor lysis syndrome prophylaxis | ||
+ | **[[:Category:Antivirals|Antiviral]] prophylaxis | ||
+ | **[[:Category:PCP_prophylaxis|PCP (Pneumocystis jiroveci pneumonia)]] prophylaxis | ||
+ | **Growth factor support | ||
+ | '''28-day cycle for 6 cycles''' | ||
+ | </div></div> | ||
+ | ===References=== | ||
+ | # '''COMPLEMENT 2:''' Robak T, Warzocha K, Govind Babu K, Kulyaba Y, Kuliczkowski K, Abdulkadyrov K, Loscertales J, Kriachok I, Kłoczko J, Rekhtman G, Homenda W, Błoński JZ, McKeown A, Gorczyca MM, Carey JL, Chang CN, Lisby S, Gupta IV, Grosicki S. Ofatumumab plus fludarabine and cyclophosphamide in relapsed chronic lymphocytic leukemia: results from the COMPLEMENT 2 trial. Leuk Lymphoma. 2017 May;58(5):1084-1093. Epub 2016 Oct 12. [https://doi.org/10.1080/10428194.2016.1233536 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/27731748/ PubMed] [https://clinicaltrials.gov/study/NCT00824265 NCT00824265] | ||
+ | ==Rituximab monotherapy {{#subobject:5623dc|Regimen=1}}== | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #1, 4-week course {{#subobject:b7407a|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
+ | |- | ||
+ | |[https://doi.org/10.1200/jco.1998.16.8.2825 McLaughlin et al. 1998] | ||
+ | |1995-1996 | ||
+ | |style="background-color:#91cf61"|Phase 2 | ||
+ | |style="background-color:#d3d3d3"| | ||
+ | |style="background-color:#d3d3d3"| | ||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4900920/ Williams et al. 2016 (RESORT substudy)] |
− | |style="background-color:# | + | |2003-2008 |
− | |[[# | + | |style="background-color:#1a9851"|Phase 3 (E-de-esc) |
− | |style="background-color:# | + | |[[#Rituximab_monotherapy_2|Rituximab]] maintenance |
+ | |style="background-color:#fc8d59"|Seems to have inferior TTTF (primary endpoint) | ||
|- | |- | ||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#cbd5e8"> | |
− | ==== | + | ====Preceding treatment==== |
− | + | *RESORT substudy: First-line [[#Rituximab_monotherapy|Rituximab]], with progression | |
− | *[[ | + | </div> |
− | + | <div class="toccolours" style="background-color:#f2f3f4"> | |
− | ''' | + | ====Targeted therapy==== |
− | + | *[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1 | |
− | === | + | '''7-day cycle for 4 cycles''' |
− | + | </div></div><br> | |
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | = | + | ===Regimen variant #2, 8 doses {{#subobject:5ed834|Variant=1}}=== |
− | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" | |
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161365/ Furman et al. 2014 (GS-US-312-0116)] | ||
+ | |2012-05 to 2013-08 | ||
+ | |style="background-color:#1a9851"|Phase 3 (C) | ||
+ | |[[#Idelalisib_.26_Rituximab|Idelalisib & Rituximab]] | ||
+ | | style="background-color:#d73027" |Inferior PFS | ||
|- | |- | ||
− | |||
|} | |} | ||
− | + | ''Note: Reported efficacy is based on the 2019 update.'' | |
− | + | <div class="toccolours" style="background-color:#f2f3f4"> | |
− | ===Regimen {{#subobject: | + | ====Targeted therapy==== |
− | {| | + | *[[Rituximab (Rituxan)]] as follows: |
− | | | + | **Cycle 1: 375 mg/m<sup>2</sup> IV once on day 1 |
− | |[[Levels_of_Evidence#Evidence| | + | **Cycles 2 to 8: 500 mg/m<sup>2</sup> IV once on day 1 |
− | | | + | '''14-day cycle for 4 cycles, then 21-day cycle for 4 cycles''' |
− | |[[Levels_of_Evidence# | + | </div></div><br> |
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #3, 8 doses alternate schedule {{#subobject:5eac81|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5911578/ Huang et al. 2018 (CR102604)] |
− | + | |2013-2015 | |
− | + | |style="background-color:#1a9851"|Phase 3 (C) | |
− | + | |[[#Ibrutinib_monotherapy_2|Ibrutinib]] | |
− | + | | style="background-color:#fc8d59" |Seems to have inferior OS | |
− | |||
− | | | ||
− | |||
− | |style="background-color:# | ||
− | |||
− | |||
− | |||
− | |[[# | ||
− | |style="background-color:# | ||
|- | |- | ||
|} | |} | ||
− | ==== | + | <div class="toccolours" style="background-color:#f2f3f4"> |
− | + | ====Targeted therapy==== | |
*[[Rituximab (Rituxan)]] as follows: | *[[Rituximab (Rituxan)]] as follows: | ||
− | **Cycle 1: 375 mg/m<sup>2</sup> IV once on day | + | **Cycle 1: 375 mg/m<sup>2</sup> IV once on day 1, then 500 mg/m<sup>2</sup> IV once on day 15 |
− | **Cycles | + | **Cycle 2: 500 mg/m<sup>2</sup> IV once per day on days 1 & 15 |
− | + | **Cycles 3 to 6: 500 mg/m<sup>2</sup> IV once on day 1 | |
− | '''28-day cycle for | + | '''28-day cycle for 6 cycles''' |
− | + | </div></div> | |
===References=== | ===References=== | ||
− | + | # McLaughlin P, Grillo-López AJ, Link BK, Levy R, Czuczman MS, Williams ME, Heyman MR, Bence-Bruckler I, White CA, Cabanillas F, Jain V, Ho AD, Lister J, Wey K, Shen D, Dallaire BK. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998 Aug;16(8):2825-33. [https://doi.org/10.1200/jco.1998.16.8.2825 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/9704735/ PubMed] | |
− | + | # '''GS-US-312-0116:''' Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, Barrientos JC, Zelenetz AD, Kipps TJ, Flinn I, Ghia P, Eradat H, Ervin T, Lamanna N, Coiffier B, Pettitt AR, Ma S, Stilgenbauer S, Cramer P, Aiello M, Johnson DM, Miller LL, Li D, Jahn TM, Dansey RD, Hallek M, O'Brien SM. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014 Mar 13;370(11):997-1007. Epub 2014 Jan 22. [https://doi.org/10.1056/NEJMoa1315226 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161365/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24450857/ PubMed] [https://clinicaltrials.gov/study/NCT01539512 NCT01539512] | |
− | # ''' | + | ## '''Update:''' Sharman JP, Coutre SE, Furman RR, Cheson BD, Pagel JM, Hillmen P, Barrientos JC, Zelenetz AD, Kipps TJ, Flinn IW, Ghia P, Eradat H, Ervin T, Lamanna N, Coiffier B, Pettitt AR, Ma S, Tausch E, Cramer P, Huang J, Mitra S, Hallek M, O'Brien SM, Stilgenbauer S. Final results of a randomized, phase III study of rituximab with or without idelalisib followed by open-label idelalisib in patients with relapsed chronic lymphocytic leukemia. J Clin Oncol. 2019 Jun 1;37(16):1391-1402. Epub 2019 Apr 17. [https://doi.org/10.1200/JCO.18.01460 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10448866/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30995176/ PubMed] |
− | # | + | <!-- Presented in part at the American Society of Clinical Oncology 2012 Annual Meeting, Chicago, IL, USA. --> |
− | <!-- | + | # '''RESORT substudy:''' Williams ME, Hong F, Gascoyne RD, Wagner LI, Krauss JC, Habermann TM, Swinnen LJ, Schuster SJ, Peterson CG, Sborov MD, Martin SE, Weiss M, Ehmann WC, Horning SJ, Kahl BS; Eastern Cooperative Oncology Group. Rituximab extended schedule or retreatment trial for low tumour burden non-follicular indolent B-cell non-Hodgkin lymphomas: Eastern Cooperative Oncology Group Protocol E4402. Br J Haematol. 2016 Jun;173(6):867-75. Epub 2016 Mar 11. [https://doi.org/10.1111/bjh.14007 link to original article] '''dosing details in abstract have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4900920/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26970533/ PubMed] [https://clinicaltrials.gov/study/NCT01406782 NCT01406782] |
− | # ''' | + | # '''CR102604:''' Huang X, Qiu L, Jin J, Zhou D, Chen X, Hou M, Hu J, Hu Y, Ke X, Li J, Liang Y, Liu T, Lv Y, Ren H, Sun A, Wang J, Zhao C, Salman M, Sun S, Howes A, Wang J, Wu P, Li J. Ibrutinib versus rituximab in relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma: a randomized, open-label phase 3 study. Cancer Med. 2018 Apr;7(4):1043-1055. Epub 2018 Mar 13. [https://doi.org/10.1002/cam4.1337 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5911578/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29533000/ PubMed] [https://clinicaltrials.gov/study/NCT01973387 NCT01973387] |
− | # | + | ==Venetoclax & Rituximab {{#subobject:68691a|Regimen=1}}== |
− | + | VenR: '''<u>Ven</u>'''etoclax & '''<u>R</u>'''ituximab | |
− | == | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | {| class="wikitable" style=" | + | ===Regimen {{#subobject:4584a5|Variant=1}}=== |
+ | {| class="wikitable" style="color:white; background-color:#404040" | ||
+ | |<small>'''FDA-recommended dose'''</small> | ||
|- | |- | ||
− | |||
|} | |} | ||
− | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" | |
− | + | !style="width: 20%"|Study | |
− | + | !style="width: 20%"|Dates of enrollment | |
− | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | |
− | | | + | !style="width: 20%"|Comparator |
− | |[[Levels_of_Evidence#Evidence| | + | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] |
− | | | + | |- |
− | |[[Levels_of_Evidence#Efficacy| | + | |[https://doi.org/10.1056/NEJMoa1713976 Seymour et al. 2018 (MURANO)] |
+ | |2014-03-31 to 2015-09-23 | ||
+ | |style="background-color:#1a9851"|Phase 3 (E-RT-switch-ooc) | ||
+ | |[[#Bendamustine_.26_Rituximab_.28BR.29_2|BR]] | ||
+ | | style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>PFS24: 84.9% vs 36.3%<br>(HR 0.17, 95% CI 0.11-0.25)<br><br>Superior OS<sup>1</sup> (secondary endpoint)<br>OS48: 85.3% vs 66.8%<br>(HR 0.41, 95% CI 0.26-0.65) | ||
|- | |- | ||
− | |[ | + | |[https://www.clinicaltrials.gov/study/NCT04965493 Awaiting publication (BRUIN CLL-322)] |
− | | | + | |2021-2025 |
− | |style="background-color:# | + | |style="background-color:#1a9851"|Phase 3 (C) |
− | + | |[[#Pirtobrutinib.2C_Venetoclax.2C_Rituximab|Pirtobrutinib, Venetoclax, Rituximab]] | |
− | + | | style="background-color:#d3d3d3" |TBD if different primary endpoint of PFS | |
− | |||
− | |||
− | |[[# | ||
− | |style="background-color:# | ||
|- | |- | ||
|} | |} | ||
− | + | ''<sup>1</sup>Reported efficacy for OS in MURANO is based on the 2020 update.'' | |
− | '''' | + | <div class="toccolours" style="background-color:#f2f3f4"> |
− | ==== | + | ====Targeted therapy==== |
− | *[[ | + | *[[Venetoclax (Venclexta)]] as follows: |
+ | **Week 1: 20 mg PO once per day | ||
+ | **Week 2: 50 mg PO once per day | ||
+ | **Week 3: 100 mg PO once per day | ||
+ | **Week 4: 200 mg PO once per day | ||
+ | **Weeks 5 up to 104: 400 mg PO once per day | ||
*[[Rituximab (Rituxan)]] as follows: | *[[Rituximab (Rituxan)]] as follows: | ||
− | ** | + | **Week 6: 375 mg/m<sup>2</sup> IV once on day 1 |
− | ** | + | **Weeks 10, 14, 18, 22, 26: 500 mg/m<sup>2</sup> IV once on day 1 |
− | + | '''Up to 2-year course''' | |
− | + | </div></div> | |
− | ''' | ||
===References=== | ===References=== | ||
− | # | + | # '''MURANO:''' Seymour JF, Kipps TJ, Eichhorst B, Hillmen P, D'Rozario J, Assouline S, Owen C, Gerecitano J, Robak T, De la Serna J, Jaeger U, Cartron G, Montillo M, Humerickhouse R, Punnoose EA, Li Y, Boyer M, Humphrey K, Mobasher M, Kater AP. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018 Mar 22;378(12):1107-1120. [https://doi.org/10.1056/NEJMoa1713976 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/29562156/ PubMed] [https://clinicaltrials.gov/study/NCT02005471 NCT02005471] |
− | # | + | ## '''Update:''' Kater AP, Seymour JF, Hillmen P, Eichhorst B, Langerak AW, Owen C, Verdugo M, Wu J, Punnoose EA, Jiang Y, Wang J, Boyer M, Humphrey K, Mobasher M, Kipps TJ. Fixed duration of venetoclax-rituximab in relapsed/refractory chronic lymphocytic leukemia eradicates minimal residual disease and prolongs survival: post-treatment follow-up of the MURANO phase III study. J Clin Oncol. 2019 Feb 1;37(4):269-277. Epub 2018 Dec 3. [https://doi.org/10.1200/JCO.18.01580 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30523712/ PubMed] |
+ | ## '''Update:''' Kater AP, Wu JQ, Kipps T, Eichhorst B, Hillmen P, D'Rozario J, Assouline S, Owen C, Robak T, de la Serna J, Jaeger U, Cartron G, Montillo M, Dubois J, Eldering E, Mellink C, Van Der Kevie-Kersemaekers AM, Kim SY, Chyla B, Punnoose E, Bolen CR, Assaf ZJ, Jiang Y, Wang J, Lefebure M, Boyer M, Humphrey K, Seymour JF. Venetoclax Plus Rituximab in Relapsed Chronic Lymphocytic Leukemia: 4-Year Results and Evaluation of Impact of Genomic Complexity and Gene Mutations From the MURANO Phase III Study. J Clin Oncol. 2020 Dec 1;38(34):4042-4054. Epub 2020 Sep 28. [https://doi.org/10.1200/jco.20.00948 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768340/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32986498/ PubMed] | ||
+ | ## '''Update:''' Seymour JF, Kipps TJ, Eichhorst BF, D'Rozario J, Owen CJ, Assouline S, Lamanna N, Robak T, de la Serna J, Jaeger U, Cartron G, Montillo M, Mellink C, Chyla B, Panchal A, Lu T, Wu JQ, Jiang Y, Lefebure M, Boyer M, Kater AP. Enduring undetectable MRD and updated outcomes in relapsed/refractory CLL after fixed-duration venetoclax-rituximab. Blood. 2022 Aug 25;140(8):839-850. [https://doi.org/10.1182/blood.2021015014 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9412011/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35605176/ PubMed] | ||
+ | # '''BRUIN CLL-322:''' [https://clinicaltrials.gov/study/NCT04965493 NCT04965493] | ||
+ | ==Zanubrutinib monotherapy {{#subobject:67ytze|Regimen=1}}== | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen {{#subobject:1gc1aa|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9928683/ Hillmen et al. 2022 (ALPINE)] | ||
+ | |2018-2020 | ||
+ | |style="background-color:#1a9851"|Phase 3 (E-switch-ic) | ||
+ | |[[#Ibrutinib_monotherapy_2|Ibrutinib]] | ||
+ | | style="background-color:#1a9850" |Superior PFS<sup>1</sup> (secondary endpoint)<br>PFS24: 78.4% vs 65.9%<br>(HR 0.65, 95% CI 0.49-0.86)<br><br>Superior ORR (primary endpoint) | ||
+ | |- | ||
+ | |} | ||
+ | ''<sup>1</sup>Reported efficacy is based on the 2022 update.''<br> | ||
+ | <div class="toccolours" style="background-color:#fdcdac"> | ||
+ | ====Prior treatment criteria==== | ||
+ | *ALPINE: At least 1 prior systemic therapy; prior BTKi not allowed | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
+ | ====Targeted therapy==== | ||
+ | *[[Zanubrutinib (Brukinsa)]] 160 mg PO twice per day on days 1 to 28 | ||
+ | '''28-day cycles''' | ||
+ | </div></div> | ||
+ | ===References=== | ||
+ | <!-- #'''ALPINE:''' Brown JR, Hillmen P, Eichhorst B, Lamanna N, O'Brien S, Tam CS, Qiu L, Kazmierczak M, Zhou K, Šimkovič M, Mayer J, Gillespie-Twardy A, Shadman M, Ferrajoli A, Ganly PS, Weinkove R, Salmi T, Wu K, Novotny W, Jurczak W. CLL-115 First Interim Analysis of ALPINE Study: Results of a Phase 3 Randomized Study of Zanubrutinib vs Ibrutinib in Patients With Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL). Clin Lymphoma Myeloma Leuk. 2022 Oct;22 Suppl 2:S266. [https://doi.org/10.1016/s2152-2650(22)01324-6 link to original abstract]--> | ||
+ | #'''ALPINE:''' Hillmen P, Eichhorst B, Brown JR, Lamanna N, O'Brien SM, Tam CS, Qiu L, Kazmierczak M, Zhou K, Šimkovič M, Mayer J, Gillespie-Twardy A, Shadman M, Ferrajoli A, Ganly PS, Weinkove R, Grosicki S, Mital A, Robak T, Österborg A, Yimer HA, Salmi T, Ji M, Yecies J, Idoine A, Wu K, Huang J, Jurczak W. Zanubrutinib Versus Ibrutinib in Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma: Interim Analysis of a Randomized Phase III Trial. J Clin Oncol. 2023 Feb 10;41(5):1035-1045. Epub 2022 Nov 17. [https://doi.org/10.1200/jco.22.00510 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9928683/ link to PMC article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/36395435/ PubMed] [https://clinicaltrials.gov/study/NCT03734016 NCT03734016] | ||
+ | ##'''Update:''' Brown JR, Eichhorst B, Hillmen P, Jurczak W, Kaźmierczak M, Lamanna N, O'Brien SM, Tam CS, Qiu L, Zhou K, Simkovic M, Mayer J, Gillespie-Twardy A, Ferrajoli A, Ganly PS, Weinkove R, Grosicki S, Mital A, Robak T, Osterborg A, Yimer HA, Salmi T, Wang MD, Fu L, Li J, Wu K, Cohen A, Shadman M. Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. N Engl J Med. 2023 Jan 26;388(4):319-332. Epub 2022 Dec 13. [https://doi.org/10.1056/nejmoa2211582 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36511784/ PubMed] | ||
+ | ##'''HRQoL analysis:''' Tam CS, Lamanna N, O'Brien SM, Qiu L, Yang K, Barnes G, Wu K, Salmi T, Brown JR. Health-related quality of life outcomes associated with zanubrutinib versus ibrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma: results from the ALPINE Trial. Curr Med Res Opin. 2023 Nov;39(11):1497-1503. Epub 2023 Oct 27. [https://doi.org/10.1080/03007995.2023.2262378 link to original article] [https://pubmed.ncbi.nlm.nih.gov/37752892/ PubMed] | ||
− | == | + | =Relapsed or refractory, non-randomized or retrospective data= |
− | {| class="wikitable" style=" | + | ==Alemtuzumab monotherapy {{#subobject:ab5318|Regimen=1}}== |
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #1 {{#subobject:132852|Variant=1}}=== | ||
+ | {| class="wikitable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | |- | ||
+ | |[https://doi.org/10.1182/blood.v99.10.3554 Keating et al. 2002] | ||
+ | |1998 | ||
+ | |style="background-color:#91cf61"|Phase 2 (RT) | ||
+ | |- | ||
+ | |[https://doi.org/10.1200/jco.2002.06.119 Rai et al. 2002] | ||
+ | |Not reported-1994 | ||
+ | |style="background-color:#91cf61"|Phase 2 (RT) | ||
|- | |- | ||
− | |||
|} | |} | ||
− | + | ''Note: total course varies depending on reference.'' | |
− | ===Regimen {{#subobject: | + | <div class="toccolours" style="background-color:#f2f3f4"> |
− | {| | + | ====Targeted therapy==== |
− | | | + | *[[Alemtuzumab (Campath)]] by the following criteria: |
− | |[[Levels_of_Evidence#Evidence| | + | **Starting dose: 3 mg IV once per day |
− | + | **If tolerated in terms of infusion reactions: 10 mg IV once per day | |
− | + | **If tolerated in terms of infusion reactions: 30 mg IV once per day | |
+ | **Once 30 mg dose is tolerated: 30 mg IV over 2 hours, 3 times per week | ||
+ | ====Supportive therapy==== | ||
+ | *''Note: see references for details, as they differ by paper.'' | ||
+ | *[[Diphenhydramine (Benadryl)]] 50 mg PO once per infusion; 30 minutes prior to alemtuzumab | ||
+ | *[[Acetaminophen (Tylenol)]] 650 mg PO once per infusion; 30 minutes prior to alemtuzumab | ||
+ | *[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] 160/800 mg PO 3 times per week, starting on day 8, continuing at a minimum until 2 months after treatment is complete | ||
+ | *[[Famciclovir (Famvir)]] 250 mg PO twice per day, starting on day 8, continuing at a minimum until 2 months after treatment is complete | ||
+ | '''12- to 16-week course''' | ||
+ | </div></div><br> | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #2 {{#subobject:893a|Variant=1}}=== | ||
+ | {| class="wikitable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1182/blood-2003-10-3729 Lozanski et al. 2004] |
− | | | + | |Not reported |
− | + | |style="background-color:#91cf61"|Phase 2 (RT) | |
− | |style="background-color:# | ||
|- | |- | ||
|} | |} | ||
− | ==== | + | <div class="toccolours" style="background-color:#f2f3f4"> |
− | *[[ | + | ====Targeted therapy==== |
− | *[[ | + | *[[Alemtuzumab (Campath)]] 3 mg IV once on day 1, then 10 mg IV once on day 2, then 30 mg IV once on day 3, then 30 mg IV 3 days per week |
− | * | + | ====Supportive therapy==== |
− | + | *[[:Category:Granulocyte colony-stimulating factors|G-CSF]] or [[Sargramostim (Leukine) | GM-CSF]] per institutional protocol | |
− | *[[ | + | *[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] 160/800 mg PO 3 times per week during therapy and continued for 6 months after treatment is complete |
− | + | *[[Acyclovir (Zovirax)]] 800 mg PO three times per day during therapy and continued for 6 months after treatment is complete; similar medication can be used if intolerant of acyclovir | |
− | ''' | + | '''12-week course''' |
− | + | </div></div> | |
===References=== | ===References=== | ||
− | + | # Keating MJ, Flinn I, Jain V, Binet JL, Hillmen P, Byrd J, Albitar M, Brettman L, Santabarbara P, Wacker B, Rai KR. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood. 2002 May 15;99(10):3554-61. [https://doi.org/10.1182/blood.v99.10.3554 link to original article] '''dosing details in abstract have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/11986207/ PubMed] | |
− | # | + | <!-- This work was presented in part at the Forty-Second Annual Meeting of the American Society of Hematology, San Francisco, CA, December 1-5, 2000. --> |
− | # | + | # Rai KR, Freter CE, Mercier RJ, Cooper MR, Mitchell BS, Stadtmauer EA, Santábarbara P, Wacker B, Brettman L. Alemtuzumab in previously treated chronic lymphocytic leukemia patients who also had received fludarabine. J Clin Oncol. 2002 Sep 15;20(18):3891-7. [https://doi.org/10.1200/jco.2002.06.119 link to original article] '''dosing details in abstract have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/12228210/ PubMed] |
− | + | # Lozanski G, Heerema NA, Flinn IW, Smith L, Harbison J, Webb J, Moran M, Lucas M, Lin T, Hackbarth ML, Proffitt JH, Lucas D, Grever MR, Byrd JC. Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions. Blood. 2004 May 1;103(9):3278-81. Epub 2004 Jan 15. [https://doi.org/10.1182/blood-2003-10-3729 link to original article] '''dosing details in abstract have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/14726385/ PubMed] | |
− | == | + | ==Alemtuzumab & Rituximab {{#subobject:b3ab64|Regimen=1}}== |
− | {| class="wikitable" style=" | + | <div class="toccolours" style="background-color:#eeeeee"> |
+ | ===Regimen {{#subobject:ed4d6e|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | |- | ||
+ | |[https://doi.org/10.1182/blood-2002-07-1952 Faderl et al. 2003] | ||
+ | |Not reported | ||
+ | |style="background-color:#91cf61"|Phase 2 | ||
|- | |- | ||
− | |||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#f2f3f4"> | |
− | + | ====Targeted therapy==== | |
− | ===Regimen {{#subobject: | + | *[[Alemtuzumab (Campath)]] 3 mg IV once on day 1, then 10 mg IV once on day 2, then 30 mg IV once on day 3 of week 1, then 30 mg IV once per day on days 10, 12, 17, 19, 24, 26 (i.e. days 3 and 5 of weeks 2 to 4) |
− | {| | + | *[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22 |
− | | | + | **For patients with WBC count more than 50 x 10<sup>9</sup>/L, the first dose was split into 100 mg/m<sup>2</sup> IV once on day 1, then 275 mg/m<sup>2</sup> IV once on day 2 |
− | |[[Levels_of_Evidence#Evidence| | + | ====Supportive therapy==== |
− | + | *Prophylactic [[Trimethoprim-Sulfamethoxazole (Bactrim DS)]], given during therapy and continuing at a minimum until 2 months after treatment is complete | |
− | |[[Levels_of_Evidence#Efficacy| | + | *Prophylactic [[Valacyclovir (Valtrex)]] (or equivalent), given during therapy and continuing at a minimum until 2 months after treatment is complete |
+ | '''28-day cycle for 1 to 2 cycles depending on response and toxicity''' | ||
+ | </div></div> | ||
+ | ===References=== | ||
+ | # Faderl S, Thomas DA, O'Brien S, Garcia-Manero G, Kantarjian HM, Giles FJ, Koller C, Ferrajoli A, Verstovsek S, Pro B, Andreeff M, Beran M, Cortes J, Wierda W, Tran N, Keating MJ. Experience with alemtuzumab plus rituximab in patients with relapsed and refractory lymphoid malignancies. Blood. 2003 May 1;101(9):3413-5. Epub 2003 Jan 9. [https://doi.org/10.1182/blood-2002-07-1952 link to original article] '''dosing details in abstract have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/12522009/ PubMed] | ||
+ | ==Bendamustine & Ofatumumab {{#subobject:4eab04|Regimen=1}}== | ||
+ | BendOfa: '''<u>Bend</u>'''amustine & '''<u>Ofa</u>'''tumumab | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen {{#subobject:c1d63f|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 80%; text-align:center;" | ||
+ | !style="width: 25%"|Study | ||
+ | !style="width: 25%"|Dates of enrollment | ||
+ | !style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]] | ||
|- | |- | ||
− | + | |[https://doi.org/10.1038/leu.2013.334 Cortelezzi et al. 2013 (GIMEMA CLL0809)] | |
− | | | + | |2010-2011 |
− | + | |style="background-color:#91cf61"|Phase 2 | |
− | |style="background-color:# | + | | style="background-color:#bfd3e6" |ORR: 72% (95% CI, 57–84%) |
− | |||
− | |||
− | |style="background-color:# | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[ | + | *[[Bendamustine]] 70 mg/m<sup>2</sup> IV once per day on days 1 & 2 |
− | *[[ | + | ====Targeted therapy==== |
− | + | *[[Ofatumumab (Arzerra)]] as follows: | |
− | ====Supportive | + | **Cycle 1: 300 mg IV once on day 1, then 1000 mg IV once on day 7 |
− | * | + | **Cycles 2 to 6: 1000 mg IV once on day 1 |
− | + | ====Supportive therapy==== | |
+ | *[[Acetaminophen (Tylenol)]] 1000 mg PO once per infusion, prior to ofatumumab | ||
+ | *[[Diphenhydramine (Benadryl)]] 50 mg PO once per infusion, prior to ofatumumab | ||
+ | *[[Methylprednisolone (Solumedrol)]] 40 mg IV once per infusion, prior to ofatumumab | ||
+ | *[[Allopurinol (Zyloprim)]] or [[Rasburicase (Elitek)]] required for prophylaxis against TLS; dose not specified | ||
+ | *[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] required; dose not specified | ||
+ | *[[Acyclovir (Zovirax)]] required; dose not specified | ||
'''28-day cycle for up to 6 cycles''' | '''28-day cycle for up to 6 cycles''' | ||
− | + | </div></div> | |
===References=== | ===References=== | ||
− | + | # '''GIMEMA CLL0809:''' Cortelezzi A, Sciumè M, Liberati AM, Vincenti D, Cuneo A, Reda G, Laurenti L, Zaja F, Marasca R, Chiarenza A, Gritti G, Orsucci L, Storti S, Angelucci E, Cascavilla N, Gobbi M, Mauro FR, Morabito F, Fabris S, Piciocchi A, Vignetti M, Neri A, Rossi D, Giannarelli D, Guarini A, Foà R. Bendamustine in combination with ofatumumab in relapsed or refractory chronic lymphocytic leukemia: a GIMEMA multicenter phase II trial. Leukemia. 2014 Mar;28(3):642-8. Epub 2013 Nov 13. [https://doi.org/10.1038/leu.2013.334 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/24220274/ PubMed] [https://clinicaltrials.gov/study/NCT01244451 NCT01244451] | |
− | |||
− | == | + | ==CFAR {{#subobject:6cf406|Regimen=1}}== |
− | {| class="wikitable" style=" | + | CFAR: '''<u>C</u>'''yclophosphamide, '''<u>F</u>'''ludarabine, '''<u>A</u>'''lemtuzumab, '''<u>R</u>'''ituximab |
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen {{#subobject:40c38d|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 80%; text-align:center;" | ||
+ | !style="width: 25%"|Study | ||
+ | !style="width: 25%"|Dates of enrollment | ||
+ | !style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]] | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123326/ Badoux et al. 2011 (MDACC DM02-593)] | ||
+ | |2002-2006 | ||
+ | |style="background-color:#91cf61"|Phase 2 | ||
+ | | style="background-color:#bfd3e6" |ORR: 65% | ||
|- | |- | ||
− | |||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#f2f3f4"> | |
− | === | + | ====Chemotherapy==== |
− | + | *[[Cyclophosphamide (Cytoxan)]] 250 mg/m<sup>2</sup> IV once per day on days 3 to 5 | |
− | + | *[[Fludarabine (Fludara)]] 25 mg/m<sup>2</sup> IV once per day on days 3 to 5 | |
− | + | ====Targeted therapy==== | |
− | + | *[[Alemtuzumab (Campath)]] 30 mg IV once per day on days 1, 3, 5 | |
− | + | *[[Rituximab (Rituxan)]] as follows: | |
− | + | **Cycle 1: 375 mg/m<sup>2</sup> IV once on day 2 | |
− | + | **Cycles 2 to 6: 500 mg/m<sup>2</sup> IV once on day 2 | |
− | | | + | ====Supportive therapy==== |
− | | | + | *[[Allopurinol (Zyloprim)]] as follows: |
− | |style=" | + | **Cycle 1: 300 mg PO once per day on days 1 to 7 |
+ | *[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] 160/800 mg PO twice per day | ||
+ | *Antiviral prophylaxis with ONE of the following: | ||
+ | **[[Valacyclovir (Valtrex)]] 500 mg PO once per day | ||
+ | **[[Valganciclovir (Valcyte)]] 450 mg PO twice per day | ||
+ | *[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 6 | ||
+ | *At physician's discretion: | ||
+ | **[[Acetaminophen (Tylenol)]] 650 mg PO once per day on days 1, 2, 3, 5; 30 minutes prior to rituximab/[[Alemtuzumab (Campath)]] | ||
+ | **[[Diphenhydramine (Benadryl)]] 25 to 50 mg IV or PO once per day on days 1, 2, 3, 5; 30 minutes prior to rituximab/[[Alemtuzumab (Campath)]] | ||
+ | **[[Hydrocortisone (Cortef)]] 100 mg IV once per day on days 1, 2, 3, 5; 30 minutes prior to alemtuzumab | ||
+ | '''28-day cycle for 6 cycles''' | ||
+ | </div></div> | ||
+ | ===References=== | ||
+ | # '''MDACC DM02-593:''' Badoux XC, Keating MJ, Wang X, O'Brien SM, Ferrajoli A, Faderl S, Burger J, Koller C, Lerner S, Kantarjian H, Wierda WG. Cyclophosphamide, fludarabine, alemtuzumab, and rituximab as salvage therapy for heavily pretreated patients with chronic lymphocytic leukemia. Blood. 2011 Aug 25;118(8):2085-93. Epub 2011 Jun 13. [https://doi.org/10.1182/blood-2011-03-341032 link to original article] '''dosing details in abstract have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123326/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21670470/ PubMed] [https://clinicaltrials.gov/study/NCT01082939 NCT01082939] | ||
+ | ==DFCR {{#subobject:b079e8|Regimen=1}}== | ||
+ | DFCR: '''<u>D</u>'''uvelisib, '''<u>F</u>'''ludarabine, '''<u>C</u>'''yclophosphamide, '''<u>R</u>'''ituximab | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen {{#subobject:3a84a1|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7895867/ Davids et al. 2020 (DFCI 14-193)] |
− | |style="background-color:# | + | |2014-2016 |
+ | |style="background-color:#91cf61"|Phase 1b/2 | ||
|- | |- | ||
|} | |} | ||
+ | ''Note: This is the phase 2 dosing.'' | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
+ | ====Targeted therapy==== | ||
+ | *[[Duvelisib (Copiktra)]] 25 mg PO twice per day | ||
+ | *[[Rituximab (Rituxan)]] as follows: | ||
+ | **Cycle 1: 375 mg/m<sup>2</sup> IV once on day 1 | ||
+ | **Cycles 2 to 6: 500 mg/m<sup>2</sup> IV once on day 1 | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[ | + | *[[Fludarabine (Fludara)]] as follows: |
− | + | **Cycles 1 to 6: 25 mg/m<sup>2</sup> IV once per day on days 1 to 3 | |
− | '''28-day cycle for up to | + | *[[Cyclophosphamide (Cytoxan)]] as follows: |
− | + | **Cycles 1 to 6: 250 mg/m<sup>2</sup> IV once per day on days 1 to 3 | |
+ | '''28-day cycle for up to 26 cycles (2 years) | ||
+ | </div></div> | ||
===References=== | ===References=== | ||
− | + | #'''DFCI 14-193:''' Davids MS, Fisher DC, Tyekucheva S, McDonough M, Hanna J, Lee B, Francoeur K, Montegaard J, Odejide O, Armand P, Arnason J, Brown JR. A phase 1b/2 study of duvelisib in combination with FCR (DFCR) for frontline therapy for younger CLL patients. Leukemia. 2021 Apr;35(4):1064-1072. Epub 2020 Aug 20. [https://doi.org/10.1038/s41375-020-01010-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7895867/ link to PMC article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/32820271/ PubMed] [https://clinicaltrials.gov/study/NCT02158091 NCT02158091] | |
− | # | + | ==Fludarabine & Alemtuzumab {{#subobject:29fdc1|Regimen=1}}== |
− | + | FluCam: '''<u>Flu</u>'''darabine & '''<u>Cam</u>'''path (Alemtuzumab) | |
− | == | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | + | ===Regimen {{#subobject:3a84a1|Variant=1}}=== | |
− | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" | |
− | + | !style="width: 33%"|Study | |
− | + | !style="width: 33%"|Dates of enrollment | |
− | + | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | |
− | |||
− | ===Regimen {{#subobject: | ||
− | {| | ||
− | | | ||
− | |[[Levels_of_Evidence#Evidence| | ||
− | |||
− | |||
|- | |- | ||
− | + | |[https://doi.org/10.1200/jco.2005.01.9950 Elter et al. 2005] | |
− | + | |Not reported | |
− | + | |style="background-color:#91cf61"|Phase 2 | |
− | | | ||
− | |||
− | |||
− | |style="background-color:# | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[ | + | *[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV once per day on days 1 to 3 |
− | *[[ | + | ====Targeted therapy==== |
− | *[[ | + | *[[Alemtuzumab (Campath)]] as follows: |
− | + | **Cycle 1: 3 mg IV once on day 1, then 10 mg IV once on day 2, then 30 mg IV once on day 3 | |
− | '''28-day cycle for | + | **Cycles 2 to 6: 30 mg IV once per day on days 1 to 3 |
− | + | ====Supportive therapy==== | |
+ | *[[Trimethoprim-Sulfamethoxazole (Bactrim DS) | Trimethoprim/Sulfamethoxazole]] 960 mg (paper did not specify which component was 960 mg) PO once per day, started on day 1 and continued at least 2 months after treatment is complete | ||
+ | *[[Valacyclovir (Valtrex)]] 500 mg PO twice per day, started on day 1 and continued at least 2 months after treatment is complete | ||
+ | **If patients experienced CMV (cytomegalovirus) reactivation, valacyclovir was replaced by (val)ganciclovir 500 mg PO or IV three times per day | ||
+ | *[[Fluconazole (Diflucan)]] 100 mg PO once per day, started if patients had evidence of fungal infection, continued until resolution | ||
+ | *[[Acetaminophen (Tylenol)]] 1000 mg PO once on day 1, prior to first dose of alemtuzumab, then with subsequent doses if clinically indicated | ||
+ | *[[Clemastine (Tavist)]] 2 mg IV once on day 1, prior to first dose of alemtuzumab, then with subsequent doses if clinically indicated | ||
+ | *[[Prednisone (Sterapred)]] 100 mg IV once on day 1, prior to first dose of alemtuzumab, then with subsequent doses if clinically indicated | ||
+ | *For patients with WBC count more than 50 x 10<sup>9</sup>/L, bulky disease, or history of hyperuricemia: [[Allopurinol (Zyloprim)]] 300 mg PO once on day 1, prior to first dose of alemtuzumab, and used later if clinically indicated | ||
+ | '''28-day cycle for 6 cycles''' | ||
+ | </div></div> | ||
===References=== | ===References=== | ||
− | + | # Elter T, Borchmann P, Schulz H, Reiser M, Trelle S, Schnell R, Jensen M, Staib P, Schinköthe T, Stützer H, Rech J, Gramatzki M, Aulitzky W, Hasan I, Josting A, Hallek M, Engert A. Fludarabine in combination with alemtuzumab is effective and feasible in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: results of a phase II trial. J Clin Oncol. 2005 Oct 1;23(28):7024-31. Epub 2005 Sep 6. [https://doi.org/10.1200/jco.2005.01.9950 link to original article] '''dosing details in abstract have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/16145065/ PubMed] | |
− | + | ==Fludarabine & Ibrutinib {{#subobject:30udc1|Regimen=1}}== | |
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | == | + | ===Regimen {{#subobject:t454a1|Variant=1}}=== |
− | {| class="wikitable" style=" | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8932338/ Pleyer et al. 2020 (NIH 15-H-0172)] |
− | + | |2015-2019 | |
− | + | |style="background-color:#91cf61"|Phase 2 | |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | | | ||
− | |||
− | |style="background-color:# | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[Fludarabine (Fludara)]] | + | *[[Fludarabine (Fludara)]] as follows: |
− | * | + | **Cycles 3 & 4: 25 mg/m<sup>2</sup> IV once per day on days 1 to 5 |
− | + | ====Targeted therapy==== | |
− | ==== | + | *[[Ibrutinib (Imbruvica)]] 420 mg PO once per day on days 1 to 28 |
− | + | '''28-day cycles''' | |
− | *[[ | + | </div></div> |
− | |||
− | |||
− | |||
− | |||
− | '''28-day | ||
− | |||
===References=== | ===References=== | ||
− | + | # '''NIH 15-H-0172:''' Pleyer C, Tian X, Rampertaap S, Mu R, Soto S, Superata J, Gaglione E, Sun C, Lotter J, Stetler-Stevenson M, Yuan CM, Maric I, Pittaluga S, Rosenzweig S, Fleisher T, Wiestner A, Ahn IE. A phase II study of ibrutinib and short-course fludarabine in previously untreated patients with chronic lymphocytic leukemia. Am J Hematol. 2020 Nov;95(11):E310-E313. Epub 2020 Sep 8. [https://doi.org/10.1002/ajh.25968 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8932338/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32808680/ PubMed] [https://clinicaltrials.gov/study/NCT02514083 NCT02514083] | |
− | + | ==Fludarabine & Prednisone {{#subobject:a00ad0|Regimen=1}}== | |
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | == | + | ===Regimen {{#subobject:b907b6|Variant=1}}=== |
− | {| class="wikitable" style=" | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | |- | ||
+ | |[https://doi.org/10.1182/blood.V82.6.1695.1695 O'Brien et al. 1993] | ||
+ | |1988-1991 | ||
+ | |style="background-color:#91cf61"|Phase 2 | ||
|- | |- | ||
− | |||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#f2f3f4"> | |
− | + | ====Chemotherapy==== | |
− | + | *[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5 | |
− | ===Regimen #1 {{#subobject: | + | ====Glucocorticoid therapy==== |
− | {| | + | *[[Prednisone (Sterapred)]] 30 mg/m<sup>2</sup> PO once per day on days 1 to 5 |
− | | | + | '''28-day cycles''' |
− | |[[Levels_of_Evidence#Evidence| | + | </div></div> |
− | + | ===References=== | |
− | + | # O'Brien S, Kantarjian H, Beran M, Smith T, Koller C, Estey E, Robertson LE, Lerner S, Keating M. Results of fludarabine and prednisone therapy in 264 patients with chronic lymphocytic leukemia with multivariate analysis-derived prognostic model for response to treatment. Blood. 1993 Sep 15;82(6):1695-700. [https://doi.org/10.1182/blood.V82.6.1695.1695 link to original article] '''dosing details in abstract have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/8400226/ PubMed] | |
+ | ## '''Update:''' Keating MJ, O'Brien S, Lerner S, Koller C, Beran M, Robertson LE, Freireich EJ, Estey E, Kantarjian H. Long-term follow-up of patients with chronic lymphocytic leukemia (CLL) receiving fludarabine regimens as initial therapy. Blood. 1998 Aug 15;92(4):1165-71. [https://doi.org/10.1182/blood.V92.4.1165 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9694704/ PubMed] | ||
+ | ==HDMP-R {{#subobject:b15642|Regimen=1}}== | ||
+ | HDMP-R: '''<u>H</u>'''igh '''<u>D</u>'''ose, '''<u>M</u>'''ethyl'''<u>P</u>'''rednisolone, '''<u>R</u>'''ituximab | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #1, 3 cycles {{#subobject:89350e|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5289283/ Castro et al. 2008] |
− | | | + | |Not reported |
− | + | | style="background-color:#ffffbe" |Phase 2, fewer than 20 pts | |
− | |style="background-color:# | ||
|- | |- | ||
|} | |} | ||
− | ==== | + | <div class="toccolours" style="background-color:#f2f3f4"> |
− | *[[ | + | ====Glucocorticoid therapy==== |
− | + | *[[Methylprednisolone (Solumedrol)]] 1000 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1 to 5 | |
− | + | ====Targeted therapy==== | |
− | *[[ | + | *[[Rituximab (Rituxan)]] as follows: |
− | **Cycle 1: | + | **Cycle 1: 375 mg/m<sup>2</sup> IV once per day on days 1, 3, 5, 8, 17, 22 |
− | **Cycles 2 | + | **Cycles 2 & 3: 375 mg/m<sup>2</sup> IV once per day on days 1, 7, 14, 21 |
− | + | '''28-day cycle for 3 cycles''' | |
− | + | </div></div><br> | |
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | + | ===Regimen variant #2, 6 cycles {{#subobject:323ca5|Variant=1}}=== | |
− | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" | |
− | + | !style="width: 33%"|Study | |
− | + | !style="width: 33%"|Dates of enrollment | |
− | + | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | |
− | '''28-day cycle for | ||
− | |||
− | ===Regimen #2 {{#subobject: | ||
− | {| | ||
− | | | ||
− | |[[Levels_of_Evidence#Evidence| | ||
− | |||
− | |||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.3109/10428194.2011.562572 Pileckyte et al. 2011 (LT-CLL-001)] |
− | | | + | |2007-09 to 2009-01 |
− | + | |style="background-color:#91cf61"|Phase 2 | |
− | |style="background-color:# | ||
|- | |- | ||
|} | |} | ||
− | ==== | + | <div class="toccolours" style="background-color:#f2f3f4"> |
− | *[[ | + | ====Glucocorticoid therapy==== |
− | + | *[[Methylprednisolone (Solumedrol)]] 1000 mg/m<sup>2</sup> IV over 4 hours once per day on days 1 to 5 | |
+ | ====Targeted therapy==== | ||
*[[Rituximab (Rituxan)]] as follows: | *[[Rituximab (Rituxan)]] as follows: | ||
− | **Cycle 1: 375 mg/m<sup>2</sup> IV once on day | + | **Cycle 1: 50 mg IV once on day 1, then 150 mg IV once on day 2, then remainder of a 375 mg/m<sup>2</sup> dose IV once on day 3, then 500 mg/m<sup>2</sup> IV once on day 5 |
− | **Cycles 2 to 6: 500 mg/m<sup>2</sup> IV once on | + | **Cycles 2 to 6: 500 mg/m<sup>2</sup> IV once per day on days 1 & 5 |
− | + | ====Supportive therapy==== | |
− | ====Supportive | + | *[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Trimethoprim/sulfamethoxazole]] "or an equivalent antibiotic throughout the treatment period and up to 6 months after the completion of therapy" |
− | + | '''21-day cycle for 6 cycles''' | |
− | + | </div></div> | |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | ''' | ||
− | |||
===References=== | ===References=== | ||
− | + | # Castro JE, Sandoval-Sus JD, Bole J, Rassenti L, Kipps TJ. Rituximab in combination with high-dose methylprednisolone for the treatment of fludarabine refractory high-risk chronic lymphocytic leukemia. Leukemia. 2008 Nov;22(11):2048-53. Epub 2008 Aug 28. [https://doi.org/10.1038/leu.2008.214 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5289283/ link to PMC article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/18754025/ PubMed] | |
− | # | + | # '''LT-CLL-001:''' Pileckyte R, Jurgutis M, Valceckiene V, Stoskus M, Gineikiene E, Sejoniene J, Degulys A, Zvirblis T, Griskevicius L. Dose-dense high-dose methylprednisolone and rituximab in the treatment of relapsed or refractory high-risk chronic lymphocytic leukemia. Leuk Lymphoma. 2011 Jun;52(6):1055-65. [https://doi.org/10.3109/10428194.2011.562572 link to original article] '''dosing details in abstract have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/21599591/ PubMed] [https://clinicaltrials.gov/study/NCT00558181 NCT00558181] |
− | # | ||
− | == | + | ==Ibrutinib & Ofatumumab {{#subobject:2a71b9|Regimen=1}}== |
− | {| class="wikitable" style=" | + | <div class="toccolours" style="background-color:#eeeeee"> |
+ | ===Regimen variant #1, concurrent ibrutinib and ofatumumab {{#subobject:e85085|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536539/ Jaglowski et al. 2015 (PCYC-1109-CA)] | ||
+ | |2011-2012 | ||
+ | |style="background-color:#91cf61"|Phase 2 | ||
+ | |- | ||
+ | |} | ||
+ | <div class="toccolours" style="background-color:#fdcdac"> | ||
+ | ====Prior treatment criteria==== | ||
+ | *Failure of two or more prior therapies, or Richter transformation | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
+ | ====Targeted therapy==== | ||
+ | *[[Ibrutinib (Imbruvica)]] 420 mg PO once per day on days 1 to 28 | ||
+ | *[[Ofatumumab (Arzerra)]] as follows: | ||
+ | **Cycle 1: 300 mg IV once on day 1, then 2000 mg IV once per day on days 8, 15, 22 | ||
+ | **Cycle 2: 2000 mg IV once per day on days 1, 8, 15, 22 | ||
+ | **Cycles 3 to 6: 2000 mg IV once on day 1 | ||
+ | '''28-day cycles''' | ||
+ | </div></div><br> | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #2, ibrutinib lead-in {{#subobject:3ac7f5|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536539/ Jaglowski et al. 2015 (PCYC-1109-CA)] | ||
+ | |2011-2012 | ||
+ | |style="background-color:#91cf61"|Phase 2 | ||
|- | |- | ||
− | |||
|} | |} | ||
− | ===Regimen {{#subobject: | + | <div class="toccolours" style="background-color:#fdcdac"> |
− | {| | + | ====Prior treatment criteria==== |
− | | | + | *Failure of two or more prior therapies, or Richter transformation |
− | |[[Levels_of_Evidence#Evidence| | + | </div> |
− | + | <div class="toccolours" style="background-color:#f2f3f4"> | |
− | + | ====Targeted therapy==== | |
+ | *[[Ibrutinib (Imbruvica)]] 420 mg PO once per day on days 1 to 28 | ||
+ | *[[Ofatumumab (Arzerra)]] as follows: | ||
+ | **Cycle 2: 300 mg IV once on day 1, then 2000 mg IV once per day on days 8, 15, 22 | ||
+ | **Cycle 3: 2000 mg IV once per day on days 1, 8, 15, 22 | ||
+ | **Cycles 4 to 7: 2000 mg IV once on day 1 | ||
+ | '''28-day cycles''' | ||
+ | </div></div><br> | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #3, ofatumumab lead-in {{#subobject:a6c1e7|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536539/ Jaglowski et al. 2015 (PCYC-1109-CA)] |
− | | | + | |2011-2012 |
− | + | |style="background-color:#91cf61"|Phase 2 | |
− | |style="background-color:# | ||
|- | |- | ||
|} | |} | ||
− | ==== | + | <div class="toccolours" style="background-color:#fdcdac"> |
− | *[[ | + | ====Prior treatment criteria==== |
− | + | *Failure of two or more prior therapies, or Richter transformation | |
− | '''28-day | + | </div> |
− | + | <div class="toccolours" style="background-color:#f2f3f4"> | |
+ | ====Targeted therapy==== | ||
+ | *[[Ibrutinib (Imbruvica)]] as follows: | ||
+ | **Cycle 3 onwards: 420 mg PO once per day on days 1 to 28 | ||
+ | *[[Ofatumumab (Arzerra)]] as follows: | ||
+ | **Cycle 1: 300 mg IV once on day 1, then 2000 mg IV once per day on days 8, 15, 22 | ||
+ | **Cycle 2: 2000 mg IV once per day on days 1, 8, 15, 22 | ||
+ | **Cycles 3 to 6: 2000 mg IV once on day 1 | ||
+ | '''28-day cycles''' | ||
+ | </div></div> | ||
===References=== | ===References=== | ||
− | # | + | <!-- Presented in part as a poster presentation at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, May 30 to June 3, 2014, and as an oral presentation at the 2012 ASCO Annual Meeting, Chicago, IL, June 1 to 5, 2012. --> |
− | + | # '''PCYC-1109-CA:''' Jaglowski SM, Jones JA, Nagar V, Flynn JM, Andritsos LA, Maddocks KJ, Woyach JA, Blum KA, Grever MR, Smucker K, Ruppert AS, Heerema NA, Lozanski G, Stefanos M, Munneke B, West JS, Neuenburg JK, James DF, Hall N, Johnson AJ, Byrd JC. Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab in chronic lymphocytic leukemia: a phase 1b/2 study. Blood. 2015 Aug 13;126(7):842-50. Epub 2015 Jun 26. [https://doi.org/10.1182/blood-2014-12-617522 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536539/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26116658/ PubMed] [https://clinicaltrials.gov/study/NCT01217749 NCT01217749] | |
− | ==Ibrutinib | + | ==Ibrutinib & Rituximab {{#subobject:503e48|Regimen=1}}== |
− | {| class="wikitable" style=" | + | <div class="toccolours" style="background-color:#eeeeee"> |
+ | ===Regimen {{#subobject:673f95|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | |- | ||
+ | |[https://doi.org/10.1016/S1470-2045(14)70335-3 Burger et al. 2014 (MDACC 2011-0785)] | ||
+ | |2012 | ||
+ | |style="background-color:#91cf61"|Phase 2 | ||
|- | |- | ||
− | |||
|} | |} | ||
− | + | ''Note: Only 4 patients in the published study were untreated.'' | |
− | === | + | <div class="toccolours" style="background-color:#fdcdac"> |
− | + | ====Eligibility criteria==== | |
− | + | *Patients with high-risk CLL (del17p or TP53 mutation, PFS less than 36 months from initial therapy, or relapsed CLL with del11q) | |
− | + | </div> | |
− | + | <div class="toccolours" style="background-color:#f2f3f4"> | |
− | |[[Levels_of_Evidence# | + | ====Targeted therapy==== |
+ | *[[Ibrutinib (Imbruvica)]] 420 mg PO once per day on days 1 to 28 | ||
+ | *[[Rituximab (Rituxan)]] as follows: | ||
+ | **Cycle 1: 375 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22 | ||
+ | **Cycles 2 to 6: 375 mg/m<sup>2</sup> IV once on day 1 | ||
+ | '''28-day cycles''' | ||
+ | </div></div> | ||
+ | ===References=== | ||
+ | <!-- # '''Abstract:''' Michael J. Keating, William G. Wierda, Julia Hoellenriegel, Ghayathri Jeyakumar, Alessandra Ferrajoli, Stefan H. Faderl, Marylou Cardenas-Turanzas, Susan Lerner, Gracy Zacharian, Xuelin Huang, Hagop M. Kantarjian, Susan O'Brien. Ibrutinib In Combination With Rituximab (iR) Is Well Tolerated and Induces a High Rate Of Durable Remissions In Patients With High-Risk Chronic Lymphocytic Leukemia (CLL): New, Updated Results Of a Phase II Trial In 40 Patients. Blood Nov 2013,122(21)675. [https://doi.org/10.1182/blood.V122.21.675.675 link to original abstract] --> | ||
+ | # '''MDACC 2011-0785:''' Burger JA, Keating MJ, Wierda WG, Hartmann E, Hoellenriegel J, Rosin NY, de Weerdt I, Jeyakumar G, Ferrajoli A, Cardenas-Turanzas M, Lerner S, Jorgensen JL, Nogueras-González GM, Zacharian G, Huang X, Kantarjian H, Garg N, Rosenwald A, O'Brien S. Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study. Lancet Oncol. 2014 Sep;15(10):1090-9. Epub 2014 Aug 20. [https://doi.org/10.1016/S1470-2045(14)70335-3 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4174348/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25150798/ PubMed] [https://clinicaltrials.gov/study/NCT01520519 NCT01520519] | ||
+ | ## '''Update:''' Jain P, Keating MJ, Wierda WG, Sivina M, Thompson PA, Ferrajoli A, Estrov Z, Kantarjian H, O'Brien S, Burger JA. Long-term follow-up of treatment with ibrutinib and rituximab in patients with high-risk chronic lymphocytic leukemia. Clin Cancer Res. 2017 May 1;23(9):2154-2158. Epub 2016 Oct 19. [https://doi.org/10.1158/1078-0432.ccr-16-1948 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5397369/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27797975/ PubMed] | ||
+ | ==Ibrutinib, Venetoclax, Obinutuzumab {{#subobject:78gu1g|Regimen=1}}== | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen {{#subobject:52rgcc|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7605394/ Rogers et al. 2020 (OSU-14266)] |
− | | | + | |2015-2017 |
− | + | |style="background-color:#91cf61"|Phase 2 | |
− | |style="background-color:# | ||
|- | |- | ||
− | |[ | + | |} |
− | |style="background-color:# | + | <div class="toccolours" style="background-color:#f2f3f4"> |
− | | | + | ====Targeted therapy==== |
− | |style=" | + | *[[Ibrutinib (Imbruvica)]] as follows: |
+ | **Cycle 2 onwards: 420 mg PO once per day on days 1 to 28 | ||
+ | *[[Venetoclax (Venclexta)]] as follows: | ||
+ | **Cycle 3: 20 mg PO once per day on days 1 to 7, then 50 mg PO once per day on days 8 to 14, then 100 mg PO once per day on days 15 to 21, then 200 mg PO once per day on days 22 to 28 | ||
+ | **Cycles 4 to 14: 400 mg PO once per day on days 1 to 28 | ||
+ | *[[Obinutuzumab (Gazyva)]] as follows: | ||
+ | **Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15 | ||
+ | **Cycles 2 to 8: 1000 mg IV once on day 1 | ||
+ | '''28-day cycles''' | ||
+ | </div></div> | ||
+ | ===References=== | ||
+ | # '''OSU-14266:''' Rogers KA, Huang Y, Ruppert AS, Abruzzo LV, Andersen BL, Awan FT, Bhat SA, Dean A, Lucas M, Banks C, Grantier C, Heerema NA, Lozanski G, Maddocks KJ, Valentine TR, Weiss DM, Jones JA, Woyach JA, Byrd JC. Phase II Study of Combination Obinutuzumab, Ibrutinib, and Venetoclax in Treatment-Naïve and Relapsed or Refractory Chronic Lymphocytic Leukemia. J Clin Oncol. 2020 Nov 1;38(31):3626-3637. Epub 2020 Aug 14. [https://doi.org/10.1200/jco.20.00491 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7605394/ link to PMC article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/32795224/ PubMed] [https://clinicaltrials.gov/study/NCT02427451 NCT02427451] | ||
+ | ==Idelalisib monotherapy {{#subobject:b872c5|Regimen=1}}== | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen {{#subobject:5cabd0|Variant=1}}=== | ||
+ | {| class="wikitable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123414/ Brown et al. 2014 (Gilead 101-02)] |
− | |style="background-color:# | + | |2008-2011 |
− | + | |style="background-color:#91cf61"|Phase 1, >20 pts | |
− | |||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4039496/ Gopal et al. 2014 (DELTA)] |
− | | | + | |2011-2012 |
− | |style="background-color:# | + | |style="background-color:#91cf61"|Phase 2 (RT) |
− | |||
|- | |- | ||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#f2f3f4"> | |
− | ==== | + | ====Targeted therapy==== |
− | *[[ | + | *[[Idelalisib (Zydelig)]] 150 mg PO twice per day |
− | + | '''Continued indefinitely''' | |
− | ''' | + | </div></div> |
− | |||
===References=== | ===References=== | ||
− | # | + | # '''DELTA:''' Gopal AK, Kahl BS, de Vos S, Wagner-Johnston ND, Schuster SJ, Jurczak WJ, Flinn IW, Flowers CR, Martin P, Viardot A, Blum KA, Goy AH, Davies AJ, Zinzani PL, Dreyling M, Johnson D, Miller LL, Holes L, Li D, Dansey RD, Godfrey WR, Salles GA. PI3Kd inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014 Mar 13;370(11):1008-18. Epub 2014 Jan 22. [https://doi.org/10.1056/NEJMoa1314583 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4039496/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24450858/ PubMed] [https://clinicaltrials.gov/study/NCT01282424 NCT01282424] |
− | + | ## '''Update:''' '''Abstract:''' Ajay K. Gopal, MD, Brad S. Kahl, MD, Sven de Vos, MD, PhD, Nina D. Wagner-Johnston, MD, Stephen J. Schuster, MD, Wojciech Jurczak, MD, PhD, Ian W. Flinn, MD, PhD, Christopher R. Flowers, MD, Peter Martin, MD, Andreas Viardot, MD, Kristie A. Blum, MD, Andre Goy, MD, Andrew Davies, BM PhD, Pier Luigi Zinzani, MD, Martin H. Dreyling, MD, PhD, Leanne M. Holes, Bess Sorensen, PhD, Wayne R. Godfrey, MD and Gilles Andre Salles, MD, PhD. Mature Follow up from a Phase 2 Study of PI3K-Delta Inhibitor Idelalisib in Patients with Double (Rituximab and Alkylating agent)-Refractory Indolent B-Cell Non-Hodgkin Lymphoma (iNHL). ASH Annual Meeting 2014, Abstract 1708. | |
− | + | # '''Gilead 101-02:''' Brown JR, Byrd JC, Coutre SE, Benson DM, Flinn IW, Wagner-Johnston ND, Spurgeon SE, Kahl BS, Bello C, Webb HK, Johnson DM, Peterman S, Li D, Jahn TM, Lannutti BJ, Ulrich RG, Yu AS, Miller LL, Furman RR. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110d, for relapsed/refractory chronic lymphocytic leukemia. Blood. 2014 May 29;123(22):3390-7. Epub 2014 Mar 10. [https://doi.org/10.1182/blood-2013-11-535047 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123414/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24615777/ PubMed] [https://clinicaltrials.gov/study/NCT00710528 NCT00710528] | |
− | + | ==Lenalidomide monotherapy {{#subobject:a19994|Regimen=1}}== | |
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | + | ===Regimen variant #1 {{#subobject:5e49d5|Variant=1}}=== | |
− | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" | |
− | + | !style="width: 33%"|Study | |
− | == | + | !style="width: 33%"|Dates of enrollment |
− | {| class="wikitable" style=" | + | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] |
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.2005.05.0401 Chanan-Khan et al. 2006] |
− | + | |2004-2006 | |
− | + | |style="background-color:#91cf61"|Phase 2 | |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | | | ||
− | |||
− | |style="background-color:# | ||
|- | |- | ||
|} | |} | ||
− | ==== | + | <div class="toccolours" style="background-color:#f2f3f4"> |
− | *[[ | + | ====Targeted therapy==== |
− | *[[ | + | *[[Lenalidomide (Revlimid)]] 5 mg PO once per day, escalated by 5 mg every 1 to 2 weeks to a target maximum dose of 25 mg PO once per day on days 1 to 21 |
− | + | ====Supportive therapy==== | |
− | + | *[[Allopurinol (Zyloprim)]] 300 mg PO once per day, starting 2 to 3 days prior to lenalidomide, and continued up to a total of 14 days | |
− | + | '''28-day cycles''' | |
− | + | </div></div><br> | |
− | '''28-day | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | + | ===Regimen variant #2 {{#subobject:787570|Variant=1}}=== | |
− | === | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | + | !style="width: 33%"|Study | |
− | + | !style="width: 33%"|Dates of enrollment | |
− | + | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | |
− | + | |- | |
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4082321/ Ferrajoli et al. 2008 (MDACC 2005-0175)] | ||
+ | |2005-2007 | ||
+ | |style="background-color:#91cf61"|Phase 2 | ||
|- | |- | ||
− | |||
|} | |} | ||
− | ===Regimen {{#subobject: | + | <div class="toccolours" style="background-color:#f2f3f4"> |
− | {| | + | ====Targeted therapy==== |
− | | | + | *[[Lenalidomide (Revlimid)]] as follows: |
− | |[[Levels_of_Evidence#Evidence| | + | **Cycle 1: 10 mg PO once per day on days 1 to 28 |
− | + | **Cycle 2: 15 mg PO once per day on days 1 to 28 | |
− | + | **Cycle 3: 20 mg PO once per day on days 1 to 28 | |
+ | **Cycle 4 onwards: 25 mg PO once per day on days 1 to 28 | ||
+ | '''28-day cycles''' | ||
+ | </div></div><br> | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #3 {{#subobject:a12f10|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.2008.21.1169 Witzig et al. 2009 (CC-5013-NHL-001)] |
− | | | + | |2005-2006 |
− | + | |style="background-color:#ffffbe"|Phase 2, fewer than 20 patients in this subgroup | |
− | |style="background-color:# | ||
|- | |- | ||
|} | |} | ||
− | ==== | + | ''Note: Patients studied in this trial and in this subgroup had a diagnosis of SLL.'' |
− | *[[ | + | <div class="toccolours" style="background-color:#f2f3f4"> |
− | + | ====Targeted therapy==== | |
− | + | *[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21 | |
− | + | '''28-day cycles''' | |
− | + | </div></div> | |
− | |||
− | ''' | ||
− | |||
===References=== | ===References=== | ||
− | + | <!-- Presented in part at the XI International Workshop on Chronic Lymphocytic Leukemia, September 16–18, 2005, Brooklyn, NY; the 47th Annual Meeting of the American Society of Hematology, December 10–13, 2005, Atlanta, GA; and the 41st Annual Meeting of the American Society of Clinical Oncology, May 13–17, 2005, Orlando, FL. --> | |
− | + | # Chanan-Khan A, Miller KC, Musial L, Lawrence D, Padmanabhan S, Takeshita K, Porter CW, Goodrich DW, Bernstein ZP, Wallace P, Spaner D, Mohr A, Byrne C, Hernandez-Ilizaliturri F, Chrystal C, Starostik P, Czuczman MS. Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study. J Clin Oncol. 2006 Dec 1;24(34):5343-9. Epub 2006 Nov 6. [https://doi.org/10.1200/jco.2005.05.0401 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/17088571/ PubMed] | |
− | ==Ofatumumab | + | # '''MDACC 2005-0175:''' Ferrajoli A, Lee BN, Schlette EJ, O'Brien SM, Gao H, Wen S, Wierda WG, Estrov Z, Faderl S, Cohen EN, Li C, Reuben JM, Keating MJ. Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood. 2008 Jun 1;111(11):5291-7. Epub 2008 Mar 11. [https://doi.org/10.1182/blood-2007-12-130120 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4082321/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18334676/ PubMed] [https://clinicaltrials.gov/study/NCT00267059 NCT00267059] |
− | {| class="wikitable" style=" | + | <!-- Presented in part in poster format at the 43rd Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 1-5, 2007, the 49th Annual Meeting of the American Society of Hematology, Atlanta, GA, December 8-11, 2007, and the 13th Annual Meeting of the European Hematology Association, Copenhagen, Denmark, June 12-15, 2008. --> |
+ | # '''CC-5013-NHL-001:''' Witzig TE, Wiernik PH, Moore T, Reeder C, Cole C, Justice G, Kaplan H, Voralia M, Pietronigro D, Takeshita K, Ervin-Haynes A, Zeldis JB, Vose JM. Lenalidomide oral monotherapy produces durable responses in relapsed or refractory indolent non-Hodgkin's Lymphoma. J Clin Oncol. 2009 Nov 10;27(32):5404-9. Epub 2009 Oct 5. [https://doi.org/10.1200/jco.2008.21.1169 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/19805688/ PubMed] [https://clinicaltrials.gov/study/NCT00179673 NCT00179673] | ||
+ | ==Lenalidomide & Ofatumumab {{#subobject:2f1b19|Regimen=1}}== | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen {{#subobject:fe2be4|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5118034/ Vitale et al. 2016 (MDACC 2009-0283)] | ||
+ | |2010-2011 | ||
+ | |style="background-color:#91cf61"|Phase 2 | ||
|- | |- | ||
− | |||
|} | |} | ||
− | ===Regimen #1 {{#subobject: | + | <div class="toccolours" style="background-color:#f2f3f4"> |
− | {| | + | ====Targeted therapy==== |
− | | | + | *[[Lenalidomide (Revlimid)]] as follows: |
− | |[[Levels_of_Evidence#Evidence| | + | **Cycle 1: 10 mg PO once per day on days 9 to 28 |
− | + | **Cycles 2 to 24: 10 mg PO once per day | |
− | + | *[[Ofatumumab (Arzerra)]] as follows: | |
+ | **Cycle 1: 300 mg IV once on day 1, then 1000 mg IV once per day on days 8, 15, 22 | ||
+ | **Cycles 3 to 6, 8, 10, 12, 14, 16, 18, 20, 22, 24: 1000 mg IV once on day 1 | ||
+ | ====Supportive therapy==== | ||
+ | *Cycle 1: [[Allopurinol (Zyloprim)]] 300 mg PO once per day on days 1 to 14 | ||
+ | *[[:Category:Granulocyte colony-stimulating factors|G-CSF]] use allowed per [https://doi.org/10.1200/jco.2006.06.4451 2006 ASCO guidelines] | ||
+ | *"No anti-infectious, venous thromboembolism (VTE), or TFR prophylaxis was mandated" | ||
+ | '''28-day cycle for 24 cycles''' | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#cbd5e7"> | ||
+ | ====Subsequent treatment==== | ||
+ | *MDACC 2009-0283, patients with a sustained PR or CR: [[#Lenalidomide_monotherapy_3|Lenalidomide]] maintenance | ||
+ | </div></div> | ||
+ | ===References=== | ||
+ | # '''MDACC 2009-0283:''' Vitale C, Falchi L, Ten Hacken E, Gao H, Shaim H, Van Roosbroeck K, Calin G, O'Brien S, Faderl S, Wang X, Wierda WG, Rezvani K, Reuben JM, Burger JA, Keating MJ, Ferrajoli A. Ofatumumab and Lenalidomide for Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia: Correlation between Responses and Immune Characteristics. Clin Cancer Res. 2016 May 15;22(10):2359-67. Epub 2016 Jan 5. [https://doi.org/10.1158/1078-0432.ccr-15-2476 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5118034/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26733610/ PubMed] [https://clinicaltrials.gov/study/NCT01002755 NCT01002755] | ||
+ | ==Lenalidomide & Rituximab (R<sup>2</sup>) {{#subobject:e5598d|Regimen=1}}== | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #1 {{#subobject:cbc465|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.2005.05.0401 Chanan-Khan et al. 2006] |
− | | | + | |2004-2006 |
− | |style="background-color:# | + | |style="background-color:#91cf61"|Phase 2 |
− | |||
|- | |- | ||
− | |[ | + | |} |
− | + | ''Note: this lenalidomide dosing was the result of a mid-protocol amendment due to TLS in two of the first 29 patients enrolled.'' | |
− | |style=" | + | <div class="toccolours" style="background-color:#f2f3f4"> |
− | + | ====Targeted therapy==== | |
− | | | + | *[[Lenalidomide (Revlimid)]] 5 mg PO once per day, escalated by 5 mg every 1 to 2 weeks to a target maximum dose of 25 mg PO once per day on days 1 to 21 |
− | + | *[[Rituximab (Rituxan)]] as follows: | |
− | + | **Cycle 1: 375 mg/m<sup>2</sup> IV once per day on days 1, 8, 15 | |
− | |[[# | + | **Cycle 2 onwards: 375 mg/m<sup>2</sup> IV once per day on days 1 & 15 |
− | + | ====Supportive therapy==== | |
+ | *[[Allopurinol (Zyloprim)]] 300 mg PO once per day, starting 2 to 3 days prior to chemotherapy, and continued up to a total of 14 days | ||
+ | '''28-day cycles''' | ||
+ | </div></div><br> | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #2 {{#subobject:3b76d7|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878047/ Badoux et al. 2013 (MDACC 2007-0208)] |
− | | | + | |2008-2009 |
− | + | |style="background-color:#91cf61"|Phase 2 | |
− | |style="background-color:# | ||
|- | |- | ||
|} | |} | ||
− | + | <div class="toccolours" style="background-color:#f2f3f4"> | |
− | ==== | + | ====Targeted therapy==== |
− | *[[ | + | *[[Lenalidomide (Revlimid)]] as follows: |
− | **Cycle 1: | + | **Cycle 1: 10 mg PO once per day on days 9 to 28 |
− | **Cycle | + | **Cycles 2 to 12: 10 mg PO once per day on days 1 to 28 |
− | **Cycles 3 to | + | *[[Rituximab (Rituxan)]] as follows: |
+ | **Cycle 1: 375 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22 | ||
+ | **Cycle 2: no rituximab given | ||
+ | **Cycles 3 to 12: 375 mg/m<sup>2</sup> IV once on day 1 | ||
+ | ====Supportive therapy==== | ||
+ | *Cycle 1: [[Allopurinol (Zyloprim)]] (dose/schedule not specified) on days 1 to 14 | ||
+ | *No mandatory antibacterial, antiviral, DVT, or tumor flare prophylaxis | ||
+ | *Growth factor use allowed per [https://doi.org/10.1200/jco.2006.06.4451 2006 ASCO guidelines] | ||
+ | '''28-day cycle for 12 cycles''' | ||
+ | </div> | ||
+ | <div class="toccolours" style="background-color:#cbd5e7"> | ||
+ | ====Subsequent treatment==== | ||
+ | *MDACC 2007-0208, responders: [[#Lenalidomide_monotherapy_3|Lenalidomide]] maintenance could continue indefinitely | ||
+ | </div></div> | ||
− | === | + | ===References=== |
− | + | <!-- Presented in part at the XI International Workshop on Chronic Lymphocytic Leukemia, September 16–18, 2005, Brooklyn, NY; the 47th Annual Meeting of the American Society of Hematology, December 10–13, 2005, Atlanta, GA; and the 41st Annual Meeting of the American Society of Clinical Oncology, May 13–17, 2005, Orlando, FL. --> | |
− | + | # Chanan-Khan A, Miller KC, Musial L, Lawrence D, Padmanabhan S, Takeshita K, Porter CW, Goodrich DW, Bernstein ZP, Wallace P, Spaner D, Mohr A, Byrne C, Hernandez-Ilizaliturri F, Chrystal C, Starostik P, Czuczman MS. Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study. J Clin Oncol. 2006 Dec 1;24(34):5343-9. Epub 2006 Nov 6. [https://doi.org/10.1200/jco.2005.05.0401 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/17088571/ PubMed] | |
− | ''' | + | <!-- Presented in part at the 53rd Annual Meeting of the American Society of Hematology, San Diego, CA, December 10-13, 2011, and the 52nd Annual Meeting of the American Society of Hematology, Orlando, FL, December 4-7, 2010. --> |
− | + | # '''MDACC 2007-0208:''' Badoux XC, Keating MJ, Wen S, Wierda WG, O'Brien SM, Faderl S, Sargent R, Burger JA, Ferrajoli A. Phase II Study of Lenalidomide and Rituximab As Salvage Therapy for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia. J Clin Oncol. 2013 Feb 10;31(5):584-91. Epub 2012 Dec 26. [https://doi.org/10.1200/jco.2012.42.8623 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878047/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23270003/ PubMed] [https://clinicaltrials.gov/study/NCT00759603 NCT00759603] | |
− | ===Regimen | + | ==Lisocabtagene maraleucel monotherapy {{#subobject:6e6u14|Regimen=1}}== |
− | {| | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | | | + | ===Regimen {{#subobject:6nvha6|Variant=1}}=== |
− | |[[Levels_of_Evidence#Evidence| | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1016/S0140-6736(23)01052-8 Siddiqi et al. 2023 (TRANSCEND CLL 004)] |
− | |style="background-color:# | + | |2018-01-02 to 2022-06-16 |
+ | | style="background-color:#91cf61" |Phase 1/2 | ||
|- | |- | ||
|} | |} | ||
− | '' | + | ''Note: this is the dose-level 2 of the phase 1/2 trial.'' |
− | == | + | <div class="toccolours" style="background-color:#f2f3f4"> |
− | + | ====Immunotherapy==== | |
− | + | *[[Lisocabtagene maraleucel (Breyanzi)]] target dose of 100 x 10<sup>6</sup> CAR T cells IV once on day 0 | |
− | + | '''One course''' | |
− | + | </div></div> | |
− | ==== | ||
− | *[[ | ||
− | |||
− | |||
− | |||
− | ''' | ||
− | |||
− | |||
− | |||
===References=== | ===References=== | ||
− | # | + | #'''TRANSCEND CLL 004:'''Siddiqi T, Maloney DG, Kenderian SS, Brander DM, Dorritie K, Soumerai J, Riedell PA, Shah NN, Nath R, Fakhri B, Stephens DM, Ma S, Feldman T, Solomon SR, Schuster SJ, Perna SK, Tuazon SA, Ou SS, Papp E, Peiser L, Chen Y, Wierda WG. Lisocabtagene maraleucel in chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1-2 study. Lancet. 2023 Aug 19;402(10402):641-654. Epub 2023 Jun 5. [https://doi.org/10.1016/S0140-6736(23)01052-8 link to original article] '''dosing details in abstract have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/37295445/ PubMed] [https://clinicaltrials.gov/study/NCT03331198 NCT03331198] |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | == | + | ==Obinutuzumab monotherapy {{#subobject:97dd49|Regimen=1}}== |
− | {| class="wikitable" style=" | + | <div class="toccolours" style="background-color:#eeeeee"> |
+ | ===Regimen {{#subobject:a20fcb|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | |- | ||
+ | |[https://doi.org/10.1182/blood-2012-01-404368 Salles et al. 2012 (GAUGUIN)] | ||
+ | |2008-2009 | ||
+ | |style="background-color:#91cf61"|Phase 1/2 | ||
|- | |- | ||
− | |||
|} | |} | ||
+ | ''Note: Dose here is the phase II dose reported in the Cartron et al. 2014 update.'' | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
+ | ====Targeted therapy==== | ||
+ | *[[Obinutuzumab (Gazyva)]] as follows: | ||
+ | **Cycle 1: 1000 mg IV once per day on days 1, 8, 15 | ||
+ | **Cycle 2 onwards: 1000 mg IV once on day 1 | ||
+ | ====Supportive therapy==== | ||
+ | *[[Acetaminophen (Tylenol)]] 650 to 1000 mg PO once on cycle 1 day 1; 30 minutes prior to obinutuzumab, repeat for those at risk of tumor lysis or with history of reaction | ||
+ | *[[:Category:Antihistamines|Antihistamine]] (no drug or dose specified) PO once on cycle 1 day 1; 30 minutes prior to obinutuzumab, repeat for those at risk of tumor lysis or with history of reaction | ||
+ | *For patients at "high risk" of severe infusion reaction, including those with a history of severe rituximab reactions: [[:Category:Steroids|Corticosteroids]] (no drug/dose/route specified) once on cycle 1 day 1, prior to obinutuzumab | ||
+ | '''21-day cycle for up to 8 cycles''' | ||
+ | </div></div> | ||
+ | ===References=== | ||
+ | # '''GAUGUIN:''' Salles G, Morschhauser F, Lamy T, Milpied N, Thieblemont C, Tilly H, Bieska G, Asikanius E, Carlile D, Birkett J, Pisa P, Cartron G. Phase 1 study results of the type II glycoengineered humanized anti-CD20 monoclonal antibody obinutuzumab (GA101) in B-cell lymphoma patients. Blood. 2012 May 31;119(22):5126-32. Epub 2012 Mar 19. [https://doi.org/10.1182/blood-2012-01-404368 link to original article] [https://pubmed.ncbi.nlm.nih.gov/22431570/ PubMed] [https://clinicaltrials.gov/study/NCT00517530 NCT00517530] | ||
+ | ## '''Subgroup analysis:''' Morschhauser FA, Cartron G, Thieblemont C, Solal-Céligny P, Haioun C, Bouabdallah R, Feugier P, Bouabdallah K, Asikanius E, Lei G, Wenger M, Wassner-Fritsch E, Salles GA. Obinutuzumab (GA101) monotherapy in relapsed/refractory diffuse large B-cell lymphoma or mantle-cell lymphoma: results from the phase II GAUGUIN study. J Clin Oncol. 2013 Aug 10;31(23):2912-9. Epub 2013 Jul 8. [https://doi.org/10.1200/jco.2012.46.9585 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/23835718/ PubMed] | ||
+ | ## '''Subgroup analysis:''' Salles GA, Morschhauser F, Solal-Céligny P, Thieblemont C, Lamy T, Tilly H, Gyan E, Lei G, Wenger M, Wassner-Fritsch E, Cartron G. Obinutuzumab (GA101) in patients with relapsed/refractory indolent non-Hodgkin lymphoma: results from the phase II GAUGUIN study. J Clin Oncol. 2013 Aug 10;31(23):2920-6. Epub 2013 Jul 8. [https://doi.org/10.1200/jco.2012.46.9718 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/23835715/ PubMed] | ||
+ | ## '''Subgroup analysis:''' Cartron G, de Guibert S, Dilhuydy MS, Morschhauser F, Leblond V, Dupuis J, Mahe B, Bouabdallah R, Lei G, Wenger M, Wassner-Fritsch E, Hallek M. Obinutuzumab (GA101) in relapsed/refractory chronic lymphocytic leukemia: final data from the phase 1/2 GAUGUIN study. Blood. 2014 Oct 2;124(14):2196-202. Epub 2014 Aug 20. [https://doi.org/10.1182/blood-2014-07-586610 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/25143487/ PubMed] | ||
− | == | + | ==OFAR {{#subobject:bd6061|Regimen=1}}== |
− | + | OFAR: '''<u>O</u>'''xaliplatin, '''<u>F</u>'''ludarabine, '''<u>A</u>'''ra-C (Cytarabine), '''<u>R</u>'''ituximab | |
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | + | ===Regimen {{#subobject:bd771f|Variant=1}}=== | |
− | + | {| class="wikitable sortable" style="width: 80%; text-align:center;" | |
− | + | !style="width: 25%"|Study | |
− | + | !style="width: 25%"|Dates of enrollment | |
− | + | !style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]] | |
− | + | !style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]] | |
− | |style=" | + | |- |
− | |style=" | + | |[https://doi.org/10.1200/jco.2007.11.8513 Tsimberidou et al. 2008] |
− | |- | + | |2004-2006 |
− | |[ | + | |style="background-color:#91cf61"|Phase 1/2 |
− | |style="background-color:# | + | | style="background-color:#1a9850" |Likely has true ORR > 20% |
− | |||
− | |style="background-color:# | ||
|- | |- | ||
|} | |} | ||
− | + | ''Note: the manuscript does not specify what sequence the rituximab is given in.'' | |
− | + | <div class="toccolours" style="background-color:#f2f3f4"> | |
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[ | + | *[[Oxaliplatin (Eloxatin)]] 25 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 4, '''given first (see note)''' |
+ | *[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV once per day on days 2 & 3, '''given second, within 30 minutes of completion of oxaliplatin (see note)''' | ||
+ | *[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV over 2 hours once per day on days 2 & 3, '''given third, 4 hours after start of fludarabine (see note)''' | ||
+ | ====Targeted therapy==== | ||
+ | *[[Rituximab (Rituxan)]] as follows (see note): | ||
+ | **Cycle 1: 375 mg/m<sup>2</sup> IV over 4 to 6 hours once on day 3 | ||
+ | **Cycles 2 to 6: 375 mg/m<sup>2</sup> IV over 4 to 6 hours once on day 1 | ||
+ | ====Supportive therapy==== | ||
+ | *[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 6 | ||
+ | *Herpes zoster and PCP (Pneumocystis jiroveci pneumonia) prophylaxis used | ||
+ | '''28-day cycle for up to 6 cycles''' | ||
+ | </div></div> | ||
− | ''' | + | ===References=== |
+ | # Tsimberidou AM, Wierda WG, Plunkett W, Kurzrock R, O'Brien S, Wen S, Ferrajoli A, Ravandi-Kashani F, Garcia-Manero G, Estrov Z, Kipps TJ, Brown JR, Fiorentino A, Lerner S, Kantarjian HM, Keating MJ. Phase I-II study of oxaliplatin, fludarabine, cytarabine, and rituximab combination therapy in patients with Richter's syndrome or fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol. 2008 Jan 10;26(2):196-203. [https://doi.org/10.1200/jco.2007.11.8513 link to original article] '''dosing details in abstract have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/18182662/ PubMed] | ||
− | ===Regimen | + | ==PCR {{#subobject:d3f558|Regimen=1}}== |
− | {| | + | PCR: '''<u>P</u>'''entostatin, '''<u>C</u>'''yclophosphamide, '''<u>R</u>'''ituximab |
− | | | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | |[[Levels_of_Evidence#Evidence| | + | ===Regimen {{#subobject:ebf988|Variant=1}}=== |
− | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" | |
− | + | !style="width: 33%"|Study | |
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.2005.04.3836 Lamanna et al. 2006] |
− | | | + | |2001-2004 |
− | + | |style="background-color:#91cf61"|Phase 2 | |
− | |style="background-color:# | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[ | + | *[[Pentostatin (Nipent)]] 4 mg/m<sup>2</sup> IV once on day 1, '''given second''' |
− | + | *[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1, '''given first''' | |
− | ''' | + | ====Targeted therapy==== |
+ | *[[Rituximab (Rituxan)]] '''given third''', as follows: | ||
+ | **Cycles 2 to 6: 375 mg/m<sup>2</sup> IV once on day 1 | ||
+ | ====Supportive therapy==== | ||
+ | *At least 1.5 L of IVF | ||
+ | *[[Dexamethasone (Decadron)]] 20 mg (route not specified) once on day 1 | ||
+ | *[[Granisetron]] 2 mg (route not specified) once on day 1 | ||
+ | *[[Filgrastim (Neupogen)]] by the following weight-based criteria: | ||
+ | **70 kg or less: 300 mcg SC once per day from day 3 until ANC greater than 5000/μL once or 1500/μL for 2 days | ||
+ | **More than 70 kg: 480 mcg SC once per day from day 3 until ANC greater than 5000/μL once or 1500/μL for 2 days | ||
+ | *[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] 1 DS tablet PO twice per day on MWF | ||
+ | *[[Acyclovir (Zovirax)]] 800 mg PO twice per day | ||
+ | '''21-day cycle for 6 cycles''' | ||
+ | </div></div> | ||
===References=== | ===References=== | ||
− | # | + | # Lamanna N, Kalaycio M, Maslak P, Jurcic JG, Heaney M, Brentjens R, Zelenetz AD, Horgan D, Gencarelli A, Panageas KS, Scheinberg DA, Weiss MA. Pentostatin, cyclophosphamide, and rituximab is an active, well-tolerated regimen for patients with previously treated chronic lymphocytic leukemia. J Clin Oncol. 2006 Apr 1;24(10):1575-81. Epub 2006 Mar 6. [https://doi.org/10.1200/jco.2005.04.3836 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/16520464/ PubMed] |
− | + | ==Pirtobrutinib monotherapy {{#subobject:f44ug8|Regimen=1}}== | |
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | # | + | ===Regimen {{#subobject:ch1f36|Variant=1}}=== |
− | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" | |
− | + | !style="width: 33%"|Study | |
− | + | !style="width: 33%"|Dates of enrollment | |
− | == | + | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | {| class="wikitable" style=" | + | |- |
+ | |[https://doi.org/10.1056/nejmoa2300696 Mato et al. 2023 (BRUIN<sub>CLL</sub>)] | ||
+ | |2019-03-21 to 2022-07-29 | ||
+ | | style="background-color:#91cf61" |Phase 1/2 (RT) | ||
|- | |- | ||
− | |||
|} | |} | ||
− | ===Regimen # | + | ''Note: This was the RP2D.'' |
− | {| | + | <div class="toccolours" style="background-color:#f2f3f4"> |
− | | | + | ====Targeted therapy==== |
− | |[[Levels_of_Evidence#Evidence| | + | *[[Pirtobrutinib (Jaypirca)]] 200 mg PO once per day |
+ | '''Continued indefinitely''' | ||
+ | </div></div> | ||
+ | ===References=== | ||
+ | #'''BRUIN<sub>CLL</sub>:''' Mato AR, Woyach JA, Brown JR, Ghia P, Patel K, Eyre TA, Munir T, Lech-Maranda E, Lamanna N, Tam CS, Shah NN, Coombs CC, Ujjani CS, Fakhri B, Cheah CY, Patel MR, Alencar AJ, Cohen JB, Gerson JN, Flinn IW, Ma S, Jagadeesh D, Rhodes JM, Hernandez-Ilizaliturri F, Zinzani PL, Seymour JF, Balbas M, Nair B, Abada P, Wang C, Ruppert AS, Wang D, Tsai DE, Wierda WG, Jurczak W. Pirtobrutinib after a Covalent BTK Inhibitor in Chronic Lymphocytic Leukemia. N Engl J Med. 2023 Jul 6;389(1):33-44. [https://doi.org/10.1056/nejmoa2300696 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/37407001/ PubMed] [https://clinicaltrials.gov/study/NCT03740529 NCT03740529] | ||
+ | |||
+ | ==R-BAC {{#subobject:f44525|Regimen=1}}== | ||
+ | R-BAC: '''<u>R</u>'''ituximab, '''<u>B</u>'''endamustine, '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine) | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen {{#subobject:c74f36|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1002/ajh.23391 Visco et al. 2013] |
− | | | + | |2010-2012 |
− | + | |style="background-color:#ffffbe"|Pilot, fewer than 20 patients reported | |
− | |||
− | |style="background-color:# | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
+ | ====Targeted therapy==== | ||
+ | *[[Rituximab (Rituxan)]] as follows: | ||
+ | **Cycle 1: 375 mg/m<sup>2</sup> IV once on day 1 | ||
+ | **Cycles 2 to 4: 500 mg/m<sup>2</sup> IV once on day 1 | ||
====Chemotherapy==== | ====Chemotherapy==== | ||
− | *[[ | + | *[[Bendamustine]] 70 mg/m<sup>2</sup> IV once per day on days 1 & 2 |
− | + | *[[Cytarabine (Ara-C)]] 800 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 3, '''beginning 2 hours after bendamustine''' | |
− | + | ====Supportive therapy==== | |
+ | *Primary prophylaxis with [[:Category:Granulocyte_colony-stimulating_factors|granulocyte colony-stimulating factor]] was routinely used starting from Day 5 after chemotherapy completion, and lasting for 3 to 6 days or until neutrophil count recovery. | ||
+ | '''28-day cycle for up to 4 cycles''' | ||
+ | </div></div> | ||
+ | ===References=== | ||
+ | # Visco C, Finotto S, Pomponi F, Sartori R, Laveder F, Trentin L, Paolini R, Di Bona E, Ruggeri M, Rodeghiero F. The combination of rituximab, bendamustine, and cytarabine for heavily pretreated relapsed/refractory cytogenetically high-risk patients with chronic lymphocytic leukemia. Am J Hematol. 2013 Apr;88(4):289-93. Epub 2013 Feb 28. [https://doi.org/10.1002/ajh.23391 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/23450436/ PubMed] | ||
− | ==== | + | ==Ruxolitinib monotherapy {{#subobject:ccaffa |Regimen=1}}== |
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | + | ===Regimen {{#subobject:cbe4fe |Variant=1}}=== | |
− | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" | |
− | + | !style="width: 33%"|Study | |
− | + | !style="width: 33%"|Dates of enrollment | |
− | + | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | |
− | |||
− | |||
− | ===Regimen | ||
− | {| | ||
− | | | ||
− | |[[Levels_of_Evidence#Evidence| | ||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356368/ Jain et al. 2017 (MDACC 2013-0044)] |
− | |style="background-color:# | + | |2014-2015 |
+ | |style="background-color:#ffffbe"|Phase 2, fewer than 20 pts in this subgroup | ||
|- | |- | ||
|} | |} | ||
− | + | ''Note: this was a trial focused on symptom control, not efficacy.'' | |
− | + | <div class="toccolours" style="background-color:#f2f3f4"> | |
− | + | ====Targeted therapy==== | |
− | ==== | + | *[[Ruxolitinib (Jakafi)]] 10 mg PO twice per day |
− | *[[ | + | '''Continued indefinitely''' |
− | + | </div></div> | |
− | |||
− | |||
− | ''' | ||
− | |||
===References=== | ===References=== | ||
− | # Keating | + | # '''MDACC 2013-0044:''' Jain P, Keating M, Renner S, Cleeland C, Xuelin H, Gonzalez GN, Harris D, Li P, Liu Z, Veletic I, Rozovski U, Jain N, Thompson P, Bose P, DiNardo C, Ferrajoli A, O'Brien S, Burger J, Wierda W, Verstovsek S, Kantarjian H, Estrov Z. Ruxolitinib for symptom control in patients with chronic lymphocytic leukaemia: a single-group, phase 2 trial. Lancet Haematol. 2017 Feb;4(2):e67-e74. Epub 2017 Jan 11. [https://doi.org/10.1016/S2352-3026(16)30194-6 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356368/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28089238/ PubMed] [https://clinicaltrials.gov/study/NCT02131584 NCT02131584] |
− | + | ==Venetoclax monotherapy {{#subobject:b479ff|Regimen=1}}== | |
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | + | ===Regimen variant #1, standard lead-in {{#subobject:1aa538|Variant=1}}=== | |
− | + | {| class="wikitable" style="color:white; background-color:#404040" | |
− | == | + | |<small>'''FDA-recommended dose'''</small> |
− | {| class="wikitable" style=" | ||
|- | |- | ||
− | |||
|} | |} | ||
− | + | {| class="wikitable" style="width: 80%; text-align:center;" | |
− | {| | + | !style="width: 25%"|Study |
− | | | + | !style="width: 25%"|Dates of enrollment |
− | |[[Levels_of_Evidence#Evidence| | + | !style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]] |
+ | !style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]] | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7107002/ Roberts et al. 2015 (M12-175)] | ||
+ | |2011-2014 | ||
+ | |style="background-color:#91cf61"|Phase 1/2 (RT) | ||
+ | | style="background-color:#e0ecf4" |ORR: 79% | ||
+ | |- | ||
+ | |[https://doi.org/10.1016/S1470-2045(16)30019-5 Stilgenbauer et al. 2016 (M13-982)] | ||
+ | |2013-2014 | ||
+ | |style="background-color:#91cf61"|Phase 2 (RT) | ||
+ | | style="background-color:#e0ecf4" |ORR: 79% (95% CI, 70.5-87) | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6027999/ Jones et al. 2017 (M14-032 ibrutinib cohort)] | ||
+ | |2014-2016 | ||
+ | |style="background-color:#91cf61"|Phase 2 (RT) | ||
+ | | style="background-color:#bfd3e6" |ORR: 65% (95% CI 53-74) | ||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5922273/ Coutre et al. 2018 (M14-032 idelalisib cohort)] |
− | |style="background-color:# | + | |2014 to not reported |
+ | |style="background-color:#91cf61"|Phase 2 (RT) | ||
+ | | style="background-color:#bfd3e6" |ORR: 67% | ||
|- | |- | ||
|} | |} | ||
− | ==== | + | ''This is the dosing schedule used in the phase II expansion cohort of M12-175. See papers for supportive care details during initial dosing.'' |
− | *[[ | + | <div class="toccolours" style="background-color:#fdcdac"> |
− | * | + | ====Biomarker eligibility criteria==== |
− | + | *M13-982: 17p deletion | |
− | + | </div> | |
− | ==== | + | <div class="toccolours" style="background-color:#f2f3f4"> |
− | + | ====Targeted therapy==== | |
− | + | *[[Venetoclax (Venclexta)]] as follows: | |
− | + | **Cycle 1: 20 mg PO once per day on days 1 to 7, then 50 mg PO once per day on days 8 to 14, then 100 mg PO once per day on days 15 to 21, then 200 mg PO once per day on days 22 to 28 | |
− | + | **Cycle 2 onwards: 400 mg PO once per day on days 1 to 28 | |
− | + | '''28-day cycles''' | |
− | + | </div></div><br> | |
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | + | ===Regimen variant #2, modified lead-in {{#subobject:65ad03|Variant=1}}=== | |
− | = | + | {| class="wikitable sortable" style="width: 80%; text-align:center;" |
− | + | !style="width: 25%"|Study | |
+ | !style="width: 25%"|Dates of enrollment | ||
+ | !style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]] | ||
+ | |- | ||
+ | |[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5922273/ Coutre et al. 2018 (M14-032 idelalisib cohort)] | ||
+ | |2014 to not reported | ||
+ | |style="background-color:#91cf61"|Phase 2 | ||
+ | | style="background-color:#bfd3e6" |ORR: 67% | ||
|- | |- | ||
− | |||
|} | |} | ||
+ | ''Note: This dosing schedule was intended for high-risk patients with "clinical signs of progression during screening." See paper for supportive care details during initial dosing.'' | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
+ | ====Targeted therapy==== | ||
+ | *[[Venetoclax (Venclexta)]] as follows: | ||
+ | **Cycle 1: 20 mg PO once on day 1, then 50 mg PO once per day on days 2 & 3, then 100 mg PO once per day on days 4 to 7, then 200 mg PO once per day on days 8 to 14, then 400 mg PO once per day on days 15 to 28 | ||
+ | **Cycle 2 onwards: 400 mg PO once per day on days 1 to 28 | ||
+ | '''28-day cycles''' | ||
+ | </div></div> | ||
+ | ===References=== | ||
+ | <!-- # '''Abstract:''' Shuo Ma, John Francis Seymour, Mark C. Lanasa, Thomas J. Kipps, Jacqueline Claudia Barrientos, Matthew Steven Davids, Tanita Mason-Bright, Nikita Rudersdorf, Jianning Yang, Wijith Munasinghe, Ming Zhu, Elisa Cerri, Sari H. Enschede, Rod Humerickhouse, Andrew Warwick Roberts. ABT-199 (GDC-0199) combined with rituximab (R) in patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): Interim results of a phase 1b study. J Clin Oncol 32:5s, 2014 (suppl; abstr 7013) [https://doi.org/10.1200/jco.2014.32.15_suppl.7013 link to abstract] --> | ||
+ | # '''M12-175:''' Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF, Kipps TJ, Anderson MA, Brown JR, Gressick L, Wong S, Dunbar M, Zhu M, Desai MB, Cerri E, Heitner Enschede S, Humerickhouse RA, Wierda WG, Seymour JF. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016 Jan 28;374(4):311-22. Epub 2015 Dec 6. [https://doi.org/10.1056/NEJMoa1513257 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7107002/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26639348/ PubMed] [https://clinicaltrials.gov/study/NCT01328626 NCT01328626] | ||
+ | <!-- Stilgenbauer S, Eichhorst, B.F., Schetelig, J., Coutre, S., Seymour, J.F., Munir, T., Puvvada, S.D., Wendtner, C.M., Roberts, A.W., Jurczak, W., Mulligan, S. and Boettcher, S., 2015. Venetoclax (ABT-199/GDC-0199) monotherapy induces deep remissions, including complete remission and undetectable MRD, in ultra-high risk relapsed/refractory chronic lymphocytic leukemia with 17p deletion: results of the pivotal international phase 2 study. Blood 2015;126:Abstract LBA-6 --> | ||
+ | # '''M13-982:''' Stilgenbauer S, Eichhorst B, Schetelig J, Coutre S, Seymour JF, Munir T, Puvvada SD, Wendtner CM, Roberts AW, Jurczak W, Mulligan SP, Böttcher S, Mobasher M, Zhu M, Desai M, Chyla B, Verdugo M, Heitner Enschede S, Cerri E, Humerickhouse R, Gordon G, Hallek M, Wierda WG. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 2016 Jun;17(6):768-78. Epub 2016 May 10. [https://doi.org/10.1016/S1470-2045(16)30019-5 link to original article] '''dosing details in abstract have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/27178240/ PubMed] [https://clinicaltrials.gov/study/NCT01889186 NCT01889186] | ||
+ | ## '''Update:''' Stilgenbauer S, Eichhorst B, Schetelig J, Hillmen P, Seymour JF, Coutre S, Jurczak W, Mulligan SP, Schuh A, Assouline S, Wendtner CM, Roberts AW, Davids MS, Bloehdorn J, Munir T, Böttcher S, Zhou L, Salem AH, Desai M, Chyla B, Arzt J, Kim SY, Verdugo M, Gordon G, Hallek M, Wierda WG. Venetoclax for patients with chronic lymphocytic leukemia with 17p deletion: results from the full population of a phase II pivotal trial. J Clin Oncol. 2018 Jul 1;36(19):1973-1980. Epub 2018 May 1. [https://doi.org/10.1200/jco.2017.76.6840 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29715056/ PubMed] | ||
+ | # '''M14-032 ibrutinib cohort:''' Jones JA, Mato AR, Wierda WG, Davids MS, Choi M, Cheson BD, Furman RR, Lamanna N, Barr PM, Zhou L, Chyla B, Salem AH, Verdugo M, Humerickhouse RA, Potluri J, Coutre S, Woyach J, Byrd JC. Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial. Lancet Oncol. 2018 Jan;19(1):65-75. Epub 2017 Dec 12. [https://doi.org/10.1016/s1470-2045(17)30909-9 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6027999/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29246803/ PubMed] [https://clinicaltrials.gov/study/NCT02141282 NCT02141282] | ||
+ | # '''M14-032 idelalisib cohort:''' Coutre S, Choi M, Furman RR, Eradat H, Heffner L, Jones JA, Chyla B, Zhou L, Agarwal S, Waskiewicz T, Verdugo M, Humerickhouse RA, Potluri J, Wierda WG, Davids MS. Venetoclax for patients with chronic lymphocytic leukemia who progressed during or after idelalisib therapy. Blood. 2018 Apr 12;131(15):1704-1711. Epub 2018 Jan 5. [https://doi.org/10.1182/blood-2017-06-788133 link to original article] '''dosing details in supplement have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5922273/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29305552/ PubMed] [https://clinicaltrials.gov/study/NCT02141282 NCT02141282] | ||
− | ===Regimen | + | ==Zanubrutinib & Obinutuzumab {{#subobject:7ygqqd |Regimen=1}}== |
− | {| | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | | | + | ===Regimen {{#subobject:it81db |Variant=1}}=== |
− | |[[Levels_of_Evidence#Evidence| | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7556127/ Tam et al. 2020] |
− | |style="background-color:# | + | |2016 to not reported |
+ | |style="background-color:#91cf61"|Phase 1b, >20 pts in this subgroup | ||
|- | |- | ||
|} | |} | ||
+ | <div class="toccolours" style="background-color:#f2f3f4"> | ||
+ | ====Targeted therapy==== | ||
+ | *[[Zanubrutinib (Brukinsa)]] 160 mg PO twice per day or 320 mg PO once per day on days 1 to 28 | ||
+ | *[[Obinutuzumab (Gazyva)]] as follows: | ||
+ | **Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15 | ||
+ | **Cycles 2 to 6: 1000 mg IV once on day 1 | ||
+ | '''28-day cycles''' | ||
+ | </div></div> | ||
+ | ===References=== | ||
+ | #Tam CS, Quach H, Nicol A, Badoux X, Rose H, Prince HM, Leahy MF, Eek R, Wickham N, Patil SS, Huang J, Prathikanti R, Cohen A, Elstrom R, Reed W, Schneider J, Flinn IW. Zanubrutinib (BGB-3111) plus obinutuzumab in patients with chronic lymphocytic leukemia and follicular lymphoma. Blood Adv. 2020 Oct 13;4(19):4802-4811. [https://doi.org/10.1182/bloodadvances.2020002183 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7556127/ link to PMC article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/33022066/ PubMed] [https://clinicaltrials.gov/study/NCT02569476 NCT02569476] | ||
− | + | =Consolidation and/or maintenance after subsequent lines of therapy= | |
− | ==== | + | ==Busulfan & Fludarabine, then allo HSCT {{#subobject:ed545b|Regimen=1}}== |
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | + | ===Regimen {{#subobject:e2c4bf|Variant=1}}=== | |
− | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" | |
− | + | !style="width: 33%"|Study | |
− | ===Regimen | + | !style="width: 33%"|Dates of enrollment |
− | {| | + | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | | | + | |- |
− | |[[Levels_of_Evidence#Evidence| | + | |[https://doi.org/10.1182/blood.V91.3.756 Slavin et al. 1998] |
+ | |Not reported | ||
+ | | style="background-color:#91cf61" |Phase 2 | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.2003.12.011 Schetelig et al. 2003] |
− | |style="background-color:# | + | |1998-2001 |
+ | |style="background-color:#91cf61"|Phase 2 | ||
|- | |- | ||
|} | |} | ||
− | === | + | {{#lst:Allogeneic HSCT|e2c4bf}} |
− | + | </div></div> | |
− | + | ===References=== | |
− | + | # Slavin S, Nagler A, Naparstek E, Kapelushnik Y, Aker M, Cividalli G, Varadi G, Kirschbaum M, Ackerstein A, Samuel S, Amar A, Brautbar C, Ben-Tal O, Eldor A, Or R. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood. 1998 Feb 1;91(3):756-63. [https://doi.org/10.1182/blood.V91.3.756 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/9446633/ PubMed] | |
− | === | + | # Schetelig J, Thiede C, Bornhauser M, Schwerdtfeger R, Kiehl M, Beyer J, Sayer HG, Kroger N, Hensel M, Scheffold C, Held TK, Hoffken K, Ho AD, Kienast J, Neubauer A, Zander AR, Fauser AA, Ehninger G, Siegert W; Cooperative German Transplant Study Group. Evidence of a graft-versus-leukemia effect in chronic lymphocytic leukemia after reduced-intensity conditioning and allogeneic stem-cell transplantation: the Cooperative German Transplant Study Group. J Clin Oncol. 2003 Jul 15;21(14):2747-53. [https://doi.org/10.1200/jco.2003.12.011 link to original article] '''contains reference to protocol''' [https://pubmed.ncbi.nlm.nih.gov/12860954/ PubMed] |
− | + | ==Cyclophosphamide & Fludarabine (FC), then allo HSCT {{#subobject:1a1ed9|Regimen=1}}== | |
− | + | FluCy: '''<u>Flu</u>'''darabine & '''<u>Cy</u>'''clophosphamide | |
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | ===Regimen | + | ===Regimen {{#subobject:886e40|Variant=1}}=== |
− | {| | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
− | | | + | !style="width: 33%"|Study |
− | |[[Levels_of_Evidence#Evidence| | + | !style="width: 33%"|Dates of enrollment |
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1182/blood-2010-03-275420 Dreger et al. 2010 (GCLLSG CLL3X)] |
− | |style="background-color:# | + | |2001-2007 |
+ | | style="background-color:#91cf61" |Phase 2 | ||
|- | |- | ||
|} | |} | ||
+ | {{#lst:Allogeneic HSCT|886e40}} | ||
+ | </div></div> | ||
+ | ===References=== | ||
+ | <!-- Presented in part in abstract form at the 50th annual meeting of the American Society of Hematology, San Francisco, CA, December 6-9, 2008. --> | ||
+ | # '''GCLLSG CLL3X:''' Dreger P, Döhner H, Ritgen M, Böttcher S, Busch R, Dietrich S, Bunjes D, Cohen S, Schubert J, Hegenbart U, Beelen D, Zeis M, Stadler M, Hasenkamp J, Uharek L, Scheid C, Humpe A, Zenz T, Winkler D, Hallek M, Kneba M, Schmitz N, Stilgenbauer S; German CLL Study Group. Allogeneic stem cell transplantation provides durable disease control in poor-risk chronic lymphocytic leukemia: long-term clinical and MRD results of the German CLL Study Group CLL3X trial. Blood. 2010 Oct 7;116(14):2438-47. Epub 2010 Jul 1. [https://doi.org/10.1182/blood-2010-03-275420 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/20595516/ PubMed] [https://clinicaltrials.gov/study/NCT00281983 NCT00281983] | ||
+ | ## '''Update:''' Dreger P, Schnaiter A, Zenz T, Böttcher S, Rossi M, Paschka P, Bühler A, Dietrich S, Busch R, Ritgen M, Bunjes D, Zeis M, Stadler M, Uharek L, Scheid C, Hegenbart U, Hallek M, Kneba M, Schmitz N, Döhner H, Stilgenbauer S. TP53, SF3B1, and NOTCH1 mutations and outcome of allotransplantation for chronic lymphocytic leukemia: six-year follow-up of the GCLLSG CLL3X trial. Blood. 2013 Apr 18;121(16):3284-8. Epub 2013 Feb 22. [https://doi.org/10.1182/blood-2012-11-469627 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23435461/ PubMed] | ||
+ | ## '''Update:''' Krämer I, Stilgenbauer S, Dietrich S, Böttcher S, Zeis M, Stadler M, Bittenbring J, Uharek L, Scheid C, Hegenbart U, Ho A, Hallek M, Kneba M, Schmitz N, Döhner H, Dreger P. Allogeneic hematopoietic cell transplantation for high-risk CLL: 10-year follow-up of the GCLLSG CLL3X trial. Blood. 2017 Sep 21;130(12):1477-1480. Epub 2017 Jul 17. [https://doi.org/10.1182/blood-2017-04-775841 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28716861/ PubMed] | ||
− | + | ==Fludarabine & TBI, then allo HSCT {{#subobject:53c6af|Regimen=1}}== | |
− | ==== | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | + | ===Regimen {{#subobject:7fa6ce|Variant=1}}=== | |
− | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" | |
− | + | !style="width: 33%"|Study | |
− | ===Regimen | + | !style="width: 33%"|Dates of enrollment |
− | {| | + | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] |
− | | | ||
− | |[[Levels_of_Evidence#Evidence| | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1200/jco.2005.04.569 Sorror et al. 2005] |
− | |style="background-color:# | + | |1997-2003 |
+ | | style="background-color:#91cf61" |Phase 2 | ||
|- | |- | ||
|} | |} | ||
− | + | {{#lst:Allogeneic HSCT|7fa6ce}} | |
− | + | </div></div> | |
− | + | ===References=== | |
− | |||
− | |||
− | |||
− | |||
− | ===References=== | ||
− | |||
− | |||
− | |||
<!-- Presented in part at the Tandem Bone Marrow Transplantation meeting, February 13-17, 2004, Orlando, FL (for part of the patient population). --> | <!-- Presented in part at the Tandem Bone Marrow Transplantation meeting, February 13-17, 2004, Orlando, FL (for part of the patient population). --> | ||
− | # Sorror ML, Maris MB, Sandmaier BM, Storer BE, Stuart MJ, Hegenbart U, Agura E, Chauncey TR, Leis J, Pulsipher M, McSweeney P, Radich JP, Bredeson C, Bruno B, Langston A, Loken MR, Al-Ali H, Blume KG, Storb R, Maloney DG. Hematopoietic cell transplantation after nonmyeloablative conditioning for advanced chronic lymphocytic leukemia. J Clin Oncol. 2005 Jun 1;23(16):3819-29. Epub 2005 Apr 4. [ | + | # Sorror ML, Maris MB, Sandmaier BM, Storer BE, Stuart MJ, Hegenbart U, Agura E, Chauncey TR, Leis J, Pulsipher M, McSweeney P, Radich JP, Bredeson C, Bruno B, Langston A, Loken MR, Al-Ali H, Blume KG, Storb R, Maloney DG. Hematopoietic cell transplantation after nonmyeloablative conditioning for advanced chronic lymphocytic leukemia. J Clin Oncol. 2005 Jun 1;23(16):3819-29. Epub 2005 Apr 4. [https://doi.org/10.1200/jco.2005.04.569 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/15809448/ PubMed] |
− | ## '''Update:''' Sorror ML, Storer BE, Sandmaier BM, Maris M, Shizuru J, Maziarz R, Agura E, Chauncey TR, Pulsipher MA, McSweeney PA, Wade JC, Bruno B, Langston A, Radich J, Niederwieser D, Blume KG, Storb R, Maloney DG. Five-year follow-up of patients with advanced chronic lymphocytic leukemia treated with allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. J Clin Oncol. 2008 Oct 20;26(30):4912-20. Epub 2008 Sep 15. [ | + | ## '''Update:''' Sorror ML, Storer BE, Sandmaier BM, Maris M, Shizuru J, Maziarz R, Agura E, Chauncey TR, Pulsipher MA, McSweeney PA, Wade JC, Bruno B, Langston A, Radich J, Niederwieser D, Blume KG, Storb R, Maloney DG. Five-year follow-up of patients with advanced chronic lymphocytic leukemia treated with allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. J Clin Oncol. 2008 Oct 20;26(30):4912-20. Epub 2008 Sep 15. [https://doi.org/10.1200/jco.2007.15.4757 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2652085/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18794548/ PubMed] |
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | |||
− | ===Regimen {{#subobject: | + | ==Lenalidomide monotherapy {{#subobject:2f1ml9|Regimen=1}}== |
− | {| | + | <div class="toccolours" style="background-color:#eeeeee"> |
− | | | + | ===Regimen {{#subobject:3cbbe4|Variant=1}}=== |
− | |[[Levels_of_Evidence#Evidence| | + | {| class="wikitable sortable" style="width: 60%; text-align:center;" |
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878047/ Badoux et al. 2013 (MDACC 2007-0208)] |
− | |style="background-color:# | + | |2008-2009 |
+ | |style="background-color:#91cf61"|Phase 2 | ||
|- | |- | ||
− | |[ | + | |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5118034/ Vitale et al. 2016 (MDACC 2009-0283)] |
− | |style="background-color:# | + | |2010-2011 |
+ | |style="background-color:#91cf61"|Phase 2 | ||
|- | |- | ||
|} | |} | ||
− | ==== | + | <div class="toccolours" style="background-color:#cbd5e8"> |
− | + | ====Preceding treatment==== | |
− | *[[ | + | *MDACC 2007-0208: Salvage [[#Lenalidomide_.26_Rituximab_.28R2.29_2|R<sup>2</sup>]] x 12 |
− | + | *MDACC 2009-0283: Salvage [[#Lenalidomide_.26_Ofatumumab|Lenalidomide & Ofatumumab]] x 24 | |
− | ''' | + | </div> |
− | + | <div class="toccolours" style="background-color:#f2f3f4"> | |
+ | ====Targeted therapy==== | ||
+ | *[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 28 | ||
+ | '''28-day cycles''' | ||
+ | </div></div> | ||
===References=== | ===References=== | ||
− | + | # '''MDACC 2007-0208:''' Badoux XC, Keating MJ, Wen S, Wierda WG, O'Brien SM, Faderl S, Sargent R, Burger JA, Ferrajoli A. Phase II Study of Lenalidomide and Rituximab As Salvage Therapy for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia. J Clin Oncol. 2013 Feb 10;31(5):584-91. Epub 2012 Dec 26. [https://doi.org/10.1200/jco.2012.42.8623 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878047/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23270003/ PubMed] [https://clinicaltrials.gov/study/NCT00759603 NCT00759603] | |
− | + | # '''MDACC 2009-0283:''' Vitale C, Falchi L, Ten Hacken E, Gao H, Shaim H, Van Roosbroeck K, Calin G, O'Brien S, Faderl S, Wang X, Wierda WG, Rezvani K, Reuben JM, Burger JA, Keating MJ, Ferrajoli A. Ofatumumab and Lenalidomide for Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia: Correlation between Responses and Immune Characteristics. Clin Cancer Res. 2016 May 15;22(10):2359-67. Epub 2016 Jan 5. [https://doi.org/10.1158/1078-0432.ccr-15-2476 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5118034/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26733610/ PubMed] [https://clinicaltrials.gov/study/NCT01002755 NCT01002755] | |
− | |||
− | |||
− | |||
− | == | + | ==Ofatumumab monotherapy {{#subobject:9a07b6|Regimen=1}}== |
− | {| class="wikitable" style=" | + | <div class="toccolours" style="background-color:#eeeeee"> |
+ | ===Regimen variant #1 {{#subobject:134c67|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 100%; text-align:center;" | ||
+ | !style="width: 20%"|Study | ||
+ | !style="width: 20%"|Dates of enrollment | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
+ | !style="width: 20%"|Comparator | ||
+ | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | ||
+ | |- | ||
+ | |[https://doi.org/10.1016/S1470-2045(15)00143-6 van Oers et al. 2015 (PROLONG)] | ||
+ | |2010-2014 | ||
+ | |style="background-color:#1a9851"|Phase 3 (E-RT-esc) | ||
+ | |[[Chronic_lymphocytic_leukemia_-_null_regimens#Observation_2|Observation]] | ||
+ | |style="background-color:#1a9850"|Superior PFS (primary endpoint)<br>Median PFS: 29.4 vs 15.2 mo<br>(HR 0.50, 95% CI 0.38-0.66) | ||
|- | |- | ||
− | |||
|} | |} | ||
− | + | ''Note: Treatment offered to patients in their second or third CR or PR; prior treatment was not specified.'' | |
− | + | </div> | |
− | ===Regimen {{#subobject: | + | <div class="toccolours" style="background-color:#f2f3f4"> |
− | {| | + | ====Targeted therapy==== |
− | | | + | *[[Ofatumumab (Arzerra)]] as follows: |
− | |[[Levels_of_Evidence#Evidence| | + | **Cycle 1: 300 mg IV once on day 1, then 1000 mg IV once on day 7 |
+ | **Cycles 2 to 13: 1000 mg IV once on day 1 | ||
+ | ====Supportive therapy==== | ||
+ | *[[Acetaminophen (Tylenol)]] 1000 mg PO once per infusion, 30 to 120 minutes prior to ofatumumab | ||
+ | *[[Diphenhydramine (Benadryl)]] (or equivalent [[:Category:Antihistamines|antihistamine]]) 50 mg IV or PO once per infusion, 30 to 120 minutes prior to ofatumumab | ||
+ | *[[Prednisolone (Millipred)]] (or equivalent [[:Category:Steroids|glucocorticoid]]) 50 mg IV once per infusion, 30 to 120 minutes prior to ofatumumab | ||
+ | '''8-week cycle for up to 13 cycles (2 years)''' | ||
+ | </div></div><br> | ||
+ | <div class="toccolours" style="background-color:#eeeeee"> | ||
+ | ===Regimen variant #2 {{#subobject:e5c8d5|Variant=1}}=== | ||
+ | {| class="wikitable sortable" style="width: 60%; text-align:center;" | ||
+ | !style="width: 33%"|Study | ||
+ | !style="width: 33%"|Dates of enrollment | ||
+ | !style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]] | ||
|- | |- | ||
− | |[ | + | |[https://doi.org/10.1111/bjh.13380 Österborg et al. 2015 (GEN416)] |
− | |style="background-color:# | + | |2009-2011 |
+ | |style="background-color:#91cf61"|Phase 2 | ||
|- | |- | ||
|} | |} | ||
− | ==== | + | <div class="toccolours" style="background-color:#cbd5e8"> |
− | *[[ | + | ====Preceding treatment==== |
− | *[[Ofatumumab (Arzerra)]] | + | *Second-line [[#Ofatumumab_monotherapy_3|Ofatumumab]] x 8 |
− | + | </div> | |
− | * | + | <div class="toccolours" style="background-color:#f2f3f4"> |
+ | ====Targeted therapy==== | ||
+ | *[[Ofatumumab (Arzerra)]] 2000 mg IV once on day 1 | ||
+ | ====Supportive therapy==== | ||
+ | *[[Acetaminophen (Tylenol)]] 1000 mg PO once on day 1, prior to ofatumumab | ||
+ | *[[Cetirizine (Zyrtec)]] (or equivalent [[:Category:Antihistamines|antihistamine]]) 10 mg PO once on day 1, prior to ofatumumab | ||
+ | '''Monthly cycle for up to 24 cycles (2 years)''' | ||
+ | </div></div> | ||
+ | ===References=== | ||
+ | # '''GEN416:''' Österborg A, Wierda WG, Mayer J, Hess G, Hillmen P, Schetelig J, Schuh A, Smolej L, Beck C, Dreyfus B, Hellman A, Kozlowski P, Pfreundschuh M, Rizzi R, Spacek M, Phillips JL, Gupta IV, Williams V, Jewell RC, Nebot N, Lisby S, Dyer MJ. Ofatumumab retreatment and maintenance in fludarabine-refractory chronic lymphocytic leukaemia patients. Br J Haematol. 2015 Jul;170(1):40-9. Epub 2015 Mar 30. [https://doi.org/10.1111/bjh.13380 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/25825041/ PubMed] [https://clinicaltrials.gov/study/NCT00802737 NCT00802737] | ||
+ | # '''PROLONG:''' van Oers MH, Kuliczkowski K, Smolej L, Petrini M, Offner F, Grosicki S, Levin MD, Gupta I, Phillips J, Williams V, Manson S, Lisby S, Geisler C; PROLONG study investigators. Ofatumumab maintenance versus observation in relapsed chronic lymphocytic leukaemia (PROLONG): an open-label, multicentre, randomised phase 3 study. Lancet Oncol. 2015 Oct;16(13):1370-9. Epub 2015 Sep 13. [https://doi.org/10.1016/S1470-2045(15)00143-6 link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/26377300/ PubMed] [https://clinicaltrials.gov/study/NCT00802737 NCT00802737] | ||
− | == | + | ==Rituximab monotherapy {{#subobject:a88421|Regimen=1}}== |
− | + | <div class="toccolours" style="background-color:#eeeeee"> | |
− | + | ===Regimen {{#subobject:d67fca|Variant=1}}=== | |
− | + | {| class="wikitable sortable" style="width: 100%; text-align:center;" | |
− | + | !style="width: 20%"|Study | |
− | + | !style="width: 20%"|Dates of enrollment | |
− | + | !style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]] | |
− | + | !style="width: 20%"|Comparator | |
− | + | !style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]] | |
− | + | |- | |
− | + | |[https://doi.org/10.1016/s2352-3026(16)30045-x Greil et al. 2016 (AGMT CLL-8a)] | |
− | + | |2010-2013 | |
− | + | |style="background-color:#1a9851"|Phase 3 (E-esc) | |
− | + | |[[Chronic_lymphocytic_leukemia_-_null_regimens#Observation_2|Observation]] | |
− | + | |style="background-color:#1a9850"|Superior PFS (primary endpoint)<br>Median PFS: 47 vs 35.5 mo<br>(HR 0.50, 95% CI 0.33-0.75) | |
− | + | |- | |
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|} | |} | ||
− | + | <div class="toccolours" style="background-color:#cbd5e8"> | |
− | + | ====Preceding treatment==== | |
− | == | + | *Second-line [[Regimen_classes#Rituximab-containing_regimen|rituximab-containing chemoimmunotherapy]] |
− | + | </div> | |
− | + | <div class="toccolours" style="background-color:#f2f3f4"> | |
− | ==== | + | ====Targeted therapy==== |
− | *[[ | + | *[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1 |
− | + | '''3-month cycle for 8 cycles (2 years)''' | |
− | + | </div></div> | |
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− | ==== | ||
− | *[[ | ||
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− | ''' | ||
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===References=== | ===References=== | ||
− | # | + | # '''AGMT CLL-8a:''' Greil R, Obrtlíková P, Smolej L, Kozák T, Steurer M, Andel J, Burgstaller S, Mikušková E, Gercheva L, Nösslinger T, Papajík T, Ladická M, Girschikofsky M, Hrubiško M, Jäger U, Fridrik M, Pecherstorfer M, Králiková E, Burcoveanu C, Spasov E, Petzer A, Mihaylov G, Raynov J, Oexle H, Zabernigg A, Flochová E, Palášthy S, Stehlíková O, Doubek M, Altenhofer P, Pleyer L, Melchardt T, Klingler A, Mayer J, Egle A. Rituximab maintenance versus observation alone in patients with chronic lymphocytic leukaemia who respond to first-line or second-line rituximab-containing chemoimmunotherapy: final results of the AGMT CLL-8a Mabtenance randomised trial. Lancet Haematol. 2016 Jul;3(7):e317-29. Epub 2016 Jun 16. [https://doi.org/10.1016/s2352-3026(16)30045-x link to original article] '''dosing details in manuscript have been reviewed by our editors''' [https://pubmed.ncbi.nlm.nih.gov/27374465/ PubMed] [https://clinicaltrials.gov/study/NCT01118234 NCT01118234] |
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=Prognosis= | =Prognosis= | ||
These are various staging and risk prediction systems that are in approximate chronological order. | These are various staging and risk prediction systems that are in approximate chronological order. | ||
==Original Rai staging (1975)== | ==Original Rai staging (1975)== | ||
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*'''Stage 0:''' bone marrow and blood lymphocytosis only | *'''Stage 0:''' bone marrow and blood lymphocytosis only | ||
*'''Stage I:''' lymphocytosis with enlarged nodes | *'''Stage I:''' lymphocytosis with enlarged nodes | ||
Line 3,978: | Line 4,850: | ||
*'''Stage III:''' lymphocytosis with anemia | *'''Stage III:''' lymphocytosis with anemia | ||
*'''Stage IV:''' lymphocytosis with thrombocytopenia | *'''Stage IV:''' lymphocytosis with thrombocytopenia | ||
− | # Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. Clinical staging of chronic lymphocytic leukemia. Blood. 1975 Aug;46(2):219-34. [ | + | # Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. Clinical staging of chronic lymphocytic leukemia. Blood. 1975 Aug;46(2):219-34. [https://doi.org/10.1182/blood.V87.12.4990.bloodjournal87124990 link to original article] [https://pubmed.ncbi.nlm.nih.gov/8652811/ PubMed] |
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==Binet staging (1981)== | ==Binet staging (1981)== | ||
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*'''Group A:''' no anemia, no thrombocytopenia, less than three involved areas | *'''Group A:''' no anemia, no thrombocytopenia, less than three involved areas | ||
*'''Group B:''' no anemia, no thrombocytopenia, three or more involved areas (counting as one each of the following: axillary, cervical, inguinal, lymph nodes, whether unilateral or bilateral, spleen and liver) | *'''Group B:''' no anemia, no thrombocytopenia, three or more involved areas (counting as one each of the following: axillary, cervical, inguinal, lymph nodes, whether unilateral or bilateral, spleen and liver) | ||
− | *'''Group C:''' anemia (hemoglobin less than 10 g/dL) and/or thrombocytopenia (platelets less than 100 | + | *'''Group C:''' anemia (hemoglobin less than 10 g/dL) and/or thrombocytopenia (platelets less than 100 x 10<sup>9</sup>/L) |
− | # Binet JL, Auquier A, Dighiero G, Chastang C, Piguet H, Goasguen J, Vaugier G, Potron G, Colona P, Oberling F, Thomas M, Tchernia G, Jacquillat C, Boivin P, Lesty C, Duault MT, Monconduit M, Belabbes S, Gremy F. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer. 1981 Jul 1;48(1):198-206. [ | + | # Binet JL, Auquier A, Dighiero G, Chastang C, Piguet H, Goasguen J, Vaugier G, Potron G, Colona P, Oberling F, Thomas M, Tchernia G, Jacquillat C, Boivin P, Lesty C, Duault MT, Monconduit M, Belabbes S, Gremy F. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer. 1981 Jul 1;48(1):198-206. [https://doi.org/10.1002/1097-0142(19810701)48:1%3C198::AID-CNCR2820480131%3E3.0.CO;2-V link to original article] [https://pubmed.ncbi.nlm.nih.gov/7237385/ PubMed] |
− | + | ==Risk by cytogenetics== | |
− | ==Risk by | + | *''Classic NEJM paper establishing abnormal karyotype as an adverse prognostic marker'' |
− | + | # Han T, Ozer H, Sadamori N, Emrich L, Gomez GA, Henderson ES, Bloom ML, Sandberg AA. Prognostic importance of cytogenetic abnormalities in patients with chronic lymphocytic leukemia. N Engl J Med. 1984 Feb 2;310(5):288-92. [https://doi.org/10.1056/NEJM198402023100504link to original article] [https://pubmed.ncbi.nlm.nih.gov/6690952/ PubMed] | |
− | + | *''Large retrospective series looking at cytogenetic complexity'' | |
− | + | # Baliakas P, Jeromin S, Iskas M, Puiggros A, Plevova K, Nguyen-Khac F, Davis Z, Rigolin GM, Visentin A, Xochelli A, Delgado J, Baran-Marszak F, Stalika E, Abrisqueta P, Durechova K, Papaioannou G, Eclache V, Dimou M, Iliakis T, Collado R, Doubek M, Calasanz MJ, Ruiz-Xiville N, Moreno C, Jarosova M, Leeksma AC, Panayiotidis P, Podgornik H, Cymbalista F, Anagnostopoulos A, Trentin L, Stavroyianni N, Davi F, Ghia P, Kater AP, Cuneo A, Pospisilova S, Espinet B, Athanasiadou A, Oscier D, Haferlach C, Stamatopoulos K; ERIC, the European Research Initiative on CLL. Cytogenetic complexity in chronic lymphocytic leukemia: definitions, associations, and clinical impact. Blood. 2019 Mar 14;133(11):1205-1216. Epub 2019 Jan 2. [https://doi.org/10.1182/blood-2018-09-873083 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6509568/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30602617/ PubMed] | |
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− | ''Classic NEJM paper establishing abnormal karyotype as an adverse prognostic marker'' | ||
− | # Han T, Ozer H, Sadamori N, Emrich L, Gomez GA, Henderson ES, Bloom ML, Sandberg AA. Prognostic importance of cytogenetic abnormalities in patients with chronic lymphocytic leukemia. N Engl J Med. 1984 Feb 2;310(5):288-92. [ | ||
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==Risk by lymphocyte doubling time== | ==Risk by lymphocyte doubling time== | ||
− | # Montserrat E, Sanchez-Bisono J, Viñolas N, Rozman C. Lymphocyte doubling time in chronic lymphocytic leukaemia: analysis of its prognostic significance. Br J Haematol. 1986 Mar;62(3):567-75. [ | + | # Montserrat E, Sanchez-Bisono J, Viñolas N, Rozman C. Lymphocyte doubling time in chronic lymphocytic leukaemia: analysis of its prognostic significance. Br J Haematol. 1986 Mar;62(3):567-75. [https://doi.org/10.1111/j.1365-2141.1986.tb02969.x link to original article] [https://pubmed.ncbi.nlm.nih.gov/3954968/ PubMed] |
− | # Molica S, Alberti A. Prognostic value of the lymphocyte doubling time in chronic lymphocytic leukemia. Cancer. 1987 Dec 1;60(11):2712-6. [ | + | # Molica S, Alberti A. Prognostic value of the lymphocyte doubling time in chronic lymphocytic leukemia. Cancer. 1987 Dec 1;60(11):2712-6. [https://doi.org/10.1002/1097-0142(19871201)60:11%3C2712::AID-CNCR2820601122%3E3.0.CO;2-1 link to original article] [https://pubmed.ncbi.nlm.nih.gov/3677006/ PubMed] |
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==Risk by FISH== | ==Risk by FISH== | ||
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*''Classic 2000 NEJM paper establishing that 17p deletion has the worst prognosis:'' | *''Classic 2000 NEJM paper establishing that 17p deletion has the worst prognosis:'' | ||
− | # Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L, Döhner K, Bentz M, Lichter P. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000 Dec 28;343(26):1910-6. [ | + | # Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L, Döhner K, Bentz M, Lichter P. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000 Dec 28;343(26):1910-6. [https://doi.org/10.1056/NEJM200012283432602 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11136261/ PubMed] |
*''This article and abstract explore the significance of 13q deletions in more detail:'' | *''This article and abstract explore the significance of 13q deletions in more detail:'' | ||
− | # Van Dyke DL, Shanafelt TD, Call TG, Zent CS, Smoley SA, Rabe KG, Schwager SM, Sonbert JC, Slager SL, Kay NE. A comprehensive evaluation of the prognostic significance of 13q deletions in patients with B-chronic lymphocytic leukaemia. Br J Haematol. 2010 Feb;148(4):544-50. Epub 2009 Nov 6. [ | + | # Van Dyke DL, Shanafelt TD, Call TG, Zent CS, Smoley SA, Rabe KG, Schwager SM, Sonbert JC, Slager SL, Kay NE. A comprehensive evaluation of the prognostic significance of 13q deletions in patients with B-chronic lymphocytic leukaemia. Br J Haematol. 2010 Feb;148(4):544-50. Epub 2009 Nov 6. [https://doi.org/10.1111/j.1365-2141.2009.07982.x link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2866061/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19895615/ PubMed] |
− | # '''Abstract:''' Claudia Haferlach, Melanie Zenger, Vera Grossmann, Frank Dicker, Sabine Jeromin, Alexander Kohlmann, Susanne Schnittger, Wolfgang Kern, Torsten Haferlach. The Impact of Homozygosity and Size of the 13q Deletion in Patients with CLL. Blood 2012 120:3892 abstract 3892 [ | + | # '''Abstract:''' Claudia Haferlach, Melanie Zenger, Vera Grossmann, Frank Dicker, Sabine Jeromin, Alexander Kohlmann, Susanne Schnittger, Wolfgang Kern, Torsten Haferlach. The Impact of Homozygosity and Size of the 13q Deletion in Patients with CLL. Blood 2012 120:3892 abstract 3892 [https://doi.org/10.1182/blood.V120.21.3892.3892 link to abstract] |
− | + | ==Risk by TP53 mutation== | |
+ | # Zenz T, Eichhorst B, Busch R, Denzel T, Häbe S, Winkler D, Bühler A, Edelmann J, Bergmann M, Hopfinger G, Hensel M, Hallek M, Döhner H, Stilgenbauer S. TP53 mutation and survival in chronic lymphocytic leukemia. J Clin Oncol. 2010 Oct 10;28(29):4473-9. Epub 2010 Aug 9. [https://doi.org/10.1200/JCO.2009.27.8762 link to original article] [https://pubmed.ncbi.nlm.nih.gov/20697090/ PubMed] | ||
==Risk by CD38 expression== | ==Risk by CD38 expression== | ||
− | + | # Damle RN, Wasil T, Fais F, Ghiotto F, Valetto A, Allen SL, Buchbinder A, Budman D, Dittmar K, Kolitz J, Lichtman SM, Schulman P, Vinciguerra VP, Rai KR, Ferrarini M, Chiorazzi N. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood. 1999 Sep 15;94(6):1840-7. [https://doi.org/10.1182/blood.V94.6.1840 link to original article] [https://pubmed.ncbi.nlm.nih.gov/10477712/ PubMed] | |
− | + | # '''Review:''' Malavasi F, Deaglio S, Damle R, Cutrona G, Ferrarini M, Chiorazzi N. CD38 and chronic lymphocytic leukemia: a decade later. Blood. 2011 Sep 29;118(13):3470-8. [https://doi.org/10.1182/blood-2011-06-275610 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3574275/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21765022/ PubMed] | |
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− | # Damle RN, Wasil T, Fais F, Ghiotto F, Valetto A, Allen SL, Buchbinder A, Budman D, Dittmar K, Kolitz J, Lichtman SM, Schulman P, Vinciguerra VP, Rai KR, Ferrarini M, Chiorazzi N. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood. 1999 Sep 15;94(6):1840-7. [ | ||
− | # '''Review:''' Malavasi F, Deaglio S, Damle R, Cutrona G, Ferrarini M, Chiorazzi N. CD38 and chronic lymphocytic leukemia: a decade later. Blood. 2011 Sep 29;118(13):3470-8. [ | ||
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==Risk by ZAP-70 expression (2003)== | ==Risk by ZAP-70 expression (2003)== | ||
− | + | # Crespo M, Bosch F, Villamor N, Bellosillo B, Colomer D, Rozman M, Marcé S, López-Guillermo A, Campo E, Montserrat E. ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med. 2003 May 1;348(18):1764-75. [https://doi.org/10.1056/NEJMoa023143 link to original article] [https://pubmed.ncbi.nlm.nih.gov/12724482/ PubMed] | |
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− | # Crespo M, Bosch F, Villamor N, Bellosillo B, Colomer D, Rozman M, Marcé S, López-Guillermo A, Campo E, Montserrat E. ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med. 2003 May 1;348(18):1764-75. [ | ||
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==Prognostic scoring system using molecular and cytogenetic features (2012)== | ==Prognostic scoring system using molecular and cytogenetic features (2012)== | ||
− | + | # Rossi D, Rasi S, Spina V, Bruscaggin A, Monti S, Ciardullo C, Deambrogi C, Khiabanian H, Serra R, Bertoni F, Forconi F, Laurenti L, Marasca R, Dal-Bo M, Rossi FM, Bulian P, Nomdedeu J, Del Poeta G, Gattei V, Pasqualucci L, Rabadan R, Foà R, Dalla-Favera R, Gaidano G. Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia. Blood. 2013 Feb 21;121(8):1403-12. Epub 2012 Dec 13. [https://doi.org/10.1182/blood-2012-09-458265 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3578955/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23243274/ PubMed] | |
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− | # Rossi D, Rasi S, Spina V, Bruscaggin A, Monti S, Ciardullo C, Deambrogi C, Khiabanian H, Serra R, Bertoni F, Forconi F, Laurenti L, Marasca R, Dal-Bo M, Rossi FM, Bulian P, Nomdedeu J, Del Poeta G, Gattei V, Pasqualucci L, Rabadan R, Foà R, Dalla-Favera R, Gaidano G. Integrated mutational and cytogenetic analysis | ||
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==CLL-IPI (2016)== | ==CLL-IPI (2016)== | ||
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*[https://www.qxmd.com/calculate/calculator_375/cll-ipi QxMD calculator] | *[https://www.qxmd.com/calculate/calculator_375/cll-ipi QxMD calculator] | ||
− | # International CLL-IPI working group. An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncol. 2016 Jun;17(6):779-90. Epub 2016 May 13. [ | + | # International CLL-IPI working group. An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncol. 2016 Jun;17(6):779-90. Epub 2016 May 13. [https://doi.org/10.1016/S1470-2045(16)30029-8 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27185642/ PubMed] |
− | + | ==Prognostic scoring system using clinical features (2019)== | |
− | [[ | + | # Soumerai JD, Ni A, Darif M, Londhe A, Xing G, Mun Y, Kay NE, Shanafelt TD, Rabe KG, Byrd JC, Chanan-Khan AA, Furman RR, Hillmen P, Jones J, Seymour JF, Sharman JP, Ferrante L, Mobasher M, Stark T, Reddy V, Dreiling LK, Bhargava P, Howes A, James DF, Zelenetz AD. Prognostic risk score for patients with relapsed or refractory chronic lymphocytic leukaemia treated with targeted therapies or chemoimmunotherapy: a retrospective, pooled cohort study with external validations. Lancet Haematol. 2019 Jul;6(7):e366-e374. Epub 2019 May 17. Erratum in: Lancet Haematol. 2019 Jul;6(7):e348. [https://doi.org/10.1016/s2352-3026(19)30085-7 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6620111/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31109827/ PubMed] |
− | [[Category: | + | [[Category:Chronic lymphocytic leukemia regimens]] |
− | [[Category: | + | [[Category:Disease-specific pages]] |
− | [[Category: | + | [[Category:Indolent lymphomas]] |
Latest revision as of 02:07, 31 July 2024
Page editor | Section editor | ||
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Jon Arnason, MD Beth Israel Deaconess Medical Center Boston, MA, USA |
Sanjai Sharma, MD Sequoia Regional Cancer Center Visalia, CA, USA |
Are you looking for a regimen but can't find it here? It is possible that we've moved it to the historical regimens page. For placebo or observational studies in this condition, other than watchful waiting, please visit this page. If you still can't find it, please let us know so we can add it!
Note: there are several regimens on this page that are specific to small lymphocytic lymphoma (SLL). The vast majority of the regimens here were evaluated in patients with CLL or in mixed populations of patients with CLL and SLL.
- We have moved How I Treat articles to a dedicated page.
86 regimens on this page
133 variants on this page
|
Guidelines
Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.
ASBMT
- 2016: Kharfan-Dabaja et al. Clinical practice recommendations for use of allogeneic hematopoietic cell transplantation in chronic lymphocytic leukemia on behalf of the guidelines committee of the American Society for Blood and Marrow Transplantation PubMed
ESMO
- 2021: Eichhorst et al. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2015: Eichhorst et al. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2011: Eichhorst et al. Chronic lymphocytic leukemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2010: Eichhorst et al. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2009: Eichhorst et al. Chronic lymphocytic leukemia: ESMO minimum clinical recommendations for diagnosis, treatment and follow-up PubMed
- 2008: Eichhorst et al. Chronic lymphocytic leukemia: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
- 2007: Hallek. Chronic lymphocytic leukemia: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
- 2005: Hallek et al. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of chronic lymphocytic leukemia PubMed
- 2016: Ladetto et al. ESMO consensus conference on malignant lymphoma: general perspectives and recommendations for prognostic tools in mature B-cell lymphomas and chronic lymphocytic leukaemia PubMed
- 2013: Ghielmini et al. ESMO Guidelines consensus conference on malignant lymphoma 2011 part 1: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL) link to PMC article PubMed
International Workshop on Chronic Lymphocytic Leukemia (iwCLL)
- 2018: Hallek et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL PubMed
- 2008: Hallek et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines PubMed
- 1996: Cheson et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment PubMed
NCCN
First-line therapy, randomized data
Acalabrutinib monotherapy
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
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Byrd et al. 2021 (ACE-CL-001 untreated) | 2014-2015 | Phase 1/2 | ||
Sharman et al. 2020 (ELEVATE TN) | 2015-2017 | Phase 3 (E-RT-switch-ooc) | 1. Acalabrutinib & Obinutuzumab | Not reported |
2. Chlorambucil & Obinutuzumab | Superior PFS (primary endpoint) Median PFS: NYR vs 22.6 mo (HR 0.20, 95% CI 0.13-0.30) |
Note: Byrd et al. 2021 reports on a treatment-naive cohort from a trial that mostly enrolled patients in relapse.
Targeted therapy
- Acalabrutinib (Calquence) 100 mg PO twice per day or 200 mg PO once per day
Continued indefinitely
References
- ELEVATE TN: Sharman JP, Egyed M, Jurczak W, Skarbnik A, Pagel JM, Flinn IW, Kamdar M, Munir T, Walewska R, Corbett G, Fogliatto LM, Herishanu Y, Banerji V, Coutre S, Follows G, Walker P, Karlsson K, Ghia P, Janssens A, Cymbalista F, Woyach JA, Salles G, Wierda WG, Izumi R, Munugalavadla V, Patel P, Wang MH, Wong S, Byrd JC. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020 Apr 18;395(10232):1278-1291. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT02475681
- ACE-CL-001 untreated: Byrd JC, Woyach JA, Furman RR, Martin P, O'Brien S, Brown JR, Stephens DM, Barrientos JC, Devereux S, Hillmen P, Pagel JM, Hamdy A, Izumi R, Patel P, Wang MH, Jain N, Wierda WG. Acalabrutinib in treatment-naive chronic lymphocytic leukemia. Blood. 2021 Jun 17;137(24):3327-3338. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT02029443
Acalabrutinib & Obinutuzumab
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
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Sharman et al. 2020 (ELEVATE TN) | 2015-2017 | Phase 3 (E-RT-switch-ooc) | 1. Acalabrutinib | Not reported |
2. Chlorambucil & Obinutuzumab | Superior PFS (primary endpoint) Median PFS: NYR vs 22.6 mo (HR 0.10, 95% CI 0.06-0.17) |
Targeted therapy
- Acalabrutinib (Calquence) 100 mg PO twice per day
- Obinutuzumab (Gazyva) as follows:
- Cycle 2: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15
- Cycles 3 to 7: 1000 mg IV once on day 1
28-day cycles
References
- ELEVATE TN: Sharman JP, Egyed M, Jurczak W, Skarbnik A, Pagel JM, Flinn IW, Kamdar M, Munir T, Walewska R, Corbett G, Fogliatto LM, Herishanu Y, Banerji V, Coutre S, Follows G, Walker P, Karlsson K, Ghia P, Janssens A, Cymbalista F, Woyach JA, Salles G, Wierda WG, Izumi R, Munugalavadla V, Patel P, Wang MH, Wong S, Byrd JC. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020 Apr 18;395(10232):1278-1291. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT02475681
Alemtuzumab monotherapy
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
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Hillmen et al. 2007 (CAM 307) | 2001-2004 | Phase 3 (E-RT-switch-ooc) | Chlorambucil | Superior PFS1 (primary endpoint) Median PFS: 15 vs 12 mo (aHR 0.58, 95% CI 0.43-0.77) |
1Median PFS is not reported in the manuscript and is estimated from the K-M curve (Figure 1A)
Eligibility criteria
- This regimen was intended for patients who were at least 18 years old with flow cytometry–confirmed diagnosis of B-cell CLL, Rai stage I through IV with evidence of progression according to the National Cancer Institute Working Group (NCI-WG) 1996 criteria, no previous chemotherapy for CLL, a life expectancy of at least 12 weeks, WHO performance status of 0 to 2, and adequate renal and liver function.
Targeted therapy
- Alemtuzumab (Campath) as follows:
- Starting dose: 3 mg IV once per day
- Once tolerated in terms of infusion reactions: 10 mg IV once per day
- Once tolerated in terms of infusion reactions: 30 mg IV once per day
- Once 30 mg dose is tolerated: 30 mg IV over 2 hours, 3 times per week
Supportive therapy
- See references for details, as they differ by paper.
- Diphenhydramine (Benadryl) 50 mg PO once per infusion, 30 minutes prior to alemtuzumab
- Acetaminophen (Tylenol) 650 mg PO once per infusion, 30 minutes prior to alemtuzumab
- Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg PO 3 times per week, starting on day 8, continuing at a minimum until 2 months after treatment is complete
- Famciclovir (Famvir) 250 mg PO twice per day, starting on day 8, continuing at a minimum until 2 months after treatment is complete
12- to 16-week course; total course varies depending on reference
References
- CAM 307: Hillmen P, Skotnicki AB, Robak T, Jaksic B, Dmoszynska A, Wu J, Sirard C, Mayer J. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol. 2007 Dec 10;25(35):5616-23. Epub 2007 Nov 5. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT00046683
Bendamustine monotherapy
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Knauf et al. 2009 | 2002-2006 | Phase 3 (E-RT-switch-ic) | Chlorambucil | Superior PFS (co-primary endpoint) Median PFS: 21.6 vs 8.3 mo |
Zhou et al. 2022 (SIM-79-001) | 2009-2016 | Phase 3 (E-switch-ic) | Chlorambucil | Superior PFS (secondary endpoint) Median PFS: 16.5 vs 9.6 mo Superior ORR (primary endpoint) |
Eligibility criteria
- This regimen was intended for previously untreated CLL patients up to 75 years old with Binet stage B or C disease in need for treatment per the NCI-WG guidelines or IWCLL guidelines.
References
- Knauf WU, Lissichkov T, Aldaoud A, Liberati A, Loscertales J, Herbrecht R, Juliusson G, Postner G, Gercheva L, Goranov S, Becker M, Fricke HJ, Huguet F, Del Giudice I, Klein P, Tremmel L, Merkle K, Montillo M. Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009 Sep 10;27(26):4378-84. Epub 2009 Aug 3. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Update: Knauf WU, Lissitchkov T, Aldaoud A, Liberati AM, Loscertales J, Herbrecht R, Juliusson G, Postner G, Gercheva L, Goranov S, Becker M, Fricke HJ, Huguet F, Del Giudice I, Klein P, Merkle K, Montillo M. Bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukaemia: updated results of a randomized phase III trial. Br J Haematol. 2012 Oct;159(1):67-77. Epub 2012 Aug 4. link to original article PubMed
- Retrospective: Kolibaba KS, Sterchele JA, Joshi AD, Forsyth M, Alwon E, Beygi H, Kennealey GT. Demographics, treatment patterns, safety, and real-world effectiveness in patients aged 70 years and over with chronic lymphocytic leukemia receiving bendamustine with or without rituximab: a retrospective study. Ther Adv Hematol. 2013 Jun;4(3):157-71. link to PMC article PubMed
- SIM-79-001: Zhou D, Xu W, Ma H, Zhao C, Hu Y, Zhao Y, Wu D, Zhao X, He Y, Yan J, Wang C, Meng F, Jin J, Zhang X, Yu K, Hu J, Lv Y. Bendamustine versus chlorambucil in treatment of chronic lymphocytic leukaemia in China: a randomized, open-label, parallel-controlled, phase III clinical trial. Invest New Drugs. 2022 Apr;40(2):349-360. Epub 2022 Jan 15. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01109264
Bendamustine & Rituximab (BR)
BR: Bendamustine & Rituximab
R-B: Rituximab & Bendamustine
Regimen variant #1, 6 cycles
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Fischer et al. 2012 (GCLLSG CLL2M untreated) | 2007-2008 | Phase 2 | ||
Eichhorst et al. 2016 (GCLLSG CLL10) | 2008-2011 | Phase 3 (E-switch-ic) | FCR | Inconclusive whether non-inferior PFS (primary endpoint) Median PFS: 41.7 vs 55.2 mo (HR 1.64, 90.4% CI 1.31-2.06) |
Michallet et al. 2018 (MABLE) | 2010-2014 | Phase 3b (E-switch-ic) | R-Clb | Superior PFS (secondary endpoint) Median PFS: 39.6 vs 29.9 mo (HR 0.52, 95% CI 0.34-0.81) |
Woyach et al. 2018 (Alliance A041202) | 2013-2016 | Phase 3 (C) | 1. Ibrutinib 2. Ibrutinib & Rituximab |
Inferior PFS |
Eichhorst et al. 2023 (GAIA) | 2016-12-13 to 2019-10-13 | Phase 3 (C) | 1. Venetoclax & Obinutuzumab 2. Ibrutinib, Venetoclax, Obinutuzumab |
Inferior PFS |
3. Venetoclax & Rituximab | Did not meet primary endpoint of PFS | |||
Tam et al. 2022 (SEQUOIACLL) | 2017-2019 | Phase 3 (C) | Zanubrutinib | Inferior PFS |
Eligibility criteria
- GAIA: Older than 65 years old
Biomarker eligibility criteria
- SEQUOIACLL: No 17p deletion
Chemotherapy
- Bendamustine 90 mg/m2 IV once per day on days 1 & 2
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 0 or 1
- Cycle 2 up to 6: 500 mg/m2 IV once on day 1
28-day cycle for up to 6 cycles
Regimen variant #2, 6 cycles with escalation
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Woyach et al. 2018 (Alliance A041202) | 2013-2016 | Phase 3 (C) | 1. Ibrutinib 2. Ibrutinib & Rituximab |
Inferior PFS |
Chemotherapy
- Bendamustine as follows:
- Cycle 1: 70 mg/m2 IV once per day on days 1 & 2
- Cycles 2 to 6: 90 mg/m2 IV once per day on days 1 & 2
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 0
- Cycle 2 up to 6: 500 mg/m2 IV once on day 1
28-day cycle for 6 cycles
Regimen variant #3, 6 cycles with maintenance rituximab
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Wang et al. 2022 (SHINE) | 2013-05 to 2014-11 | Phase 3 (C) | BR & Ibrutinib | Seems to have inferior PFS |
Note: the cycle timing changes during rituximab maintenance; the dosing does not change.
Chemotherapy
- Bendamustine as follows:
- Cycles 1 to 6: 90 mg/m2 IV once per day on days 1 & 2
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycles 1 to 6: 375 mg/m2 IV once on day 1
- Cycles 7 to 18: 375 mg/m2 IV once on day 1
28-day cycle for 6 cycles, then 8-week cycle for 12 cycles
References
- GCLLSG CLL2M untreated: Fischer K, Cramer P, Busch R, Böttcher S, Bahlo J, Schubert J, Pflüger KH, Schott S, Goede V, Isfort S, von Tresckow J, Fink AM, Bühler A, Winkler D, Kreuzer KA, Staib P, Ritgen M, Kneba M, Döhner H, Eichhorst BF, Hallek M, Stilgenbauer S, Wendtner CM. Bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. 2012 Sep 10;30(26):3209-16. Epub 2012 Aug 6. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00274989
- Retrospective: Kolibaba KS, Sterchele JA, Joshi AD, Forsyth M, Alwon E, Beygi H, Kennealey GT. Demographics, treatment patterns, safety, and real-world effectiveness in patients aged 70 years and over with chronic lymphocytic leukemia receiving bendamustine with or without rituximab: a retrospective study. Ther Adv Hematol. 2013 Jun;4(3):157-71. link to PMC article PubMed
- GCLLSG CLL10: Eichhorst B, Fink AM, Bahlo J, Busch R, Kovacs G, Maurer C, Lange E, Köppler H, Kiehl M, Sökler M, Schlag R, Vehling-Kaiser U, Köchling G, Plöger C, Gregor M, Plesner T, Trneny M, Fischer K, Döhner H, Kneba M, Wendtner CM, Klapper W, Kreuzer KA, Stilgenbauer S, Böttcher S, Hallek M; International Group of Investigators; GCLLSG. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016 Jul;17(7):928-42. Epub 2016 May 20. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00769522
- MABLE: Michallet AS, Aktan M, Hiddemann W, Ilhan O, Johansson P, Laribi K, Meddeb B, Moreno C, Raposo J, Schuh A, Ünal A, Widenius T, Bernhardt A, Kellershohn K, Messeri D, Osborne S, Leblond V. Rituximab plus bendamustine or chlorambucil for chronic lymphocytic leukemia: primary analysis of the randomized, open-label MABLE study. Haematologica. 2018 Apr;103(4):698-706. Epub 2018 Feb 1. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01056510
- Alliance A041202: Woyach JA, Ruppert AS, Heerema NA, Zhao W, Booth AM, Ding W, Bartlett NL, Brander DM, Barr PM, Rogers KA, Parikh SA, Coutre S, Hurria A, Brown JR, Lozanski G, Blachly JS, Ozer HG, Major-Elechi B, Fruth B, Nattam S, Larson RA, Erba H, Litzow M, Owen C, Kuzma C, Abramson JS, Little RF, Smith SE, Stone RM, Mandrekar SJ, Byrd JC. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018 Dec 27;379(26):2517-2528. Epub 2018 Dec 1. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01886872
- Update: Woyach JA, Perez Burbano G, Ruppert AS, Miller C, Heerema NA, Zhao W, Wall A, Ding W, Bartlett NL, Brander DM, Barr PM, Rogers KA, Parikh SA, Stephens DM, Brown JR, Lozanski G, Blachly J, Nattam S, Larson RA, Erba H, Litzow M, Luger S, Owen C, Kuzma C, Abramson JS, Little RF, Dinner S, Stone RM, Uy G, Stock W, Mandrekar SJ, Byrd JC. Follow-up from the A041202 study shows continued efficacy of ibrutinib regimens for older adults with CLL. Blood. 2024 Apr 18;143(16):1616-1627. link to original article link to PMC article PubMed
- SHINE: Wang ML, Jurczak W, Jerkeman M, Trotman J, Zinzani PL, Belada D, Boccomini C, Flinn IW, Giri P, Goy A, Hamlin PA, Hermine O, Hernández-Rivas JÁ, Hong X, Kim SJ, Lewis D, Mishima Y, Özcan M, Perini GF, Pocock C, Song Y, Spurgeon SE, Storring JM, Walewski J, Zhu J, Qin R, Henninger T, Deshpande S, Howes A, Le Gouill S, Dreyling M; SHINE Investigators. Ibrutinib plus Bendamustine and Rituximab in Untreated Mantle-Cell Lymphoma. N Engl J Med. 2022 Jun 30;386(26):2482-2494. Epub 2022 Jun 3. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01776840
- SEQUOIACLL: Tam CS, Brown JR, Kahl BS, Ghia P, Giannopoulos K, Jurczak W, Šimkovič M, Shadman M, Österborg A, Laurenti L, Walker P, Opat S, Chan H, Ciepluch H, Greil R, Tani M, Trněný M, Brander DM, Flinn IW, Grosicki S, Verner E, Tedeschi A, Li J, Tian T, Zhou L, Marimpietri C, Paik JC, Cohen A, Huang J, Robak T, Hillmen P. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022 Aug;23(8):1031-1043. Epub 2022 Jul 7. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT03336333
- HRQoL analysis: Ghia P, Barnes G, Yang K, Tam CS, Robak T, Brown JR, Kahl BS, Tian T, Szeto A, Paik JC, Shadman M. Health-related quality-of-life in treatment-naive CLL/SLL patients treated with zanubrutinib versus bendamustine plus rituximab. Curr Med Res Opin. 2023 Nov;39(11):1505-1511. Epub 2023 Oct 12. link to original article PubMed
- GAIA: Eichhorst B, Niemann CU, Kater AP, Fürstenau M, von Tresckow J, Zhang C, Robrecht S, Gregor M, Juliusson G, Thornton P, Staber PB, Tadmor T, Lindström V, da Cunha-Bang C, Schneider C, Poulsen CB, Illmer T, Schöttker B, Nösslinger T, Janssens A, Christiansen I, Baumann M, Frederiksen H, van der Klift M, Jäger U, Leys MBL, Hoogendoorn M, Lotfi K, Hebart H, Gaska T, Koene H, Enggaard L, Goede J, Regelink JC, Widmer A, Simon F, De Silva N, Fink AM, Bahlo J, Fischer K, Wendtner CM, Kreuzer KA, Ritgen M, Brüggemann M, Tausch E, Levin MD, van Oers M, Geisler C, Stilgenbauer S, Hallek M; GCLLSG, the HOVON and Nordic CLL Study Groups, the SAKK, the Israeli CLL Association, and Cancer Trials Ireland. First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia. N Engl J Med. 2023 May 11;388(19):1739-1754. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT02950051
- Update: Fürstenau M, Kater AP, Robrecht S, von Tresckow J, Zhang C, Gregor M, Thornton P, Staber PB, Tadmor T, Lindström V, Juliusson G, Janssens A, Levin MD, da Cunha-Bang C, Schneider C, Goldschmidt N, Vandenberghe E, Rossi D, Benz R, Nösslinger T, Heintel D, Poulsen CB, Christiansen I, Frederiksen H, Enggaard L, Posthuma EFM, Issa DE, Visser HPJ, Bellido M, Kutsch N, Dürig J, Stehle A, Vöhringer M, Böttcher S, Schulte C, Simon F, Fink AM, Fischer K, Holmes EE, Kreuzer KA, Ritgen M, Brüggemann M, Tausch E, Stilgenbauer S, Hallek M, Niemann CU, Eichhorst B. First-line venetoclax combinations versus chemoimmunotherapy in fit patients with chronic lymphocytic leukaemia (GAIA/CLL13): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2024 Jun;25(6):744-759. Erratum in: Lancet Oncol. 2024 Jul;25(7):e284. link to original article PubMed
- ACE-CL-311: NCT03836261
- BRUIN CLL-313: NCT05023980
- CRISTALLO: NCT04285567
Bendamustine & Rituximab (BR) & Ibrutinib
BR & Ibrutinib: Bendamustine, Rituximab, Ibrutinib
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Wang et al. 2022 (SHINE) | 2013-05 to 2014-11 | Phase 3 (E-esc) | BR | Seems to have superior PFS (primary endpoint) Median PFS: 80.6 vs 52.9 mo (HR 0.75, 95% CI 0.59-0.96) |
Note: the cycle timing changes during rituximab maintenance; the dosing does not change.
Chemotherapy
- Bendamustine as follows:
- Cycles 1 to 6: 90 mg/m2 IV once per day on days 1 & 2
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycles 1 to 6: 375 mg/m2 IV once on day 1
- Cycles 7 to 18: 375 mg/m2 IV once on day 1
- Ibrutinib (Imbruvica) as follows:
- Cycles 1 to 6: 560 mg PO once per day on days 1 to 28
- Cycle 7 onwards: 560 mg PO once per day on days 1 to 56
28-day cycle for 6 cycles, then 8-week cycles
References
- SHINE: Wang ML, Jurczak W, Jerkeman M, Trotman J, Zinzani PL, Belada D, Boccomini C, Flinn IW, Giri P, Goy A, Hamlin PA, Hermine O, Hernández-Rivas JÁ, Hong X, Kim SJ, Lewis D, Mishima Y, Özcan M, Perini GF, Pocock C, Song Y, Spurgeon SE, Storring JM, Walewski J, Zhu J, Qin R, Henninger T, Deshpande S, Howes A, Le Gouill S, Dreyling M; SHINE Investigators. Ibrutinib plus Bendamustine and Rituximab in Untreated Mantle-Cell Lymphoma. N Engl J Med. 2022 Jun 30;386(26):2482-2494. Epub 2022 Jun 3. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01776840
Cladribine & Cyclophosphamide (CC)
CC: Cladribine, Cyclophosphamide
Regimen variant #1, 0.36/650
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Robak et al. 2006 (PALG CLL2) | 1998-2003 | Phase 3 (E-esc) | 1. Cladribine | Might have superior CR rate (primary endpoint) |
2. CMC | Seems to have inferior CR rate (primary endpoint) |
Chemotherapy
- Cladribine (Leustatin) 0.12 mg/kg IV over 2 hours once per day on days 1 to 3
- Cyclophosphamide (Cytoxan) 650 mg/m2 IV once on day 1
Supportive therapy
- No routine prophylactic antibiotics, antiviral agents, or growth factor administration was planned.
28-day cycle for up to 6 cycles
Regimen variant #2, 0.36/750
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Robak et al. 2010 (PALG-CLL3) | 2004-2007 | Phase 3 (E-switch-ic) | FC | Did not meet primary endpoint of CR rate |
Chemotherapy
- Cladribine (Leustatin) 0.12 mg/kg IV over 30 minutes once per day on days 1 to 3
- Cyclophosphamide (Cytoxan) 250 mg/m2 IV over 30 to 60 minutes once per day on days 1 to 3
Supportive therapy
- "No routine prophylaxis with antibiotics, antiviral agents, or growth factors."
28-day cycle for up to 6 cycles
References
- PALG CLL2: Robak T, Blonski JZ, Gora-Tybor J, Jamroziak K, Dwilewicz-Trojaczek J, Tomaszewska A, Konopka L, Ceglarek B, Dmoszynska A, Kowal M, Kloczko J, Stella-Holowiecka B, Sulek K, Calbecka M, Zawilska K, Kuliczkowski K, Skotnicki AB, Warzocha K, Kasznicki M; PALG. Cladribine alone and in combination with cyclophosphamide or cyclophosphamide plus mitoxantrone in the treatment of progressive chronic lymphocytic leukemia: report of a prospective, multicenter, randomized trial of the Polish Adult Leukemia Group (PALG CLL2). Blood. 2006 Jul 15;108(2):473-9. Epub 2006 Mar 21. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Update: Robak T, Blonski JZ, Gora-Tybor J, Calbecka M, Dwilewicz-Trojaczek J, Boguradzki P, Dmoszynska A, Kowal M, Kloczko J, Piszcz J, Stella-Holowiecka B, Sulek K, Kuliczkowski K, Potoczek S, Warzocha K, Lech-Maranda E, Skotnicki AB, Piotrowska M, Moskwa A, Zawilska K, Jamroziak K. Long-term results of the Polish Adult Leukemia Group PALG-CLL2 phase III randomized study comparing cladribine-based combinations in chronic lymphocytic leukemia. Leuk Lymphoma. 2014 Mar;55(3):606-10. Epub 2013 Nov 14. link to original article PubMed
- PALG-CLL3: Robak T, Jamroziak K, Gora-Tybor J, Stella-Holowiecka B, Konopka L, Ceglarek B, Warzocha K, Seferynska I, Piszcz J, Calbecka M, Kostyra A, Dwilewicz-Trojaczek J, Dmoszyñska A, Zawilska K, Hellmann A, Zdunczyk A, Potoczek S, Piotrowska M, Lewandowski K, Blonski JZ. Comparison of cladribine plus cyclophosphamide with fludarabine plus cyclophosphamide as first-line therapy for chronic lymphocytic leukemia: a phase III randomized study by the Polish Adult Leukemia Group (PALG-CLL3 Study). J Clin Oncol. 2010 Apr 10;28(11):1863-9. Epub 2010 Mar 8. link to original article dosing details in manuscript have been reviewed by our editors PubMed
Chlorambucil & Obinutuzumab (GClb)
GClb: GA101 (Obinutuzumab) & Chlorambucil
Regimen variant #1, 6 cycles
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Goede et al. 2014 (GCLLSG CLL11) | 2010-2012 | Phase 3 (E-RT-esc) | 1. Chlorambucil | Superior OS (secondary endpoint) Median OS: NYR vs NYR (HR 0.41, 95% CI 0.23-0.74) Superior PFS (primary endpoint) Median PFS: 26.7 vs 11.1 mo (HR 0.18, 95% CI 0.13-0.24) |
2. Chlorambucil & Rituximab | Superior PFS (primary endpoint) (HR 0.39, 95% CI 0.31-0.49) | |||
Moreno et al. 2018 (iLLUMINATE) | 2014-10-06 to 2015-10-12 | Phase 3 (C) | Ibrutinib & Obinutuzumab | Inferior PFS |
Sharman et al. 2020 (ELEVATE TN) | 2015-2017 | Phase 3 (C) | 1. Acalabrutinib 2. Acalabrutinib & Obinutuzumab |
Inferior PFS |
Kater et al. 2022 (GLOW) | 2018-05 to 2019-04 | Phase 3 (C) | Ibrutinib & Venetoclax | Inferior PFS |
Eligibility criteria
- GLOW: At least 65 years old or 18 to 64 years old with a Cumulative Illness Rating Scale (CIRS) score greater than 6
Chemotherapy
- Chlorambucil (Leukeran) 0.5 mg/kg PO once per day on days 1 & 15
Targeted therapy
- Obinutuzumab (Gazyva) as follows:
- Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15
- Cycles 2 to 6: 1000 mg IV once on day 1
28-day cycle for 6 cycles
Regimen variant #2, 12 cycles
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Fischer et al. 2019 (GCLLSG CLL14) | 2015-08-07 to 2016-08-04 | Phase 3 (C) | Venetoclax & Obinutuzumab | Inferior PFS |
Note: Obinutuzumab is only given for the first six cycles.
Chemotherapy
- Chlorambucil (Leukeran) 0.5 mg/kg PO once per day on days 1 & 15
Targeted therapy
- Obinutuzumab (Gazyva) as follows:
- Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15
- Cycles 2 to 6: 1000 mg IV once on day 1
28-day cycle for 12 cycles
References
- GCLLSG CLL11: Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, Chagorova T, de la Serna J, Dilhuydy MS, Illmer T, Opat S, Owen CJ, Samoylova O, Kreuzer KA, Stilgenbauer S, Döhner H, Langerak AW, Ritgen M, Kneba M, Asikanius E, Humphrey K, Wenger M, Hallek M. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014 Mar 20;370(12):1101-10. Epub 2014 Jan 8. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01010061
- Update: Goede V, Fischer K, Engelke A, Schlag R, Lepretre S, Casado Montero LF, Montillo M, Fegan C, Asikanius E, Humphrey K, Fingerle-Rowson G, Hallek M. Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study. Leukemia. 2015 Jul;29(7):1602-4. Epub 2015 Jan 30. link to original article PubMed
- iLLUMINATE: Moreno C, Greil R, Demirkan F, Tedeschi A, Anz B, Larratt L, Simkovic M, Samoilova O, Novak J, Ben-Yehuda D, Strugov V, Gill D, Gribben JG, Hsu E, Lih CJ, Zhou C, Clow F, James DF, Styles L, Flinn IW. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019 Jan;20(1):43-56. Epub 2018 Nov 30. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT02264574
- GCLLSG CLL14: Fischer K, Al-Sawaf O, Bahlo J, Fink AM, Tandon M, Dixon M, Robrecht S, Warburton S, Humphrey K, Samoylova O, Liberati AM, Pinilla-Ibarz J, Opat S, Sivcheva L, Le Dû K, Fogliatto LM, Niemann CU, Weinkove R, Robinson S, Kipps TJ, Boettcher S, Tausch E, Humerickhouse R, Eichhorst B, Wendtner CM, Langerak AW, Kreuzer KA, Ritgen M, Goede V, Stilgenbauer S, Mobasher M, Hallek M. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019 Jun 6;380(23):2225-2236. Epub 2019 Jun 4. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT02242942
- Update: Al-Sawaf O, Zhang C, Tandon M, Sinha A, Fink AM, Robrecht S, Samoylova O, Liberati AM, Pinilla-Ibarz J, Opat S, Sivcheva L, Le Dû K, Fogliatto LM, Niemann CU, Weinkove R, Robinson S, Kipps TJ, Tausch E, Schary W, Ritgen M, Wendtner CM, Kreuzer KA, Eichhorst B, Stilgenbauer S, Hallek M, Fischer K. Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2020 Sep;21(9):1188-1200. link to original article PubMed
- Update: Al-Sawaf O, Zhang C, Lu T, Liao MZ, Panchal A, Robrecht S, Ching T, Tandon M, Fink AM, Tausch E, Schneider C, Ritgen M, Böttcher S, Kreuzer KA, Chyla B, Miles D, Wendtner CM, Eichhorst B, Stilgenbauer S, Jiang Y, Hallek M, Fischer K. Minimal Residual Disease Dynamics after Venetoclax-Obinutuzumab Treatment: Extended Off-Treatment Follow-up From the Randomized CLL14 Study. J Clin Oncol. 2021 Dec 20;39(36):4049-4060. Epub 2021 Oct 28. link to original article link to PMC article PubMed
- ELEVATE TN: Sharman JP, Egyed M, Jurczak W, Skarbnik A, Pagel JM, Flinn IW, Kamdar M, Munir T, Walewska R, Corbett G, Fogliatto LM, Herishanu Y, Banerji V, Coutre S, Follows G, Walker P, Karlsson K, Ghia P, Janssens A, Cymbalista F, Woyach JA, Salles G, Wierda WG, Izumi R, Munugalavadla V, Patel P, Wang MH, Wong S, Byrd JC. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020 Apr 18;395(10232):1278-1291. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT02475681
- GLOW: Kater AP, Owen C, Moreno C, Follows G, Munir T, Levin MD, Benjamini O, Janssens A, Osterborg A, Robak T, Simkovic M, Stevens D, Voloshin S, Vorobyev V, Ysebaert L, Qin R, Steele AJ, Schuier N, Baeten K, Caces DB, Niemann CU. Fixed-Duration Ibrutinib-Venetoclax in Patients with Chronic Lymphocytic Leukemia and Comorbidities. NEJM Evid. 2022 Jul;1(7):EVIDoa2200006. Epub 2022 May 13. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT03462719
- Update: Niemann CU, Munir T, Moreno C, Owen C, Follows GA, Benjamini O, Janssens A, Levin MD, Robak T, Simkovic M, Voloshin S, Vorobyev V, Yagci M, Ysebaert L, Qi K, Qi Q, Sinet P, Parisi L, Srinivasan S, Schuier N, Baeten K, Howes A, Caces DB, Kater AP. Fixed-duration ibrutinib-venetoclax versus chlorambucil-obinutuzumab in previously untreated chronic lymphocytic leukaemia (GLOW): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2023 Dec;24(12):1423-1433. Epub 2023 Nov 6. link to original article PubMed
- UNITY-CLL: NCT02612311
Chlorambucil & Ofatumumab
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Hillmen et al. 2015 (COMPLEMENT 1) | 2008-2011 | Phase 3 (E-RT-esc) | Chlorambucil | Superior PFS (primary endpoint) Median PFS: 22.4 vs 13.1 mo (HR 0.57, 95% CI 0.45-0.72) |
Chemotherapy
- Chlorambucil (Leukeran) 10 mg/m2 PO once per day on days 1 to 7
Targeted therapy
- Ofatumumab (Arzerra) as follows:
- Cycle 1: 300 mg IV once on day 1, then 1000 mg IV once on day 8
- Cycles 2 to 3 up to 12: 1000 mg IV once on day 1
Supportive therapy
- Premedication for ofatumumab included Acetaminophen (Tylenol), antihistamines, and glucocorticoids (no doses or further information provided)
28-day cycle for a minimum of 3 cycles, and then given until best response up to a maximum of 12 cycles
References
- COMPLEMENT 1: Hillmen P, Robak T, Janssens A, Babu KG, Kloczko J, Grosicki S, Doubek M, Panagiotidis P, Kimby E, Schuh A, Pettitt AR, Boyd T, Montillo M, Gupta IV, Wright O, Dixon I, Carey JL, Chang CN, Lisby S, McKeown A, Offner F; COMPLEMENT 1 Study Investigators. Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial. Lancet. 2015 May 9;385(9980):1873-83. Epub 2015 Apr 13. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT00748189
- Update: Offner F, Robak T, Janssens A, Govind Babu K, Kloczko J, Grosicki S, Mayer J, Panagiotidis P, Schuh A, Pettitt A, Montillo M, Werner O, Vincent G, Khanna S, Hillmen P. A five-year follow-up of untreated patients with chronic lymphocytic leukaemia treated with ofatumumab and chlorambucil: final analysis of the Complement 1 phase 3 trial. Br J Haematol. 2020 Sep;190(5):736-740. Epub 2020 Mar 31. link to original article PubMed
Chlorambucil & Rituximab (RClb)
RClb: Rituximab & Chlorambucil
CLB-R: ChLoramBucil & Rituximab
Regimen variant #1, Clb 0.5 mg/kg q2wk
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Goede et al. 2014 (GCLLSG CLL11) | 2010-2012 | Phase 3 (E-esc) | 1. Chlorambucil | Superior PFS (primary endpoint) Median PFS: 16.3 vs 11.1 mo (HR 0.44, 95% CI 0.34-0.57) |
2. Chlorambucil & Obinutuzumab | Inferior PFS (primary endpoint) | |||
Awaiting publication (D822BC00001) | 2020-2024 | Phase 3 (C) | Acalabrutinib | TBD if different primary endpoint of PFS |
Chemotherapy
- Chlorambucil (Leukeran) 0.5 mg/kg PO once per day on days 1 & 15
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 1
- Cycles 2 to 6: 500 mg/m2 IV once on day 1
28-day cycle for 6 cycles
Regimen variant #2, Clb 8 mg/m2/d, 1 week out of 4
Study | Dates of enrollment | Evidence |
---|---|---|
Foà et al. 2014 (ML21445) | 2008-2013 | Non-randomized part of phase 2 RCT |
Chemotherapy
- Chlorambucil (Leukeran) 8 mg/m2 PO once per day on days 1 to 7
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 3: 375 mg/m2 IV once on day 1
- Cycles 4 to 8: 500 mg/m2 IV once on day 1
28-day cycle for up to 8 cycles
Subsequent treatment
- ML21445, PR or better: Observation versus Rituximab maintenance
Regimen variant #3, Clb 10 mg/m2/d, 1 week out of 4
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Hillmen et al. 2014 (NCRI CLL208) | 2007-2009 | Phase 2 | ||
Michallet et al. 2018 (MABLE) | 2010-2014 | Phase 3b (E-switch-ic) | BR | Inferior PFS (secondary endpoint) |
Chemotherapy
- Chlorambucil (Leukeran) 10 mg/m2 PO once per day on days 1 to 7
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 1
- Cycles 2 to 6: 500 mg/m2 IV once on day 1
28-day cycle for 6 cycles
Subsequent treatment
- NCRI CLL208, patients not achieving CR: Optional chlorambucil consolidation x up to 6 cycles
- MABLE, patients not achieving CR: Optional chlorambucil consolidation x up to 6 cycles or until CR
References
- GCLLSG CLL11: Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, Chagorova T, de la Serna J, Dilhuydy MS, Illmer T, Opat S, Owen CJ, Samoylova O, Kreuzer KA, Stilgenbauer S, Döhner H, Langerak AW, Ritgen M, Kneba M, Asikanius E, Humphrey K, Wenger M, Hallek M. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014 Mar 20;370(12):1101-10. Epub 2014 Jan 8. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01010061
- Update: Goede V, Fischer K, Engelke A, Schlag R, Lepretre S, Casado Montero LF, Montillo M, Fegan C, Asikanius E, Humphrey K, Fingerle-Rowson G, Hallek M. Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study. Leukemia. 2015 Jul;29(7):1602-4. Epub 2015 Jan 30. link to original article PubMed
- ML21445: Foà R, Del Giudice I, Cuneo A, Del Poeta G, Ciolli S, Di Raimondo F, Lauria F, Cencini E, Rigolin GM, Cortelezzi A, Nobile F, Callea V, Brugiatelli M, Massaia M, Molica S, Trentin L, Rizzi R, Specchia G, Di Serio F, Orsucci L, Ambrosetti A, Montillo M, Zinzani PL, Ferrara F, Morabito F, Mura MA, Soriani S, Peragine N, Tavolaro S, Bonina S, Marinelli M, De Propris MS, Starza ID, Piciocchi A, Alietti A, Runggaldier EJ, Gamba E, Mauro FR, Chiaretti S, Guarini A. Chlorambucil plus rituximab with or without maintenance rituximab as first-line treatment for elderly chronic lymphocytic leukemia patients. Am J Hematol. 2014 May;89(5):480-6. Epub 2014 Feb 18. link to original article dosing details in manuscript have been reviewed by our editors PubMed EudraCT 2008-001612-20
- NCRI CLL08: Hillmen P, Gribben JG, Follows GA, Milligan D, Sayala HA, Moreton P, Oscier DG, Dearden CE, Kennedy DB, Pettitt AR, Nathwani A, Varghese A, Cohen D, Rawstron A, Oertel S, Pocock CF. Rituximab plus chlorambucil as first-line treatment for chronic lymphocytic leukemia: Final analysis of an open-label phase II study. J Clin Oncol. 2014 Apr 20;32(12):1236-41. Epub 2014 Mar 17. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00532129
- MABLE: Michallet AS, Aktan M, Hiddemann W, Ilhan O, Johansson P, Laribi K, Meddeb B, Moreno C, Raposo J, Schuh A, Ünal A, Widenius T, Bernhardt A, Kellershohn K, Messeri D, Osborne S, Leblond V. Rituximab plus bendamustine or chlorambucil for chronic lymphocytic leukemia: primary analysis of the randomized, open-label MABLE study. Haematologica. 2018 Apr;103(4):698-706. Epub 2018 Feb 1. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01056510
- D822BC00001: contains dosing details on CT.gov NCT04075292
Cladribine monotherapy
Regimen variant #1, 0.6 mg/kg
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Robak et al. 2006 (PALG CLL2) | 1998-2003 | Phase 3 (C) | 1. CC | Might have inferior CR rate |
2. CMC | Inferior CR rate |
Chemotherapy
- Cladribine (Leustatin) 0.12 mg/kg IV over 2 hours once per day on days 1 to 5
Supportive therapy
- No routine prophylactic antibiotics, antiviral agents, or growth factor administration was planned.
28-day cycle for up to 6 cycles
Regimen variant #2, 0.7 mg/m2
Study | Dates of enrollment | Evidence |
---|---|---|
Saven et al. 1995 | 1988-1993 | Phase 2 |
Chemotherapy
- Cladribine (Leustatin) 0.1 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose per cycle: 0.7 mg/m2)
28- to 35-day cycles, repeated until maximum response or limiting toxicity
Regimen variant #3, 5 mg/m2
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Mulligan et al. 2014 | 1997-2004 | Phase 3 (E-switch-ic) | 1. Chlorambucil 2. Fludarabine |
Did not meet primary endpoint of ORR Superior PFS (secondary endpoint) |
Chemotherapy
- Cladribine (Leustatin) 5 mg/m2 SC or IV over 2 hours once per day on days 1 to 5
28-day cycle for up to 6 cycles
Regimen variant #4, 10 mg/m2
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Mulligan et al. 2014 | 1997-2004 | Phase 3 (E-switch-ic) | 1. Chlorambucil 2. Fludarabine |
Did not meet primary endpoint of ORR Superior PFS (secondary endpoint) |
Chemotherapy
- Cladribine (Leustatin) 10 mg/m2 PO once per day on days 1 to 5
28-day cycle for up to 6 cycles
References
- Saven A, Lemon RH, Kosty M, Beutler E, Piro LD. 2-Chlorodeoxyadenosine activity in patients with untreated chronic lymphocytic leukemia. J Clin Oncol. 1995 Mar;13(3):570-4. link to original article dosing details in abstract have been reviewed by our editors PubMed
- PALG CLL2: Robak T, Blonski JZ, Gora-Tybor J, Jamroziak K, Dwilewicz-Trojaczek J, Tomaszewska A, Konopka L, Ceglarek B, Dmoszynska A, Kowal M, Kloczko J, Stella-Holowiecka B, Sulek K, Calbecka M, Zawilska K, Kuliczkowski K, Skotnicki AB, Warzocha K, Kasznicki M; Polish Adult Leukemia Group. Cladribine alone and in combination with cyclophosphamide or cyclophosphamide plus mitoxantrone in the treatment of progressive chronic lymphocytic leukemia: report of a prospective, multicenter, randomized trial of the Polish Adult Leukemia Group (PALG CLL2). Blood. 2006 Jul 15;108(2):473-9. Epub 2006 Mar 21. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Update: Robak T, Blonski JZ, Gora-Tybor J, Calbecka M, Dwilewicz-Trojaczek J, Boguradzki P, Dmoszynska A, Kowal M, Kloczko J, Piszcz J, Stella-Holowiecka B, Sulek K, Kuliczkowski K, Potoczek S, Warzocha K, Lech-Maranda E, Skotnicki AB, Piotrowska M, Moskwa A, Zawilska K, Jamroziak K. Long-term results of the Polish Adult Leukemia Group PALG-CLL2 phase III randomized study comparing cladribine-based combinations in chronic lymphocytic leukemia. Leuk Lymphoma. 2014 Mar;55(3):606-10. Epub 2013 Nov 14. link to original article PubMed
- Mulligan SP, Karlsson K, Strömberg M, Jønsson V, Gill D, Hammerström J, Hertzberg M, McLennan R, Uggla B, Norman J, Wallvik J, Sundström G, Johansson H, Brandberg Y, Liliemark J, Juliusson G; Scandinavian Lymphoma Group; ALLG. Cladribine prolongs progression-free survival and time to second treatment compared to fludarabine and high-dose chlorambucil in chronic lymphocytic leukemia. Leuk Lymphoma. 2014 Dec;55(12):2769-77. Epub 2014 Apr 16. link to original article dosing details in manuscript have been reviewed by our editors PubMed
FCA
FCA: Fludarabine, Cyclophosphamide, Alemtuzumab
FCCam: Fludarabine, Cyclophosphamide, Campath (Alemtuzumab)
Regimen variant #1
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Geisler et al. 2014 (HOVON-68) | 2006-2010 | Phase 3 (E-esc) | FC | Superior PFS (primary endpoint) PFS36: 53% vs 37% |
Eligibility criteria
- HOVON-68: This regimen was intended for patients with previously untreated CLL diagnosed and in need of treatment according to the National Cancer Institute guidelines, 18 to 75 years old, with WHO performance status less than 3 and no severe comorbidities, with high-risk CLL as defined by the presence of either unmutated IGHV, 17p deletion, 11q deletion, or trisomy 12 by FISH.
Chemotherapy
- Fludarabine (Fludara) 40 mg/m2 PO once per day on days 1 to 3
- Cyclophosphamide (Cytoxan) 250 mg/m2 PO once per day on days 1 to 3
Targeted therapy
- Alemtuzumab (Campath) as follows:
- Cycle 1: 30 mg SC once per day on days -1, 0, and 1
- Cycles 2 to 6: 30 mg SC once on day 1
Supportive therapy
- Cotrimoxazole 400/80 mg PO once per day until 6 months after end of treatment
- One of the following:
- Acyclovir (Zovirax) 400 mg PO three times per day until 3 months after end of treatment
- Valacyclovir (Valtrex) 500 mg PO twice per day until 3 months after end of treatment
28-day cycle for 6 cycles
Regimen variant #2
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Lepretre et al. 2012 (GOELAMS CLL2007FMP) | 2007-2009 | Phase 3 (E-switch-ic) | FCR | Did not meet primary endpoint of PFS36 |
Note: GOELAMS CLL2007FMP was halted prematurely due to excess mortality.
Chemotherapy
- Fludarabine (Fludara) 40 mg/m2 PO once per day on days 1 to 3
- Cyclophosphamide (Cytoxan) 250 mg/m2 PO once per day on days 1 to 3
Targeted therapy
- Alemtuzumab (Campath) 30 mg SC once per day on day 1 to 3
28-day cycle for 6 cycles
References
- GOELAMS CLL2007FMP: Lepretre S, Aurran T, Mahé B, Cazin B, Tournilhac O, Maisonneuve H, Casasnovas O, Delmer A, Leblond V, Royer B, Corront B, Chevret S, Delépine R, Vaudaux S, Van Den Neste E, Béné MC, Letestu R, Cymbalista F, Feugier P. Excess mortality after treatment with fludarabine and cyclophosphamide in combination with alemtuzumab in previously untreated patients with chronic lymphocytic leukemia in a randomized phase 3 trial. Blood. 2012 May 31;119(22):5104-10. Epub 2012 Feb 14. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00564512
- HOVON-68: Geisler CH, van T' Veer MB, Jurlander J, Walewski J, Tjønnfjord G, Itälä Remes M, Kimby E, Kozak T, Polliack A, Wu KL, Wittebol S, Abrahamse-Testroote MC, Doorduijn J, Ghidey Alemayehu W, van Oers MH. Frontline low-dose alemtuzumab with fludarabine and cyclophosphamide prolongs progression-free survival in high-risk CLL. Blood. 2014 May 22;123(21):3255-62. Epub 2014 Apr 15. link to original article dosing details in manuscript have been reviewed by our editors PubMed NTR529
FCR
FCR: Fludarabine, Cyclophosphamide, Rituximab
R-FC: Rituximab, Fludarabine, Cyclophosphamide
Regimen variant #1, 20/150/375-500 ("FCR-Lite")
Study | Dates of enrollment | Evidence |
---|---|---|
Foon et al. 2009 | 2003-2007 | Phase 2 |
Chemotherapy
- Fludarabine (Fludara) as follows:
- Cycle 1: 20 mg/m2 IV over 30 minutes once per day on days 2 to 4
- Cycles 2 to 6: 20 mg/m2 IV over 30 minutes once per day on days 1 to 3
- Cyclophosphamide (Cytoxan) as follows:
- Cycle 1: 150 mg/m2 IV over 60 minutes once per day on days 2 to 4
- Cycles 2 to 6: 150 mg/m2 IV over 60 minutes once per day on days 1 to 3
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 1, then 500 mg/m2 IV once on day 14
- Cycles 2 to 6: 500 mg/m2 IV once per day on days 1 & 14
Supportive therapy
- Diphenhydramine (Benadryl) 25 mg PO once per day on days 1 & 14, prior to rituximab
- Acetaminophen (Tylenol) 650 mg PO once per day on days 1 & 14, prior to rituximab
- Dexamethasone (Decadron) 10 mg IV or PO once per day on days 1 & 14, prior to rituximab
- Cycle 1: Allopurinol (Zyloprim) 300 mg PO once per day on days 1 to 10
- Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg PO twice per day three times per week, for 6 months past last dose of chemotherapy
- Acyclovir (Zovirax) 400 mg PO three times per day, for 6 months past last dose of chemotherapy
- One of the following:
- Filgrastim (Neupogen) (dose not specified), starting 24 hours after chemotherapy
- Pegfilgrastim (Neulasta) (dose not specified), given 24 hours after chemotherapy
28-day cycle for 6 cycles
Subsequent treatment
- Indefinite rituximab maintenance
Regimen variant #2, 24/150/375-500, oral FC
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Munir et al. 2017 (ADMIRE) | 2009-2012 | Randomized phase 2b (C) | FCM-R | Did not meet primary endpoint of CR rate |
Howard et al. 2017 (ARCTICCLL) | 2009-2012 | Randomized phase 2b (C) | FCM-miniR | Superior CR rate (primary endpoint) |
Hillmen et al. 2023 (FLAIR) | 2014-09-19 to 2018-07-19 | Phase 3 (C) | Ibrutinib & Rituximab | Inferior PFS |
Hillmen et al. 2023 (FLAIR part 2) | 2017-07-20 to 2021-03-24 | Phase 3 (C) | 1. Ibrutinib & Venetoclax | Inferior PFS/OS |
2. Ibrutinib | Not reported |
Note: in contrast to other variants, FC was given over 5 days not 3. ARCTIC should not be confused with the trial by the same name in NSCLC. FLAIR was a platform trial with distinct enrollments, such that Hillmen et al. 2023 is labeled as FLAIR part 2.
Chemotherapy
- Fludarabine (Fludara) 24 mg/m2 PO once per day on days 1 to 5
- Cyclophosphamide (Cytoxan) 150 mg/m2/day PO on days 1 to 5
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 1
- Cycles 2 to 6: 500 mg/m2 IV once on day 1
28-day cycle for 6 cycles
Regimen variant #3, 25/250/375
Study | Dates of enrollment | Evidence |
---|---|---|
Tam et al. 2006 | 2000-2005 | Phase 2 |
Chemotherapy
- Fludarabine (Fludara) 25 mg/m2 IV over 15 to 30 minutes once per day on days 1 to 3
- Cyclophosphamide (Cytoxan) 250 mg/m2 IV over 15 to 30 minutes once per day on days 1 to 3
Targeted therapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
28-day cycle for up to 6 cycles or "attainment of maximum response"
Regimen variant #4, 25/250/375-500, IV FC
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Keating et al. 2005 | 1999-2001 | Phase 2 | |||
Hallek et al. 2010 (GCLLSG CLL8) | 2003-2006 | Phase 3 (E-RT-esc) | FC | Superior PFS (primary endpoint) PFS36: 65% vs 45% (HR 0.56, 95% CI 0.46-0.69) Superior OS1 (secondary endpoint) Median OS: NYR vs 86 mo (HR 0.68, 95% CI 0.54-0.89) |
Equivalent HRQoL |
Herling et al. 2020 (GCLLSG CLL7) | 2005-2010 | Phase 3 (E-esc) | Watchful waiting | Superior EFS (primary endpoint) Median EFS: NYR vs 18.5 mo (HR 0.22, 95% CI 0.15-0.33) |
|
Lepretre et al. 2012 (GOELAMS CLL2007FMP) | 2007-2009 | Phase 3 (C) | FCCam | Did not meet primary endpoint of PFS36 | |
Eichhorst et al. 2016 (GCLLSG CLL10) | 2008-2011 | Phase 3 (C) | BR | Inconclusive whether non-inferior PFS | |
Assouline et al. 2016 (SAWYER) | 2012-08-20 to 2013-06-17 | Randomized Phase 1b (C) | FCR (SC Rituximab) | Not reported | |
Shanafelt et al. 2019 (ECOG E1912) | 2014-2016 | Phase 3 (C) | Ibrutinib & Rituximab | Inferior OS | |
Eichhorst et al. 2023 (GAIA) | 2016-12-13 to 2019-10-13 | Phase 3 (C) | 1. Venetoclax & Obinutuzumab 2. Ibrutinib, Venetoclax, Obinutuzumab |
Inferior PFS | |
3. Venetoclax & Rituximab | Did not meet primary endpoint of PFS |
1Reported efficacy for GCLLSG CLL8 is based on the 2016 update.
Note: ECOG E1912 used alternate rituximab dosing in cycle 1: 50 mg/m2 IV once on day 1, then 325 mg/m2 IV once on day 2.
Eligibility criteria
- GAIA: 65 years old or younger
Chemotherapy
- Fludarabine (Fludara) 25 mg/m2 IV once per day on days 1 to 3
- Cyclophosphamide (Cytoxan) 250 mg/m2 IV once per day on days 1 to 3
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 0
- Cycles 2 to 6: 500 mg/m2 IV once on day 1
Supportive therapy
- Note: these vary according to reference.
- Diphenhydramine (Benadryl) 25 mg IV once per infusion, 30 minutes prior to rituximab
- Acetaminophen (Tylenol) 650 mg PO once per infusion, 30 minutes prior to rituximab
- Cycle 1: Allopurinol (Zyloprim) 300 mg PO once per day on days 1 to 7
- Some patients received:
- Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg PO twice per week
- Valacyclovir (Valtrex) 500 mg PO once per day
- PCP (Pneumocystis jirovecii pneumonia) prophylaxis recommended for severe leukopenia greater than 7 days
- No routine prophylaxis with antiviral medications or G-CSF
28-day cycle for 6 cycles
Regimen variant #5, 25/250/375-500, PO FC
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Lepretre et al. 2012 (GOELAMS CLL2007FMP) | 2007-2009 | Phase 3 (C) | FCCam | Did not meet primary endpoint of PFS36 |
Chemotherapy
- Fludarabine (Fludara) 25 mg/m2 PO once per day on days 1 to 3
- Cyclophosphamide (Cytoxan) 250 mg/m2 PO once per day on days 1 to 3
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 0
- Cycles 2 to 6: 500 mg/m2 IV once on day 1
28-day cycle for 6 cycles
Regimen variant #6, 25/250/500
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Awan et al. 2014 (LUCID) | 2006 to not reported | Phase 3 (C) | FCR+L | Did not meet primary endpoint of CR rate |
Chemotherapy
- Fludarabine (Fludara) as follows:
- Cycle 1: 25 mg/m2 IV over at least 10 to 30 minutes once per day on days 2 to 4
- Cycles 2 to 6: 25 mg/m2 IV over at least 10 to 30 minutes once per day on days 1 to 3
- Cyclophosphamide (Cytoxan) as follows:
- Cycle 1: 250 mg/m2 IV over at least 10 to 30 minutes once per day on days 2 to 4
- Cycles 2 to 6: 250 mg/m2 IV over at least 10 to 30 minutes once per day on days 1 to 3
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 50 mg/m2 IV over 4 hours once on day 1, then 450 mg/m2 IV once on day 3
- Cycles 2 to 6: 500 mg/m2 IV once on day 1
Supportive therapy
- Cotrimoxazole or equivalent
- Acyclovir (Zovirax) 400 mg PO twice per day or equivalent
- Growth factors at physician discretion
28-day cycle for 6 cycles
Regimen variant #7, 40/250/375-500, oral FC
Study | Dates of enrollment | Evidence |
---|---|---|
Dartigeas et al. 2017 (CLL 2007 SA) | 2007-2014 | Non-randomized part of phase 3 RCT |
Chemotherapy
- Fludarabine (Fludara) 40 mg/m2 PO once per day on days 1 to 3
- Cyclophosphamide (Cytoxan) 250 mg/m2 PO once per day on days 1 to 3
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 1, then 500 mg/m2 IV once on day 14
- Cycle 2: 500 mg/m2 IV once per day on days 1 & 14
- Cycles 3 & 4: 500 mg/m2 IV once on day 1
1-month cycle for 4 cycles
Subsequent treatment
- Rituximab maintenance versus observation
References
- Keating MJ, O'Brien S, Albitar M, Lerner S, Plunkett W, Giles F, Andreeff M, Cortes J, Faderl S, Thomas D, Koller C, Wierda W, Detry MA, Lynn A, Kantarjian H. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol. 2005 Jun 20;23(18):4079-88. Epub 2005 Mar 14. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Update: Tam CS, O'Brien S, Wierda W, Kantarjian H, Wen S, Do KA, Thomas DA, Cortes J, Lerner S, Keating MJ. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood. 2008 Aug 15;112(4):975-80. Epub 2008 Apr 14. link to original article link to PMC article PubMed
- Update: Thompson PA, Tam CS, O'Brien SM, Wierda WG, Stingo F, Plunkett W, Smith SC, Kantarjian HM, Freireich EJ, Keating MJ. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood. 2016 Jan 21;127(3):303-9. Epub 2015 Oct 22. link to original article link to PMC article PubMed
- Update: Thompson PA, Bazinet A, Wierda WG, Tam CS, O'Brien SM, Saha S, Peterson CB, Plunkett W, Keating MJ. Sustained remissions in CLL after frontline FCR treatment with very-long-term follow-up. Blood. 2023 Nov 23;142(21):1784-1788. link to original article PubMed
- Tam CS, Wolf M, Prince HM, Januszewicz EH, Westerman D, Lin KI, Carney D, Seymour JF. Fludarabine, cyclophosphamide, and rituximab for the treatment of patients with chronic lymphocytic leukemia or indolent non-Hodgkin lymphoma. Cancer. 2006 Jun 1;106(11):2412-20. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Foon KA, Boyiadzis M, Land SR, Marks S, Raptis A, Pietragallo L, Meisner D, Laman A, Sulecki M, Butchko A, Schaefer P, Lenzer D, Tarhini A. Chemoimmunotherapy with low-dose fludarabine and cyclophosphamide and high dose rituximab in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009 Feb 1;27(4):498-503. Epub 2008 Dec 15. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Update: Foon KA, Mehta D, Lentzsch S, Kropf P, Marks S, Lenzner D, Pietragallo L, Sulecki M, Tarhini A, Boyiadzis M. Long-term results of chemoimmunotherapy with low-dose fludarabine, cyclophosphamide and high-dose rituximab as initial treatment for patients with chronic lymphocytic leukemia. Blood. 2012 Mar 29;119(13):3184-5. link to original article PubMed
- GCLLSG CLL8: Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J, Hensel M, Hopfinger G, Hess G, von Grünhagen U, Bergmann M, Catalano J, Zinzani PL, Caligaris-Cappio F, Seymour JF, Berrebi A, Jäger U, Cazin B, Trneny M, Westermann A, Wendtner CM, Eichhorst BF, Staib P, Bühler A, Winkler D, Zenz T, Böttcher S, Ritgen M, Mendila M, Kneba M, Döhner H, Stilgenbauer S; International Group of Investigators; German Chronic Lymphocytic Leukaemia Study Group. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010 Oct 2;376(9747):1164-74. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00281918
- Update: Fischer K, Bahlo J, Fink AM, Goede V, Herling CD, Cramer P, Langerbeins P, von Tresckow J, Engelke A, Maurer C, Kovacs G, Herling M, Tausch E, Kreuzer KA, Eichhorst B, Böttcher S, Seymour JF, Ghia P, Marlton P, Kneba M, Wendtner CM, Döhner H, Stilgenbauer S, Hallek M. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016 Jan 14;127(2):208-15. Epub 2015 Oct 20. link to original article PubMed
- HRQoL analysis: Kutsch N, Busch R, Bahlo J, Mayer J, Hensel M, Hopfinger G, Hess G, von Grünhagen U, Wendtner CM, Maria Fink A, Fischer K, Hallek M, Eichhorst B. FCR front-line therapy and quality of life in patients with chronic lymphocytic leukemia. Leuk Lymphoma. 2017 Feb;58(2):399-407. Epub 2016 Jun 29. link to original article PubMed
- GOELAMS CLL2007FMP: Lepretre S, Aurran T, Mahé B, Cazin B, Tournilhac O, Maisonneuve H, Casasnovas O, Delmer A, Leblond V, Royer B, Corront B, Chevret S, Delépine R, Vaudaux S, Van Den Neste E, Béné MC, Letestu R, Cymbalista F, Feugier P. Excess mortality after treatment with fludarabine and cyclophosphamide in combination with alemtuzumab in previously untreated patients with chronic lymphocytic leukemia in a randomized phase 3 trial. Blood. 2012 May 31;119(22):5104-10. Epub 2012 Feb 14. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00564512
- GCLLSG CLL7: Herling CD, Cymbalista F, Groß-Ophoff-Müller C, Bahlo J, Robrecht S, Langerbeins P, Fink AM, Al-Sawaf O, Busch R, Porcher R, Cazin B, Dreyfus B, Ibach S, Leprêtre S, Fischer K, Kaiser F, Eichhorst B, Wentner CM, Hoechstetter MA, Döhner H, Leblond V, Kneba M, Letestu R, Böttcher S, Stilgenbauer S, Hallek M, Levy V. Early treatment with FCR versus watch and wait in patients with stage Binet A high-risk chronic lymphocytic leukemia (CLL): a randomized phase 3 trial. Leukemia. 2020 Aug;34(8):2038-2050. Epub 2020 Feb 18. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00275054
- LUCID: Awan FT, Hillmen P, Hellmann A, Robak T, Hughes SG, Trone D, Shannon M, Flinn IW, Byrd JC; LUCID trial investigators. A randomized, open-label, multicentre, phase 2/3 study to evaluate the safety and efficacy of lumiliximab in combination with fludarabine, cyclophosphamide and rituximab versus fludarabine, cyclophosphamide and rituximab alone in subjects with relapsed chronic lymphocytic leukaemia. Br J Haematol. 2014 Nov;167(4):466-77. Epub 2014 Aug 8. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00391066
- SAWYER: Assouline S, Buccheri V, Delmer A, Gaidano G, Trneny M, Berthillon N, Brewster M, Catalani O, Li S, McIntyre C, Sayyed P, Badoux X. Pharmacokinetics, safety, and efficacy of subcutaneous versus intravenous rituximab plus chemotherapy as treatment for chronic lymphocytic leukaemia (SAWYER): a phase 1b, open-label, randomised controlled non-inferiority trial. Lancet Haematol. 2016 Mar;3(3):e128-38. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01292603
- GCLLSG CLL10: Eichhorst B, Fink AM, Bahlo J, Busch R, Kovacs G, Maurer C, Lange E, Köppler H, Kiehl M, Sökler M, Schlag R, Vehling-Kaiser U, Köchling G, Plöger C, Gregor M, Plesner T, Trneny M, Fischer K, Döhner H, Kneba M, Wendtner CM, Klapper W, Kreuzer KA, Stilgenbauer S, Böttcher S, Hallek M; International Group of Investigators; German CLL Study Group. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016 Jul;17(7):928-42. Epub 2016 May 20. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00769522
- ADMIRE: Munir T, Howard DR, McParland L, Pocock C, Rawstron AC, Hockaday A, Varghese A, Hamblin M, Bloor A, Pettitt A, Fegan C, Blundell J, Gribben JG, Phillips D, Hillmen P. Results of the randomized phase IIB ADMIRE trial of FCR with or without mitoxantrone in previously untreated CLL. Leukemia. 2017 Oct;31(10):2085-2093. Epub 2017 Apr 20. link to original article dosing details in manuscript have been reviewed by our editors PubMed ISRCTN42165735
- ARCTIC: Howard DR, Munir T, McParland L, Rawstron AC, Milligan D, Schuh A, Hockaday A, Allsup DJ, Marshall S, Duncombe AS, O'Dwyer JL, Smith AF, Longo R, Varghese A, Hillmen P. Results of the randomized phase IIB ARCTIC trial of low-dose rituximab in previously untreated CLL. Leukemia. 2017 Nov;31(11):2416-2425. Epub 2017 Mar 24. link to original article dosing details in supplement have been reviewed by our editors PubMed ISRCTN16544962
- CLL 2007 SA: Dartigeas C, Van Den Neste E, Léger J, Maisonneuve H, Berthou C, Dilhuydy MS, De Guibert S, Leprêtre S, Béné MC, Nguyen-Khac F, Letestu R, Cymbalista F, Rodon P, Aurran-Schleinitz T, Vilque JP, Tournilhac O, Mahé B, Laribi K, Michallet AS, Delmer A, Feugier P, Lévy V, Delépine R, Colombat P, Leblond V; CLL 2007 SA investigators; FILO. Rituximab maintenance versus observation following abbreviated induction with chemoimmunotherapy in elderly patients with previously untreated chronic lymphocytic leukaemia (CLL 2007 SA): an open-label, randomised phase 3 study. Lancet Haematol. 2018 Feb;5(2):e82-e94. Epub 2017 Dec 20. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00645606
- ECOG E1912: Shanafelt TD, Wang XV, Kay NE, Hanson CA, O'Brien S, Barrientos J, Jelinek DF, Braggio E, Leis JF, Zhang CC, Coutre SE, Barr PM, Cashen AF, Mato AR, Singh AK, Mullane MP, Little RF, Erba H, Stone RM, Litzow M, Tallman M. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019 Aug 1;381(5):432-443. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT02048813
- Update: Shanafelt TD, Wang XV, Hanson CA, Paietta EM, O'Brien S, Barrientos J, Jelinek DF, Braggio E, Leis JF, Zhang CC, Coutre SE, Barr PM, Cashen AF, Mato AR, Singh AK, Mullane MP, Little RF, Erba H, Stone RM, Litzow M, Tallman M, Kay NE. Long-term outcomes for ibrutinib-rituximab and chemoimmunotherapy in CLL: updated results of the E1912 trial. Blood. 2022 Jul 14;140(2):112-120. link to original article link to PMC article PubMed
- FLAIR: Hillmen P, Pitchford A, Bloor A, Broom A, Young M, Kennedy B, Walewska R, Furtado M, Preston G, Neilson JR, Pemberton N, Sidra G, Morley N, Cwynarski K, Schuh A, Forconi F, Elmusharaf N, Paneesha S, Fox CP, Howard DR, Hockaday A, Brown JM, Cairns DA, Jackson S, Greatorex N, Webster N, Shingles J, Dalal S, Patten PEM, Allsup D, Rawstron A, Munir T. Ibrutinib and rituximab versus fludarabine, cyclophosphamide, and rituximab for patients with previously untreated chronic lymphocytic leukaemia (FLAIR): interim analysis of a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2023 May;24(5):535-552. link to original article dosing details in manuscript have been reviewed by our editors PubMed ISRCTN01844152
- GAIA: Eichhorst B, Niemann CU, Kater AP, Fürstenau M, von Tresckow J, Zhang C, Robrecht S, Gregor M, Juliusson G, Thornton P, Staber PB, Tadmor T, Lindström V, da Cunha-Bang C, Schneider C, Poulsen CB, Illmer T, Schöttker B, Nösslinger T, Janssens A, Christiansen I, Baumann M, Frederiksen H, van der Klift M, Jäger U, Leys MBL, Hoogendoorn M, Lotfi K, Hebart H, Gaska T, Koene H, Enggaard L, Goede J, Regelink JC, Widmer A, Simon F, De Silva N, Fink AM, Bahlo J, Fischer K, Wendtner CM, Kreuzer KA, Ritgen M, Brüggemann M, Tausch E, Levin MD, van Oers M, Geisler C, Stilgenbauer S, Hallek M; GCLLSG, the HOVON and Nordic CLL Study Groups, the SAKK, the Israeli CLL Association, and Cancer Trials Ireland. First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia. N Engl J Med. 2023 May 11;388(19):1739-1754. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT02950051
- Update: Fürstenau M, Kater AP, Robrecht S, von Tresckow J, Zhang C, Gregor M, Thornton P, Staber PB, Tadmor T, Lindström V, Juliusson G, Janssens A, Levin MD, da Cunha-Bang C, Schneider C, Goldschmidt N, Vandenberghe E, Rossi D, Benz R, Nösslinger T, Heintel D, Poulsen CB, Christiansen I, Frederiksen H, Enggaard L, Posthuma EFM, Issa DE, Visser HPJ, Bellido M, Kutsch N, Dürig J, Stehle A, Vöhringer M, Böttcher S, Schulte C, Simon F, Fink AM, Fischer K, Holmes EE, Kreuzer KA, Ritgen M, Brüggemann M, Tausch E, Stilgenbauer S, Hallek M, Niemann CU, Eichhorst B. First-line venetoclax combinations versus chemoimmunotherapy in fit patients with chronic lymphocytic leukaemia (GAIA/CLL13): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2024 Jun;25(6):744-759. Erratum in: Lancet Oncol. 2024 Jul;25(7):e284. link to original article PubMed
- FLAIR part 2: Munir T, Cairns DA, Bloor A, Allsup D, Cwynarski K, Pettitt A, Paneesha S, Fox CP, Eyre TA, Forconi F, Elmusharaf N, Kennedy B, Gribben J, Pemberton N, Sheehy O, Preston G, Schuh A, Walewska R, Duley L, Howard D, Hockaday A, Jackson S, Greatorex N, Girvan S, Bell S, Brown JM, Webster N, Dalal S, de Tute R, Rawstron A, Patten PEM, Hillmen P; National Cancer Research Institute Chronic Lymphocytic Leukemia Subgroup. Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease. N Engl J Med. 2024 Jan 25;390(4):326-337. Epub 2023 Dec 10. link to original article dosing details in supplement have been reviewed by our editors PubMed ISRCTN01844152
- ACE-CL-311: NCT03836261
- CRISTALLO: NCT04285567
FCR (SC Rituximab)
FCR: Fludarabine, Cyclophosphamide, Rituximab hyaluronidase
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Assouline et al. 2016 (SAWYER) | 2012-08-20 to 2013-06-17 | Randomized Phase 1b (E-RT-switch-ic) | FCR | Not reported |
Note: other variants include oral fludarabine and/or cyclophosphamide; to be completed.
Chemotherapy
- Fludarabine (Fludara) 25 mg/m2 IV once per day on days 1 to 3
- Cyclophosphamide (Cytoxan) 250 mg/m2 IV once per day on days 1 to 3
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 0
- Rituximab and hyaluronidase human (Rituxan Hycela) as follows:
- Cycles 2 to 6: 1600 mg SC once on day 1
28-day cycle for up to 6 cycles
References
- SAWYER: Assouline S, Buccheri V, Delmer A, Gaidano G, Trneny M, Berthillon N, Brewster M, Catalani O, Li S, McIntyre C, Sayyed P, Badoux X. Pharmacokinetics, safety, and efficacy of subcutaneous versus intravenous rituximab plus chemotherapy as treatment for chronic lymphocytic leukaemia (SAWYER): a phase 1b, open-label, randomised controlled non-inferiority trial. Lancet Haematol. 2016 Mar;3(3):e128-38. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01292603
Fludarabine & Alemtuzumab
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Elter et al. 2011 (CAM 314) | 2004-2008 | Phase 3 (E-esc) | Fludarabine | Superior PFS (primary endpoint) Median PFS: 23.7 vs 16.5 mo (HR 0.61, 95% CI 0.47-0.80) Superior OS (secondary endpoint) Median OS: NYR vs 52.9 mo (HR 0.65, 95% CI 0.45-0.94) |
Chemotherapy
- Fludarabine (Fludara) 30 mg/m2 IV once per day on days 1 to 3
Targeted therapy
- Alemtuzumab (Campath) 30 mg IV once per day on days 1 to 3
28-day cycle for up to 6 cycles
References
- CAM 314: Elter T, Gercheva-Kyuchukova L, Pylylpenko H, Robak T, Jaksic B, Rekhtman G, Kyrcz-Krzemień S, Vatutin M, Wu J, Sirard C, Hallek M, Engert A. Fludarabine plus alemtuzumab versus fludarabine alone in patients with previously treated chronic lymphocytic leukaemia: a randomised phase 3 trial. Lancet Oncol. 2011 Dec;12(13):1204-13. Epub 2011 Oct 10. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT00086580
Ibrutinib monotherapy
Regimen
FDA-recommended dose |
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
O'Brien et al. 2013 (PCYC-1102 untreated) | 2010-2012 | Phase 1b/2 | ||
Farooqui et al. 2014 (NHLBI 12-H-0035) | 2011-2014 | Phase 2 | ||
Burger et al. 2015 (RESONATE-2) | 2013 to not reported | Phase 3 (E-RT-switch-ooc) | Chlorambucil | Superior PFS (primary endpoint) PFS18: 90% vs 52% (HR 0.16, 95% CI 0.09-0.28) Superior OS1 (secondary endpoint) OS60: 83% vs 68% (HR 0.45, 95% CI 0.27-0.76) |
Woyach et al. 2018 (Alliance A041202) | 2013-2016 | Phase 3 (E-switch-ooc) | 1. BR | Superior PFS2 (primary endpoint) Median PFS: NYR vs 44 mo (HR 0.36, 95% CI 0.25-0.51) |
2. Ibrutinib & Rituximab | Did not meet primary endpoint of PFS2 Median PFS: NYR vs NYR (HR 1.01, 95% CI 0.68-1.52) | |||
Burger et al. 2018 (MDACC 2013-0703) | 2013-2017 | Phase 3 (C) | Ibrutinib & Rituximab | Did not meet primary endpoint of PFS |
Langerbeins et al. 2022 (CLL12) | 2014-2019 | Phase 3 (E-esc) | Placebo | Superior EFS (primary endpoint) Median EFS: NYR vs 47.8 mo (HR 0.25, 95% CI 0.14-0.43) |
Awaiting publication (SYMPATICO) | 2017-2023 | Phase 3 (C) | VI | TBD if different primary endpoint of PFS |
Awaiting publication (GCLLSG CLL17) | 2021-2027 | Phase 3 (C) | 1. VG 2. VI |
TBD if different primary endpoint of PFS |
Awaiting publication (BRUIN CLL-314) | 2022-2028 | Phase 3 (C) | Pirtobrutinib | TBD if different primary endpoint of ORR |
1Reported efficacy for RESONATE-2 is based on the 2019 update.
2Reported efficacy for Alliance A041202 is based on the 2024 update.
Note: PCYC-1102 was intended for elderly patients. Although both 420 mg and 840 mg doses were planned, the 840 mg cohort was closed due to findings of comparable efficacy in other studies. RESONATE-2 was intended for patients older than 65 years. CLL12 was intended for patients with asymptomatic Binet stage A CLL.
Biomarker eligibility criteria
- NHLBI 12-H-0035: TP53 aberrations
References
- PCYC-1102 untreated: O'Brien S, Furman RR, Coutre SE, Sharman JP, Burger JA, Blum KA, Grant B, Richards DA, Coleman M, Wierda WG, Jones JA, Zhao W, Heerema NA, Johnson AJ, Izumi R, Hamdy A, Chang BY, Graef T, Clow F, Buggy JJ, James DF, Byrd JC. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol. 2014 Jan;15(1):48-58. Epub 2013 Dec 10. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01105247
- Update: Byrd JC, Furman RR, Coutre SE, Burger JA, Blum KA, Coleman M, Wierda WG, Jones JA, Zhao W, Heerema NA, Johnson AJ, Shaw Y, Bilotti E, Zhou C, James DF, O'Brien S. Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015 Apr 16;125(16):2497-506. Epub 2015 Feb 19. link to original article link to PMC article PubMed
- Update: O'Brien S, Furman RR, Coutre S, Flinn IW, Burger JA, Blum K, Sharman J, Wierda W, Jones J, Zhao W, Heerema NA, Johnson AJ, Luan Y, James DF, Chu AD, Byrd JC. Single-agent ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. Blood. 2018 Apr 26;131(17):1910-1919. Epub 2018 Feb 2. link to original article link to PMC article PubMed
- Update: Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum K, Sharman JP, Wierda W, Zhao W, Heerema NA, Luan Y, Liu EA, Dean JP, O'Brien S. Ibrutinib Treatment for First-Line and Relapsed/Refractory Chronic Lymphocytic Leukemia: Final Analysis of the Pivotal Phase Ib/II PCYC-1102 Study. Clin Cancer Res. 2020 Aug 1;26(15):3918-3927. Epub 2020 Mar 24. link to original article link to PMC article PubMed
- NHLBI 12-H-0035: Farooqui MZ, Valdez J, Martyr S, Aue G, Saba N, Niemann CU, Herman SE, Tian X, Marti G, Soto S, Hughes TE, Jones J, Lipsky A, Pittaluga S, Stetler-Stevenson M, Yuan C, Lee YS, Pedersen LB, Geisler CH, Calvo KR, Arthur DC, Maric I, Childs R, Young NS, Wiestner A. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol. 2015 Feb;16(2):169-76. Epub 2014 Dec 31. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01500733
- RESONATE-2: Burger JA, Tedeschi A, Barr PM, Robak T, Owen C, Ghia P, Bairey O, Hillmen P, Bartlett NL, Li J, Simpson D, Grosicki S, Devereux S, McCarthy H, Coutre S, Quach H, Gaidano G, Maslyak Z, Stevens DA, Janssens A, Offner F, Mayer J, O'Dwyer M, Hellmann A, Schuh A, Siddiqi T, Polliack A, Tam CS, Suri D, Cheng M, Clow F, Styles L, James DF, Kipps TJ; RESONATE-2 Investigators. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015 Dec 17;373(25):2425-37. Epub 2015 Dec 6. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01722487
- Update: Barr PM, Robak T, Owen C, Tedeschi A, Bairey O, Bartlett NL, Burger JA, Hillmen P, Coutre S, Devereux S, Grosicki S, McCarthy H, Li J, Simpson D, Offner F, Moreno C, Zhou C, Styles L, James D, Kipps TJ, Ghia P. Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: extended phase 3 results from RESONATE-2. Haematologica. 2018 Sep;103(9):1502-1510. Epub 2018 Jun 7. link to original article link to PMC article PubMed
- Update: Burger JA, Barr PM, Robak T, Owen C, Ghia P, Tedeschi A, Bairey O, Hillmen P, Coutre SE, Devereux S, Grosicki S, McCarthy H, Simpson D, Offner F, Moreno C, Dai S, Lal I, Dean JP, Kipps TJ. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia. 2020 Mar;34(3):787-798. Epub 2019 Oct 18. link to original article link to PMC article PubMed
- Alliance A041202: Woyach JA, Ruppert AS, Heerema NA, Zhao W, Booth AM, Ding W, Bartlett NL, Brander DM, Barr PM, Rogers KA, Parikh SA, Coutre S, Hurria A, Brown JR, Lozanski G, Blachly JS, Ozer HG, Major-Elechi B, Fruth B, Nattam S, Larson RA, Erba H, Litzow M, Owen C, Kuzma C, Abramson JS, Little RF, Smith SE, Stone RM, Mandrekar SJ, Byrd JC. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018 Dec 27;379(26):2517-2528. Epub 2018 Dec 1. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01886872
- Update: Woyach JA, Perez Burbano G, Ruppert AS, Miller C, Heerema NA, Zhao W, Wall A, Ding W, Bartlett NL, Brander DM, Barr PM, Rogers KA, Parikh SA, Stephens DM, Brown JR, Lozanski G, Blachly J, Nattam S, Larson RA, Erba H, Litzow M, Luger S, Owen C, Kuzma C, Abramson JS, Little RF, Dinner S, Stone RM, Uy G, Stock W, Mandrekar SJ, Byrd JC. Follow-up from the A041202 study shows continued efficacy of ibrutinib regimens for older adults with CLL. Blood. 2024 Apr 18;143(16):1616-1627. link to original article link to PMC article PubMed
- MDACC 2013-0703: Burger JA, Sivina M, Jain N, Kim E, Kadia T, Estrov Z, Nogueras-Gonzalez GM, Huang X, Jorgensen J, Li J, Cheng M, Clow F, Ohanian M, Andreeff M, Mathew T, Thompson P, Kantarjian H, O'Brien S, Wierda WG, Ferrajoli A, Keating MJ. Randomized trial of ibrutinib vs ibrutinib plus rituximab in patients with chronic lymphocytic leukemia. Blood. 2019 Mar 7;133(10):1011-1019. Epub 2018 Dec 7. link to original article dosing details in abstract have been reviewed by our editors link to PMC article PubMed NCT02007044
- CLL12: Langerbeins P, Zhang C, Robrecht S, Cramer P, Fürstenau M, Al-Sawaf O, von Tresckow J, Fink AM, Kreuzer KA, Vehling-Kaiser U, Tausch E, Müller L, Eckart MJ, Schlag R, Freier W, Gaska T, Balser C, Reiser M, Stauch M, Wendtner CM, Fischer K, Stilgenbauer S, Eichhorst B, Hallek M. The CLL12 trial: ibrutinib vs placebo in treatment-naïve, early-stage chronic lymphocytic leukemia. Blood. 2022 Jan 13;139(2):177-187. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT02863718
- BRUIN CLL-314: NCT05254743
- GCLLSG CLL17: NCT04608318
- SYMPATICO: NCT03112174
Ibrutinib & Obinutuzumab
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Moreno et al. 2018 (iLLUMINATE) | 2014-10-06 to 2015-10-12 | Phase 3 (E-RT-switch-ooc) | G-Clb | Superior PFS (primary endpoint) Median PFS: NYR vs 19 mo (HR 0.23, 95% CI 0.15-0.37) |
Targeted therapy
- Ibrutinib (Imbruvica) 420 mg PO once per day
- Obinutuzumab (Gazyva) as follows:
- Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15
- Cycles 2 to 6: 1000 mg IV once on day 1
28-day cycles
References
- iLLUMINATE: Moreno C, Greil R, Demirkan F, Tedeschi A, Anz B, Larratt L, Simkovic M, Samoilova O, Novak J, Ben-Yehuda D, Strugov V, Gill D, Gribben JG, Hsu E, Lih CJ, Zhou C, Clow F, James DF, Styles L, Flinn IW. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019 Jan;20(1):43-56. Epub 2018 Nov 30. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT02264574
- ECOG-ACRIN EA9161: NCT03701282
- Alliance A041702: NCT03737981
Ibrutinib & Rituximab
Regimen variant #1, limited duration
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Hillmen et al. 2023 (FLAIR) | 2014-09-19 to 2018-07-19 | Phase 3 (E-switch-ooc) | FCR | Superior PFS (primary endpoint) Median PFS: NYR vs 67 mo (HR 0.44, 95% CI 0.32-0.60) |
Targeted therapy
- Ibrutinib (Imbruvica) 420 mg PO once per day on days 1 to 28
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 1
- Cycles 2 to 6: 500 mg/m2 IV once on day 1
28-day cycle for up to 78 cycles (6 years)
Regimen variant #2, indefinite
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Shanafelt et al. 2019 (ECOG E1912) | 2014-2016 | Phase 3 (E-RT-switch-ooc) | FCR | Superior PFS (primary endpoint) PFS36: 89.4% vs 72.9% (HR 0.35, 95% CI 0.22-0.56) Superior OS1 (secondary endpoint) OS60: 95% vs 89% (HR 0.47, 95% CI 0.25-0.89) |
1Reported efficacy is based on the 2022 update.
Targeted therapy
- Ibrutinib (Imbruvica) 420 mg PO once per day on days 1 to 28
- Rituximab (Rituxan) as follows:
- Cycle 2: 50 mg/m2 IV once on day 1, then 325 mg/m2 IV once on day 2
- Cycles 3 to 7: 500 mg/m2 IV once on day 1
28-day cycles
References
- Alliance A041202: Woyach JA, Ruppert AS, Heerema NA, Zhao W, Booth AM, Ding W, Bartlett NL, Brander DM, Barr PM, Rogers KA, Parikh SA, Coutre S, Hurria A, Brown JR, Lozanski G, Blachly JS, Ozer HG, Major-Elechi B, Fruth B, Nattam S, Larson RA, Erba H, Litzow M, Owen C, Kuzma C, Abramson JS, Little RF, Smith SE, Stone RM, Mandrekar SJ, Byrd JC. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018 Dec 27;379(26):2517-2528. Epub 2018 Dec 1. link to original article link to PMC article PubMed NCT01886872
- Update: Woyach JA, Perez Burbano G, Ruppert AS, Miller C, Heerema NA, Zhao W, Wall A, Ding W, Bartlett NL, Brander DM, Barr PM, Rogers KA, Parikh SA, Stephens DM, Brown JR, Lozanski G, Blachly J, Nattam S, Larson RA, Erba H, Litzow M, Luger S, Owen C, Kuzma C, Abramson JS, Little RF, Dinner S, Stone RM, Uy G, Stock W, Mandrekar SJ, Byrd JC. Follow-up from the A041202 study shows continued efficacy of ibrutinib regimens for older adults with CLL. Blood. 2024 Apr 18;143(16):1616-1627. link to original article link to PMC article PubMed
- ECOG E1912: Shanafelt TD, Wang XV, Kay NE, Hanson CA, O'Brien S, Barrientos J, Jelinek DF, Braggio E, Leis JF, Zhang CC, Coutre SE, Barr PM, Cashen AF, Mato AR, Singh AK, Mullane MP, Little RF, Erba H, Stone RM, Litzow M, Tallman M. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019 Aug 1;381(5):432-443. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT02048813
- Update: Shanafelt TD, Wang XV, Hanson CA, Paietta EM, O'Brien S, Barrientos J, Jelinek DF, Braggio E, Leis JF, Zhang CC, Coutre SE, Barr PM, Cashen AF, Mato AR, Singh AK, Mullane MP, Little RF, Erba H, Stone RM, Litzow M, Tallman M, Kay NE. Long-term outcomes for ibrutinib-rituximab and chemoimmunotherapy in CLL: updated results of the E1912 trial. Blood. 2022 Jul 14;140(2):112-120. link to original article link to PMC article PubMed
- FLAIR: Hillmen P, Pitchford A, Bloor A, Broom A, Young M, Kennedy B, Walewska R, Furtado M, Preston G, Neilson JR, Pemberton N, Sidra G, Morley N, Cwynarski K, Schuh A, Forconi F, Elmusharaf N, Paneesha S, Fox CP, Howard DR, Hockaday A, Brown JM, Cairns DA, Jackson S, Greatorex N, Webster N, Shingles J, Dalal S, Patten PEM, Allsup D, Rawstron A, Munir T. Ibrutinib and rituximab versus fludarabine, cyclophosphamide, and rituximab for patients with previously untreated chronic lymphocytic leukaemia (FLAIR): interim analysis of a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2023 May;24(5):535-552. link to original article dosing details in manuscript have been reviewed by our editors PubMed ISRCTN01844152
Ibrutinib & Venetoclax
VI: Ventoclax & Ibrutinib
Regimen variant #1, 15 cycles
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Kater et al. 2022 (GLOW) | 2018-05 to 2019-04 | Phase 3 (E-switch-ooc) | GClb | Superior PFS1 (primary endpoint) PFS42: 74.6% vs 24.8% (HR 0.21, 95% CI 0.14-0.33) |
1Reported efficacy is based on the 2023 update.
Eligibility criteria
- GLOW: At least 65 years old or 18 to 64 years old with a Cumulative Illness Rating Scale (CIRS) score greater than 6
Targeted therapy
- Ibrutinib (Imbruvica) 420 mg PO once per day on days 1 to 28
- Venetoclax (Venclexta) as follows:
- Cycle 4: 20 mg PO once per day on days 1 to 7, then 50 mg PO once per day on days 8 to 14, then 100 mg PO once per day on days 15 to 21, then 200 mg PO once per day on days 22 to 28
- Cycles 5 to 15: 400 mg PO once per day on days 1 to 28
28-day cycle for 15 cycles
Regimen variant #2, 24 cycles
Study | Dates of enrollment | Evidence |
---|---|---|
Jain et al. 2019 (MDACC 2015-0860) | 2016-2018 | Phase 2 |
Note: the starting dose and escalation schedule of venetoclax are not clearly specified in the manuscript; the authors were contacted for clarification and informed us that they used the FDA-recommended dosing, which is replicated here.
Targeted therapy
- Ibrutinib (Imbruvica) 420 mg PO once per day on days 1 to 28
- Venetoclax (Venclexta) as follows:
- Cycle 4: 20 mg PO once per day on days 1 to 7, then 50 mg PO once per day on days 8 to 14, then 100 mg PO once per day on days 15 to 21, then 200 mg PO once per day on days 22 to 28
- Cycles 5 to 24: 400 mg PO once per day on days 1 to 28
28-day cycle for up to 24 cycles
Regimen variant #3, MRD-guided discontinuation
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Hillmen et al. 2023 (FLAIR part 2) | 2017-07-20 to 2021-03-24 | Phase 3 (E-switch-ooc) | 1. FCR | Superior PFS (primary endpoint) PFS36: 97.2% vs 76.8%% (HR 0.13, 95% CI 0.07-0.24) Superior OS (secondary endpoint) OS36: 98% vs 93% (HR 0.31, 95% CI 0.15-0.67) |
2. Ibrutinib | Not reported |
Note: See paper for details regarding MRD-guided discontinuation.
Targeted therapy
- Ibrutinib (Imbruvica) 420 mg PO once per day on days 1 to 28
- Venetoclax (Venclexta) as follows:
- Cycle 3: 20 mg PO once per day on days 1 to 7, then 50 mg PO once per day on days 8 to 14, then 100 mg PO once per day on days 15 to 21, then 200 mg PO once per day on days 22 to 28
- Cycles 4 up to 78: 400 mg PO once per day on days 1 to 28
28-day cycle for up to 78 cycles
References
- MDACC 2015-0860: Jain N, Keating M, Thompson P, Ferrajoli A, Burger J, Borthakur G, Takahashi K, Estrov Z, Fowler N, Kadia T, Konopleva M, Alvarado Y, Yilmaz M, DiNardo C, Bose P, Ohanian M, Pemmaraju N, Jabbour E, Sasaki K, Kanagal-Shamanna R, Patel K, Jorgensen J, Garg N, Wang X, Sondermann K, Cruz N, Wei C, Ayala A, Plunkett W, Kantarjian H, Gandhi V, Wierda W. Ibrutinib and venetoclax for first-line treatment of CLL. N Engl J Med. 2019 May 30;380(22):2095-2103. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT02756897
- GLOW: Kater AP, Owen C, Moreno C, Follows G, Munir T, Levin MD, Benjamini O, Janssens A, Osterborg A, Robak T, Simkovic M, Stevens D, Voloshin S, Vorobyev V, Ysebaert L, Qin R, Steele AJ, Schuier N, Baeten K, Caces DB, Niemann CU. Fixed-Duration Ibrutinib-Venetoclax in Patients with Chronic Lymphocytic Leukemia and Comorbidities. NEJM Evid. 2022 Jul;1(7):EVIDoa2200006. Epub 2022 May 13. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT03462719
- Update: Niemann CU, Munir T, Moreno C, Owen C, Follows GA, Benjamini O, Janssens A, Levin MD, Robak T, Simkovic M, Voloshin S, Vorobyev V, Yagci M, Ysebaert L, Qi K, Qi Q, Sinet P, Parisi L, Srinivasan S, Schuier N, Baeten K, Howes A, Caces DB, Kater AP. Fixed-duration ibrutinib-venetoclax versus chlorambucil-obinutuzumab in previously untreated chronic lymphocytic leukaemia (GLOW): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2023 Dec;24(12):1423-1433. Epub 2023 Nov 6. link to original article PubMed
- FLAIR part 2: Munir T, Cairns DA, Bloor A, Allsup D, Cwynarski K, Pettitt A, Paneesha S, Fox CP, Eyre TA, Forconi F, Elmusharaf N, Kennedy B, Gribben J, Pemberton N, Sheehy O, Preston G, Schuh A, Walewska R, Duley L, Howard D, Hockaday A, Jackson S, Greatorex N, Girvan S, Bell S, Brown JM, Webster N, Dalal S, de Tute R, Rawstron A, Patten PEM, Hillmen P; National Cancer Research Institute Chronic Lymphocytic Leukemia Subgroup. Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease. N Engl J Med. 2024 Jan 25;390(4):326-337. Epub 2023 Dec 10. link to original article dosing details in supplement have been reviewed by our editors PubMed ISRCTN01844152
Ibrutinib, Venetoclax, Obinutuzumab
Regimen variant #1
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Eichhorst et al. 2023 (GAIA) | 2016-12-13 to 2019-10-13 | Phase 3 (E-switch-ooc) | 1a. BR 1b. FCR |
Superior PFS2 (co-primary endpoint) PFS48: 85.5% vs 62% (HR 0.30, 97.5% CI 0.19-0.47) |
2. Venetoclax & Obinutuzumab | Might have superior PFS2 (co-primary endpoint) PFS48: 85.5% vs 81.8% (HR 0.63, 97.5% CI 0.39-1.02) | |||
3. Venetoclax & Rituximab | Superior PFS2 (co-primary endpoint) PFS48: 85.5% vs 70.1% (HR 0.38, 97.5% CI 0.24-0.59) |
1Reported efficacy is based on the 2021 update.
Note: Obinutuzumab is only given for the first six cycles.
Targeted therapy
- Ibrutinib (Imbruvica) 420 mg PO once per day on days 1 to 28
- Venetoclax (Venclexta) as follows:
- Cycle 1: 20 mg PO once per day on days 22 to 28
- Cycle 2: 50 mg PO once per day on days 1 to 7, then 100 mg PO once per day on days 8 to 14, then 200 mg PO once per day on days 15 to 21, then 400 mg PO once per day on days 22 to 28
- Cycles 3 to 12: 400 mg PO once per day
- Obinutuzumab (Gazyva) as follows:
- Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15
- Cycles 2 to 6: 1000 mg IV once on day 1
28-day cycle for up to 36 cycles
Regimen variant #2
Study | Dates of enrollment | Evidence |
---|---|---|
Rogers et al. 2020 (OSU-14266) | 2015-2017 | Phase 2 |
Targeted therapy
- Ibrutinib (Imbruvica) as follows:
- Cycle 2 onwards: 420 mg PO once per day on days 1 to 28
- Venetoclax (Venclexta) as follows:
- Cycle 3: 20 mg PO once per day on days 1 to 7, then 50 mg PO once per day on days 8 to 14, then 100 mg PO once per day on days 15 to 21, then 200 mg PO once per day on days 22 to 28
- Cycles 4 to 14: 400 mg PO once per day
- Obinutuzumab (Gazyva) as follows:
- Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15
- Cycles 2 to 8: 1000 mg IV once on day 1
28-day cycles
References
- OSU-14266: Rogers KA, Huang Y, Ruppert AS, Abruzzo LV, Andersen BL, Awan FT, Bhat SA, Dean A, Lucas M, Banks C, Grantier C, Heerema NA, Lozanski G, Maddocks KJ, Valentine TR, Weiss DM, Jones JA, Woyach JA, Byrd JC. Phase II Study of Combination Obinutuzumab, Ibrutinib, and Venetoclax in Treatment-Naïve and Relapsed or Refractory Chronic Lymphocytic Leukemia. J Clin Oncol. 2020 Nov 1;38(31):3626-3637. Epub 2020 Aug 14. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT02427451
- GAIA: Eichhorst B, Niemann CU, Kater AP, Fürstenau M, von Tresckow J, Zhang C, Robrecht S, Gregor M, Juliusson G, Thornton P, Staber PB, Tadmor T, Lindström V, da Cunha-Bang C, Schneider C, Poulsen CB, Illmer T, Schöttker B, Nösslinger T, Janssens A, Christiansen I, Baumann M, Frederiksen H, van der Klift M, Jäger U, Leys MBL, Hoogendoorn M, Lotfi K, Hebart H, Gaska T, Koene H, Enggaard L, Goede J, Regelink JC, Widmer A, Simon F, De Silva N, Fink AM, Bahlo J, Fischer K, Wendtner CM, Kreuzer KA, Ritgen M, Brüggemann M, Tausch E, Levin MD, van Oers M, Geisler C, Stilgenbauer S, Hallek M; GCLLSG, the HOVON and Nordic CLL Study Groups, the SAKK, the Israeli CLL Association, and Cancer Trials Ireland. First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia. N Engl J Med. 2023 May 11;388(19):1739-1754. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT02950051
- Update: Fürstenau M, Kater AP, Robrecht S, von Tresckow J, Zhang C, Gregor M, Thornton P, Staber PB, Tadmor T, Lindström V, Juliusson G, Janssens A, Levin MD, da Cunha-Bang C, Schneider C, Goldschmidt N, Vandenberghe E, Rossi D, Benz R, Nösslinger T, Heintel D, Poulsen CB, Christiansen I, Frederiksen H, Enggaard L, Posthuma EFM, Issa DE, Visser HPJ, Bellido M, Kutsch N, Dürig J, Stehle A, Vöhringer M, Böttcher S, Schulte C, Simon F, Fink AM, Fischer K, Holmes EE, Kreuzer KA, Ritgen M, Brüggemann M, Tausch E, Stilgenbauer S, Hallek M, Niemann CU, Eichhorst B. First-line venetoclax combinations versus chemoimmunotherapy in fit patients with chronic lymphocytic leukaemia (GAIA/CLL13): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2024 Jun;25(6):744-759. Erratum in: Lancet Oncol. 2024 Jul;25(7):e284. link to original article PubMed
Obinutuzumab monotherapy
Regimen variant #1, standard-dose (1000 mg)
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Byrd et al. 2015 (GAGE) | 2011 to not reported | Randomized Phase 2 (C) | Obinutuzumab; high-dose | Might have inferior ORR |
Targeted therapy
- Obinutuzumab (Gazyva) as follows:
- Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15
- Cycles 2 up to 8: 1000 mg IV once on day 1
Supportive therapy
- Acetaminophen (Tylenol) 650 to 1000 mg PO once per infusion, 30 to 60 minutes prior to obinutuzumab
- Antihistamine "such as" Diphenhydramine (Benadryl) 50 to 100 mg PO once per infusion, 30 to 60 minutes prior to obinutuzumab
- Prednisolone (Millipred) (or equivalent) 100 mg IV once per infusion, prior to each of the first three doses of obinutuzumab, afterwards at the discretion of treating physician
21-day cycle for up to 8 cycles
Regimen variant #2, high-dose (2000 mg), option A
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Byrd et al. 2015 (GAGE) | 2011 to not reported | Randomized Phase 2 (E-esc) | Obinutuzumab; standard-dose | Might have superior ORR (primary endpoint) |
Targeted therapy
- Obinutuzumab (Gazyva) as follows:
- Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once on day 3, then 2000 mg IV once per day on days 8 & 15
- Cycles 2 up to 8: 2000 mg IV once on day 1
Supportive therapy
- Acetaminophen (Tylenol) 650 to 1000 mg PO once per infusion, 30 to 60 minutes prior to obinutuzumab
- Antihistamine "such as" Diphenhydramine (Benadryl) 50 to 100 mg PO once per infusion, 30 to 60 minutes prior to obinutuzumab
- Prednisolone (Millipred) (or equivalent) 100 mg IV once per infusion, prior to each of the first three doses of obinutuzumab, afterwards at the discretion of treating physician
21-day cycle for up to 8 cycles
Regimen variant #3, high-dose (2000 mg), option B
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Byrd et al. 2015 (GAGE) | 2011 to not reported | Randomized Phase 2 (E-esc) | Obinutuzumab; standard-dose | Might have superior ORR (primary endpoint) |
Targeted therapy
- Obinutuzumab (Gazyva) as follows:
- Cycle 1: 100 mg IV once on day 1, then 1900 mg IV once on day 2, then 2000 mg IV once per day on days 8 & 15
- Cycles 2 up to 8: 2000 mg IV once on day 1
Supportive therapy
- Acetaminophen (Tylenol) 650 to 1000 mg PO once per infusion, 30 to 60 minutes prior to obinutuzumab
- Antihistamine "such as" Diphenhydramine (Benadryl) 50 to 100 mg PO once per infusion, 30 to 60 minutes prior to obinutuzumab
- Prednisolone (Millipred) (or equivalent) 100 mg IV once per infusion, prior to each of the first three doses of obinutuzumab, afterwards at the discretion of treating physician
21-day cycle for up to 8 cycles
References
- GAGE: Byrd JC, Flynn JM, Kipps TJ, Boxer M, Kolibaba KS, Carlile DJ, Fingerle-Rowson G, Tyson N, Hirata J, Sharman JP. Randomized phase 2 study of obinutuzumab monotherapy in symptomatic, previously untreated chronic lymphocytic leukemia. Blood. 2016 Jan 7;127(1):79-86. Epub 2015 Oct 15. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01414205
Venetoclax & Obinutuzumab
VG: Venetoclax & Gazyva (Obinutuzumab)
VO: Venetoclax & Obinutuzumab
GVE: Gazyva (Obinutuzumab) & VEnetoclax
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Fischer et al. 2019 (GCLLSG CLL14) | 2015-08-07 to 2016-08-04 | Phase 3 (E-RT-switch-ooc) | Chlorambucil & Obinutuzumab | Superior PFS1 (primary endpoint) Median PFS: NYR vs 36.4 mo (HR 0.33, 95% CI 0.25-0.45) |
Eichhorst et al. 2023 (GAIA) | 2016-12-13 to 2019-10-13 | Phase 3 (E-switch-ooc) | 1a. BR 1b. FCR |
Superior PFS2 (co-primary endpoint) PFS48: 81.8% vs 62% (HR 0.47, 97.5% CI 0.32-0.69) |
2. Ibrutinib, Venetoclax, Obinutuzumab | Might have inferior PFS2 | |||
3. Venetoclax & Rituximab | Superior PFS2 (co-primary endpoint) PFS48: 81.8% vs 70.1% (HR 0.57, 97.5% CI 0.38-0.84) | |||
Awaiting publication (GCLLSG CLL16) | 2022-2026 | Phase 3 (C) | GAVE | TBD if different primary endpoint of PFS |
Awaiting publication (MAJIC) | 2022-2029 | Phase 3 (C) | Acalabrutinib & Venetoclax | TBD if different primary endpoint of PFS |
1Reported efficacy is based on the 2021 update.
2Reported efficacy is based on the 2024 update.
Note: Obinutuzumab is only given for the first six cycles.
Targeted therapy
- Venetoclax (Venclexta) as follows:
- Cycle 1: 20 mg PO once per day on days 22 to 28
- Cycle 2: 50 mg PO once per day on days 1 to 7, then 100 mg PO once per day on days 8 to 14, then 200 mg PO once per day on days 15 to 21, then 400 mg PO once per day on days 22 to 28
- Cycles 3 to 12: 400 mg PO once per day
- Obinutuzumab (Gazyva) as follows:
- Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15
- Cycles 2 to 6: 1000 mg IV once on day 1
28-day cycle for 12 cycles
References
- GCLLSG CLL14: Fischer K, Al-Sawaf O, Bahlo J, Fink AM, Tandon M, Dixon M, Robrecht S, Warburton S, Humphrey K, Samoylova O, Liberati AM, Pinilla-Ibarz J, Opat S, Sivcheva L, Le Dû K, Fogliatto LM, Niemann CU, Weinkove R, Robinson S, Kipps TJ, Boettcher S, Tausch E, Humerickhouse R, Eichhorst B, Wendtner CM, Langerak AW, Kreuzer KA, Ritgen M, Goede V, Stilgenbauer S, Mobasher M, Hallek M. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019 Jun 6;380(23):2225-2236. Epub 2019 Jun 4. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT02242942
- Update: Al-Sawaf O, Zhang C, Tandon M, Sinha A, Fink AM, Robrecht S, Samoylova O, Liberati AM, Pinilla-Ibarz J, Opat S, Sivcheva L, Le Dû K, Fogliatto LM, Niemann CU, Weinkove R, Robinson S, Kipps TJ, Tausch E, Schary W, Ritgen M, Wendtner CM, Kreuzer KA, Eichhorst B, Stilgenbauer S, Hallek M, Fischer K. Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2020 Sep;21(9):1188-1200. link to original article PubMed
- Update: Al-Sawaf O, Zhang C, Lu T, Liao MZ, Panchal A, Robrecht S, Ching T, Tandon M, Fink AM, Tausch E, Schneider C, Ritgen M, Böttcher S, Kreuzer KA, Chyla B, Miles D, Wendtner CM, Eichhorst B, Stilgenbauer S, Jiang Y, Hallek M, Fischer K. Minimal Residual Disease Dynamics after Venetoclax-Obinutuzumab Treatment: Extended Off-Treatment Follow-up From the Randomized CLL14 Study. J Clin Oncol. 2021 Dec 20;39(36):4049-4060. Epub 2021 Oct 28. link to original article link to PMC article PubMed
- GAIA: Eichhorst B, Niemann CU, Kater AP, Fürstenau M, von Tresckow J, Zhang C, Robrecht S, Gregor M, Juliusson G, Thornton P, Staber PB, Tadmor T, Lindström V, da Cunha-Bang C, Schneider C, Poulsen CB, Illmer T, Schöttker B, Nösslinger T, Janssens A, Christiansen I, Baumann M, Frederiksen H, van der Klift M, Jäger U, Leys MBL, Hoogendoorn M, Lotfi K, Hebart H, Gaska T, Koene H, Enggaard L, Goede J, Regelink JC, Widmer A, Simon F, De Silva N, Fink AM, Bahlo J, Fischer K, Wendtner CM, Kreuzer KA, Ritgen M, Brüggemann M, Tausch E, Levin MD, van Oers M, Geisler C, Stilgenbauer S, Hallek M; GCLLSG, the HOVON and Nordic CLL Study Groups, the SAKK, the Israeli CLL Association, and Cancer Trials Ireland. First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia. N Engl J Med. 2023 May 11;388(19):1739-1754. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT02950051
- Update: Fürstenau M, Kater AP, Robrecht S, von Tresckow J, Zhang C, Gregor M, Thornton P, Staber PB, Tadmor T, Lindström V, Juliusson G, Janssens A, Levin MD, da Cunha-Bang C, Schneider C, Goldschmidt N, Vandenberghe E, Rossi D, Benz R, Nösslinger T, Heintel D, Poulsen CB, Christiansen I, Frederiksen H, Enggaard L, Posthuma EFM, Issa DE, Visser HPJ, Bellido M, Kutsch N, Dürig J, Stehle A, Vöhringer M, Böttcher S, Schulte C, Simon F, Fink AM, Fischer K, Holmes EE, Kreuzer KA, Ritgen M, Brüggemann M, Tausch E, Stilgenbauer S, Hallek M, Niemann CU, Eichhorst B. First-line venetoclax combinations versus chemoimmunotherapy in fit patients with chronic lymphocytic leukaemia (GAIA/CLL13): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2024 Jun;25(6):744-759. Erratum in: Lancet Oncol. 2024 Jul;25(7):e284. link to original article PubMed
- EVOLVE CLL/SLL: NCT04269902
- GCLLSG CLL16: NCT05197192
- MAJIC: NCT05057494
Watchful waiting
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Dighiero et al. 1998 (FRE-CLL-85) | 1980-1985 | Phase 3 (C) | Chlorambucil | Seems to have inferior PFS |
Dighiero et al. 1998 (FRE-CLL-90) | 1985-1990 | Phase 3 (C) | Chlorambucil & Prednisone | Inferior PFS |
Hoechstetter et al. 2017 (GCLLSG CLL1) | 1997-2004 | Phase 3 (C) | Fludarabine | Inferior PFS |
Herling et al. 2020 (GCLLSG CLL7) | 2005-2010 | Phase 3 (C) | FCR | Inferior EFS |
Langerbeins et al. 2022 (CLL12) | 2014-2019 | Phase 3 (C) | Ibrutinib | Inferior EFS |
Awaiting publication (GLLC-EARLY) | 2019-2024 | Phase 3 (C) | Acalabrutinib | TBD if different primary endpoint of EFS |
References
- FRE-CLL-85: Dighiero G, Maloum K, Desablens B, Cazin B, Navarro M, Leblay R, Leporrier M, Jaubert J, Lepeu G, Dreyfus B, Binet JL, Travade P; French Cooperative Group on Chronic Lymphocytic Leukemia. Chlorambucil in indolent chronic lymphocytic leukemia. N Engl J Med. 1998 May 21;338(21):1506-14. link to original article PubMed
- FRE-CLL-90: Dighiero G, Maloum K, Desablens B, Cazin B, Navarro M, Leblay R, Leporrier M, Jaubert J, Lepeu G, Dreyfus B, Binet JL, Travade P; French Cooperative Group on Chronic Lymphocytic Leukemia. Chlorambucil in indolent chronic lymphocytic leukemia. N Engl J Med. 1998 May 21;338(21):1506-14. link to original article PubMed
- GCLLSG CLL7: Herling CD, Cymbalista F, Groß-Ophoff-Müller C, Bahlo J, Robrecht S, Langerbeins P, Fink AM, Al-Sawaf O, Busch R, Porcher R, Cazin B, Dreyfus B, Ibach S, Leprêtre S, Fischer K, Kaiser F, Eichhorst B, Wentner CM, Hoechstetter MA, Döhner H, Leblond V, Kneba M, Letestu R, Böttcher S, Stilgenbauer S, Hallek M, Levy V. Early treatment with FCR versus watch and wait in patients with stage Binet A high-risk chronic lymphocytic leukemia (CLL): a randomized phase 3 trial. Leukemia. 2020 Aug;34(8):2038-2050. Epub 2020 Feb 18. link to original article link to PMC article PubMed NCT00275054
- GCLLSG CLL1: Hoechstetter MA, Busch R, Eichhorst B, Bühler A, Winkler D, Eckart MJ, Vehling-Kaiser U, Schimke H, Jäger U, Hurtz HJ, Hopfinger G, Hartmann F, Fuss H, Abenhardt W, Blau I, Freier W, Müller L, Goebeler M, Wendtner CM, Bahlo J, Fischer K, Bentz M, Emmerich B, Döhner H, Hallek M, Stilgenbauer S. Early, risk-adapted treatment with fludarabine in Binet stage A chronic lymphocytic leukemia patients: results of the CLL1 trial of the German CLL study group. Leukemia. 2017 Dec;31(12):2833-2837. Epub 2017 Aug 14. link to original article PubMed NCT00262782
- CLL12: Langerbeins P, Zhang C, Robrecht S, Cramer P, Fürstenau M, Al-Sawaf O, von Tresckow J, Fink AM, Kreuzer KA, Vehling-Kaiser U, Tausch E, Müller L, Eckart MJ, Schlag R, Freier W, Gaska T, Balser C, Reiser M, Stauch M, Wendtner CM, Fischer K, Stilgenbauer S, Eichhorst B, Hallek M. The CLL12 trial: ibrutinib vs placebo in treatment-naïve, early-stage chronic lymphocytic leukemia. Blood. 2022 Jan 13;139(2):177-187. link to original article PubMed NCT02863718
- GLLC-EARLY: NCT04178798
Zanubrutinib monotherapy
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Tam et al. 2022 (SEQUOIACLL) | 2017-2019 | Phase 3 (E-RT-switch-ooc) | BR | Superior PFS (primary endpoint) Median PFS: NYR vs NYR (HR 0.42, 95% CI 0.28-0.63) |
Biomarker eligibility criteria
- SEQUOIACLL: No 17p deletion
References
- SEQUOIACLL: Tam CS, Brown JR, Kahl BS, Ghia P, Giannopoulos K, Jurczak W, Šimkovič M, Shadman M, Österborg A, Laurenti L, Walker P, Opat S, Chan H, Ciepluch H, Greil R, Tani M, Trněný M, Brander DM, Flinn IW, Grosicki S, Verner E, Tedeschi A, Li J, Tian T, Zhou L, Marimpietri C, Paik JC, Cohen A, Huang J, Robak T, Hillmen P. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022 Aug;23(8):1031-1043. Epub 2022 Jul 7. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT03336333
First-line therapy, non-randomized or retrospective data
Alemtuzumab & Methylprednisolone
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Pettitt et al. 2012 (NCRI CLL206) | 2006-2008 | Phase 2 |
Biomarker eligibility criteria
- TP53 deletion
Targeted therapy
- Alemtuzumab (Campath) as follows:
- Cycle 1: 3 mg IV once on day 1, then 10 mg IV once on day 3, then 30 mg IV once per day on days 5, 8, 10, 12, 15, 17, 19, 22, 24, 26 (three times per week; increased as tolerated)
- Cycles 2 to 4: 30 mg SC once per day on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26 (three times per week)
Glucocorticoid therapy
- Methylprednisolone (Solumedrol) 1000 mg/m2/day (route not specified) on days 1 to 5
28-day cycle for 4 cycles
References
- NCRI CLL206: Pettitt AR, Jackson R, Carruthers S, Dodd J, Dodd S, Oates M, Johnson GG, Schuh A, Matutes E, Dearden CE, Catovsky D, Radford JA, Bloor A, Follows GA, Devereux S, Kruger A, Blundell J, Agrawal S, Allsup D, Proctor S, Heartin E, Oscier D, Hamblin TJ, Rawstron A, Hillmen P. Alemtuzumab in combination with methylprednisolone is a highly effective induction regimen for patients with chronic lymphocytic leukemia and deletion of TP53: final results of the National Cancer Research Institute CLL206 trial. J Clin Oncol. 2012 May 10;30(14):1647-55. Epub 2012 Apr 9. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00292760
AVO
AVO: Acalabrutinib, Venetoclax, Obinutuzumab
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Davids et al. 2021 (DFCI 18-226) | 2018-2019 | Phase 2 |
Targeted therapy
- Acalabrutinib (Calquence) 100 mg PO twice per day on days 1 to 28
- Venetoclax (Venclexta) as follows:
- Cycle 4: 20 mg PO once on day 1, then 50 mg PO once per day on days 2 to 7, then 100 mg PO once per day on days 8 to 14, then 200 mg PO once per day on days 15 to 21, then 400 mg PO once per day on days 22 to 28
- Cycle 5 onwards: 400 mg PO once per day on days 1 to 28
- Obinutuzumab (Gazyva) as follows:
- Cycle 2: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15
- Cycles 3 to 7: 1000 mg IV once on day 1
28-day cycles
References
- DFCI 18-226: Davids MS, Lampson BL, Tyekucheva S, Wang Z, Lowney JC, Pazienza S, Montegaard J, Patterson V, Weinstock M, Crombie JL, Ng SY, Kim AI, Jacobson CA, LaCasce AS, Armand P, Arnason JE, Fisher DC, Brown JR. Acalabrutinib, venetoclax, and obinutuzumab as frontline treatment for chronic lymphocytic leukaemia: a single-arm, open-label, phase 2 study. Lancet Oncol. 2021 Oct;22(10):1391-1402. Epub 2021 Sep 14. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT03580928
Bendamustine & Obinutuzumab
G-B: Gazyva (Obinutuzumab), Bendamustine
Regimen
Study | Dates of enrollment | Evidence | Efficacy |
---|---|---|---|
Brown et al. 2015 (GALTON) | 2011 to not reported | Phase 1b | ORR: 90% |
Sharman et al. 2020 (GIBB) | 2015-2016 | Phase 2 | CR rate: 50% |
Chemotherapy
- Bendamustine as follows:
- Cycle 1: 90 mg/m2 IV once per day on days 2 & 3
- Cycles 2 to 6: 90 mg/m2 IV once per day on days 1 & 2
Targeted therapy
- Obinutuzumab (Gazyva) as follows:
- Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15
- Cycles 2 to 6: 1000 mg IV once on day 1
Supportive therapy
- Acetaminophen (Tylenol) (dose not specified) once per infusion, prior to obinutuzumab
- Antihistamine e.g. Diphenhydramine (Benadryl) once per infusion, prior to obinutuzumab
- Highly potent corticosteroid (e.g. Prednisolone (Millipred) 100 mg IV) once, prior to first dose of obinutuzumab
- Allopurinol (Zyloprim) or Rasburicase (Elitek) recommended for tumor lysis syndrome prophylaxis
- PCP prophylaxis recommended
- Antiviral prophylaxis recommended
28-day cycle for 6 cycles
References
- GALTON: Brown JR, O'Brien S, Kingsley CD, Eradat H, Pagel JM, Lymp J, Hirata J, Kipps TJ. Obinutuzumab plus fludarabine/cyclophosphamide or bendamustine in the initial therapy of CLL patients: the phase 1b GALTON trial. Blood. 2015 Apr 30;125(18):2779-85. Epub 2015 Mar 13. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01300247
- GIBB: Sharman JP, Burke JM, Yimer HA, Boxer MA, Babu S, Li J, Mun Y, Danilov AV; GIBB study investigators. Phase 2, multicenter GIBB study of obinutuzumab plus bendamustine in previously untreated patients with chronic lymphocytic leukemia. Leuk Lymphoma. 2021 Apr;62(4):791-800. Epub 2020 Nov 26. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT02320487
CFAR
CFAR: Cyclophosphamide, Fludarabine, Alemtuzumab, Rituximab
Regimen
Study | Dates of enrollment | Evidence | Efficacy |
---|---|---|---|
Parikh et al. 2011 | 2005-2008 | Phase 2 | ORR: 92% |
Note: the doses of cyclophosphamide and fludarabine are lower than in the r/r CFAR regimen.
Chemotherapy
- Cyclophosphamide (Cytoxan) 200 mg/m2 IV once per day on days 3 to 5
- Fludarabine (Fludara) 20 mg/m2 IV once per day on days 3 to 5
Targeted therapy
- Alemtuzumab (Campath) 30 mg IV once per day on days 1, 3, 5
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 2
- Cycles 2 to 6: 500 mg/m2 IV once on day 2
Supportive therapy
- Pegfilgrastim (Neulasta) 6 mg SC once on day 6
- Acetaminophen (Tylenol) 500 mg PO once per day on days 1, 2, 3, 5, prior to rituximab/Alemtuzumab (Campath)
- Diphenhydramine (Benadryl) 25 to 50 mg IV or PO once per day on days 1, 2, 3, 5, prior to rituximab/Alemtuzumab (Campath)
- Hydrocortisone (Cortef) 100 mg IV once per day on days 1, 2, 3, 5, prior to rituximab/Alemtuzumab (Campath)
- Cycle 1: Allopurinol (Zyloprim) 300 mg PO once per day for at least days 1 to 7
- Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg PO once per day during treatment and for at least 3 to 6 months after last course
- Antiviral prophylaxis with ONE of the following:
- Valacyclovir (Valtrex) 500 mg PO once per day during treatment and for at least 3 to 6 months after last course
- OR Valganciclovir (Valcyte) 450 mg PO twice per day during treatment and for at least 3 to 6 months after last course
28-day cycle for 6 cycles
References
- Parikh SA, Keating MJ, O'Brien S, Wang X, Ferrajoli A, Faderl S, Burger J, Koller C, Estrov Z, Badoux X, Lerner S, Wierda WG. Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, alemtuzumab, and rituximab for high-risk chronic lymphocytic leukemia. Blood. 2011 Aug 25;118(8):2062-8. Epub 2011 Jul 12. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed
G-FC
G-FC: Gazyva (Obinutuzumab), Fludarabine, Cyclophosphamide
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Brown et al. 2015 (GALTON) | 2011 to not reported | Phase 1b |
Targeted therapy
- Obinutuzumab (Gazyva) as follows:
- Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15
- Cycles 2 to 6: 1000 mg IV once on day 1
Chemotherapy
- Fludarabine (Fludara) as follows:
- Cycle 1: 25 mg/m2 IV once per day on days 2 to 4
- Cycles 2 to 6: 25 mg/m2 IV once per day on days 1 to 3
- Cyclophosphamide (Cytoxan) as follows:
- Cycle 1: 250 mg/m2 IV once per day on days 2 to 4
- Cycles 2 to 6: 250 mg/m2 IV once per day on days 1 to 3
Supportive therapy
- Acetaminophen (Tylenol) (dose not specified) once per infusion, prior to obinutuzumab
- Antihistamine e.g. Diphenhydramine (Benadryl) once per infusion, prior to obinutuzumab
- Highly potent corticosteroid (e.g. Prednisolone (Millipred) 100 mg IV) once, prior to first dose of obinutuzumab
- Allopurinol (Zyloprim) or Rasburicase (Elitek) recommended for tumor lysis syndrome prophylaxis
- PCP prophylaxis recommended
- Antiviral prophylaxis recommended
28-day cycle for 6 cycles
References
- GALTON: Brown JR, O'Brien S, Kingsley CD, Eradat H, Pagel JM, Lymp J, Hirata J, Kipps TJ. Obinutuzumab plus fludarabine/cyclophosphamide or bendamustine in the initial therapy of CLL patients: the phase 1b GALTON trial. Blood. 2015 Apr 30;125(18):2779-85. Epub 2015 Mar 13. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01300247
HDMP-R
HDMP-R: High Dose, MethylPrednisolone & Rituximab
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Castro et al. 2009 | Not reported | Phase 2 |
Glucocorticoid therapy
- Methylprednisolone (Solumedrol) 1000 mg/m2 IV over 90 minutes once per day on days 1 to 3
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 total divided over 2 days IV once on days 1 & 2, then 375 mg/m2 IV once per day on days 8, 15, 22
- Cycles 2 & 3: 375 mg/m2 IV once per day on days 1, 8, 15, 22
Supportive therapy
- Cimetidine (Tagamet) as premedication for methylprednisolone
- Acetaminophen (Tylenol) as premedication for rituximab
- Diphenhydramine (Benadryl) as premedication for rituximab
- Trimethoprim-Sulfamethoxazole (Bactrim DS) (or equivalent) prophylaxis during therapy and continuing for 2 months after treatment is complete
- Acyclovir (Zovirax) (or equivalent) prophylaxis during therapy and continuing for 2 months after treatment is complete
- Fluconazole (Diflucan) (or equivalent) prophylaxis during therapy and continuing for 2 months after treatment is complete
- Allopurinol (Zyloprim) 300 mg PO once per day, started 3 days before the start of therapy and continued during treatment
- Patients with glucose greater than 200 on days of treatment received regular insulin SC sliding scale on days of treatment
28-day cycle for 3 cycles
References
- Castro JE, James DF, Sandoval-Sus JD, Jain S, Bole J, Rassenti L, Kipps TJ. Rituximab in combination with high-dose methylprednisolone for the treatment of chronic lymphocytic leukemia. Leukemia. 2009 Oct;23(10):1779-89. Epub 2009 Aug 20. link to original article dosing details in abstract have been reviewed by our editors link to PMC article PubMed
iFCR
iFCR: ibrutinib, Fludarabine, Cyclophosphamide, Rituximab
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Davids et al. 2019 (DFCI 14-296) | 2014-10 to 2018-04 | Phase 2 |
Note: Patients with undetectable minimal residual disease in bone marrow after 2 years were required to discontinue treatment, after a protocol amendment.
Targeted therapy
- Ibrutinib (Imbruvica) as follows:
- Lead-in: 420 mg PO once per day on days 1 to 7
- Cycle 1 onwards: 420 mg PO once per day on days 1 to 28
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 1
- Cycles 2 to 6: 500 mg/m2 IV once on day 1
Chemotherapy
- Fludarabine (Fludara) as follows:
- Cycles 1 to 6: 25 mg/m2 IV once per day on days 1 to 3
- Cyclophosphamide (Cytoxan) as follows:
- Cycles 1 to 6: 250 mg/m2 IV once per day on days 1 to 3
7-day lead-in, then 28-day cycles (see note)
References
- DFCI 14-296: Davids MS, Brander DM, Kim HT, Tyekucheva S, Bsat J, Savell A, Hellman JM, Bazemore J, Francoeur K, Alencar A, Shune L, Omaira M, Jacobson CA, Armand P, Ng S, Crombie J, LaCasce AS, Arnason J, Hochberg EP, Takvorian RW, Abramson JS, Fisher DC, Brown JR; Blood Cancer Research Partnership of the Leukemia & Lymphoma Society. Ibrutinib plus fludarabine, cyclophosphamide, and rituximab as initial treatment for younger patients with chronic lymphocytic leukaemia: a single-arm, multicentre, phase 2 trial. Lancet Haematol. 2019 Aug;6(8):e419-e428. Epub 2019 Jun 14. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT02251548
Lenalidomide & Rituximab (R2)
Regimen variant #1
Study | Dates of enrollment | Evidence |
---|---|---|
James et al. 2014 (CRC014) | 2008 to not reported | Phase 2 |
Targeted therapy
- Lenalidomide (Revlimid) with escalation in the absence of grade 2 or higher toxicities as follows:
- Cycle 1: 2.5 mg PO once per day on days 1 to 7, then 5 mg PO once per day on days 8 to 21
- Cycle 2: 5 mg PO once per day on days 1 to 21
- Cycles 3 up to 7: 10 mg PO once per day on days 1 to 21
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once per day on days 31 & 33
- Cycle 2: 375 mg/m2 IV once per day on days 1, 8, 15, 22
- Cycles 3 up to 7: 375 mg/m2 IV once on day 1
Supportive therapy
- Allopurinol (Zyloprim) prior to starting lenalidomide and with any dose escalation
- Aspirin 81 mg PO once per day
35-day course, then 28-day cycle for up to 6 cycles
Regimen variant #2
Study | Dates of enrollment | Evidence |
---|---|---|
Fowler et al. 2014 (MDACC 2008-0042) | 2008-2011 | Phase 2 |
Note: This combination was only studied in SLL (as opposed to CLL). Lenalidomide is dose-escalated to avoid tumor flare.
Targeted therapy
- Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21, then escalated by 5 mg/month to goal of 20 mg PO once per day
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
28-day cycle for up to 12 cycles
References
- CRC014: James DF, Werner L, Brown JR, Wierda WG, Barrientos JC, Castro JE, Greaves A, Johnson AJ, Rassenti LZ, Rai KR, Neuberg D, Kipps TJ. Lenalidomide and rituximab for the initial treatment of patients with chronic lymphocytic leukemia: a multicenter clinical-translational study from the Chronic Lymphocytic Leukemia Research Consortium. J Clin Oncol. 2014 Jul 1;32(19):2067-73. Epub 2014 May 27. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00628238
- MDACC 2008-0042: Fowler NH, Davis RE, Rawal S, Nastoupil L, Hagemeister FB, McLaughlin P, Kwak LW, Romaguera JE, Fanale MA, Fayad LE, Westin JR, Shah J, Orlowski RZ, Wang M, Turturro F, Oki Y, Claret LC, Feng L, Baladandayuthapani V, Muzzafar T, Tsai KY, Samaniego F, Neelapu SS. Safety and activity of lenalidomide and rituximab in untreated indolent lymphoma: an open-label, phase 2 trial. Lancet Oncol. 2014 Nov;15(12):1311-8. Epub 2014 Oct 15. link to original article dosing details in abstract have been reviewed by our editors link to PMC article PubMed NCT00695786
O-FC
O-FC: Ofatumumab, Fludarabine, Cyclophosphamide
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Wierda et al. 2011 (407 Study) | 2007 to not reported | Phase 2 |
Targeted therapy
- Ofatumumab (Arzerra) as follows:
- Cycle 1: 300 mg IV once on day 1
- Cycles 2 to 6: 500 mg or 1000 mg IV once on day 1
Chemotherapy
- Fludarabine (Fludara) as follows:
- Cycle 1: 25 mg/m2 IV once per day on days 2 to 4
- Cycles 2 to 6: 25 mg/m2 IV once per day on days 1 to 3 (note: there was ambiguity in Wierda et al. 2011 about whether both fludarabine and cyclophosphamide are given three days per cycle, or whether fludarabine is given once per cycle and only cyclophosphamide is given three days per cycle)
- Cyclophosphamide (Cytoxan) as follows:
- Cycle 1: 250 mg/m2 IV once per day on days 2 to 4
- Cycles 2 to 6: 250 mg/m2 IV once per day on days 1 to 3
Supportive therapy
- Acetaminophen (Tylenol) 1000 mg PO once on day 1, prior to ofatumumab
- Cetirizine (Zyrtec) 10 mg (or equivalent) PO once on day 1, prior to ofatumumab
- Prednisolone (Millipred) 100 mg (or equivalent) PO once on day 1, prior to doses 1 & 2 of ofatumumab, then reduced by physician discretion for later doses
- May be used at physician discretion:
- Allopurinol (Zyloprim) for tumor lysis syndrome prophylaxis
- Antiviral prophylaxis
- PCP (Pneumocystis jiroveci pneumonia) prophylaxis
- Growth factor support
28-day cycle for 6 cycles
References
- 407 Study: Wierda WG, Kipps TJ, Dürig J, Griskevicius L, Stilgenbauer S, Mayer J, Smolej L, Hess G, Griniute R, Hernandez-Ilizaliturri FJ, Padmanabhan S, Gorczyca M, Chang CN, Chan G, Gupta I, Nielsen TG, Russell CA; 407 Study Investigators. Chemoimmunotherapy with O-FC in previously untreated patients with chronic lymphocytic leukemia. Blood. 2011 Jun 16;117(24):6450-8. Epub 2011 Apr 15. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00410163
PCO
PCO: Pentostatin, Cyclophosphamide, Ofatumumab
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Shanafelt et al. 2013 (MC0983 arm 1) | 2010-2011 | Phase 2 |
Strati et al. 2016 (MC0983 arm 2) | 2011-2012 | Phase 2 |
Tedeschi et al. 2015 | 2011-2013 | Phase 2 |
Chemotherapy
- Pentostatin (Nipent) 2 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Targeted therapy
- Ofatumumab (Arzerra) as follows:
- Cycle 1: 300 mg IV once on day 1, then 1000 mg IV once on day 8
- Cycles 2 to 6: 1000 mg IV once on day 1
Supportive therapy
- Best described in Shanafelt et al. 2013:
- Methylprednisolone (Solumedrol) 80 mg IV once, prior to ofatumumab
- Cycle 1: Allopurinol (Zyloprim) 300 mg PO once per day on days 1 to 14
- Pegfilgrastim (Neulasta) 6 mg SC once on day 2
- Trimethoprim-Sulfamethoxazole (Bactrim DS) or similar for PJP prophylaxis for one year from start of treatment
- Valacyclovir (Valtrex) or similar for HSV prophylaxis for one year from start of treatment
21-day cycle for 6 cycles
Subsequent treatment
- MC0983 arm 2: Ofatumumab consolidation
References
- MC0983 arm 1: Shanafelt T, Lanasa MC, Call TG, Beaven AW, Leis JF, LaPlant B, Bowen D, Conte M, Jelinek DF, Hanson CA, Kay NE, Zent CS. Ofatumumab-based chemoimmunotherapy is effective and well tolerated in patients with previously untreated chronic lymphocytic leukemia (CLL). Cancer. 2013 Nov 1;119(21):3788-96. Epub 2013 Aug 6. Erratum in: Cancer. 2014 Mar 15;120(6):926. Dosage error in article text. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT01024010
- Tedeschi A, Rossi D, Motta M, Quaresmini G, Rossi M, Coscia M, Anastasia A, Rossini F, Cortelezzi A, Nador G, Scarfò L, Cairoli R, Frustaci AM, Dalceggio D, Picardi P, De Paoli L, Orlandi E, Rambaldi A, Massaia M, Gaidano G, Montillo M; Rete Ematologica Lombarda–CLL Workgroup. A phase II multi-center trial of pentostatin plus cyclophosphamide with ofatumumab in older previously untreated chronic lymphocytic leukemia patients. Haematologica. 2015 Dec;100(12):e501-4. Epub 2015 Aug 20. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01681563
- MC0983 arm 2: Strati P, Lanasa M, Call TG, Leis JF, Brander DM, LaPlant BR, Pettinger AM, Ding W, Parikh SA, Hanson CA, Chanan-Khan AA, Bowen DA, Conte M, Kay NE, Shanafelt TD. Ofatumumab monotherapy as a consolidation strategy in patients with previously untreated chronic lymphocytic leukaemia: a phase 2 trial. Lancet Haematol. 2016 Sep;3(9):e407-14. Epub 2016 Aug 1. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01024010
PCR
PCR: Pentostatin, Cyclophosphamide, Rituximab
Regimen variant #1, 2/600/100->375
Study | Dates of enrollment | Evidence |
---|---|---|
Kay et al. 2007 | 2002-2005 | Phase 2 |
Shanafelt et al. 2007 | Not reported | Phase 2 |
Chemotherapy
- Pentostatin (Nipent) 2 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 100 mg/m2 IV once on day 1, then 375 mg/m2 IV once per day on days 3 & 5
- Cycles 2 to 6: 375 mg/m2 IV once on day 1
Supportive therapy
- Note: see references for details, as they differ by paper.
- Filgrastim (Neupogen) once per day, starting on day 3 for up to 10 days or until ANC greater than 1000/μL for 2 straight days
- Cycle 1: Allopurinol (Zyloprim) 300 mg PO once per day on days 1 to 15
- Prophylactic Trimethoprim-Sulfamethoxazole (Bactrim DS) for 1 year
- Prophylactic Acyclovir (Zovirax) for 1 year
28-day cycle for 6 cycles
Regimen variant #2, 4/600/375
Study | Dates of enrollment | Evidence |
---|---|---|
Samaniego et al. 2015 (MDACC 2004-0818) | 2005 to not reported | Phase 2 |
Note: this regimen was specifically studied in SLL, not CLL.
Chemotherapy
- Pentostatin (Nipent) 4 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Targeted therapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
Supportive therapy
- Ondansetron (Zofran) 8 mg (route not specified) once on day 1, prior to chemotherapy
- Diphenhydramine (Benadryl) 25 mg (route not specified) once on day 1, prior to chemotherapy
- 500 ml of 5% dextrose/one-half normal saline before and after each pentostatin dose
- Filgrastim (Neupogen) at the discretion of the treating physician
- Cycle 1: Allopurinol (Zyloprim) 300 mg PO once per day on days 1 to 15
- Trimethoprim-Sulfamethoxazole (Bactrim DS) once per day three days per week during and for 1 month following therapy
- Acyclovir (Zovirax) 400 mg PO twice per day during and for 1 month following therapy
21-day cycle for 6 cycles
References
- Kay NE, Geyer SM, Call TG, Shanafelt TD, Zent CS, Jelinek DF, Tschumper R, Bone ND, Dewald GW, Lin TS, Heerema NA, Smith L, Grever MR, Byrd JC. Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia. Blood. 2007 Jan 15;109(2):405-11. Epub 2006 Sep 28. link to original article dosing details in abstract have been reviewed by our editors link to PMC article PubMed
- Shanafelt TD, Lin T, Geyer SM, Zent CS, Leung N, Kabat B, Bowen D, Grever MR, Byrd JC, Kay NE. Pentostatin, cyclophosphamide, and rituximab regimen in older patients with chronic lymphocytic leukemia. Cancer. 2007 Jun 1;109(11):2291-8. link to original article PubMed
- MDACC 2004-0818: Samaniego F, Hagemeister F, Romaguera JE, Fanale MA, Pro B, McLaughlin P, Rodriguez MA, Neelapu SS, Fayad L, Younes A, Feng L, Berkova Z, Khashab T, Sehgal L, Vega-Vasquez F, Kwak LW. Pentostatin, cyclophosphamide and rituximab for previously untreated advanced stage, low-grade B-cell lymphomas. Br J Haematol. 2015 Jun;169(6):814-23. Epub 2015 Mar 31. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00496873
RCC
RCC: Rituximab, Cladribine, Cyclophosphamide
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Robak et al. 2018 (PALG CLL4) | 2009-07 to 2011-12 | Non-randomized part of phase 3b RCT |
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 1
- Cycles 2 to 6: 500 mg/m2 IV once on day 1
Chemotherapy
- Cladribine (Leustatin) 0.12 mg/kg IV once per day on days 2 to 4
- Cyclophosphamide (Cytoxan) 250 mg/m2 IV over 15 to 30 minutes once per day on days 2 to 4
28-day cycle for 6 cycles
Subsequent treatment
- Observation versus Rituximab maintenance
References
- PALG CLL4: Robak T, Błoński J, Skotnicki AB, Piotrowska M, Wróbel T, Rybka J, Kłoczko J, Bołkun Ł, Budziszewska BK, Walczak U, Uss A, Fidecka M, Smolewski P. Rituximab, cladribine, and cyclophosphamide (RCC) induction with rituximab maintenance in chronic lymphocytic leukemia: PALG - CLL4 (ML21283) trial. Eur J Haematol. 2018 May;100(5):465-474. Epub 2018 Mar 22. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00718549
Rituximab monotherapy
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Hainsworth et al. 2003 | 2000-2001 | Phase 2 |
Williams et al. 2016 (RESORT substudy) | 2003-2008 | Non-randomized part of phase 3 RCT |
Targeted therapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- In Hainsworth et al. 2003, optional alternate initial dosing for patients with WBC count more than 100 x 109/L: 100 mg IV once on day 1, with remainder of the 375 mg/m2 dosage given on day 2
Supportive therapy
- Acetaminophen (Tylenol) 650 mg PO once on day 1; 30 minutes prior to rituximab
- Diphenhydramine (Benadryl) 50 mg PO or IV once on day 1; 30 minutes prior to rituximab
- In Hainsworth et al. 2003, if WBC count more than 50 x 109/L or massive lymphadenopathy: Allopurinol (Zyloprim) 300 mg PO once per day, starting 3 days before the first dose of rituximab
- In Hainsworth et al. 2003, one of the following:
- Cimetidine (Tagamet) 300 mg IV once on day 1; 30 minutes prior to rituximab
- Ranitidine (Zantac) 50 mg IV once on day 1; 30 minutes prior to rituximab
7-day cycle for 4 cycles
References
- Hainsworth JD, Litchy S, Barton JH, Houston GA, Hermann RC, Bradof JE, Greco FA; Minnie Pearl Cancer Research Network. Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol. 2003 May 1;21(9):1746-51. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- RESORT substudy: Williams ME, Hong F, Gascoyne RD, Wagner LI, Krauss JC, Habermann TM, Swinnen LJ, Schuster SJ, Peterson CG, Sborov MD, Martin SE, Weiss M, Ehmann WC, Horning SJ, Kahl BS; Eastern Cooperative Oncology Group. Rituximab extended schedule or retreatment trial for low tumour burden non-follicular indolent B-cell non-Hodgkin lymphomas: Eastern Cooperative Oncology Group Protocol E4402. Br J Haematol. 2016 Jun;173(6):867-75. Epub 2016 Mar 11. link to original article dosing details in abstract have been reviewed by our editors link to PMC article PubMed NCT01406782
Ruxolitinib monotherapy
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Jain et al. 2017 (MDACC 2013-0044) | 2014-2015 | Phase 2 |
Note: this was a trial focused on symptom control, not efficacy.
References
- MDACC 2013-0044: Jain P, Keating M, Renner S, Cleeland C, Xuelin H, Gonzalez GN, Harris D, Li P, Liu Z, Veletic I, Rozovski U, Jain N, Thompson P, Bose P, DiNardo C, Ferrajoli A, O'Brien S, Burger J, Wierda W, Verstovsek S, Kantarjian H, Estrov Z. Ruxolitinib for symptom control in patients with chronic lymphocytic leukaemia: a single-group, phase 2 trial. Lancet Haematol. 2017 Feb;4(2):e67-e74. Epub 2017 Jan 11. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT02131584
Zanubrutinib & Obinutuzumab
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Tam et al. 2020 | 2016 to not reported | Phase 1b, >20 pts in this subgroup |
Targeted therapy
- Zanubrutinib (Brukinsa) 160 mg PO twice per day or 320 mg PO once per day
- Obinutuzumab (Gazyva) as follows:
- Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15
- Cycles 2 to 6: 1000 mg IV once on day 1
28-day cycles
References
- Tam CS, Quach H, Nicol A, Badoux X, Rose H, Prince HM, Leahy MF, Eek R, Wickham N, Patil SS, Huang J, Prathikanti R, Cohen A, Elstrom R, Reed W, Schneider J, Flinn IW. Zanubrutinib (BGB-3111) plus obinutuzumab in patients with chronic lymphocytic leukemia and follicular lymphoma. Blood Adv. 2020 Oct 13;4(19):4802-4811. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT02569476
Consolidation and/or maintenance after first-line therapy
Alemtuzumab monotherapy
Regimen variant #1, 6-week course
Study | Dates of enrollment | Evidence |
---|---|---|
Varghese et al. 2017 (NCRN CLL 207) | 2006-2010 | Phase 2 |
Preceding treatment
- First-line Chemotherapy (details not specified)
Targeted therapy
- Alemtuzumab (Campath) 30 mg SC once per day on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26, 29, 31, 33, 36, 38, 40 (three times per week)
6-week course
Regimen variant #2, 12-week course
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Wendtner et al. 2004 (GCLLSG CLL4B) | Not reported | Phase 3 (E-esc) | Observation | Superior PFS1 (primary endpoint) |
1Reported efficacy is based on the 2009 update.
Note: this study closed early due to high rates of infections in the experimental arm. Alemtuzumab dose is increased only if tolerated.
Targeted therapy
- Alemtuzumab (Campath) as follows:
- Cycle 1: 3 mg SC once on day 1, then 10 mg SC once on day 2, then 30 mg SC once on day 5
- Cycles 2 to 12: 30 mg SC once per day on days 1, 3, 5 (three times per week)
7-day cycle for 12 cycles
References
- GCLLSG CLL4B: Wendtner CM, Ritgen M, Schweighofer CD, Fingerle-Rowson G, Campe H, Jäger G, Eichhorst B, Busch R, Diem H, Engert A, Stilgenbauer S, Döhner H, Kneba M, Emmerich B, Hallek M; German CLL Study Group. Consolidation with alemtuzumab in patients with chronic lymphocytic leukemia (CLL) in first remission--experience on safety and efficacy within a randomized multicenter phase III trial of the German CLL Study Group (GCLLSG). Leukemia. 2004 Jun;18(6):1093-101. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Update: Schweighofer CD, Ritgen M, Eichhorst BF, Busch R, Abenhardt W, Kneba M, Hallek M, Wendtner CM. Consolidation with alemtuzumab improves progression-free survival in patients with chronic lymphocytic leukaemia (CLL) in first remission: long-term follow-up of a randomized phase III trial of the German CLL Study Group (GCLLSG). Br J Haematol. 2009 Jan;144(1):95-8. Epub 2008 Oct 30. link to original article PubMed
- NCRN CLL207: Varghese AM, Howard DR, Pocock C, Rawstron AC, Follows G, McCarthy H, Dearden C, Fegan C, Milligan D, Smith AF, Gregory W, Hillmen P; NCRI CLL Sub-Group. Eradication of minimal residual disease improves overall and progression-free survival in patients with chronic lymphocytic leukaemia, evidence from NCRN CLL207: a phase II trial assessing alemtuzumab consolidation. Br J Haematol. 2017 Feb;176(4):573-582. Epub 2016 Dec 29. link to original article dosing details in abstract have been reviewed by our editors PubMed
Lenalidomide monotherapy
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Fink et al. 2017 (GCLLSG CLLM1) | 2012-2016 | Phase 3 (E-esc) | Observation | Superior PFS (primary endpoint) Median PFS: NYR vs 13.3 mo (HR 0.17, 95% CI 0.07-0.38) |
Note that while the NCT01556776 NCT record] reports dose increases beyond 15 mg PO once per day, the abstract states that 15 mg PO once per day was the "target dose". Lenalidomide dose is only increased if tolerated.
Preceding treatment
- GCLLSG CLLM1: First-line chemoimmunotherapy
Targeted therapy
- Lenalidomide (Revlimid) as follows:
- Cycle 1: 5 mg PO once per day on days 1 to 28
- Cycles 2 to 6: 10 mg PO once per day on days 1 to 28
- Cycle 7 onwards: 15 mg PO once per day on days 1 to 28
28-day cycles
References
- GCLLSG CLLM1: Fink AM, Bahlo J, Robrecht S, Al-Sawaf O, Aldaoud A, Hebart H, Jentsch-Ullrich K, Dörfel S, Fischer K, Wendtner CM, Nösslinger T, Ghia P, Bosch F, Kater AP, Döhner H, Kneba M, Kreuzer KA, Tausch E, Stilgenbauer S, Ritgen M, Böttcher S, Eichhorst B, Hallek M. Lenalidomide maintenance after first-line therapy for high-risk chronic lymphocytic leukaemia (CLLM1): final results from a randomised, double-blind, phase 3 study. Lancet Haematol. 2017 Oct;4(10):e475-e486. Epub 2017 Sep 12. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT01556776
Ofatumumab monotherapy
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Strati et al. 2016 (MC0983 arm 2) | 2011-2012 | Phase 2 |
Preceding treatment
- First-line PCO x 6
References
- MC0983 arm 2: Strati P, Lanasa M, Call TG, Leis JF, Brander DM, LaPlant BR, Pettinger AM, Ding W, Parikh SA, Hanson CA, Chanan-Khan AA, Bowen DA, Conte M, Kay NE, Shanafelt TD. Ofatumumab monotherapy as a consolidation strategy in patients with previously untreated chronic lymphocytic leukaemia: a phase 2 trial. Lancet Haematol. 2016 Sep;3(9):e407-14. Epub 2016 Aug 1. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01024010
Rituximab monotherapy
Regimen variant #1, 1 year
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Foà et al. 2014 (ML21445) | 2008-2013 | Randomized Phase 2 (E-esc) | Observation | Might have superior PFS (secondary endpoint) |
Preceding treatment
- ML21445: First-line Clb-R
Regimen variant #2, 2 years, given q3mo
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Bosch et al. 2009 | 2005-11 to 2007-11 | Phase 2 | ||
Robak et al. 2018 (PALG CLL4) | 2009-07 to 2011-12 | Phase 3b (E-esc) | Observation | Seems to have superior PFS |
Greil et al. 2016 (AGMT CLL-8a) | 2010-2013 | Phase 3 (E-esc) | Observation | Superior PFS (primary endpoint) Median PFS: 47 vs 35.5 mo (HR 0.50, 95% CI 0.33-0.75) |
Preceding treatment
- Bosch et al. 2009: First-line R-FCM
- PALG CLL4: First-line RCC x 6
- AGMT CLL-8a: First-line rituximab-containing chemoimmunotherapy
Targeted therapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
3-month cycle for 8 cycles (2 years)
Regimen variant #3, 2 years, given q8wk
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Dartigeas et al. 2017 (CLL 2007 SA) | 2007-2014 | Phase 3 (E-esc) | Observation | Superior PFS (primary endpoint) Median PFS: 59.3 vs 49 mo (HR 0.55, 95% CI 0.40-0.75) |
Note the higher dose used here.
Preceding treatment
- First-line FCR x 4
Targeted therapy
- Rituximab (Rituxan) 500 mg/m2 IV once on day 1
8-week cycle for up to 13 cycles (2 years)
Regimen variant #4, 2 years, given q6mo
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Hainsworth et al. 2003 | 2000-2001 | Phase 2 | ||
Hochster et al. 2009 (ECOG E1496) | Not reported | Phase 3 (E-esc) | Observation | Superior PFS (primary endpoint) Median PFS: 4.3 vs 1.3 y (HR 0.40, 95% CI 0.30-0.50) |
ECOG E1496 included patients with SLL, but they were grouped into an "other" non-follicular lymphoma category.
Targeted therapy
- Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1, 8, 15, 22
Supportive therapy
- Acetaminophen (Tylenol) 650 mg PO once per day on days 1, 8, 15, 22; 30 minutes prior to rituximab
- Diphenhydramine (Benadryl) 50 mg IV once per day on days 1, 8, 15, 22; 30 minutes prior to rituximab
- One of the following:
- Cimetidine (Tagamet) 300 mg IV once per day on days 1, 8, 15, 22; 30 minutes prior to rituximab
- Ranitidine (Zantac) 50 mg IV once per day on days 1, 8, 15, 22; 30 minutes prior to rituximab
6-month cycle for 4 cycles (2 years)
Regimen variant #5, indefinite 375 mg/m2 q3mo
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Williams et al. 2016 (RESORT substudy) | 2003-2008 | Phase 3 (E-esc) | Rituximab salvage | Seems to have superior TTTF |
Intended for patients with SLL.
Preceding treatment
- First-line Rituximab
Regimen variant #6, indefinite 500 mg/m2 q3mo
Study | Dates of enrollment | Evidence |
---|---|---|
Foon et al. 2009 | 2003-2007 | Phase 2 |
Preceding treatment
- First-line FCR-Lite x 6
References
- Hainsworth JD, Litchy S, Barton JH, Houston GA, Hermann RC, Bradof JE, Greco FA; Minnie Pearl Cancer Research Network. Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol. 2003 May 1;21(9):1746-51. link to original article PubMed
- Foon KA, Boyiadzis M, Land SR, Marks S, Raptis A, Pietragallo L, Meisner D, Laman A, Sulecki M, Butchko A, Schaefer P, Lenzer D, Tarhini A. Chemoimmunotherapy with low-dose fludarabine and cyclophosphamide and high dose rituximab in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009 Feb 1;27(4):498-503. Epub 2008 Dec 15. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Update: Foon KA, Mehta D, Lentzsch S, Kropf P, Marks S, Lenzner D, Pietragallo L, Sulecki M, Tarhini A, Boyiadzis M. Long-term results of chemoimmunotherapy with low-dose fludarabine, cyclophosphamide and high-dose rituximab as initial treatment for patients with chronic lymphocytic leukemia. Blood. 2012 Mar 29;119(13):3184-5. link to original article PubMed
- ECOG E1496: Hochster H, Weller E, Gascoyne RD, Habermann TM, Gordon LI, Ryan T, Zhang L, Colocci N, Frankel S, Horning SJ. Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG1496 Study. J Clin Oncol. 2009 Apr 1;27(10):1607-14. Epub 2009 Mar 2. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00003204
- Bosch F, Abrisqueta P, Villamor N, Terol MJ, González-Barca E, Ferra C, González Diaz M, Abella E, Delgado J, Carbonell F, García Marco JA, Escoda L, Ferrer S, Monzó E, González Y, Estany C, Jarque I, Salamero O, Muntañola A, Montserrat E. Rituximab, fludarabine, cyclophosphamide, and mitoxantrone: a new, highly active chemoimmunotherapy regimen for chronic lymphocytic leukemia. J Clin Oncol. 2009 Sep 20;27(27):4578-84. Epub 2009 Aug 24. link to original article dosing details in manuscript have been reviewed by our editors PubMed EudraCT 2005-001569-33
- Update: Abrisqueta P, Villamor N, Terol MJ, González-Barca E, González M, Ferrà C, Abella E, Delgado J, García-Marco JA, González Y, Carbonell F, Ferrer S, Monzó E, Jarque I, Muntañola A, Constants M, Escoda L, Calvo X, Bobillo S, Montoro JB, Montserrat E, Bosch F. Rituximab maintenance after first-line therapy with rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) for chronic lymphocytic leukemia. Blood. 2013 Dec 5;122(24):3951-9. Epub 2013 Oct 11. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- ML21445: Foà R, Del Giudice I, Cuneo A, Del Poeta G, Ciolli S, Di Raimondo F, Lauria F, Cencini E, Rigolin GM, Cortelezzi A, Nobile F, Callea V, Brugiatelli M, Massaia M, Molica S, Trentin L, Rizzi R, Specchia G, Di Serio F, Orsucci L, Ambrosetti A, Montillo M, Zinzani PL, Ferrara F, Morabito F, Mura MA, Soriani S, Peragine N, Tavolaro S, Bonina S, Marinelli M, De Propris MS, Starza ID, Piciocchi A, Alietti A, Runggaldier EJ, Gamba E, Mauro FR, Chiaretti S, Guarini A. Chlorambucil plus rituximab with or without maintenance rituximab as first-line treatment for elderly chronic lymphocytic leukemia patients. Am J Hematol. 2014 May;89(5):480-6. Epub 2014 Feb 18. link to original article dosing details in manuscript have been reviewed by our editors PubMed EudraCT 2008-001612-20
- RESORT substudy: Williams ME, Hong F, Gascoyne RD, Wagner LI, Krauss JC, Habermann TM, Swinnen LJ, Schuster SJ, Peterson CG, Sborov MD, Martin SE, Weiss M, Ehmann WC, Horning SJ, Kahl BS; Eastern Cooperative Oncology Group. Rituximab extended schedule or retreatment trial for low tumour burden non-follicular indolent B-cell non-Hodgkin lymphomas: Eastern Cooperative Oncology Group Protocol E4402. Br J Haematol. 2016 Jun;173(6):867-75. Epub 2016 Mar 11. link to original article dosing details in abstract have been reviewed by our editors link to PMC article PubMed NCT01406782
- AGMT CLL-8a: Greil R, Obrtlíková P, Smolej L, Kozák T, Steurer M, Andel J, Burgstaller S, Mikušková E, Gercheva L, Nösslinger T, Papajík T, Ladická M, Girschikofsky M, Hrubiško M, Jäger U, Fridrik M, Pecherstorfer M, Králiková E, Burcoveanu C, Spasov E, Petzer A, Mihaylov G, Raynov J, Oexle H, Zabernigg A, Flochová E, Palášthy S, Stehlíková O, Doubek M, Altenhofer P, Pleyer L, Melchardt T, Klingler A, Mayer J, Egle A. Rituximab maintenance versus observation alone in patients with chronic lymphocytic leukaemia who respond to first-line or second-line rituximab-containing chemoimmunotherapy: final results of the AGMT CLL-8a Mabtenance randomised trial. Lancet Haematol. 2016 Jul;3(7):e317-29. Epub 2016 Jun 16. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01118234
- CLL 2007 SA: Dartigeas C, Van Den Neste E, Léger J, Maisonneuve H, Berthou C, Dilhuydy MS, De Guibert S, Leprêtre S, Béné MC, Nguyen-Khac F, Letestu R, Cymbalista F, Rodon P, Aurran-Schleinitz T, Vilque JP, Tournilhac O, Mahé B, Laribi K, Michallet AS, Delmer A, Feugier P, Lévy V, Delépine R, Colombat P, Leblond V; CLL 2007 SA investigators; FILO. Rituximab maintenance versus observation following abbreviated induction with chemoimmunotherapy in elderly patients with previously untreated chronic lymphocytic leukaemia (CLL 2007 SA): an open-label, randomised phase 3 study. Lancet Haematol. 2018 Feb;5(2):e82-e94. Epub 2017 Dec 20. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00645606
- PALG CLL4: Robak T, Błoński J, Skotnicki AB, Piotrowska M, Wróbel T, Rybka J, Kłoczko J, Bołkun Ł, Budziszewska BK, Walczak U, Uss A, Fidecka M, Smolewski P. Rituximab, cladribine, and cyclophosphamide (RCC) induction with rituximab maintenance in chronic lymphocytic leukemia: PALG - CLL4 (ML21283) trial. Eur J Haematol. 2018 May;100(5):465-474. Epub 2018 Mar 22. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00718549
Relapsed or refractory, randomized data
Acalabrutinib monotherapy
Regimen
FDA-recommended dose |
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Byrd et al. 2015 (ACE-CL-001 r/r) | 2014 to not reported | Phase 1/2 | ORR: 95% | |
Byrd et al. 2021 (ACE-CL-006) | 2015-2017 | Phase 3 (E-switch-ic) | Ibrutinib | Non-inferior PFS (primary endpoint) Median PFS: 38.4 vs 38.4 mo (HR 1.00, 95% CI 0.79-1.27) |
Ghia et al. 2020 (ASCEND) | 2017-02-21 to 2018-01-17 | Phase 3 (E-RT-switch-ooc) | Investigator's choice of: 1a. BR 1b. Idelalisib & Rituximab |
Superior PFS (primary endpoint) Median PFS: NYR vs 16.5 mo (HR 0.31, 95% CI 0.20-0.49) |
Biomarker eligibility criteria
- ACE-CL-006: del(17)(p13.1) or del(11)(q22.3)
Prior treatment criteria
- ACE-CL-006 & ASCEND: At least 1 prior systemic therapy
References
- ACE-CL-001 r/r: Byrd JC, Harrington B, O'Brien S, Jones JA, Schuh A, Devereux S, Chaves J, Wierda WG, Awan FT, Brown JR, Hillmen P, Stephens DM, Ghia P, Barrientos JC, Pagel JM, Woyach J, Johnson D, Huang J, Wang X, Kaptein A, Lannutti BJ, Covey T, Fardis M, McGreivy J, Hamdy A, Rothbaum W, Izumi R, Diacovo TG, Johnson AJ, Furman RR. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016 Jan 28;374(4):323-32. Epub 2015 Dec 7. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT02029443
- ASCEND: Ghia P, Pluta A, Wach M, Lysak D, Kozak T, Simkovic M, Kaplan P, Kraychok I, Illes A, de la Serna J, Dolan S, Campbell P, Musuraca G, Jacob A, Avery E, Lee JH, Liang W, Patel P, Quah C, Jurczak W. ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. J Clin Oncol. 2020 Sep 1;38(25):2849-2861. Epub 2020 May 27. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT02970318
- ACE-CL-006: Byrd JC, Hillmen P, Ghia P, Kater AP, Chanan-Khan A, Furman RR, O'Brien S, Yenerel MN, Illés A, Kay N, Garcia-Marco JA, Mato A, Pinilla-Ibarz J, Seymour JF, Lepretre S, Stilgenbauer S, Robak T, Rothbaum W, Izumi R, Hamdy A, Patel P, Higgins K, Sohoni S, Jurczak W. Acalabrutinib Versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia: Results of the First Randomized Phase III Trial. J Clin Oncol. 2021 Nov 1;39(31):3441-3452. Epub 2021 Jul 26. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT02477696
Bendamustine monotherapy
Regimen variant #1, 70 mg/m2
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Robak et al. 2016 (Aptevo 16201) | 2011-2013 | Randomized Phase 2 (C) | Bendamustine & Otlertuzumab | Seems to have inferior PFS |
Chemotherapy
- Bendamustine 70 mg/m2 IV over 30 minutes once per day on days 1 & 2
28-day cycle for 6 cycles
Regimen variant #2, 100 mg/m2
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Niederle et al. 2013 (WiSP RI05) | 2001-2006 | Phase 3 (E-switch-ic) | Fludarabine | Seems to have non-inferior PFS (primary endpoint) Median PFS: 20.1 vs 14.8 mo (HR 0.87, 90% CI 0.60-1.27) |
Regimen variant #3, 120 mg/m2
Study | Dates of enrollment | Evidence |
---|---|---|
Friedberg et al. 2008 | 2003-09 to 2005-02 | Phase 2 |
Kahl et al. 2010 (SDX-105-01 part 2) | 2005-2007 | Phase 3b |
Chemotherapy
- Bendamustine 120 mg/m2 IV once per day on days 1 & 2
21-day cycle for 6 to 8 (SDX-105-01 part 2) or up to 12 (Friedberg et al. 2008) cycles
References
- Friedberg JW, Cohen P, Chen L, Robinson KS, Forero-Torres A, La Casce AS, Fayad LE, Bessudo A, Camacho ES, Williams ME, van der Jagt RH, Oliver JW, Cheson BD. Bendamustine in patients with rituximab-refractory indolent and transformed non-Hodgkin's lymphoma: results from a phase II multicenter, single-agent study. J Clin Oncol. 2008 Jan 10;26(2):204-10. Erratum in: J Clin Oncol. 2008 Apr 10;26(11) 1911. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- SDX-105-01 part 2: Kahl BS, Bartlett NL, Leonard JP, Chen L, Ganjoo K, Williams ME, Czuczman MS, Robinson KS, Joyce R, van der Jagt RH, Cheson BD. Bendamustine is effective therapy in patients with rituximab-refractory, indolent B-cell non-Hodgkin lymphoma: results from a multicenter study. Cancer. 2010 Jan 1;116(1):106-14. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00069758
- Retrospective: Kolibaba KS, Sterchele JA, Joshi AD, Forsyth M, Alwon E, Beygi H, Kennealey GT. Demographics, treatment patterns, safety, and real-world effectiveness in patients aged 70 years and over with chronic lymphocytic leukemia receiving bendamustine with or without rituximab: a retrospective study. Ther Adv Hematol. 2013 Jun;4(3):157-71. link to PMC article PubMed
- WiSP RI05: Niederle N, Megdenberg D, Balleisen L, Heit W, Knauf W, Weiß J, Freier W, Hinke A, Ibach S, Eimermacher H. Bendamustine compared to fludarabine as second-line treatment in chronic lymphocytic leukemia. Ann Hematol. 2013 May;92(5):653-60. Epub 2013 Jan 23. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01423032
- Aptevo 16201: Robak T, Hellmann A, Kloczko J, Loscertales J, Lech-Maranda E, Pagel JM, Mato A, Byrd JC, Awan FT, Hebart H, Garcia-Marco JA, Hill BT, Hallek M, Eisenfeld AJ, Stromatt SC, Jaeger U. Randomized phase 2 study of otlertuzumab and bendamustine versus bendamustine in patients with relapsed chronic lymphocytic leukaemia. Br J Haematol. 2017 Feb;176(4):618-628. Epub 2016 Dec 15. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01188681
Bendamustine & Rituximab (BR)
BR: Bendamustine & Rituximab
R-B: Rituximab & Bendamustine
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Fischer et al. 2011 (GCLLSG CLL2M r/r) | 2006-2007 | Phase 2 | ||
Michallet et al. 2018 (MABLE) | 2010-2014 | Phase 3b (E-switch-ic) | R-Clb | Superior CR rate1 (primary endpoint) |
Chanan-Khan et al. 2015 (HELIOS) | 2012-2014 | Phase 3 (C) | BR & Ibrutinib | Inferior OS2 |
Zelenetz et al. 2017 (Tugela) | 2012-2014 | Phase 3 (C) | BR & Idelalisib | Inferior PFS |
Seymour et al. 2018 (MURANO) | 2014-03-31 to 2015-09-23 | Phase 3 (C) | Venetoclax & Rituximab | Inferior OS |
Ghia et al. 2020 (ASCEND) | 2017-02-21 to 2018-01-17 | Phase 3 (C) | Acalabrutinib | Inferior PFS |
Awaiting publication (BRUIN CLL-321) | 2021-2024 | Phase 3 (C) | Pirtobrutinib | TBD if different primary endpoint of PFS |
1Reported efficacy for MABLE is for 2L patients only.
2Reported efficacy for HELIOS is based on the 2020 update.
Prior treatment criteria
- ASCEND: At least 1 prior systemic therapy
Chemotherapy
- Bendamustine 70 mg/m2 IV once per day on days 1 & 2
- HELIOS gave 1st cycle on days 2 & 3
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 0
- HELIOS gave on day 1
- Cycles 2 to 6: 500 mg/m2 IV once on day 1
- Cycle 1: 375 mg/m2 IV once on day 0
28-day cycle for up to 6 cycles
References
- GCLLSG CLL2M r/r: Fischer K, Cramer P, Busch R, Stilgenbauer S, Bahlo J, Schweighofer CD, Böttcher S, Staib P, Kiehl M, Eckart MJ, Kranz G, Goede V, Elter T, Bühler A, Winkler D, Kneba M, Döhner H, Eichhorst BF, Hallek M, Wendtner CM; GCLLSG. Bendamustine combined with rituximab in patients with relapsed and/or refractory chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. 2011 Sep 10;29(26):3559-66. Epub 2011 Aug 15. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00274989
- Retrospective: Kolibaba KS, Sterchele JA, Joshi AD, Forsyth M, Alwon E, Beygi H, Kennealey GT. Demographics, treatment patterns, safety, and real-world effectiveness in patients aged 70 years and over with chronic lymphocytic leukemia receiving bendamustine with or without rituximab: a retrospective study. Ther Adv Hematol. 2013 Jun;4(3):157-71. link to PMC article PubMed
- HELIOS: Chanan-Khan A, Cramer P, Demirkan F, Fraser G, Silva RS, Grosicki S, Pristupa A, Janssens A, Mayer J, Bartlett NL, Dilhuydy MS, Pylypenko H, Loscertales J, Avigdor A, Rule S, Villa D, Samoilova O, Panagiotidis P, Goy A, Mato A, Pavlovsky MA, Karlsson C, Mahler M, Salman M, Sun S, Phelps C, Balasubramanian S, Howes A, Hallek M; HELIOS investigators. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol. 2016 Feb;17(2):200-11. Epub 2015 Dec 5. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01611090
- Update: Fraser G, Cramer P, Demirkan F, Silva RS, Grosicki S, Pristupa A, Janssens A, Mayer J, Bartlett NL, Dilhuydy MS, Pylypenko H, Loscertales J, Avigdor A, Rule S, Villa D, Samoilova O, Panagiotidis P, Goy A, Pavlovsky MA, Karlsson C, Hallek M, Mahler M, Salman M, Sun S, Phelps C, Balasubramanian S, Howes A, Chanan-Khan A. Updated results from the phase 3 HELIOS study of ibrutinib, bendamustine, and rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma. Leukemia. 2019 Apr;33(4):969-980. Epub 2018 Oct 12. link to original article link to PMC article PubMed
- Update: Fraser GAM, Chanan-Khan A, Demirkan F, Santucci Silva R, Grosicki S, Janssens A, Mayer J, Bartlett NL, Dilhuydy MS, Loscertales J, Avigdor A, Rule S, Samoilova O, Pavlovsky MA, Goy A, Mato A, Hallek M, Salman M, Tamegnon M, Sun S, Connor A, Nottage K, Schuier N, Balasubramanian S, Howes A, Cramer P. Final 5-year findings from the phase 3 HELIOS study of ibrutinib plus bendamustine and rituximab in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Leuk Lymphoma. 2020 Dec;61(13):3188-3197. Epub 2020 Aug 6. link to original article link to PMC article PubMed
- Tugela: Zelenetz AD, Barrientos JC, Brown JR, Coiffier B, Delgado J, Egyed M, Ghia P, Illés Á, Jurczak W, Marlton P, Montillo M, Morschhauser F, Pristupa AS, Robak T, Sharman JP, Simpson D, Smolej L, Tausch E, Adewoye AH, Dreiling LK, Kim Y, Stilgenbauer S, Hillmen P. Idelalisib or placebo in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia: interim results from a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2017 Mar;18(3):297-311. Epub 2017 Jan 28. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT01569295
- MABLE: Michallet AS, Aktan M, Hiddemann W, Ilhan O, Johansson P, Laribi K, Meddeb B, Moreno C, Raposo J, Schuh A, Ünal A, Widenius T, Bernhardt A, Kellershohn K, Messeri D, Osborne S, Leblond V. Rituximab plus bendamustine or chlorambucil for chronic lymphocytic leukemia: primary analysis of the randomized, open-label MABLE study. Haematologica. 2018 Apr;103(4):698-706. Epub 2018 Feb 1. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01056510
- MURANO: Seymour JF, Kipps TJ, Eichhorst B, Hillmen P, D'Rozario J, Assouline S, Owen C, Gerecitano J, Robak T, De la Serna J, Jaeger U, Cartron G, Montillo M, Humerickhouse R, Punnoose EA, Li Y, Boyer M, Humphrey K, Mobasher M, Kater AP. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018 Mar 22;378(12):1107-1120. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT02005471
- Update: Kater AP, Seymour JF, Hillmen P, Eichhorst B, Langerak AW, Owen C, Verdugo M, Wu J, Punnoose EA, Jiang Y, Wang J, Boyer M, Humphrey K, Mobasher M, Kipps TJ. Fixed duration of venetoclax-rituximab in relapsed/refractory chronic lymphocytic leukemia eradicates minimal residual disease and prolongs survival: post-treatment follow-up of the MURANO phase III study. J Clin Oncol. 2019 Feb 1;37(4):269-277. Epub 2018 Dec 3. link to original article PubMed
- Update: Kater AP, Wu JQ, Kipps T, Eichhorst B, Hillmen P, D'Rozario J, Assouline S, Owen C, Robak T, de la Serna J, Jaeger U, Cartron G, Montillo M, Dubois J, Eldering E, Mellink C, Van Der Kevie-Kersemaekers AM, Kim SY, Chyla B, Punnoose E, Bolen CR, Assaf ZJ, Jiang Y, Wang J, Lefebure M, Boyer M, Humphrey K, Seymour JF. Venetoclax Plus Rituximab in Relapsed Chronic Lymphocytic Leukemia: 4-Year Results and Evaluation of Impact of Genomic Complexity and Gene Mutations From the MURANO Phase III Study. J Clin Oncol. 2020 Dec 1;38(34):4042-4054. Epub 2020 Sep 28. link to original article link to PMC article PubMed
- Update: Seymour JF, Kipps TJ, Eichhorst BF, D'Rozario J, Owen CJ, Assouline S, Lamanna N, Robak T, de la Serna J, Jaeger U, Cartron G, Montillo M, Mellink C, Chyla B, Panchal A, Lu T, Wu JQ, Jiang Y, Lefebure M, Boyer M, Kater AP. Enduring undetectable MRD and updated outcomes in relapsed/refractory CLL after fixed-duration venetoclax-rituximab. Blood. 2022 Aug 25;140(8):839-850. link to original article link to PMC article PubMed
- ASCEND: Ghia P, Pluta A, Wach M, Lysak D, Kozak T, Simkovic M, Kaplan P, Kraychok I, Illes A, de la Serna J, Dolan S, Campbell P, Musuraca G, Jacob A, Avery E, Lee JH, Liang W, Patel P, Quah C, Jurczak W. ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. J Clin Oncol. 2020 Sep 1;38(25):2849-2861. Epub 2020 May 27. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT02970318
- BRUIN CLL-321: NCT04666038
Bendamustine & Rituximab (BR) & Ibrutinib
BR & Ibrutinib: Bendamustine, Rituximab, Ibrutinib
IBR: Ibrutinib, Bendamustine, Rituximab
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Brown et al. 2015 (PCYC-1108) | 2011 to not reported | Phase 2 | ||
Chanan-Khan et al. 2015 (HELIOS) | 2012-2014 | Phase 3 (E-RT-esc) | BR | Superior PFS (primary endpoint) Median PFS: NYR vs 13.3 mo (HR 0.20, 95% CI 0.15-0.28) Superior OS1 (secondary endpoint) Median OS: NYR vs NYR (HR 0.61, 95% CI 0.455-0.82) |
1Reported efficacy for HELIOS is based on the 2020 update.
Note: PCYC-1108 also evaluated FCR-ibrutinib (non-randomized) but accrual to that arm was extremely low and it was prematurely discontinued.
Chemotherapy
- Bendamustine as follows:
- Cycles 1 to 6: 70 mg/m2 IV once per day on days 1 & 2
- HELIOS gave 1st cycle on days 2 & 3
- Cycles 1 to 6: 70 mg/m2 IV once per day on days 1 & 2
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 1
- PCYC-1108 gave the option of splitting the dose between days 1 & 2
- Cycles 2 to 6: 500 mg/m2 IV once on day 1
- Cycle 1: 375 mg/m2 IV once on day 1
- Ibrutinib (Imbruvica) 420 mg PO once per day on days 1 to 28
28-day cycles
References
- PCYC-1108: Brown JR, Barrientos JC, Barr PM, Flinn IW, Burger JA, Tran A, Clow F, James DF, Graef T, Friedberg JW, Rai K, O'Brien S. The Bruton tyrosine kinase inhibitor ibrutinib with chemoimmunotherapy in patients with chronic lymphocytic leukemia. Blood. 2015 May 7;125(19):2915-22. Epub 2015 Mar 9. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01292135
- HELIOS: Chanan-Khan A, Cramer P, Demirkan F, Fraser G, Silva RS, Grosicki S, Pristupa A, Janssens A, Mayer J, Bartlett NL, Dilhuydy MS, Pylypenko H, Loscertales J, Avigdor A, Rule S, Villa D, Samoilova O, Panagiotidis P, Goy A, Mato A, Pavlovsky MA, Karlsson C, Mahler M, Salman M, Sun S, Phelps C, Balasubramanian S, Howes A, Hallek M; HELIOS investigators. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol. 2016 Feb;17(2):200-11. Epub 2015 Dec 5. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01611090
- Update: Fraser G, Cramer P, Demirkan F, Silva RS, Grosicki S, Pristupa A, Janssens A, Mayer J, Bartlett NL, Dilhuydy MS, Pylypenko H, Loscertales J, Avigdor A, Rule S, Villa D, Samoilova O, Panagiotidis P, Goy A, Pavlovsky MA, Karlsson C, Hallek M, Mahler M, Salman M, Sun S, Phelps C, Balasubramanian S, Howes A, Chanan-Khan A. Updated results from the phase 3 HELIOS study of ibrutinib, bendamustine, and rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma. Leukemia. 2019 Apr;33(4):969-980. Epub 2018 Oct 12. link to original article link to PMC article PubMed
- Update: Fraser GAM, Chanan-Khan A, Demirkan F, Santucci Silva R, Grosicki S, Janssens A, Mayer J, Bartlett NL, Dilhuydy MS, Loscertales J, Avigdor A, Rule S, Samoilova O, Pavlovsky MA, Goy A, Mato A, Hallek M, Salman M, Tamegnon M, Sun S, Connor A, Nottage K, Schuier N, Balasubramanian S, Howes A, Cramer P. Final 5-year findings from the phase 3 HELIOS study of ibrutinib plus bendamustine and rituximab in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Leuk Lymphoma. 2020 Dec;61(13):3188-3197. Epub 2020 Aug 6. link to original article link to PMC article PubMed
Bendamustine & Rituximab (BR) & Idelalisib
BR & Idelalisib: Bendamustine, Rituximab, Idelalisib
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Zelenetz et al. 2017 (Tugela) | 2012-2014 | Phase 3 (E-esc) | BR | Superior PFS (primary endpoint) Median PFS: 20.8 vs 11.1 mo (HR 0.33, 95% CI 0.25-0.44) |
Chemotherapy
- Bendamustine as follows:
- Cycles 1 to 6: 70 mg/m2 IV once per day on days 1 & 2
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 0
- Cycles 2 to 6: 500 mg/m2 IV once on day 1
- Idelalisib (Zydelig) 150 mg PO twice per day on days 1 to 28
28-day cycles
References
- Tugela: Zelenetz AD, Barrientos JC, Brown JR, Coiffier B, Delgado J, Egyed M, Ghia P, Illés Á, Jurczak W, Marlton P, Montillo M, Morschhauser F, Pristupa AS, Robak T, Sharman JP, Simpson D, Smolej L, Tausch E, Adewoye AH, Dreiling LK, Kim Y, Stilgenbauer S, Hillmen P. Idelalisib or placebo in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia: interim results from a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2017 Mar;18(3):297-311. Epub 2017 Jan 28. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01569295
Duvelisib monotherapy
Regimen
FDA-recommended dose |
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Flinn et al. 2018 (DUO) | 2014-01-21 to 2015-12-09 | Phase 3 (E-RT-switch-ooc) | Ofatumumab | Superior PFS (primary endpoint) Median PFS: 13.3 vs 9.9 mo (HR 0.52) |
References
- DUO: Flinn IW, Hillmen P, Montillo M, Nagy Z, Illés Á, Etienne G, Delgado J, Kuss BJ, Tam CS, Gasztonyi Z, Offner F, Lunin S, Bosch F, Davids MS, Lamanna N, Jaeger U, Ghia P, Cymbalista F, Portell CA, Skarbnik AP, Cashen AF, Weaver DT, Kelly VM, Turnbull B, Stilgenbauer S. The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL. Blood. 2018 Dec 6;132(23):2446-2455. Epub 2018 Oct 4. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT02004522
FCR
FCR: Fludarabine, Cyclophosphamide, Rituximab
R-FC: Rituximab, Fludarabine, Cyclophosphamide
Regimen variant #1
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Awan et al. 2014 (LUCID) | 2006 to not reported | Phase 3 (C) | FCR+L | Did not meet primary endpoint of CR rate |
Chemotherapy
- Fludarabine (Fludara) as follows:
- Cycle 1: 25 mg/m2 IV over at least 10 to 30 minutes once per day on days 2 to 4
- Cycles 2 to 6: 25 mg/m2 IV over at least 10 to 30 minutes once per day on days 1 to 3
- Cyclophosphamide (Cytoxan) as follows:
- Cycle 1: 250 mg/m2 IV over at least 10 to 30 minutes once per day on days 2 to 4
- Cycles 2 to 6: 250 mg/m2 IV over at least 10 to 30 minutes once per day on days 1 to 3
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 50 mg/m2 IV over 4 hours once on day 1, then 450 mg/m2 IV once on day 3
- Cycles 2 to 6: 500 mg/m2 IV once on day 1
Supportive therapy
- Cotrimoxazole or an equivalent
- Acyclovir (Zovirax) 400 mg PO twice per day or equivalent
28-day cycle for 6 cycles
Regimen variant #2
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Robak et al. 2010 (REACH) | 2003-2007 | Phase 3 (E-RT-esc) | FC | Superior PFS (primary endpoint) Median PFS: 30.6 vs 20.6 mo (HR 0.65) |
Chemotherapy
- Fludarabine (Fludara) as follows:
- Cycle 1: 25 mg/m2 IV once per day on days 2 to 4
- Cycles 2 to 6: 25 mg/m2 IV once per day on days 1 to 3
- Cyclophosphamide (Cytoxan) as follows:
- Cycle 1: 250 mg/m2 IV once per day on days 2 to 4
- Cycles 2 to 6: 250 mg/m2 IV once per day on days 1 to 3
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 1
- Cycles 2 to 6: 500 mg/m2 IV once on day 1
Supportive therapy
- Note: varied according to reference.
- Diphenhydramine (Benadryl) 25 mg IV once on day 1; 30 minutes prior to rituximab
- Acetaminophen (Tylenol) 650 mg PO once on day 1; 30 minutes prior to rituximab
- Allopurinol (Zyloprim) as follows:
- Cycle 1: 300 mg PO once per day on days 1 to 7
- Some patients received:
- Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg PO twice per week
- Valacyclovir (Valtrex) 500 mg PO once per day
28-day cycle for 6 cycles
Regimen variant #3
Study | Dates of enrollment | Evidence |
---|---|---|
Wierda et al. 2005 | 1999-2001 | Phase 2 |
Chemotherapy
- Fludarabine (Fludara) as follows:
- Cycle 1: 25 mg/m2 IV once per day on days 2 to 4
- Cycles 2 to 6: 25 mg/m2 IV once per day on days 1 to 3
- Cyclophosphamide (Cytoxan) as follows:
- Cycle 1: 250 mg/m2 IV once per day on days 2 to 4
- Cycles 2 to 6: 250 mg/m2 IV once per day on days 1 to 3
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 1
- Cycles 2 to 6: 500 mg/m2 IV once on day 1
Supportive therapy
- Diphenhydramine (Benadryl) 25 to 50 mg PO once on day 1, prior to rituximab
- Acetaminophen (Tylenol) 650 mg PO once on day 1, prior to rituximab
- Ondansetron (Zofran) 24 mg IV once, prior to chemotherapy
28-day cycle for up to 6 cycles
Regimen variant #4
Study | Dates of enrollment | Evidence |
---|---|---|
Tam et al. 2006 | 2000-2005 | Phase 2 |
Chemotherapy
- Fludarabine (Fludara) 25 mg/m2 IV over 15 to 30 minutes once per day on days 1 to 3
- Cyclophosphamide (Cytoxan) 250 mg/m2 IV over 15 to 30 minutes once per day on days 1 to 3
Targeted therapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
28-day cycle for up to 6 cycles or "attainment of maximum response"
References
- Wierda W, O'Brien S, Wen S, Faderl S, Garcia-Manero G, Thomas D, Do KA, Cortes J, Koller C, Beran M, Ferrajoli A, Giles F, Lerner S, Albitar M, Kantarjian H, Keating M. Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. J Clin Oncol. 2005 Jun 20;23(18):4070-8. Epub 2005 Mar 14. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Update: Badoux XC, Keating MJ, Wang X, O'Brien SM, Ferrajoli A, Faderl S, Burger J, Koller C, Lerner S, Kantarjian H, Wierda WG. Fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy is highly effective treatment for relapsed patients with CLL. Blood. 2011 Mar 17;117(11):3016-24. Epub 2011 Jan 18. link to original article link to PMC article PubMed
- Tam CS, Wolf M, Prince HM, Januszewicz EH, Westerman D, Lin KI, Carney D, Seymour JF. Fludarabine, cyclophosphamide, and rituximab for the treatment of patients with chronic lymphocytic leukemia or indolent non-Hodgkin lymphoma. Cancer. 2006 Jun 1;106(11):2412-20. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- REACH: Robak T, Dmoszynska A, Solal-Céligny P, Warzocha K, Loscertales J, Catalano J, Afanasiev BV, Larratt L, Geisler CH, Montillo M, Zyuzgin I, Ganly PS, Dartigeas C, Rosta A, Maurer J, Mendila M, Saville MW, Valente N, Wenger MK, Moiseev SI. Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia. J Clin Oncol. 2010 Apr 1;28(10):1756-65. Epub 2010 Mar 1. link to original article dosing details in manuscript have been reviewed by our editors PubMed content property of HemOnc.org NCT00090051
- LUCID: Awan FT, Hillmen P, Hellmann A, Robak T, Hughes SG, Trone D, Shannon M, Flinn IW, Byrd JC; LUCID trial investigators. A randomized, open-label, multicentre, phase 2/3 study to evaluate the safety and efficacy of lumiliximab in combination with fludarabine, cyclophosphamide and rituximab versus fludarabine, cyclophosphamide and rituximab alone in subjects with relapsed chronic lymphocytic leukaemia. Br J Haematol. 2014 Nov;167(4):466-77. Epub 2014 Aug 8. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00391066
Fludarabine monotherapy
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Johnson et al. 1996 | 1990-1992 | Phase 3 (E-de-esc) | CAP | Seems to have superior ORR |
Niederle et al. 2013 (WiSP RI05) | 2001-2006 | Phase 3 (C) | Bendamustine | Seems to have non-inferior PFS |
Note: This was an experimental arm that did not meet its primary endpoint; included here because it was eventually used to establish this regimen as a standard comparator.
Chemotherapy
- Fludarabine (Fludara) 25 mg/m2 IV once per day on days 1 to 5
28-day cycle for varying durations: 6 to 10 cycles (Johnson et al. 1996); 8 cycles (WiSP RI05)
References
- Johnson S, Smith AG, Löffler H, Osby E, Juliusson G, Emmerich B, Wyld PJ, Hiddemann W; FRE-CLL. Multicentre prospective randomised trial of fludarabine versus cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of advanced-stage chronic lymphocytic leukaemia. Lancet. 1996 May 25;347(9013):1432-8. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- WiSP RI05: Niederle N, Megdenberg D, Balleisen L, Heit W, Knauf W, Weiß J, Freier W, Hinke A, Ibach S, Eimermacher H. Bendamustine compared to fludarabine as second-line treatment in chronic lymphocytic leukemia. Ann Hematol. 2013 May;92(5):653-60. Epub 2013 Jan 23. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01423032
Ibrutinib monotherapy
Regimen
FDA-recommended dose |
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Byrd et al. 2013 (PCYC-1102 relapsed) | 2010-2011 | Phase 2 (RT) | ||
Farooqui et al. 2014 (NHLBI 12-H-0035) | 2011-2014 | Phase 2, fewer than 20 pts | ||
Byrd et al. 2014 (RESONATE) | 2012-06 to 2013-04 | Phase 3 (E-RT-switch-ooc) | Ofatumumab | Superior PFS1 (primary endpoint) Median PFS: 44.1 vs 8.1 mo (HR 0.15, 95% CI 0.11-0.20) |
O'Brien et al. 2016 (RESONATE-17) | 2013 | Phase 2 | ||
Huang et al. 2018 (CR102604) | 2013-2015 | Phase 3 (E-switch-ooc) | Rituximab | Superior PFS (primary endpoint) PFS18: 74% vs 11.9% (HR 0.18, 95% CI 0.105-0.31) Superior OS (secondary endpoint) OS24: 79.8% vs 57.6% (HR 0.45, 95% CI 0.22-0.90) |
Sharman et al. 2021 (GENUINE) | 2015-02-06 to 2016-12-19 | Phase 3 (C) | Ibrutinib & Ublituximab | Seems to have inferior ORR |
Byrd et al. 2021 (ACE-CL-006) | 2015-2017 | Phase 3 (C) | Acalabrutinib | Non-inferior PFS |
Hillmen et al. 2022 (ALPINE) | 2018-2020 | Phase 3 (C) | Zanubrutinib | Inferior PFS2 |
1Reported efficacy for RESONATE is based on the second 2019 update.
2Reported efficacy for ALPINE is based on the 2022 update.
Note: Both 420 mg and 840 mg doses were investigated in PCYC-1102: "the similar response in the two dose groups provide support for the use of the 420-mg dose of ibrutinib for relapsed CLL." The others used the 420 mg dose.
Biomarker eligibility criteria
- RESONATE-17: 17p deletion
- GENUINE: 17p deletion, 11q deletion, or TP53 mutation
- ACE-CL-006: del(17)(p13.1) or del(11)(q22.3)
Prior treatment criteria
- ACE-CL-006 & ALPINE: At least 1 prior systemic therapy
References
- PCYC-1102 relapsed: Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, Grant B, Sharman JP, Coleman M, Wierda WG, Jones JA, Zhao W, Heerema NA, Johnson AJ, Sukbuntherng J, Chang BY, Clow F, Hedrick E, Buggy JJ, James DF, O'Brien S. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013 Jul 4;369(1):32-42. Epub 2013 Jun 19. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01105247
- Update: Byrd JC, Furman RR, Coutre SE, Burger JA, Blum KA, Coleman M, Wierda WG, Jones JA, Zhao W, Heerema NA, Johnson AJ, Shaw Y, Bilotti E, Zhou C, James DF, O'Brien S. Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015 Apr 16;125(16):2497-506. Epub 2015 Feb 19. link to original article link to PMC article PubMed
- Update: O'Brien S, Furman RR, Coutre S, Flinn IW, Burger JA, Blum K, Sharman J, Wierda W, Jones J, Zhao W, Heerema NA, Johnson AJ, Luan Y, James DF, Chu AD, Byrd JC. Single-agent ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. Blood. 2018 Apr 26;131(17):1910-1919. Epub 2018 Feb 2. link to original article link to PMC article PubMed
- Update: Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum K, Sharman JP, Wierda W, Zhao W, Heerema NA, Luan Y, Liu EA, Dean JP, O'Brien S. Ibrutinib Treatment for First-Line and Relapsed/Refractory Chronic Lymphocytic Leukemia: Final Analysis of the Pivotal Phase Ib/II PCYC-1102 Study. Clin Cancer Res. 2020 Aug 1;26(15):3918-3927. Epub 2020 Mar 24. link to original article link to PMC article PubMed
- RESONATE: Byrd JC, Brown JR, O'Brien S, Barrientos JC, Kay NE, Reddy NM, Coutre S, Tam CS, Mulligan SP, Jaeger U, Devereux S, Barr PM, Furman RR, Kipps TJ, Cymbalista F, Pocock C, Thornton P, Caligaris-Cappio F, Robak T, Delgado J, Schuster SJ, Montillo M, Schuh A, de Vos S, Gill D, Bloor A, Dearden C, Moreno C, Jones JJ, Chu AD, Fardis M, McGreivy J, Clow F, James DF, Hillmen P; the RESONATE Investigators. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014 Jul 17;371(3):213-23. Epub 2014 May 31. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01578707
- Update: Brown JR, Hillmen P, O'Brien S, Barrientos JC, Reddy NM, Coutre SE, Tam CS, Mulligan SP, Jaeger U, Barr PM, Furman RR, Kipps TJ, Cymbalista F, Thornton P, Caligaris-Cappio F, Delgado J, Montillo M, De Vos S, Moreno C, Pagel JM, Munir T, Burger JA, Chung D, Lin J, Gau L, Chang B, Cole G, Hsu E, James DF, Byrd JC. Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL. Leukemia. 2018 Jan;32(1):83-91. Epub 2017 Jun 8. link to original article link to PMC article PubMed
- Update: Byrd JC, Hillmen P, O'Brien S, Barrientos JC, Reddy NM, Coutre S, Tam CS, Mulligan SP, Jaeger U, Barr PM, Furman RR, Kipps TJ, Thornton P, Moreno C, Montillo M, Pagel JM, Burger JA, Woyach JA, Dai S, Vezan R, James DF, Brown JR. Long-term follow-up of the RESONATE phase 3 trial of ibrutinib vs ofatumumab. Blood. 2019 May 9;133(19):2031-2042. Epub 2019 Mar 6. link to original article link to PMC article PubMed
- Update: Munir T, Brown JR, O'Brien S, Barrientos JC, Barr PM, Reddy NM, Coutre S, Tam CS, Mulligan SP, Jaeger U, Kipps TJ, Moreno C, Montillo M, Burger JA, Byrd JC, Hillmen P, Dai S, Szoke A, Dean JP, Woyach JA. Final analysis from RESONATE: Up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma. Am J Hematol. 2019 Dec;94(12):1353-1363. Epub 2019 Oct 13. link to original article link to PMC article PubMed
- NHLBI 12-H-0035: Farooqui MZ, Valdez J, Martyr S, Aue G, Saba N, Niemann CU, Herman SE, Tian X, Marti G, Soto S, Hughes TE, Jones J, Lipsky A, Pittaluga S, Stetler-Stevenson M, Yuan C, Lee YS, Pedersen LB, Geisler CH, Calvo KR, Arthur DC, Maric I, Childs R, Young NS, Wiestner A. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol. 2015 Feb;16(2):169-76. Epub 2014 Dec 31. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01500733
- RESONATE-17: O'Brien S, Jones JA, Coutre SE, Mato AR, Hillmen P, Tam C, Österborg A, Siddiqi T, Thirman MJ, Furman RR, Ilhan O, Keating MJ, Call TG, Brown JR, Stevens-Brogan M, Li Y, Clow F, James DF, Chu AD, Hallek M, Stilgenbauer S. Ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia with 17p deletion (RESONATE-17): a phase 2, open-label, multicentre study. Lancet Oncol. 2016 Oct;17(10):1409-1418. Epub 2016 Sep 13. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT01744691
- Retrospective: Ryan CE, Sahaf B, Logan AC, O'Brien S, Byrd JC, Hillmen P, Brown JR, Dyer MJ, Mato AR, Keating MJ, Jaglowski S, Clow F, Rezvani AR, Styles L, Coutre SE, Miklos DB. Ibrutinib efficacy and tolerability in patients with relapsed chronic lymphocytic leukemia following allogeneic HCT. Blood. 2016 Dec 22;128(25):2899-2908. link to original article link to PMC article PubMed
- CR102604: Huang X, Qiu L, Jin J, Zhou D, Chen X, Hou M, Hu J, Hu Y, Ke X, Li J, Liang Y, Liu T, Lv Y, Ren H, Sun A, Wang J, Zhao C, Salman M, Sun S, Howes A, Wang J, Wu P, Li J. Ibrutinib versus rituximab in relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma: a randomized, open-label phase 3 study. Cancer Med. 2018 Apr;7(4):1043-1055. Epub 2018 Mar 13. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01973387
- GENUINE: Sharman JP, Brander DM, Mato AR, Ghosh N, Schuster SJ, Kambhampati S, Burke JM, Lansigan F, Schreeder MT, Lunin SD, Zweibach A, Shtivelband M, Travis PM, Chandler JC, Kolibaba KS, Sportelli P, Miskin HP, Weiss MS, Flinn IW. Ublituximab plus ibrutinib versus ibrutinib alone for patients with relapsed or refractory high-risk chronic lymphocytic leukaemia (GENUINE): a phase 3, multicentre, open-label, randomised trial. Lancet Haematol. 2021 Apr;8(4):e254-e266. Epub 2021 Feb 22. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT02301156
- ACE-CL-006: Byrd JC, Hillmen P, Ghia P, Kater AP, Chanan-Khan A, Furman RR, O'Brien S, Yenerel MN, Illés A, Kay N, Garcia-Marco JA, Mato A, Pinilla-Ibarz J, Seymour JF, Lepretre S, Stilgenbauer S, Robak T, Rothbaum W, Izumi R, Hamdy A, Patel P, Higgins K, Sohoni S, Jurczak W. Acalabrutinib Versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia: Results of the First Randomized Phase III Trial. J Clin Oncol. 2021 Nov 1;39(31):3441-3452. Epub 2021 Jul 26. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT02477696
- ALPINE: Hillmen P, Eichhorst B, Brown JR, Lamanna N, O'Brien SM, Tam CS, Qiu L, Kazmierczak M, Zhou K, Šimkovič M, Mayer J, Gillespie-Twardy A, Shadman M, Ferrajoli A, Ganly PS, Weinkove R, Grosicki S, Mital A, Robak T, Österborg A, Yimer HA, Salmi T, Ji M, Yecies J, Idoine A, Wu K, Huang J, Jurczak W. Zanubrutinib Versus Ibrutinib in Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma: Interim Analysis of a Randomized Phase III Trial. J Clin Oncol. 2023 Feb 10;41(5):1035-1045. Epub 2022 Nov 17. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT03734016
- Update: Brown JR, Eichhorst B, Hillmen P, Jurczak W, Kaźmierczak M, Lamanna N, O'Brien SM, Tam CS, Qiu L, Zhou K, Simkovic M, Mayer J, Gillespie-Twardy A, Ferrajoli A, Ganly PS, Weinkove R, Grosicki S, Mital A, Robak T, Osterborg A, Yimer HA, Salmi T, Wang MD, Fu L, Li J, Wu K, Cohen A, Shadman M. Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. N Engl J Med. 2023 Jan 26;388(4):319-332. Epub 2022 Dec 13. link to original article PubMed
- HRQoL analysis: Tam CS, Lamanna N, O'Brien SM, Qiu L, Yang K, Barnes G, Wu K, Salmi T, Brown JR. Health-related quality of life outcomes associated with zanubrutinib versus ibrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma: results from the ALPINE Trial. Curr Med Res Opin. 2023 Nov;39(11):1497-1503. Epub 2023 Oct 27. link to original article PubMed
Ibrutinib & Ublituximab
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Sharman et al. 2021 (GENUINE) | 2015-02-06 to 2016-12-19 | Phase 3 (E-esc) | Ibrutinib | Seems to have superior ORR (primary endpoint) |
Biomarker eligibility criteria
- 17p deletion, 11q deletion, or TP53 mutation
Targeted therapy
- Ibrutinib (Imbruvica) 420 mg PO once per day on days 1 to 28
- Ublituximab (Briumvi) as follows:
- Cycle 1: 150 mg IV over 4 hours once on day 1, then 750 mg IV over 4 hours once on day 2, then 900 mg IV over 3 hours once per day on days 8 & 15
- Cycles 2 to 5: 900 mg IV over 90 minutes once on day 1
- Cycle 6 onwards: 900 mg IV once on day 1
28-day cycle for 5 cycles, then 12-week cycles
References
- GENUINE: Sharman JP, Brander DM, Mato AR, Ghosh N, Schuster SJ, Kambhampati S, Burke JM, Lansigan F, Schreeder MT, Lunin SD, Zweibach A, Shtivelband M, Travis PM, Chandler JC, Kolibaba KS, Sportelli P, Miskin HP, Weiss MS, Flinn IW. Ublituximab plus ibrutinib versus ibrutinib alone for patients with relapsed or refractory high-risk chronic lymphocytic leukaemia (GENUINE): a phase 3, multicentre, open-label, randomised trial. Lancet Haematol. 2021 Apr;8(4):e254-e266. Epub 2021 Feb 22. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT02301156
Idelalisib & Ofatumumab
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Jones et al. 2017 (GS-US-312-0119) | 2012-2014 | Phase 3 (E-esc) | Ofatumumab | Superior PFS (primary endpoint) Median PFS: 16.3 vs 8 mo (HR 0.27, 95% CI 0.19-0.39) |
Targeted therapy
- Idelalisib (Zydelig) 150 mg PO twice per day
- Ofatumumab (Arzerra) as follows:
- Cycle 1: 300 mg IV once on day 1, then 1000 mg IV once per day on days 8, 15, 22
- Cycle 2: 1000 mg IV once per day on days 1, 8, 15, 22
- Cycles 3 to 6: 1000 mg IV once on day 1
28-day cycle for 6 cycles
References
- GS-US-312-0119: Jones JA, Robak T, Brown JR, Awan FT, Badoux X, Coutre S, Loscertales J, Taylor K, Vandenberghe E, Wach M, Wagner-Johnston N, Ysebaert L, Dreiling L, Dubowy R, Xing G, Flinn IW, Owen C. Efficacy and safety of idelalisib in combination with ofatumumab for previously treated chronic lymphocytic leukaemia: an open-label, randomised phase 3 trial. Lancet Haematol. 2017 Mar;4(3):e114-e126. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01659021
Idelalisib & Rituximab
IdelaR: Idelalisib & Rituximab
Regimen variant #1, finite duration
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Furman et al. 2014 (GS-US-312-0116) | 2012-05 to 2013-08 | Phase 3 (E-RT-esc) | Rituximab | Superior PFS (primary endpoint) PFS6: 93% vs 46% (aHR 0.15, 95% CI 0.08-0.28) |
Note: Upon progression, idelalisib can be increased to 300 mg PO twice per day.
Targeted therapy
- Idelalisib (Zydelig) 150 mg PO twice per day on days 1 to 28
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 1, then 500 mg/m2 IV once on day 15
- Cycle 2: 500 mg/m2 IV once per day on days 1 & 15
- Cycles 3 to 6: 500 mg/m2 IV once on day 1
28-day cycle for up to 18 cycles
Regimen variant #2, indefinite
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Ghia et al. 2020 (ASCEND) | 2017-02-21 to 2018-01-17 | Phase 3 (C) | Acalabrutinib | Inferior PFS |
Prior treatment criteria
- ASCEND: At least 1 prior systemic therapy
Targeted therapy
- Idelalisib (Zydelig) 150 mg PO twice per day on days 1 to 28
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 15
- Cycles 2 to 3: 500 mg/m2 IV once per day on days 1 & 15
- Cycles 4 to 6: 500 mg/m2 IV once on day 1
28-day cycles
References
- GS-US-312-0116: Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, Barrientos JC, Zelenetz AD, Kipps TJ, Flinn I, Ghia P, Eradat H, Ervin T, Lamanna N, Coiffier B, Pettitt AR, Ma S, Stilgenbauer S, Cramer P, Aiello M, Johnson DM, Miller LL, Li D, Jahn TM, Dansey RD, Hallek M, O'Brien SM. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014 Mar 13;370(11):997-1007. Epub 2014 Jan 22. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01539512
- Update: Sharman JP, Coutre SE, Furman RR, Cheson BD, Pagel JM, Hillmen P, Barrientos JC, Zelenetz AD, Kipps TJ, Flinn IW, Ghia P, Eradat H, Ervin T, Lamanna N, Coiffier B, Pettitt AR, Ma S, Tausch E, Cramer P, Huang J, Mitra S, Hallek M, O'Brien SM, Stilgenbauer S. Final results of a randomized, phase III study of rituximab with or without idelalisib followed by open-label idelalisib in patients with relapsed chronic lymphocytic leukemia. J Clin Oncol. 2019 Jun 1;37(16):1391-1402. Epub 2019 Apr 17. link to original article link to PMC article PubMed
- ASCEND: Ghia P, Pluta A, Wach M, Lysak D, Kozak T, Simkovic M, Kaplan P, Kraychok I, Illes A, de la Serna J, Dolan S, Campbell P, Musuraca G, Jacob A, Avery E, Lee JH, Liang W, Patel P, Quah C, Jurczak W. ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. J Clin Oncol. 2020 Sep 1;38(25):2849-2861. Epub 2020 May 27. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT02970318
- BRUIN CLL-321: NCT04666038
Ofatumumab monotherapy
Regimen variant #1, 2 cycles
Study | Dates of enrollment | Evidence |
---|---|---|
Österborg et al. 2015 (GEN416) | 2009-2011 | Phase 2 |
Note: Patients in this trial were fludarabine refractory and had previously received ofatumumab; this is a re-treatment trial.
Prior treatment criteria
- Fludarabine and ofatumumab exposure, with refractory disease
Targeted therapy
- Ofatumumab (Arzerra) as follows:
- Cycle 1: 300 mg IV once on day 1, then 2000 mg IV once per day on days 8, 15, 22
- Cycle 2: 2000 mg IV once per day on days 1, 8, 15, 22
Supportive therapy
- Acetaminophen (Tylenol) 1000 mg PO once per day on days 1, 8, 15, 22, prior to ofatumumab
- Cetirizine (Zyrtec) (or equivalent) 10 mg PO once per day on days 1, 8, 15, 22, prior to ofatumumab
- Prednisolone (Millipred) 100 mg (or equivalent) PO once, prior to infusions 1, 2, and 9 (question whether this was a typo), reduced or omitted if initial infusions well-tolerated
28-day cycle for 2 cycles
Subsequent treatment
- GEN416, patients with SD or better: ofatumumab maintenance
Regimen variant #2, 6 cycles
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Coiffier et al. 2007 | 2004-2006 | Phase 1/2 | ||
Wierda et al. 2010 (Hx-CD20-406) | 2006 to not reported | Phase 2 (RT) | ||
Österborg et al. 2016 (Novartis 114242) | 2011 to not reported | Phase 3 (E-switch) | Physician's choice | Did not meet primary endpoint of PFS |
Byrd et al. 2014 (RESONATE) | 2012-06 to 2013-04 | Phase 3 (C) | Ibrutinib | Inferior PFS1 |
Jones et al. 2017 (GS-US-312-0119) | 2012-2014 | Phase 3 (C) | Idelalisib & Ofatumumab | Inferior PFS |
Flinn et al. 2018 (DUO) | 2014-01-21 to 2015-12-09 | Phase 3 (C) | Duvelisib | Inferior PFS |
1Reported efficacy for RESONATE is based on the second 2019 update.
Note: this regimen is sometimes described as 300 mg IV once on day 1, then 2000 mg IV once per week for 7 weeks, then 2000 mg IV once every 4 weeks for 16 weeks. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.
Prior treatment criteria
- Hx-CD20-406 & Novartis 114242: Fludarabine exposure, with refractory disease
Targeted therapy
- Ofatumumab (Arzerra) as follows:
- Cycle 1: 300 mg IV once on day 1, then 2000 mg IV once per day on days 8, 15, 22
- Cycle 2: 2000 mg IV once per day on days 1, 8, 15, 22
- Cycles 3 to 6: 2000 mg IV once on day 1
Supportive therapy
- Prednisolone (Millipred) 100 mg (or equivalent) PO once, prior to infusions 1, 2, and 9 (question whether this was a typo), reduced to lower doses if initial infusions well-tolerated
28-day cycle for 6 cycles
Regimen variant #3, 12 cycles
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Ghia et al. 2017 (P07714) | 2012 to not reported | Phase 3 (C) | Dinaciclib | Not reported |
Note: this trial was terminated early and no statistical tests were performed; note also that cycle 3 is "skipped".
Targeted therapy
- Ofatumumab (Arzerra) as follows:
- Cycle 1: 300 mg IV once on day 1, then 2000 mg IV once per day on days 8, 15, 22
- Cycle 2: 2000 mg IV once per day on days 1, 8, 15, 22
- Cycle 3: no treatment
- Cycles 4 to 12: 2000 mg IV once on day 1
28-day cycle for 12 cycles
References
- Coiffier B, Lepretre S, Pedersen LM, Gadeberg O, Fredriksen H, van Oers MH, Wooldridge J, Kloczko J, Holowiecki J, Hellmann A, Walewski J, Flensburg M, Petersen J, Robak T. Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1-2 study. Blood. 2008 Feb 1;111(3):1094-100. Epub 2007 Nov 14. link to original article PubMed
- Hx-CD20-406: Wierda WG, Kipps TJ, Mayer J, Stilgenbauer S, Williams CD, Hellmann A, Robak T, Furman RR, Hillmen P, Trneny M, Dyer MJ, Padmanabhan S, Piotrowska M, Kozak T, Chan G, Davis R, Losic N, Wilms J, Russell CA, Osterborg A; Hx-CD20-406 Study Investigators. Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol. 2010 Apr 1;28(10):1749-55. Epub 2010 Mar 1. link to original article dosing details in abstract have been reviewed by our editors link to PMC article PubMed NCT00349349
- Subgroup analysis: Wierda WG, Padmanabhan S, Chan GW, Gupta IV, Lisby S, Osterborg A; Hx-CD20-406 Study Investigators. Ofatumumab is active in patients with fludarabine-refractory CLL irrespective of prior rituximab: results from the phase 2 international study. Blood. 2011 Nov 10;118(19):5126-9. Epub 2011 Aug 19. link to original article link to PMC article PubMed
- Update: Österborg A, Jewell RC, Padmanabhan-Iyer S, Kipps TJ, Mayer J, Stilgenbauer S, Williams CD, Hellmann A, Furman RR, Robak T, Hillmen P, Trnêný M, Dyer MJ, Piotrowska M, Kozak T, Gupta IV, Phillips JL, Goldstein N, Struemper H, Losic N, Lisby S, Wierda WG; Hx-CD20-406 Study Investigators. Ofatumumab monotherapy in fludarabine-refractory chronic lymphocytic leukemia: final results from a pivotal study. Haematologica. 2015 Aug;100(8):e311-4. Epub 2015 Mar 13. link to original article link to PMC article PubMed
- RESONATE: Byrd JC, Brown JR, O'Brien S, Barrientos JC, Kay NE, Reddy NM, Coutre S, Tam CS, Mulligan SP, Jaeger U, Devereux S, Barr PM, Furman RR, Kipps TJ, Cymbalista F, Pocock C, Thornton P, Caligaris-Cappio F, Robak T, Delgado J, Schuster SJ, Montillo M, Schuh A, de Vos S, Gill D, Bloor A, Dearden C, Moreno C, Jones JJ, Chu AD, Fardis M, McGreivy J, Clow F, James DF, Hillmen P; the RESONATE Investigators. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014 Jul 17;371(3):213-23. Epub 2014 May 31. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01578707
- Update: Brown JR, Hillmen P, O'Brien S, Barrientos JC, Reddy NM, Coutre SE, Tam CS, Mulligan SP, Jaeger U, Barr PM, Furman RR, Kipps TJ, Cymbalista F, Thornton P, Caligaris-Cappio F, Delgado J, Montillo M, De Vos S, Moreno C, Pagel JM, Munir T, Burger JA, Chung D, Lin J, Gau L, Chang B, Cole G, Hsu E, James DF, Byrd JC. Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL. Leukemia. 2018 Jan;32(1):83-91. Epub 2017 Jun 8. link to original article link to PMC article PubMed
- Update: Byrd JC, Hillmen P, O'Brien S, Barrientos JC, Reddy NM, Coutre S, Tam CS, Mulligan SP, Jaeger U, Barr PM, Furman RR, Kipps TJ, Thornton P, Moreno C, Montillo M, Pagel JM, Burger JA, Woyach JA, Dai S, Vezan R, James DF, Brown JR. Long-term follow-up of the RESONATE phase 3 trial of ibrutinib vs ofatumumab. Blood. 2019 May 9;133(19):2031-2042. Epub 2019 Mar 6. link to original article link to PMC article PubMed
- Update: Munir T, Brown JR, O'Brien S, Barrientos JC, Barr PM, Reddy NM, Coutre S, Tam CS, Mulligan SP, Jaeger U, Kipps TJ, Moreno C, Montillo M, Burger JA, Byrd JC, Hillmen P, Dai S, Szoke A, Dean JP, Woyach JA. Final analysis from RESONATE: Up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma. Am J Hematol. 2019 Dec;94(12):1353-1363. Epub 2019 Oct 13. link to original article link to PMC article PubMed
- Retrospective: Moreno C, Montillo M, Panayiotidis P, Dimou M, Bloor A, Dupuis J, Schuh A, Norin S, Geisler C, Hillmen P, Doubek M, Trněný M, Obrtlikova P, Laurenti L, Stilgenbauer S, Smolej L, Ghia P, Cymbalista F, Jaeger U, Stamatopoulos K, Stavroyianni N, Carrington P, Zouabi H, Leblond V, Gomez-Garcia JC, Rubio M, Marasca R, Musuraca G, Rigacci L, Farina L, Paolini R, Pospisilova S, Kimby E, Bradley C, Montserrat E. Ofatumumab in poor-prognosis chronic lymphocytic leukemia: a Phase 4, non--interventional, observational study from the European Research Initiative on Chronic Lymphocytic Leukemia. Haematologica. 2015 Apr;100(4):511-6. Epub 2015 Jan 16. link to original article link to PMC article PubMed
- GEN416: Österborg A, Wierda WG, Mayer J, Hess G, Hillmen P, Schetelig J, Schuh A, Smolej L, Beck C, Dreyfus B, Hellman A, Kozlowski P, Pfreundschuh M, Rizzi R, Spacek M, Phillips JL, Gupta IV, Williams V, Jewell RC, Nebot N, Lisby S, Dyer MJ. Ofatumumab retreatment and maintenance in fludarabine-refractory chronic lymphocytic leukaemia patients. Br J Haematol. 2015 Jul;170(1):40-9. Epub 2015 Mar 30. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00802737
- Novartis 114242: Österborg A, Udvardy M, Zaritskey A, Andersson PO, Grosicki S, Mazur G, Kaplan P, Steurer M, Schuh A, Montillo M, Kriachok I, Middeke JM, Kulyaba Y, Rekhtman G, Gorczyca M, Daly S, Chang CN, Lisby S, Gupta I. Phase III, randomized study of ofatumumab versus physicians' choice of therapy and standard versus extended-length ofatumumab in patients with bulky fludarabine-refractory chronic lymphocytic leukemia. Leuk Lymphoma. 2016 Sep;57(9):2037-46. Epub 2016 Jan 19. link to original articlePubMed NCT01313689
- Update: Miklos U, Strugov V, Lewerin C, Grosicki S, Mazur G, Steurer M, Montillo M, Kriachok I, Middeke JM, Rekhtman G, Stefanelli T, Vincent G, Govindaraju S, Österborg A. Five-year survival follow-up of a phase III randomised trial comparing ofatumumab versus physicians' choice for bulky fludarabine-refractory chronic lymphocytic leukaemia: a short report. Br J Haematol. 2020 May;189(4):689-693. Epub 2020 Jan 28. link to original article PubMed
- GS-US-312-0119: Jones JA, Robak T, Brown JR, Awan FT, Badoux X, Coutre S, Loscertales J, Taylor K, Vandenberghe E, Wach M, Wagner-Johnston N, Ysebaert L, Dreiling L, Dubowy R, Xing G, Flinn IW, Owen C. Efficacy and safety of idelalisib in combination with ofatumumab for previously treated chronic lymphocytic leukaemia: an open-label, randomised phase 3 trial. Lancet Haematol. 2017 Mar;4(3):e114-e126. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01659021
- P07714: Ghia P, Scarfò L, Perez S, Pathiraja K, Derosier M, Small K, McCrary Sisk C, Patton N. Efficacy and safety of dinaciclib vs ofatumumab in patients with relapsed/refractory chronic lymphocytic leukemia. Blood. 2017 Mar 30;129(13):1876-1878. Epub 2017 Jan 26. link to original article PubMed NCT01580228
- DUO: Flinn IW, Hillmen P, Montillo M, Nagy Z, Illés Á, Etienne G, Delgado J, Kuss BJ, Tam CS, Gasztonyi Z, Offner F, Lunin S, Bosch F, Davids MS, Lamanna N, Jaeger U, Ghia P, Cymbalista F, Portell CA, Skarbnik AP, Cashen AF, Weaver DT, Kelly VM, Turnbull B, Stilgenbauer S. The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL. Blood. 2018 Dec 6;132(23):2446-2455. Epub 2018 Oct 4. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT02004522
O-FC
O-FC: Ofatumumab, Fludarabine, Cyclophosphamide
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Robak et al. 2016 (COMPLEMENT 2) | 2008 to not reported | Phase 3 (E-RT-esc) | FC | Superior PFS (primary endpoint) Median PFS: 28.9 vs 18.8 mo (HR 0.67, 95% CI 0.51-0.88) |
Targeted therapy
- Ofatumumab (Arzerra) as follows:
- Cycle 1: 300 mg IV once on day 1, then 1000 mg IV once on day 8
- Cycles 2 to 6: 1000 mg IV once on day 1
Chemotherapy
- Fludarabine (Fludara) 25 mg/m2 IV once per day on days 1 to 3
- Cyclophosphamide (Cytoxan) 250 mg/m2 IV once per day on days 1 to 3
Supportive therapy
- Acetaminophen (Tylenol) 1000 mg PO once on day 1, prior to ofatumumab
- Cetirizine (Zyrtec) 10 mg (or equivalent) PO once on day 1, prior to ofatumumab
- Prednisolone (Millipred) 100 mg (or equivalent) PO once on day 1, prior to doses 1 & 2 of ofatumumab, then reduced by physician discretion for later doses
- May be used at physician discretion:
- Allopurinol (Zyloprim) for tumor lysis syndrome prophylaxis
- Antiviral prophylaxis
- PCP (Pneumocystis jiroveci pneumonia) prophylaxis
- Growth factor support
28-day cycle for 6 cycles
References
- COMPLEMENT 2: Robak T, Warzocha K, Govind Babu K, Kulyaba Y, Kuliczkowski K, Abdulkadyrov K, Loscertales J, Kriachok I, Kłoczko J, Rekhtman G, Homenda W, Błoński JZ, McKeown A, Gorczyca MM, Carey JL, Chang CN, Lisby S, Gupta IV, Grosicki S. Ofatumumab plus fludarabine and cyclophosphamide in relapsed chronic lymphocytic leukemia: results from the COMPLEMENT 2 trial. Leuk Lymphoma. 2017 May;58(5):1084-1093. Epub 2016 Oct 12. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00824265
Rituximab monotherapy
Regimen variant #1, 4-week course
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
McLaughlin et al. 1998 | 1995-1996 | Phase 2 | ||
Williams et al. 2016 (RESORT substudy) | 2003-2008 | Phase 3 (E-de-esc) | Rituximab maintenance | Seems to have inferior TTTF (primary endpoint) |
Preceding treatment
- RESORT substudy: First-line Rituximab, with progression
Regimen variant #2, 8 doses
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Furman et al. 2014 (GS-US-312-0116) | 2012-05 to 2013-08 | Phase 3 (C) | Idelalisib & Rituximab | Inferior PFS |
Note: Reported efficacy is based on the 2019 update.
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 1
- Cycles 2 to 8: 500 mg/m2 IV once on day 1
14-day cycle for 4 cycles, then 21-day cycle for 4 cycles
Regimen variant #3, 8 doses alternate schedule
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Huang et al. 2018 (CR102604) | 2013-2015 | Phase 3 (C) | Ibrutinib | Seems to have inferior OS |
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 1, then 500 mg/m2 IV once on day 15
- Cycle 2: 500 mg/m2 IV once per day on days 1 & 15
- Cycles 3 to 6: 500 mg/m2 IV once on day 1
28-day cycle for 6 cycles
References
- McLaughlin P, Grillo-López AJ, Link BK, Levy R, Czuczman MS, Williams ME, Heyman MR, Bence-Bruckler I, White CA, Cabanillas F, Jain V, Ho AD, Lister J, Wey K, Shen D, Dallaire BK. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998 Aug;16(8):2825-33. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- GS-US-312-0116: Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, Barrientos JC, Zelenetz AD, Kipps TJ, Flinn I, Ghia P, Eradat H, Ervin T, Lamanna N, Coiffier B, Pettitt AR, Ma S, Stilgenbauer S, Cramer P, Aiello M, Johnson DM, Miller LL, Li D, Jahn TM, Dansey RD, Hallek M, O'Brien SM. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014 Mar 13;370(11):997-1007. Epub 2014 Jan 22. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01539512
- Update: Sharman JP, Coutre SE, Furman RR, Cheson BD, Pagel JM, Hillmen P, Barrientos JC, Zelenetz AD, Kipps TJ, Flinn IW, Ghia P, Eradat H, Ervin T, Lamanna N, Coiffier B, Pettitt AR, Ma S, Tausch E, Cramer P, Huang J, Mitra S, Hallek M, O'Brien SM, Stilgenbauer S. Final results of a randomized, phase III study of rituximab with or without idelalisib followed by open-label idelalisib in patients with relapsed chronic lymphocytic leukemia. J Clin Oncol. 2019 Jun 1;37(16):1391-1402. Epub 2019 Apr 17. link to original article link to PMC article PubMed
- RESORT substudy: Williams ME, Hong F, Gascoyne RD, Wagner LI, Krauss JC, Habermann TM, Swinnen LJ, Schuster SJ, Peterson CG, Sborov MD, Martin SE, Weiss M, Ehmann WC, Horning SJ, Kahl BS; Eastern Cooperative Oncology Group. Rituximab extended schedule or retreatment trial for low tumour burden non-follicular indolent B-cell non-Hodgkin lymphomas: Eastern Cooperative Oncology Group Protocol E4402. Br J Haematol. 2016 Jun;173(6):867-75. Epub 2016 Mar 11. link to original article dosing details in abstract have been reviewed by our editors link to PMC article PubMed NCT01406782
- CR102604: Huang X, Qiu L, Jin J, Zhou D, Chen X, Hou M, Hu J, Hu Y, Ke X, Li J, Liang Y, Liu T, Lv Y, Ren H, Sun A, Wang J, Zhao C, Salman M, Sun S, Howes A, Wang J, Wu P, Li J. Ibrutinib versus rituximab in relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma: a randomized, open-label phase 3 study. Cancer Med. 2018 Apr;7(4):1043-1055. Epub 2018 Mar 13. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01973387
Venetoclax & Rituximab
VenR: Venetoclax & Rituximab
Regimen
FDA-recommended dose |
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Seymour et al. 2018 (MURANO) | 2014-03-31 to 2015-09-23 | Phase 3 (E-RT-switch-ooc) | BR | Superior PFS (primary endpoint) PFS24: 84.9% vs 36.3% (HR 0.17, 95% CI 0.11-0.25) Superior OS1 (secondary endpoint) OS48: 85.3% vs 66.8% (HR 0.41, 95% CI 0.26-0.65) |
Awaiting publication (BRUIN CLL-322) | 2021-2025 | Phase 3 (C) | Pirtobrutinib, Venetoclax, Rituximab | TBD if different primary endpoint of PFS |
1Reported efficacy for OS in MURANO is based on the 2020 update.
Targeted therapy
- Venetoclax (Venclexta) as follows:
- Week 1: 20 mg PO once per day
- Week 2: 50 mg PO once per day
- Week 3: 100 mg PO once per day
- Week 4: 200 mg PO once per day
- Weeks 5 up to 104: 400 mg PO once per day
- Rituximab (Rituxan) as follows:
- Week 6: 375 mg/m2 IV once on day 1
- Weeks 10, 14, 18, 22, 26: 500 mg/m2 IV once on day 1
Up to 2-year course
References
- MURANO: Seymour JF, Kipps TJ, Eichhorst B, Hillmen P, D'Rozario J, Assouline S, Owen C, Gerecitano J, Robak T, De la Serna J, Jaeger U, Cartron G, Montillo M, Humerickhouse R, Punnoose EA, Li Y, Boyer M, Humphrey K, Mobasher M, Kater AP. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018 Mar 22;378(12):1107-1120. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT02005471
- Update: Kater AP, Seymour JF, Hillmen P, Eichhorst B, Langerak AW, Owen C, Verdugo M, Wu J, Punnoose EA, Jiang Y, Wang J, Boyer M, Humphrey K, Mobasher M, Kipps TJ. Fixed duration of venetoclax-rituximab in relapsed/refractory chronic lymphocytic leukemia eradicates minimal residual disease and prolongs survival: post-treatment follow-up of the MURANO phase III study. J Clin Oncol. 2019 Feb 1;37(4):269-277. Epub 2018 Dec 3. link to original article PubMed
- Update: Kater AP, Wu JQ, Kipps T, Eichhorst B, Hillmen P, D'Rozario J, Assouline S, Owen C, Robak T, de la Serna J, Jaeger U, Cartron G, Montillo M, Dubois J, Eldering E, Mellink C, Van Der Kevie-Kersemaekers AM, Kim SY, Chyla B, Punnoose E, Bolen CR, Assaf ZJ, Jiang Y, Wang J, Lefebure M, Boyer M, Humphrey K, Seymour JF. Venetoclax Plus Rituximab in Relapsed Chronic Lymphocytic Leukemia: 4-Year Results and Evaluation of Impact of Genomic Complexity and Gene Mutations From the MURANO Phase III Study. J Clin Oncol. 2020 Dec 1;38(34):4042-4054. Epub 2020 Sep 28. link to original article link to PMC article PubMed
- Update: Seymour JF, Kipps TJ, Eichhorst BF, D'Rozario J, Owen CJ, Assouline S, Lamanna N, Robak T, de la Serna J, Jaeger U, Cartron G, Montillo M, Mellink C, Chyla B, Panchal A, Lu T, Wu JQ, Jiang Y, Lefebure M, Boyer M, Kater AP. Enduring undetectable MRD and updated outcomes in relapsed/refractory CLL after fixed-duration venetoclax-rituximab. Blood. 2022 Aug 25;140(8):839-850. link to original article link to PMC article PubMed
- BRUIN CLL-322: NCT04965493
Zanubrutinib monotherapy
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Hillmen et al. 2022 (ALPINE) | 2018-2020 | Phase 3 (E-switch-ic) | Ibrutinib | Superior PFS1 (secondary endpoint) PFS24: 78.4% vs 65.9% (HR 0.65, 95% CI 0.49-0.86) Superior ORR (primary endpoint) |
1Reported efficacy is based on the 2022 update.
Prior treatment criteria
- ALPINE: At least 1 prior systemic therapy; prior BTKi not allowed
References
- ALPINE: Hillmen P, Eichhorst B, Brown JR, Lamanna N, O'Brien SM, Tam CS, Qiu L, Kazmierczak M, Zhou K, Šimkovič M, Mayer J, Gillespie-Twardy A, Shadman M, Ferrajoli A, Ganly PS, Weinkove R, Grosicki S, Mital A, Robak T, Österborg A, Yimer HA, Salmi T, Ji M, Yecies J, Idoine A, Wu K, Huang J, Jurczak W. Zanubrutinib Versus Ibrutinib in Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma: Interim Analysis of a Randomized Phase III Trial. J Clin Oncol. 2023 Feb 10;41(5):1035-1045. Epub 2022 Nov 17. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT03734016
- Update: Brown JR, Eichhorst B, Hillmen P, Jurczak W, Kaźmierczak M, Lamanna N, O'Brien SM, Tam CS, Qiu L, Zhou K, Simkovic M, Mayer J, Gillespie-Twardy A, Ferrajoli A, Ganly PS, Weinkove R, Grosicki S, Mital A, Robak T, Osterborg A, Yimer HA, Salmi T, Wang MD, Fu L, Li J, Wu K, Cohen A, Shadman M. Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. N Engl J Med. 2023 Jan 26;388(4):319-332. Epub 2022 Dec 13. link to original article PubMed
- HRQoL analysis: Tam CS, Lamanna N, O'Brien SM, Qiu L, Yang K, Barnes G, Wu K, Salmi T, Brown JR. Health-related quality of life outcomes associated with zanubrutinib versus ibrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma: results from the ALPINE Trial. Curr Med Res Opin. 2023 Nov;39(11):1497-1503. Epub 2023 Oct 27. link to original article PubMed
Relapsed or refractory, non-randomized or retrospective data
Alemtuzumab monotherapy
Regimen variant #1
Study | Dates of enrollment | Evidence |
---|---|---|
Keating et al. 2002 | 1998 | Phase 2 (RT) |
Rai et al. 2002 | Not reported-1994 | Phase 2 (RT) |
Note: total course varies depending on reference.
Targeted therapy
- Alemtuzumab (Campath) by the following criteria:
- Starting dose: 3 mg IV once per day
- If tolerated in terms of infusion reactions: 10 mg IV once per day
- If tolerated in terms of infusion reactions: 30 mg IV once per day
- Once 30 mg dose is tolerated: 30 mg IV over 2 hours, 3 times per week
Supportive therapy
- Note: see references for details, as they differ by paper.
- Diphenhydramine (Benadryl) 50 mg PO once per infusion; 30 minutes prior to alemtuzumab
- Acetaminophen (Tylenol) 650 mg PO once per infusion; 30 minutes prior to alemtuzumab
- Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg PO 3 times per week, starting on day 8, continuing at a minimum until 2 months after treatment is complete
- Famciclovir (Famvir) 250 mg PO twice per day, starting on day 8, continuing at a minimum until 2 months after treatment is complete
12- to 16-week course
Regimen variant #2
Study | Dates of enrollment | Evidence |
---|---|---|
Lozanski et al. 2004 | Not reported | Phase 2 (RT) |
Targeted therapy
- Alemtuzumab (Campath) 3 mg IV once on day 1, then 10 mg IV once on day 2, then 30 mg IV once on day 3, then 30 mg IV 3 days per week
Supportive therapy
- G-CSF or GM-CSF per institutional protocol
- Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg PO 3 times per week during therapy and continued for 6 months after treatment is complete
- Acyclovir (Zovirax) 800 mg PO three times per day during therapy and continued for 6 months after treatment is complete; similar medication can be used if intolerant of acyclovir
12-week course
References
- Keating MJ, Flinn I, Jain V, Binet JL, Hillmen P, Byrd J, Albitar M, Brettman L, Santabarbara P, Wacker B, Rai KR. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood. 2002 May 15;99(10):3554-61. link to original article dosing details in abstract have been reviewed by our editors PubMed
- Rai KR, Freter CE, Mercier RJ, Cooper MR, Mitchell BS, Stadtmauer EA, Santábarbara P, Wacker B, Brettman L. Alemtuzumab in previously treated chronic lymphocytic leukemia patients who also had received fludarabine. J Clin Oncol. 2002 Sep 15;20(18):3891-7. link to original article dosing details in abstract have been reviewed by our editors PubMed
- Lozanski G, Heerema NA, Flinn IW, Smith L, Harbison J, Webb J, Moran M, Lucas M, Lin T, Hackbarth ML, Proffitt JH, Lucas D, Grever MR, Byrd JC. Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions. Blood. 2004 May 1;103(9):3278-81. Epub 2004 Jan 15. link to original article dosing details in abstract have been reviewed by our editors PubMed
Alemtuzumab & Rituximab
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Faderl et al. 2003 | Not reported | Phase 2 |
Targeted therapy
- Alemtuzumab (Campath) 3 mg IV once on day 1, then 10 mg IV once on day 2, then 30 mg IV once on day 3 of week 1, then 30 mg IV once per day on days 10, 12, 17, 19, 24, 26 (i.e. days 3 and 5 of weeks 2 to 4)
- Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1, 8, 15, 22
- For patients with WBC count more than 50 x 109/L, the first dose was split into 100 mg/m2 IV once on day 1, then 275 mg/m2 IV once on day 2
Supportive therapy
- Prophylactic Trimethoprim-Sulfamethoxazole (Bactrim DS), given during therapy and continuing at a minimum until 2 months after treatment is complete
- Prophylactic Valacyclovir (Valtrex) (or equivalent), given during therapy and continuing at a minimum until 2 months after treatment is complete
28-day cycle for 1 to 2 cycles depending on response and toxicity
References
- Faderl S, Thomas DA, O'Brien S, Garcia-Manero G, Kantarjian HM, Giles FJ, Koller C, Ferrajoli A, Verstovsek S, Pro B, Andreeff M, Beran M, Cortes J, Wierda W, Tran N, Keating MJ. Experience with alemtuzumab plus rituximab in patients with relapsed and refractory lymphoid malignancies. Blood. 2003 May 1;101(9):3413-5. Epub 2003 Jan 9. link to original article dosing details in abstract have been reviewed by our editors PubMed
Bendamustine & Ofatumumab
BendOfa: Bendamustine & Ofatumumab
Regimen
Study | Dates of enrollment | Evidence | Efficacy |
---|---|---|---|
Cortelezzi et al. 2013 (GIMEMA CLL0809) | 2010-2011 | Phase 2 | ORR: 72% (95% CI, 57–84%) |
Chemotherapy
- Bendamustine 70 mg/m2 IV once per day on days 1 & 2
Targeted therapy
- Ofatumumab (Arzerra) as follows:
- Cycle 1: 300 mg IV once on day 1, then 1000 mg IV once on day 7
- Cycles 2 to 6: 1000 mg IV once on day 1
Supportive therapy
- Acetaminophen (Tylenol) 1000 mg PO once per infusion, prior to ofatumumab
- Diphenhydramine (Benadryl) 50 mg PO once per infusion, prior to ofatumumab
- Methylprednisolone (Solumedrol) 40 mg IV once per infusion, prior to ofatumumab
- Allopurinol (Zyloprim) or Rasburicase (Elitek) required for prophylaxis against TLS; dose not specified
- Trimethoprim-Sulfamethoxazole (Bactrim DS) required; dose not specified
- Acyclovir (Zovirax) required; dose not specified
28-day cycle for up to 6 cycles
References
- GIMEMA CLL0809: Cortelezzi A, Sciumè M, Liberati AM, Vincenti D, Cuneo A, Reda G, Laurenti L, Zaja F, Marasca R, Chiarenza A, Gritti G, Orsucci L, Storti S, Angelucci E, Cascavilla N, Gobbi M, Mauro FR, Morabito F, Fabris S, Piciocchi A, Vignetti M, Neri A, Rossi D, Giannarelli D, Guarini A, Foà R. Bendamustine in combination with ofatumumab in relapsed or refractory chronic lymphocytic leukemia: a GIMEMA multicenter phase II trial. Leukemia. 2014 Mar;28(3):642-8. Epub 2013 Nov 13. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01244451
CFAR
CFAR: Cyclophosphamide, Fludarabine, Alemtuzumab, Rituximab
Regimen
Study | Dates of enrollment | Evidence | Efficacy |
---|---|---|---|
Badoux et al. 2011 (MDACC DM02-593) | 2002-2006 | Phase 2 | ORR: 65% |
Chemotherapy
- Cyclophosphamide (Cytoxan) 250 mg/m2 IV once per day on days 3 to 5
- Fludarabine (Fludara) 25 mg/m2 IV once per day on days 3 to 5
Targeted therapy
- Alemtuzumab (Campath) 30 mg IV once per day on days 1, 3, 5
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 2
- Cycles 2 to 6: 500 mg/m2 IV once on day 2
Supportive therapy
- Allopurinol (Zyloprim) as follows:
- Cycle 1: 300 mg PO once per day on days 1 to 7
- Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg PO twice per day
- Antiviral prophylaxis with ONE of the following:
- Valacyclovir (Valtrex) 500 mg PO once per day
- Valganciclovir (Valcyte) 450 mg PO twice per day
- Pegfilgrastim (Neulasta) 6 mg SC once on day 6
- At physician's discretion:
- Acetaminophen (Tylenol) 650 mg PO once per day on days 1, 2, 3, 5; 30 minutes prior to rituximab/Alemtuzumab (Campath)
- Diphenhydramine (Benadryl) 25 to 50 mg IV or PO once per day on days 1, 2, 3, 5; 30 minutes prior to rituximab/Alemtuzumab (Campath)
- Hydrocortisone (Cortef) 100 mg IV once per day on days 1, 2, 3, 5; 30 minutes prior to alemtuzumab
28-day cycle for 6 cycles
References
- MDACC DM02-593: Badoux XC, Keating MJ, Wang X, O'Brien SM, Ferrajoli A, Faderl S, Burger J, Koller C, Lerner S, Kantarjian H, Wierda WG. Cyclophosphamide, fludarabine, alemtuzumab, and rituximab as salvage therapy for heavily pretreated patients with chronic lymphocytic leukemia. Blood. 2011 Aug 25;118(8):2085-93. Epub 2011 Jun 13. link to original article dosing details in abstract have been reviewed by our editors link to PMC article PubMed NCT01082939
DFCR
DFCR: Duvelisib, Fludarabine, Cyclophosphamide, Rituximab
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Davids et al. 2020 (DFCI 14-193) | 2014-2016 | Phase 1b/2 |
Note: This is the phase 2 dosing.
Targeted therapy
- Duvelisib (Copiktra) 25 mg PO twice per day
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 1
- Cycles 2 to 6: 500 mg/m2 IV once on day 1
Chemotherapy
- Fludarabine (Fludara) as follows:
- Cycles 1 to 6: 25 mg/m2 IV once per day on days 1 to 3
- Cyclophosphamide (Cytoxan) as follows:
- Cycles 1 to 6: 250 mg/m2 IV once per day on days 1 to 3
28-day cycle for up to 26 cycles (2 years)
References
- DFCI 14-193: Davids MS, Fisher DC, Tyekucheva S, McDonough M, Hanna J, Lee B, Francoeur K, Montegaard J, Odejide O, Armand P, Arnason J, Brown JR. A phase 1b/2 study of duvelisib in combination with FCR (DFCR) for frontline therapy for younger CLL patients. Leukemia. 2021 Apr;35(4):1064-1072. Epub 2020 Aug 20. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT02158091
Fludarabine & Alemtuzumab
FluCam: Fludarabine & Campath (Alemtuzumab)
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Elter et al. 2005 | Not reported | Phase 2 |
Chemotherapy
- Fludarabine (Fludara) 30 mg/m2 IV once per day on days 1 to 3
Targeted therapy
- Alemtuzumab (Campath) as follows:
- Cycle 1: 3 mg IV once on day 1, then 10 mg IV once on day 2, then 30 mg IV once on day 3
- Cycles 2 to 6: 30 mg IV once per day on days 1 to 3
Supportive therapy
- Trimethoprim/Sulfamethoxazole 960 mg (paper did not specify which component was 960 mg) PO once per day, started on day 1 and continued at least 2 months after treatment is complete
- Valacyclovir (Valtrex) 500 mg PO twice per day, started on day 1 and continued at least 2 months after treatment is complete
- If patients experienced CMV (cytomegalovirus) reactivation, valacyclovir was replaced by (val)ganciclovir 500 mg PO or IV three times per day
- Fluconazole (Diflucan) 100 mg PO once per day, started if patients had evidence of fungal infection, continued until resolution
- Acetaminophen (Tylenol) 1000 mg PO once on day 1, prior to first dose of alemtuzumab, then with subsequent doses if clinically indicated
- Clemastine (Tavist) 2 mg IV once on day 1, prior to first dose of alemtuzumab, then with subsequent doses if clinically indicated
- Prednisone (Sterapred) 100 mg IV once on day 1, prior to first dose of alemtuzumab, then with subsequent doses if clinically indicated
- For patients with WBC count more than 50 x 109/L, bulky disease, or history of hyperuricemia: Allopurinol (Zyloprim) 300 mg PO once on day 1, prior to first dose of alemtuzumab, and used later if clinically indicated
28-day cycle for 6 cycles
References
- Elter T, Borchmann P, Schulz H, Reiser M, Trelle S, Schnell R, Jensen M, Staib P, Schinköthe T, Stützer H, Rech J, Gramatzki M, Aulitzky W, Hasan I, Josting A, Hallek M, Engert A. Fludarabine in combination with alemtuzumab is effective and feasible in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: results of a phase II trial. J Clin Oncol. 2005 Oct 1;23(28):7024-31. Epub 2005 Sep 6. link to original article dosing details in abstract have been reviewed by our editors PubMed
Fludarabine & Ibrutinib
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Pleyer et al. 2020 (NIH 15-H-0172) | 2015-2019 | Phase 2 |
Chemotherapy
- Fludarabine (Fludara) as follows:
- Cycles 3 & 4: 25 mg/m2 IV once per day on days 1 to 5
Targeted therapy
- Ibrutinib (Imbruvica) 420 mg PO once per day on days 1 to 28
28-day cycles
References
- NIH 15-H-0172: Pleyer C, Tian X, Rampertaap S, Mu R, Soto S, Superata J, Gaglione E, Sun C, Lotter J, Stetler-Stevenson M, Yuan CM, Maric I, Pittaluga S, Rosenzweig S, Fleisher T, Wiestner A, Ahn IE. A phase II study of ibrutinib and short-course fludarabine in previously untreated patients with chronic lymphocytic leukemia. Am J Hematol. 2020 Nov;95(11):E310-E313. Epub 2020 Sep 8. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT02514083
Fludarabine & Prednisone
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
O'Brien et al. 1993 | 1988-1991 | Phase 2 |
Chemotherapy
- Fludarabine (Fludara) 30 mg/m2 IV over 30 minutes once per day on days 1 to 5
Glucocorticoid therapy
- Prednisone (Sterapred) 30 mg/m2 PO once per day on days 1 to 5
28-day cycles
References
- O'Brien S, Kantarjian H, Beran M, Smith T, Koller C, Estey E, Robertson LE, Lerner S, Keating M. Results of fludarabine and prednisone therapy in 264 patients with chronic lymphocytic leukemia with multivariate analysis-derived prognostic model for response to treatment. Blood. 1993 Sep 15;82(6):1695-700. link to original article dosing details in abstract have been reviewed by our editors PubMed
- Update: Keating MJ, O'Brien S, Lerner S, Koller C, Beran M, Robertson LE, Freireich EJ, Estey E, Kantarjian H. Long-term follow-up of patients with chronic lymphocytic leukemia (CLL) receiving fludarabine regimens as initial therapy. Blood. 1998 Aug 15;92(4):1165-71. link to original article PubMed
HDMP-R
HDMP-R: High Dose, MethylPrednisolone, Rituximab
Regimen variant #1, 3 cycles
Study | Dates of enrollment | Evidence |
---|---|---|
Castro et al. 2008 | Not reported | Phase 2, fewer than 20 pts |
Glucocorticoid therapy
- Methylprednisolone (Solumedrol) 1000 mg/m2 IV over 90 minutes once per day on days 1 to 5
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once per day on days 1, 3, 5, 8, 17, 22
- Cycles 2 & 3: 375 mg/m2 IV once per day on days 1, 7, 14, 21
28-day cycle for 3 cycles
Regimen variant #2, 6 cycles
Study | Dates of enrollment | Evidence |
---|---|---|
Pileckyte et al. 2011 (LT-CLL-001) | 2007-09 to 2009-01 | Phase 2 |
Glucocorticoid therapy
- Methylprednisolone (Solumedrol) 1000 mg/m2 IV over 4 hours once per day on days 1 to 5
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 50 mg IV once on day 1, then 150 mg IV once on day 2, then remainder of a 375 mg/m2 dose IV once on day 3, then 500 mg/m2 IV once on day 5
- Cycles 2 to 6: 500 mg/m2 IV once per day on days 1 & 5
Supportive therapy
- Trimethoprim/sulfamethoxazole "or an equivalent antibiotic throughout the treatment period and up to 6 months after the completion of therapy"
21-day cycle for 6 cycles
References
- Castro JE, Sandoval-Sus JD, Bole J, Rassenti L, Kipps TJ. Rituximab in combination with high-dose methylprednisolone for the treatment of fludarabine refractory high-risk chronic lymphocytic leukemia. Leukemia. 2008 Nov;22(11):2048-53. Epub 2008 Aug 28. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed
- LT-CLL-001: Pileckyte R, Jurgutis M, Valceckiene V, Stoskus M, Gineikiene E, Sejoniene J, Degulys A, Zvirblis T, Griskevicius L. Dose-dense high-dose methylprednisolone and rituximab in the treatment of relapsed or refractory high-risk chronic lymphocytic leukemia. Leuk Lymphoma. 2011 Jun;52(6):1055-65. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT00558181
Ibrutinib & Ofatumumab
Regimen variant #1, concurrent ibrutinib and ofatumumab
Study | Dates of enrollment | Evidence |
---|---|---|
Jaglowski et al. 2015 (PCYC-1109-CA) | 2011-2012 | Phase 2 |
Prior treatment criteria
- Failure of two or more prior therapies, or Richter transformation
Targeted therapy
- Ibrutinib (Imbruvica) 420 mg PO once per day on days 1 to 28
- Ofatumumab (Arzerra) as follows:
- Cycle 1: 300 mg IV once on day 1, then 2000 mg IV once per day on days 8, 15, 22
- Cycle 2: 2000 mg IV once per day on days 1, 8, 15, 22
- Cycles 3 to 6: 2000 mg IV once on day 1
28-day cycles
Regimen variant #2, ibrutinib lead-in
Study | Dates of enrollment | Evidence |
---|---|---|
Jaglowski et al. 2015 (PCYC-1109-CA) | 2011-2012 | Phase 2 |
Prior treatment criteria
- Failure of two or more prior therapies, or Richter transformation
Targeted therapy
- Ibrutinib (Imbruvica) 420 mg PO once per day on days 1 to 28
- Ofatumumab (Arzerra) as follows:
- Cycle 2: 300 mg IV once on day 1, then 2000 mg IV once per day on days 8, 15, 22
- Cycle 3: 2000 mg IV once per day on days 1, 8, 15, 22
- Cycles 4 to 7: 2000 mg IV once on day 1
28-day cycles
Regimen variant #3, ofatumumab lead-in
Study | Dates of enrollment | Evidence |
---|---|---|
Jaglowski et al. 2015 (PCYC-1109-CA) | 2011-2012 | Phase 2 |
Prior treatment criteria
- Failure of two or more prior therapies, or Richter transformation
Targeted therapy
- Ibrutinib (Imbruvica) as follows:
- Cycle 3 onwards: 420 mg PO once per day on days 1 to 28
- Ofatumumab (Arzerra) as follows:
- Cycle 1: 300 mg IV once on day 1, then 2000 mg IV once per day on days 8, 15, 22
- Cycle 2: 2000 mg IV once per day on days 1, 8, 15, 22
- Cycles 3 to 6: 2000 mg IV once on day 1
28-day cycles
References
- PCYC-1109-CA: Jaglowski SM, Jones JA, Nagar V, Flynn JM, Andritsos LA, Maddocks KJ, Woyach JA, Blum KA, Grever MR, Smucker K, Ruppert AS, Heerema NA, Lozanski G, Stefanos M, Munneke B, West JS, Neuenburg JK, James DF, Hall N, Johnson AJ, Byrd JC. Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab in chronic lymphocytic leukemia: a phase 1b/2 study. Blood. 2015 Aug 13;126(7):842-50. Epub 2015 Jun 26. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01217749
Ibrutinib & Rituximab
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Burger et al. 2014 (MDACC 2011-0785) | 2012 | Phase 2 |
Note: Only 4 patients in the published study were untreated.
Eligibility criteria
- Patients with high-risk CLL (del17p or TP53 mutation, PFS less than 36 months from initial therapy, or relapsed CLL with del11q)
Targeted therapy
- Ibrutinib (Imbruvica) 420 mg PO once per day on days 1 to 28
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15, 22
- Cycles 2 to 6: 375 mg/m2 IV once on day 1
28-day cycles
References
- MDACC 2011-0785: Burger JA, Keating MJ, Wierda WG, Hartmann E, Hoellenriegel J, Rosin NY, de Weerdt I, Jeyakumar G, Ferrajoli A, Cardenas-Turanzas M, Lerner S, Jorgensen JL, Nogueras-González GM, Zacharian G, Huang X, Kantarjian H, Garg N, Rosenwald A, O'Brien S. Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study. Lancet Oncol. 2014 Sep;15(10):1090-9. Epub 2014 Aug 20. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01520519
- Update: Jain P, Keating MJ, Wierda WG, Sivina M, Thompson PA, Ferrajoli A, Estrov Z, Kantarjian H, O'Brien S, Burger JA. Long-term follow-up of treatment with ibrutinib and rituximab in patients with high-risk chronic lymphocytic leukemia. Clin Cancer Res. 2017 May 1;23(9):2154-2158. Epub 2016 Oct 19. link to original article link to PMC article PubMed
Ibrutinib, Venetoclax, Obinutuzumab
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Rogers et al. 2020 (OSU-14266) | 2015-2017 | Phase 2 |
Targeted therapy
- Ibrutinib (Imbruvica) as follows:
- Cycle 2 onwards: 420 mg PO once per day on days 1 to 28
- Venetoclax (Venclexta) as follows:
- Cycle 3: 20 mg PO once per day on days 1 to 7, then 50 mg PO once per day on days 8 to 14, then 100 mg PO once per day on days 15 to 21, then 200 mg PO once per day on days 22 to 28
- Cycles 4 to 14: 400 mg PO once per day on days 1 to 28
- Obinutuzumab (Gazyva) as follows:
- Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15
- Cycles 2 to 8: 1000 mg IV once on day 1
28-day cycles
References
- OSU-14266: Rogers KA, Huang Y, Ruppert AS, Abruzzo LV, Andersen BL, Awan FT, Bhat SA, Dean A, Lucas M, Banks C, Grantier C, Heerema NA, Lozanski G, Maddocks KJ, Valentine TR, Weiss DM, Jones JA, Woyach JA, Byrd JC. Phase II Study of Combination Obinutuzumab, Ibrutinib, and Venetoclax in Treatment-Naïve and Relapsed or Refractory Chronic Lymphocytic Leukemia. J Clin Oncol. 2020 Nov 1;38(31):3626-3637. Epub 2020 Aug 14. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT02427451
Idelalisib monotherapy
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Brown et al. 2014 (Gilead 101-02) | 2008-2011 | Phase 1, >20 pts |
Gopal et al. 2014 (DELTA) | 2011-2012 | Phase 2 (RT) |
References
- DELTA: Gopal AK, Kahl BS, de Vos S, Wagner-Johnston ND, Schuster SJ, Jurczak WJ, Flinn IW, Flowers CR, Martin P, Viardot A, Blum KA, Goy AH, Davies AJ, Zinzani PL, Dreyling M, Johnson D, Miller LL, Holes L, Li D, Dansey RD, Godfrey WR, Salles GA. PI3Kd inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014 Mar 13;370(11):1008-18. Epub 2014 Jan 22. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01282424
- Update: Abstract: Ajay K. Gopal, MD, Brad S. Kahl, MD, Sven de Vos, MD, PhD, Nina D. Wagner-Johnston, MD, Stephen J. Schuster, MD, Wojciech Jurczak, MD, PhD, Ian W. Flinn, MD, PhD, Christopher R. Flowers, MD, Peter Martin, MD, Andreas Viardot, MD, Kristie A. Blum, MD, Andre Goy, MD, Andrew Davies, BM PhD, Pier Luigi Zinzani, MD, Martin H. Dreyling, MD, PhD, Leanne M. Holes, Bess Sorensen, PhD, Wayne R. Godfrey, MD and Gilles Andre Salles, MD, PhD. Mature Follow up from a Phase 2 Study of PI3K-Delta Inhibitor Idelalisib in Patients with Double (Rituximab and Alkylating agent)-Refractory Indolent B-Cell Non-Hodgkin Lymphoma (iNHL). ASH Annual Meeting 2014, Abstract 1708.
- Gilead 101-02: Brown JR, Byrd JC, Coutre SE, Benson DM, Flinn IW, Wagner-Johnston ND, Spurgeon SE, Kahl BS, Bello C, Webb HK, Johnson DM, Peterman S, Li D, Jahn TM, Lannutti BJ, Ulrich RG, Yu AS, Miller LL, Furman RR. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110d, for relapsed/refractory chronic lymphocytic leukemia. Blood. 2014 May 29;123(22):3390-7. Epub 2014 Mar 10. link to original article link to PMC article PubMed NCT00710528
Lenalidomide monotherapy
Regimen variant #1
Study | Dates of enrollment | Evidence |
---|---|---|
Chanan-Khan et al. 2006 | 2004-2006 | Phase 2 |
Targeted therapy
- Lenalidomide (Revlimid) 5 mg PO once per day, escalated by 5 mg every 1 to 2 weeks to a target maximum dose of 25 mg PO once per day on days 1 to 21
Supportive therapy
- Allopurinol (Zyloprim) 300 mg PO once per day, starting 2 to 3 days prior to lenalidomide, and continued up to a total of 14 days
28-day cycles
Regimen variant #2
Study | Dates of enrollment | Evidence |
---|---|---|
Ferrajoli et al. 2008 (MDACC 2005-0175) | 2005-2007 | Phase 2 |
Targeted therapy
- Lenalidomide (Revlimid) as follows:
- Cycle 1: 10 mg PO once per day on days 1 to 28
- Cycle 2: 15 mg PO once per day on days 1 to 28
- Cycle 3: 20 mg PO once per day on days 1 to 28
- Cycle 4 onwards: 25 mg PO once per day on days 1 to 28
28-day cycles
Regimen variant #3
Study | Dates of enrollment | Evidence |
---|---|---|
Witzig et al. 2009 (CC-5013-NHL-001) | 2005-2006 | Phase 2, fewer than 20 patients in this subgroup |
Note: Patients studied in this trial and in this subgroup had a diagnosis of SLL.
References
- Chanan-Khan A, Miller KC, Musial L, Lawrence D, Padmanabhan S, Takeshita K, Porter CW, Goodrich DW, Bernstein ZP, Wallace P, Spaner D, Mohr A, Byrne C, Hernandez-Ilizaliturri F, Chrystal C, Starostik P, Czuczman MS. Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study. J Clin Oncol. 2006 Dec 1;24(34):5343-9. Epub 2006 Nov 6. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- MDACC 2005-0175: Ferrajoli A, Lee BN, Schlette EJ, O'Brien SM, Gao H, Wen S, Wierda WG, Estrov Z, Faderl S, Cohen EN, Li C, Reuben JM, Keating MJ. Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood. 2008 Jun 1;111(11):5291-7. Epub 2008 Mar 11. link to original article link to PMC article PubMed NCT00267059
- CC-5013-NHL-001: Witzig TE, Wiernik PH, Moore T, Reeder C, Cole C, Justice G, Kaplan H, Voralia M, Pietronigro D, Takeshita K, Ervin-Haynes A, Zeldis JB, Vose JM. Lenalidomide oral monotherapy produces durable responses in relapsed or refractory indolent non-Hodgkin's Lymphoma. J Clin Oncol. 2009 Nov 10;27(32):5404-9. Epub 2009 Oct 5. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00179673
Lenalidomide & Ofatumumab
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Vitale et al. 2016 (MDACC 2009-0283) | 2010-2011 | Phase 2 |
Targeted therapy
- Lenalidomide (Revlimid) as follows:
- Cycle 1: 10 mg PO once per day on days 9 to 28
- Cycles 2 to 24: 10 mg PO once per day
- Ofatumumab (Arzerra) as follows:
- Cycle 1: 300 mg IV once on day 1, then 1000 mg IV once per day on days 8, 15, 22
- Cycles 3 to 6, 8, 10, 12, 14, 16, 18, 20, 22, 24: 1000 mg IV once on day 1
Supportive therapy
- Cycle 1: Allopurinol (Zyloprim) 300 mg PO once per day on days 1 to 14
- G-CSF use allowed per 2006 ASCO guidelines
- "No anti-infectious, venous thromboembolism (VTE), or TFR prophylaxis was mandated"
28-day cycle for 24 cycles
Subsequent treatment
- MDACC 2009-0283, patients with a sustained PR or CR: Lenalidomide maintenance
References
- MDACC 2009-0283: Vitale C, Falchi L, Ten Hacken E, Gao H, Shaim H, Van Roosbroeck K, Calin G, O'Brien S, Faderl S, Wang X, Wierda WG, Rezvani K, Reuben JM, Burger JA, Keating MJ, Ferrajoli A. Ofatumumab and Lenalidomide for Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia: Correlation between Responses and Immune Characteristics. Clin Cancer Res. 2016 May 15;22(10):2359-67. Epub 2016 Jan 5. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01002755
Lenalidomide & Rituximab (R2)
Regimen variant #1
Study | Dates of enrollment | Evidence |
---|---|---|
Chanan-Khan et al. 2006 | 2004-2006 | Phase 2 |
Note: this lenalidomide dosing was the result of a mid-protocol amendment due to TLS in two of the first 29 patients enrolled.
Targeted therapy
- Lenalidomide (Revlimid) 5 mg PO once per day, escalated by 5 mg every 1 to 2 weeks to a target maximum dose of 25 mg PO once per day on days 1 to 21
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15
- Cycle 2 onwards: 375 mg/m2 IV once per day on days 1 & 15
Supportive therapy
- Allopurinol (Zyloprim) 300 mg PO once per day, starting 2 to 3 days prior to chemotherapy, and continued up to a total of 14 days
28-day cycles
Regimen variant #2
Study | Dates of enrollment | Evidence |
---|---|---|
Badoux et al. 2013 (MDACC 2007-0208) | 2008-2009 | Phase 2 |
Targeted therapy
- Lenalidomide (Revlimid) as follows:
- Cycle 1: 10 mg PO once per day on days 9 to 28
- Cycles 2 to 12: 10 mg PO once per day on days 1 to 28
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15, 22
- Cycle 2: no rituximab given
- Cycles 3 to 12: 375 mg/m2 IV once on day 1
Supportive therapy
- Cycle 1: Allopurinol (Zyloprim) (dose/schedule not specified) on days 1 to 14
- No mandatory antibacterial, antiviral, DVT, or tumor flare prophylaxis
- Growth factor use allowed per 2006 ASCO guidelines
28-day cycle for 12 cycles
Subsequent treatment
- MDACC 2007-0208, responders: Lenalidomide maintenance could continue indefinitely
References
- Chanan-Khan A, Miller KC, Musial L, Lawrence D, Padmanabhan S, Takeshita K, Porter CW, Goodrich DW, Bernstein ZP, Wallace P, Spaner D, Mohr A, Byrne C, Hernandez-Ilizaliturri F, Chrystal C, Starostik P, Czuczman MS. Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study. J Clin Oncol. 2006 Dec 1;24(34):5343-9. Epub 2006 Nov 6. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- MDACC 2007-0208: Badoux XC, Keating MJ, Wen S, Wierda WG, O'Brien SM, Faderl S, Sargent R, Burger JA, Ferrajoli A. Phase II Study of Lenalidomide and Rituximab As Salvage Therapy for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia. J Clin Oncol. 2013 Feb 10;31(5):584-91. Epub 2012 Dec 26. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00759603
Lisocabtagene maraleucel monotherapy
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Siddiqi et al. 2023 (TRANSCEND CLL 004) | 2018-01-02 to 2022-06-16 | Phase 1/2 |
Note: this is the dose-level 2 of the phase 1/2 trial.
Immunotherapy
- Lisocabtagene maraleucel (Breyanzi) target dose of 100 x 106 CAR T cells IV once on day 0
One course
References
- TRANSCEND CLL 004:Siddiqi T, Maloney DG, Kenderian SS, Brander DM, Dorritie K, Soumerai J, Riedell PA, Shah NN, Nath R, Fakhri B, Stephens DM, Ma S, Feldman T, Solomon SR, Schuster SJ, Perna SK, Tuazon SA, Ou SS, Papp E, Peiser L, Chen Y, Wierda WG. Lisocabtagene maraleucel in chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1-2 study. Lancet. 2023 Aug 19;402(10402):641-654. Epub 2023 Jun 5. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT03331198
Obinutuzumab monotherapy
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Salles et al. 2012 (GAUGUIN) | 2008-2009 | Phase 1/2 |
Note: Dose here is the phase II dose reported in the Cartron et al. 2014 update.
Targeted therapy
- Obinutuzumab (Gazyva) as follows:
- Cycle 1: 1000 mg IV once per day on days 1, 8, 15
- Cycle 2 onwards: 1000 mg IV once on day 1
Supportive therapy
- Acetaminophen (Tylenol) 650 to 1000 mg PO once on cycle 1 day 1; 30 minutes prior to obinutuzumab, repeat for those at risk of tumor lysis or with history of reaction
- Antihistamine (no drug or dose specified) PO once on cycle 1 day 1; 30 minutes prior to obinutuzumab, repeat for those at risk of tumor lysis or with history of reaction
- For patients at "high risk" of severe infusion reaction, including those with a history of severe rituximab reactions: Corticosteroids (no drug/dose/route specified) once on cycle 1 day 1, prior to obinutuzumab
21-day cycle for up to 8 cycles
References
- GAUGUIN: Salles G, Morschhauser F, Lamy T, Milpied N, Thieblemont C, Tilly H, Bieska G, Asikanius E, Carlile D, Birkett J, Pisa P, Cartron G. Phase 1 study results of the type II glycoengineered humanized anti-CD20 monoclonal antibody obinutuzumab (GA101) in B-cell lymphoma patients. Blood. 2012 May 31;119(22):5126-32. Epub 2012 Mar 19. link to original article PubMed NCT00517530
- Subgroup analysis: Morschhauser FA, Cartron G, Thieblemont C, Solal-Céligny P, Haioun C, Bouabdallah R, Feugier P, Bouabdallah K, Asikanius E, Lei G, Wenger M, Wassner-Fritsch E, Salles GA. Obinutuzumab (GA101) monotherapy in relapsed/refractory diffuse large B-cell lymphoma or mantle-cell lymphoma: results from the phase II GAUGUIN study. J Clin Oncol. 2013 Aug 10;31(23):2912-9. Epub 2013 Jul 8. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Subgroup analysis: Salles GA, Morschhauser F, Solal-Céligny P, Thieblemont C, Lamy T, Tilly H, Gyan E, Lei G, Wenger M, Wassner-Fritsch E, Cartron G. Obinutuzumab (GA101) in patients with relapsed/refractory indolent non-Hodgkin lymphoma: results from the phase II GAUGUIN study. J Clin Oncol. 2013 Aug 10;31(23):2920-6. Epub 2013 Jul 8. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Subgroup analysis: Cartron G, de Guibert S, Dilhuydy MS, Morschhauser F, Leblond V, Dupuis J, Mahe B, Bouabdallah R, Lei G, Wenger M, Wassner-Fritsch E, Hallek M. Obinutuzumab (GA101) in relapsed/refractory chronic lymphocytic leukemia: final data from the phase 1/2 GAUGUIN study. Blood. 2014 Oct 2;124(14):2196-202. Epub 2014 Aug 20. link to original article dosing details in manuscript have been reviewed by our editors PubMed
OFAR
OFAR: Oxaliplatin, Fludarabine, Ara-C (Cytarabine), Rituximab
Regimen
Study | Dates of enrollment | Evidence | Efficacy |
---|---|---|---|
Tsimberidou et al. 2008 | 2004-2006 | Phase 1/2 | Likely has true ORR > 20% |
Note: the manuscript does not specify what sequence the rituximab is given in.
Chemotherapy
- Oxaliplatin (Eloxatin) 25 mg/m2 IV over 2 hours once per day on days 1 to 4, given first (see note)
- Fludarabine (Fludara) 30 mg/m2 IV once per day on days 2 & 3, given second, within 30 minutes of completion of oxaliplatin (see note)
- Cytarabine (Ara-C) 1000 mg/m2 IV over 2 hours once per day on days 2 & 3, given third, 4 hours after start of fludarabine (see note)
Targeted therapy
- Rituximab (Rituxan) as follows (see note):
- Cycle 1: 375 mg/m2 IV over 4 to 6 hours once on day 3
- Cycles 2 to 6: 375 mg/m2 IV over 4 to 6 hours once on day 1
Supportive therapy
- Pegfilgrastim (Neulasta) 6 mg SC once on day 6
- Herpes zoster and PCP (Pneumocystis jiroveci pneumonia) prophylaxis used
28-day cycle for up to 6 cycles
References
- Tsimberidou AM, Wierda WG, Plunkett W, Kurzrock R, O'Brien S, Wen S, Ferrajoli A, Ravandi-Kashani F, Garcia-Manero G, Estrov Z, Kipps TJ, Brown JR, Fiorentino A, Lerner S, Kantarjian HM, Keating MJ. Phase I-II study of oxaliplatin, fludarabine, cytarabine, and rituximab combination therapy in patients with Richter's syndrome or fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol. 2008 Jan 10;26(2):196-203. link to original article dosing details in abstract have been reviewed by our editors PubMed
PCR
PCR: Pentostatin, Cyclophosphamide, Rituximab
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Lamanna et al. 2006 | 2001-2004 | Phase 2 |
Chemotherapy
- Pentostatin (Nipent) 4 mg/m2 IV once on day 1, given second
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1, given first
Targeted therapy
- Rituximab (Rituxan) given third, as follows:
- Cycles 2 to 6: 375 mg/m2 IV once on day 1
Supportive therapy
- At least 1.5 L of IVF
- Dexamethasone (Decadron) 20 mg (route not specified) once on day 1
- Granisetron 2 mg (route not specified) once on day 1
- Filgrastim (Neupogen) by the following weight-based criteria:
- 70 kg or less: 300 mcg SC once per day from day 3 until ANC greater than 5000/μL once or 1500/μL for 2 days
- More than 70 kg: 480 mcg SC once per day from day 3 until ANC greater than 5000/μL once or 1500/μL for 2 days
- Trimethoprim-Sulfamethoxazole (Bactrim DS) 1 DS tablet PO twice per day on MWF
- Acyclovir (Zovirax) 800 mg PO twice per day
21-day cycle for 6 cycles
References
- Lamanna N, Kalaycio M, Maslak P, Jurcic JG, Heaney M, Brentjens R, Zelenetz AD, Horgan D, Gencarelli A, Panageas KS, Scheinberg DA, Weiss MA. Pentostatin, cyclophosphamide, and rituximab is an active, well-tolerated regimen for patients with previously treated chronic lymphocytic leukemia. J Clin Oncol. 2006 Apr 1;24(10):1575-81. Epub 2006 Mar 6. link to original article dosing details in manuscript have been reviewed by our editors PubMed
Pirtobrutinib monotherapy
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Mato et al. 2023 (BRUINCLL) | 2019-03-21 to 2022-07-29 | Phase 1/2 (RT) |
Note: This was the RP2D.
References
- BRUINCLL: Mato AR, Woyach JA, Brown JR, Ghia P, Patel K, Eyre TA, Munir T, Lech-Maranda E, Lamanna N, Tam CS, Shah NN, Coombs CC, Ujjani CS, Fakhri B, Cheah CY, Patel MR, Alencar AJ, Cohen JB, Gerson JN, Flinn IW, Ma S, Jagadeesh D, Rhodes JM, Hernandez-Ilizaliturri F, Zinzani PL, Seymour JF, Balbas M, Nair B, Abada P, Wang C, Ruppert AS, Wang D, Tsai DE, Wierda WG, Jurczak W. Pirtobrutinib after a Covalent BTK Inhibitor in Chronic Lymphocytic Leukemia. N Engl J Med. 2023 Jul 6;389(1):33-44. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT03740529
R-BAC
R-BAC: Rituximab, Bendamustine, Ara-C (Cytarabine)
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Visco et al. 2013 | 2010-2012 | Pilot, fewer than 20 patients reported |
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 1
- Cycles 2 to 4: 500 mg/m2 IV once on day 1
Chemotherapy
- Bendamustine 70 mg/m2 IV once per day on days 1 & 2
- Cytarabine (Ara-C) 800 mg/m2 IV over 2 hours once per day on days 1 to 3, beginning 2 hours after bendamustine
Supportive therapy
- Primary prophylaxis with granulocyte colony-stimulating factor was routinely used starting from Day 5 after chemotherapy completion, and lasting for 3 to 6 days or until neutrophil count recovery.
28-day cycle for up to 4 cycles
References
- Visco C, Finotto S, Pomponi F, Sartori R, Laveder F, Trentin L, Paolini R, Di Bona E, Ruggeri M, Rodeghiero F. The combination of rituximab, bendamustine, and cytarabine for heavily pretreated relapsed/refractory cytogenetically high-risk patients with chronic lymphocytic leukemia. Am J Hematol. 2013 Apr;88(4):289-93. Epub 2013 Feb 28. link to original article dosing details in manuscript have been reviewed by our editors PubMed
Ruxolitinib monotherapy
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Jain et al. 2017 (MDACC 2013-0044) | 2014-2015 | Phase 2, fewer than 20 pts in this subgroup |
Note: this was a trial focused on symptom control, not efficacy.
References
- MDACC 2013-0044: Jain P, Keating M, Renner S, Cleeland C, Xuelin H, Gonzalez GN, Harris D, Li P, Liu Z, Veletic I, Rozovski U, Jain N, Thompson P, Bose P, DiNardo C, Ferrajoli A, O'Brien S, Burger J, Wierda W, Verstovsek S, Kantarjian H, Estrov Z. Ruxolitinib for symptom control in patients with chronic lymphocytic leukaemia: a single-group, phase 2 trial. Lancet Haematol. 2017 Feb;4(2):e67-e74. Epub 2017 Jan 11. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT02131584
Venetoclax monotherapy
Regimen variant #1, standard lead-in
FDA-recommended dose |
Study | Dates of enrollment | Evidence | Efficacy |
---|---|---|---|
Roberts et al. 2015 (M12-175) | 2011-2014 | Phase 1/2 (RT) | ORR: 79% |
Stilgenbauer et al. 2016 (M13-982) | 2013-2014 | Phase 2 (RT) | ORR: 79% (95% CI, 70.5-87) |
Jones et al. 2017 (M14-032 ibrutinib cohort) | 2014-2016 | Phase 2 (RT) | ORR: 65% (95% CI 53-74) |
Coutre et al. 2018 (M14-032 idelalisib cohort) | 2014 to not reported | Phase 2 (RT) | ORR: 67% |
This is the dosing schedule used in the phase II expansion cohort of M12-175. See papers for supportive care details during initial dosing.
Biomarker eligibility criteria
- M13-982: 17p deletion
Targeted therapy
- Venetoclax (Venclexta) as follows:
- Cycle 1: 20 mg PO once per day on days 1 to 7, then 50 mg PO once per day on days 8 to 14, then 100 mg PO once per day on days 15 to 21, then 200 mg PO once per day on days 22 to 28
- Cycle 2 onwards: 400 mg PO once per day on days 1 to 28
28-day cycles
Regimen variant #2, modified lead-in
Study | Dates of enrollment | Evidence | Efficacy |
---|---|---|---|
Coutre et al. 2018 (M14-032 idelalisib cohort) | 2014 to not reported | Phase 2 | ORR: 67% |
Note: This dosing schedule was intended for high-risk patients with "clinical signs of progression during screening." See paper for supportive care details during initial dosing.
Targeted therapy
- Venetoclax (Venclexta) as follows:
- Cycle 1: 20 mg PO once on day 1, then 50 mg PO once per day on days 2 & 3, then 100 mg PO once per day on days 4 to 7, then 200 mg PO once per day on days 8 to 14, then 400 mg PO once per day on days 15 to 28
- Cycle 2 onwards: 400 mg PO once per day on days 1 to 28
28-day cycles
References
- M12-175: Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF, Kipps TJ, Anderson MA, Brown JR, Gressick L, Wong S, Dunbar M, Zhu M, Desai MB, Cerri E, Heitner Enschede S, Humerickhouse RA, Wierda WG, Seymour JF. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016 Jan 28;374(4):311-22. Epub 2015 Dec 6. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01328626
- M13-982: Stilgenbauer S, Eichhorst B, Schetelig J, Coutre S, Seymour JF, Munir T, Puvvada SD, Wendtner CM, Roberts AW, Jurczak W, Mulligan SP, Böttcher S, Mobasher M, Zhu M, Desai M, Chyla B, Verdugo M, Heitner Enschede S, Cerri E, Humerickhouse R, Gordon G, Hallek M, Wierda WG. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 2016 Jun;17(6):768-78. Epub 2016 May 10. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT01889186
- Update: Stilgenbauer S, Eichhorst B, Schetelig J, Hillmen P, Seymour JF, Coutre S, Jurczak W, Mulligan SP, Schuh A, Assouline S, Wendtner CM, Roberts AW, Davids MS, Bloehdorn J, Munir T, Böttcher S, Zhou L, Salem AH, Desai M, Chyla B, Arzt J, Kim SY, Verdugo M, Gordon G, Hallek M, Wierda WG. Venetoclax for patients with chronic lymphocytic leukemia with 17p deletion: results from the full population of a phase II pivotal trial. J Clin Oncol. 2018 Jul 1;36(19):1973-1980. Epub 2018 May 1. link to original article PubMed
- M14-032 ibrutinib cohort: Jones JA, Mato AR, Wierda WG, Davids MS, Choi M, Cheson BD, Furman RR, Lamanna N, Barr PM, Zhou L, Chyla B, Salem AH, Verdugo M, Humerickhouse RA, Potluri J, Coutre S, Woyach J, Byrd JC. Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial. Lancet Oncol. 2018 Jan;19(1):65-75. Epub 2017 Dec 12. link to original article link to PMC article PubMed NCT02141282
- M14-032 idelalisib cohort: Coutre S, Choi M, Furman RR, Eradat H, Heffner L, Jones JA, Chyla B, Zhou L, Agarwal S, Waskiewicz T, Verdugo M, Humerickhouse RA, Potluri J, Wierda WG, Davids MS. Venetoclax for patients with chronic lymphocytic leukemia who progressed during or after idelalisib therapy. Blood. 2018 Apr 12;131(15):1704-1711. Epub 2018 Jan 5. link to original article dosing details in supplement have been reviewed by our editors link to PMC article PubMed NCT02141282
Zanubrutinib & Obinutuzumab
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Tam et al. 2020 | 2016 to not reported | Phase 1b, >20 pts in this subgroup |
Targeted therapy
- Zanubrutinib (Brukinsa) 160 mg PO twice per day or 320 mg PO once per day on days 1 to 28
- Obinutuzumab (Gazyva) as follows:
- Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15
- Cycles 2 to 6: 1000 mg IV once on day 1
28-day cycles
References
- Tam CS, Quach H, Nicol A, Badoux X, Rose H, Prince HM, Leahy MF, Eek R, Wickham N, Patil SS, Huang J, Prathikanti R, Cohen A, Elstrom R, Reed W, Schneider J, Flinn IW. Zanubrutinib (BGB-3111) plus obinutuzumab in patients with chronic lymphocytic leukemia and follicular lymphoma. Blood Adv. 2020 Oct 13;4(19):4802-4811. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT02569476
Consolidation and/or maintenance after subsequent lines of therapy
Busulfan & Fludarabine, then allo HSCT
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Slavin et al. 1998 | Not reported | Phase 2 |
Schetelig et al. 2003 | 1998-2001 | Phase 2 |
Chemotherapy
- Fludarabine (Fludara) 30 mg/m2 IV once per day on days -10 to -5 (6 consecutive days)
- Busulfan (Myleran) 4 mg/kg/day PO on days -6 to -5 (2 consecutive days)
GVHD prophylaxis
- ATG-Fresenius 10 mg/kg IV once per day on days -4 to -1 (4 consecutive days)
Immunotherapy
- Allogeneic stem cells transfused on day 0
One course
References
- Slavin S, Nagler A, Naparstek E, Kapelushnik Y, Aker M, Cividalli G, Varadi G, Kirschbaum M, Ackerstein A, Samuel S, Amar A, Brautbar C, Ben-Tal O, Eldor A, Or R. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood. 1998 Feb 1;91(3):756-63. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Schetelig J, Thiede C, Bornhauser M, Schwerdtfeger R, Kiehl M, Beyer J, Sayer HG, Kroger N, Hensel M, Scheffold C, Held TK, Hoffken K, Ho AD, Kienast J, Neubauer A, Zander AR, Fauser AA, Ehninger G, Siegert W; Cooperative German Transplant Study Group. Evidence of a graft-versus-leukemia effect in chronic lymphocytic leukemia after reduced-intensity conditioning and allogeneic stem-cell transplantation: the Cooperative German Transplant Study Group. J Clin Oncol. 2003 Jul 15;21(14):2747-53. link to original article contains reference to protocol PubMed
Cyclophosphamide & Fludarabine (FC), then allo HSCT
FluCy: Fludarabine & Cyclophosphamide
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Dreger et al. 2010 (GCLLSG CLL3X) | 2001-2007 | Phase 2 |
Chemotherapy
- Fludarabine (Fludara) 30 mg/m2 IV once per day on days -6 to -2 (5 consecutive days)
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once per day on days -6 to -2 (5 consecutive days)
GVHD prophylaxis
- ATG-Fresenius by the following donor-based criteria:
- Unrelated donors: 10 mg/kg/day IV on days -4 to -1 (4 consecutive days)
Immunotherapy
- Allogeneic stem cells transfused on day 0
One course
References
- GCLLSG CLL3X: Dreger P, Döhner H, Ritgen M, Böttcher S, Busch R, Dietrich S, Bunjes D, Cohen S, Schubert J, Hegenbart U, Beelen D, Zeis M, Stadler M, Hasenkamp J, Uharek L, Scheid C, Humpe A, Zenz T, Winkler D, Hallek M, Kneba M, Schmitz N, Stilgenbauer S; German CLL Study Group. Allogeneic stem cell transplantation provides durable disease control in poor-risk chronic lymphocytic leukemia: long-term clinical and MRD results of the German CLL Study Group CLL3X trial. Blood. 2010 Oct 7;116(14):2438-47. Epub 2010 Jul 1. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00281983
- Update: Dreger P, Schnaiter A, Zenz T, Böttcher S, Rossi M, Paschka P, Bühler A, Dietrich S, Busch R, Ritgen M, Bunjes D, Zeis M, Stadler M, Uharek L, Scheid C, Hegenbart U, Hallek M, Kneba M, Schmitz N, Döhner H, Stilgenbauer S. TP53, SF3B1, and NOTCH1 mutations and outcome of allotransplantation for chronic lymphocytic leukemia: six-year follow-up of the GCLLSG CLL3X trial. Blood. 2013 Apr 18;121(16):3284-8. Epub 2013 Feb 22. link to original article PubMed
- Update: Krämer I, Stilgenbauer S, Dietrich S, Böttcher S, Zeis M, Stadler M, Bittenbring J, Uharek L, Scheid C, Hegenbart U, Ho A, Hallek M, Kneba M, Schmitz N, Döhner H, Dreger P. Allogeneic hematopoietic cell transplantation for high-risk CLL: 10-year follow-up of the GCLLSG CLL3X trial. Blood. 2017 Sep 21;130(12):1477-1480. Epub 2017 Jul 17. link to original article PubMed
Fludarabine & TBI, then allo HSCT
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Sorror et al. 2005 | 1997-2003 | Phase 2 |
Chemotherapy
- Fludarabine (Fludara) 30 mg/m2 IV once per day on days -4 to -2
Radiotherapy
- Total body irradiation (TBI) 200 cGy at a rate of 7 cGy/min on day 0
Immunotherapy
- Allogeneic stem cells transfused on day 0
GVHD prophylaxis
- Cyclosporine 6.25 mg/kg PO twice per day starting 4 to 6 hours after transplant, tapered at day 100 over 80 days (if no GVHD)
- Mycophenolate mofetil (CellCept) 15 mg/kg PO twice per day starting 4 to 6 hours after transplant, tapered at day 40 over 56 days (if no GVHD)
One course
References
- Sorror ML, Maris MB, Sandmaier BM, Storer BE, Stuart MJ, Hegenbart U, Agura E, Chauncey TR, Leis J, Pulsipher M, McSweeney P, Radich JP, Bredeson C, Bruno B, Langston A, Loken MR, Al-Ali H, Blume KG, Storb R, Maloney DG. Hematopoietic cell transplantation after nonmyeloablative conditioning for advanced chronic lymphocytic leukemia. J Clin Oncol. 2005 Jun 1;23(16):3819-29. Epub 2005 Apr 4. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Update: Sorror ML, Storer BE, Sandmaier BM, Maris M, Shizuru J, Maziarz R, Agura E, Chauncey TR, Pulsipher MA, McSweeney PA, Wade JC, Bruno B, Langston A, Radich J, Niederwieser D, Blume KG, Storb R, Maloney DG. Five-year follow-up of patients with advanced chronic lymphocytic leukemia treated with allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. J Clin Oncol. 2008 Oct 20;26(30):4912-20. Epub 2008 Sep 15. link to original article link to PMC article PubMed
Lenalidomide monotherapy
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Badoux et al. 2013 (MDACC 2007-0208) | 2008-2009 | Phase 2 |
Vitale et al. 2016 (MDACC 2009-0283) | 2010-2011 | Phase 2 |
Preceding treatment
- MDACC 2007-0208: Salvage R2 x 12
- MDACC 2009-0283: Salvage Lenalidomide & Ofatumumab x 24
References
- MDACC 2007-0208: Badoux XC, Keating MJ, Wen S, Wierda WG, O'Brien SM, Faderl S, Sargent R, Burger JA, Ferrajoli A. Phase II Study of Lenalidomide and Rituximab As Salvage Therapy for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia. J Clin Oncol. 2013 Feb 10;31(5):584-91. Epub 2012 Dec 26. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00759603
- MDACC 2009-0283: Vitale C, Falchi L, Ten Hacken E, Gao H, Shaim H, Van Roosbroeck K, Calin G, O'Brien S, Faderl S, Wang X, Wierda WG, Rezvani K, Reuben JM, Burger JA, Keating MJ, Ferrajoli A. Ofatumumab and Lenalidomide for Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia: Correlation between Responses and Immune Characteristics. Clin Cancer Res. 2016 May 15;22(10):2359-67. Epub 2016 Jan 5. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01002755
Ofatumumab monotherapy
Regimen variant #1
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
van Oers et al. 2015 (PROLONG) | 2010-2014 | Phase 3 (E-RT-esc) | Observation | Superior PFS (primary endpoint) Median PFS: 29.4 vs 15.2 mo (HR 0.50, 95% CI 0.38-0.66) |
Note: Treatment offered to patients in their second or third CR or PR; prior treatment was not specified.
Targeted therapy
- Ofatumumab (Arzerra) as follows:
- Cycle 1: 300 mg IV once on day 1, then 1000 mg IV once on day 7
- Cycles 2 to 13: 1000 mg IV once on day 1
Supportive therapy
- Acetaminophen (Tylenol) 1000 mg PO once per infusion, 30 to 120 minutes prior to ofatumumab
- Diphenhydramine (Benadryl) (or equivalent antihistamine) 50 mg IV or PO once per infusion, 30 to 120 minutes prior to ofatumumab
- Prednisolone (Millipred) (or equivalent glucocorticoid) 50 mg IV once per infusion, 30 to 120 minutes prior to ofatumumab
8-week cycle for up to 13 cycles (2 years)
Regimen variant #2
Study | Dates of enrollment | Evidence |
---|---|---|
Österborg et al. 2015 (GEN416) | 2009-2011 | Phase 2 |
Preceding treatment
- Second-line Ofatumumab x 8
Targeted therapy
- Ofatumumab (Arzerra) 2000 mg IV once on day 1
Supportive therapy
- Acetaminophen (Tylenol) 1000 mg PO once on day 1, prior to ofatumumab
- Cetirizine (Zyrtec) (or equivalent antihistamine) 10 mg PO once on day 1, prior to ofatumumab
Monthly cycle for up to 24 cycles (2 years)
References
- GEN416: Österborg A, Wierda WG, Mayer J, Hess G, Hillmen P, Schetelig J, Schuh A, Smolej L, Beck C, Dreyfus B, Hellman A, Kozlowski P, Pfreundschuh M, Rizzi R, Spacek M, Phillips JL, Gupta IV, Williams V, Jewell RC, Nebot N, Lisby S, Dyer MJ. Ofatumumab retreatment and maintenance in fludarabine-refractory chronic lymphocytic leukaemia patients. Br J Haematol. 2015 Jul;170(1):40-9. Epub 2015 Mar 30. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00802737
- PROLONG: van Oers MH, Kuliczkowski K, Smolej L, Petrini M, Offner F, Grosicki S, Levin MD, Gupta I, Phillips J, Williams V, Manson S, Lisby S, Geisler C; PROLONG study investigators. Ofatumumab maintenance versus observation in relapsed chronic lymphocytic leukaemia (PROLONG): an open-label, multicentre, randomised phase 3 study. Lancet Oncol. 2015 Oct;16(13):1370-9. Epub 2015 Sep 13. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00802737
Rituximab monotherapy
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Greil et al. 2016 (AGMT CLL-8a) | 2010-2013 | Phase 3 (E-esc) | Observation | Superior PFS (primary endpoint) Median PFS: 47 vs 35.5 mo (HR 0.50, 95% CI 0.33-0.75) |
Preceding treatment
- Second-line rituximab-containing chemoimmunotherapy
Targeted therapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
3-month cycle for 8 cycles (2 years)
References
- AGMT CLL-8a: Greil R, Obrtlíková P, Smolej L, Kozák T, Steurer M, Andel J, Burgstaller S, Mikušková E, Gercheva L, Nösslinger T, Papajík T, Ladická M, Girschikofsky M, Hrubiško M, Jäger U, Fridrik M, Pecherstorfer M, Králiková E, Burcoveanu C, Spasov E, Petzer A, Mihaylov G, Raynov J, Oexle H, Zabernigg A, Flochová E, Palášthy S, Stehlíková O, Doubek M, Altenhofer P, Pleyer L, Melchardt T, Klingler A, Mayer J, Egle A. Rituximab maintenance versus observation alone in patients with chronic lymphocytic leukaemia who respond to first-line or second-line rituximab-containing chemoimmunotherapy: final results of the AGMT CLL-8a Mabtenance randomised trial. Lancet Haematol. 2016 Jul;3(7):e317-29. Epub 2016 Jun 16. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01118234
Prognosis
These are various staging and risk prediction systems that are in approximate chronological order.
Original Rai staging (1975)
- Stage 0: bone marrow and blood lymphocytosis only
- Stage I: lymphocytosis with enlarged nodes
- Stage II: lymphocytosis with enlarged spleen or liver or both
- Stage III: lymphocytosis with anemia
- Stage IV: lymphocytosis with thrombocytopenia
- Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. Clinical staging of chronic lymphocytic leukemia. Blood. 1975 Aug;46(2):219-34. link to original article PubMed
Binet staging (1981)
- Group A: no anemia, no thrombocytopenia, less than three involved areas
- Group B: no anemia, no thrombocytopenia, three or more involved areas (counting as one each of the following: axillary, cervical, inguinal, lymph nodes, whether unilateral or bilateral, spleen and liver)
- Group C: anemia (hemoglobin less than 10 g/dL) and/or thrombocytopenia (platelets less than 100 x 109/L)
- Binet JL, Auquier A, Dighiero G, Chastang C, Piguet H, Goasguen J, Vaugier G, Potron G, Colona P, Oberling F, Thomas M, Tchernia G, Jacquillat C, Boivin P, Lesty C, Duault MT, Monconduit M, Belabbes S, Gremy F. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer. 1981 Jul 1;48(1):198-206. link to original article PubMed
Risk by cytogenetics
- Classic NEJM paper establishing abnormal karyotype as an adverse prognostic marker
- Han T, Ozer H, Sadamori N, Emrich L, Gomez GA, Henderson ES, Bloom ML, Sandberg AA. Prognostic importance of cytogenetic abnormalities in patients with chronic lymphocytic leukemia. N Engl J Med. 1984 Feb 2;310(5):288-92. to original article PubMed
- Large retrospective series looking at cytogenetic complexity
- Baliakas P, Jeromin S, Iskas M, Puiggros A, Plevova K, Nguyen-Khac F, Davis Z, Rigolin GM, Visentin A, Xochelli A, Delgado J, Baran-Marszak F, Stalika E, Abrisqueta P, Durechova K, Papaioannou G, Eclache V, Dimou M, Iliakis T, Collado R, Doubek M, Calasanz MJ, Ruiz-Xiville N, Moreno C, Jarosova M, Leeksma AC, Panayiotidis P, Podgornik H, Cymbalista F, Anagnostopoulos A, Trentin L, Stavroyianni N, Davi F, Ghia P, Kater AP, Cuneo A, Pospisilova S, Espinet B, Athanasiadou A, Oscier D, Haferlach C, Stamatopoulos K; ERIC, the European Research Initiative on CLL. Cytogenetic complexity in chronic lymphocytic leukemia: definitions, associations, and clinical impact. Blood. 2019 Mar 14;133(11):1205-1216. Epub 2019 Jan 2. link to original article link to PMC article PubMed
Risk by lymphocyte doubling time
- Montserrat E, Sanchez-Bisono J, Viñolas N, Rozman C. Lymphocyte doubling time in chronic lymphocytic leukaemia: analysis of its prognostic significance. Br J Haematol. 1986 Mar;62(3):567-75. link to original article PubMed
- Molica S, Alberti A. Prognostic value of the lymphocyte doubling time in chronic lymphocytic leukemia. Cancer. 1987 Dec 1;60(11):2712-6. link to original article PubMed
Risk by FISH
- Classic 2000 NEJM paper establishing that 17p deletion has the worst prognosis:
- Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L, Döhner K, Bentz M, Lichter P. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000 Dec 28;343(26):1910-6. link to original article PubMed
- This article and abstract explore the significance of 13q deletions in more detail:
- Van Dyke DL, Shanafelt TD, Call TG, Zent CS, Smoley SA, Rabe KG, Schwager SM, Sonbert JC, Slager SL, Kay NE. A comprehensive evaluation of the prognostic significance of 13q deletions in patients with B-chronic lymphocytic leukaemia. Br J Haematol. 2010 Feb;148(4):544-50. Epub 2009 Nov 6. link to original article link to PMC article PubMed
- Abstract: Claudia Haferlach, Melanie Zenger, Vera Grossmann, Frank Dicker, Sabine Jeromin, Alexander Kohlmann, Susanne Schnittger, Wolfgang Kern, Torsten Haferlach. The Impact of Homozygosity and Size of the 13q Deletion in Patients with CLL. Blood 2012 120:3892 abstract 3892 link to abstract
Risk by TP53 mutation
- Zenz T, Eichhorst B, Busch R, Denzel T, Häbe S, Winkler D, Bühler A, Edelmann J, Bergmann M, Hopfinger G, Hensel M, Hallek M, Döhner H, Stilgenbauer S. TP53 mutation and survival in chronic lymphocytic leukemia. J Clin Oncol. 2010 Oct 10;28(29):4473-9. Epub 2010 Aug 9. link to original article PubMed
Risk by CD38 expression
- Damle RN, Wasil T, Fais F, Ghiotto F, Valetto A, Allen SL, Buchbinder A, Budman D, Dittmar K, Kolitz J, Lichtman SM, Schulman P, Vinciguerra VP, Rai KR, Ferrarini M, Chiorazzi N. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood. 1999 Sep 15;94(6):1840-7. link to original article PubMed
- Review: Malavasi F, Deaglio S, Damle R, Cutrona G, Ferrarini M, Chiorazzi N. CD38 and chronic lymphocytic leukemia: a decade later. Blood. 2011 Sep 29;118(13):3470-8. link to original article link to PMC article PubMed
Risk by ZAP-70 expression (2003)
- Crespo M, Bosch F, Villamor N, Bellosillo B, Colomer D, Rozman M, Marcé S, López-Guillermo A, Campo E, Montserrat E. ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med. 2003 May 1;348(18):1764-75. link to original article PubMed
Prognostic scoring system using molecular and cytogenetic features (2012)
- Rossi D, Rasi S, Spina V, Bruscaggin A, Monti S, Ciardullo C, Deambrogi C, Khiabanian H, Serra R, Bertoni F, Forconi F, Laurenti L, Marasca R, Dal-Bo M, Rossi FM, Bulian P, Nomdedeu J, Del Poeta G, Gattei V, Pasqualucci L, Rabadan R, Foà R, Dalla-Favera R, Gaidano G. Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia. Blood. 2013 Feb 21;121(8):1403-12. Epub 2012 Dec 13. link to original article link to PMC article PubMed
CLL-IPI (2016)
- International CLL-IPI working group. An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncol. 2016 Jun;17(6):779-90. Epub 2016 May 13. link to original article PubMed
Prognostic scoring system using clinical features (2019)
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