Difference between revisions of "Staging page"

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[[#top|Back to Top]]
 
[[#top|Back to Top]]
 
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{{#lst:Section editor transclusions|giei}}
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! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''
 
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! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''
 
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|-
 
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| style="background-color:#F0F0F0; width:15%" |[[File:Arnason.jpg|frameless|upright=0.3|center]]
 
−
| style="width:35%" |<big>Jon Arnason, MD<br>Beth Israel Deaconess Medical Center<br>Boston, MA</big>
 
−
|style="background-color:#F0F0F0"|[[File:Sanjaisharma.jpg|frameless|upright=0.3|center]]
 
−
|<big>[[User:Sanjaisharma|Sanjai Sharma, MD]]<br>Sequoia Regional Cancer Center<br>Visalia, CA</big>
 
−
|-
 
−
|}
 
−
''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]]. 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 CLL or in mixed populations of CLL and SLL patients.'''
 
 
{| class="wikitable" style="float:right; margin-right: 5px;"
 
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|-
 
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<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>
 
<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>
 
|}
 
|}
 +
<big>Note: there is some overlap, especially in the earlier literature, between treatment regimens for cholangiocarcinoma and those for '''[[pancreatic cancer|pancreatic adenocarcinoma]]''', '''[[periampullary adenocarcinoma]]''', and '''[[gallbladder cancer]]'''; please see those pages for additional regimens.</big><br>
 +
''Are you looking for a regimen but can't find it here? For placebo or observational studies in this condition, please visit [[Cholangiocarcinoma - null regimens|this page]]. If you still can't find it, please let us know so we can add it!''
 
{{TOC limit|limit=3}}
 
{{TOC limit|limit=3}}
 
=Guidelines=
 
=Guidelines=
−
==ASBMT==
+
==[https://asco.org/ ASCO]==
−
*'''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]
+
*'''2019:''' Shroff et al. [https://doi.org/10.1200/JCO.18.02178 Adjuvant therapy for resected biliary tract cancer: ASCO Clinical Practice Guideline]
 
==[http://www.esmo.org/ ESMO]==
 
==[http://www.esmo.org/ ESMO]==
−
*'''2016:''' Ladetto et al. [http://annonc.oxfordjournals.org/content/27/12/2149.full.pdf+html 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]
+
*'''2016:''' Valle et al. [https://www.esmo.org/Guidelines/Gastrointestinal-Cancers/Biliary-Cancer Biliary cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]
−
*'''2015:''' Eichhorst et al. [http://annonc.oxfordjournals.org/content/26/suppl_5/v78.full.pdf+html Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/26314781 PubMed]
 
−
*'''2013:''' Ghielmini et al. [http://annonc.oxfordjournals.org/content/24/3/561.full.pdf+html 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://pubmed.ncbi.nlm.nih.gov/23175624 PubMed]
 
−
=="How I Treat"==
 
−
*'''2021:''' Lew et al. [https://ashpublications.org/blood/article-abstract/138/5/361/475780/How-I-treat-chronic-lymphocytic-leukemia-after How I treat chronic lymphocytic leukemia after venetoclax]
 
−
*'''2019:''' Stephens DM, Byrd JC. How I manage ibrutinib intolerance and complications in patients with chronic lymphocytic leukemia. Blood. 2019 Mar 21;133(12):1298-1307. [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6428663/ link to PMC article]
 
−
*'''2018:''' Brown JR. How I treat CLL patients with ibrutinib. Blood. 2018 Jan 25;131(4):379-386. [https://doi.org/10.1182/blood-2017-08-764712 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29255067 PubMed]
 
−
==International Workshop on Chronic Lymphocytic Leukemia (iwCLL)==
 
−
*'''2018:''' Hallek  et al. [http://www.bloodjournal.org/content/131/25/2745.long iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL] [https://pubmed.ncbi.nlm.nih.gov/29540348 PubMed]
 
−
===Older===
 
−
*'''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]
 
−
*'''1996:''' Cheson et al. [http://www.bloodjournal.org/content/87/12/4990.long 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]
 
 
==[https://www.nccn.org/ NCCN]==
 
==[https://www.nccn.org/ NCCN]==
−
*[https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf NCCN Guidelines - Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma]
+
*[https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf NCCN Guidelines - Hepatobiliary Cancers]
−
=First-line therapy, randomized data=
+
=Adjuvant therapy=
−
==Acalabrutinib monotherapy {{#subobject:85jgb3|Regimen=1}}==
+
==Capecitabine monotherapy {{#subobject:f4c3d9|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:cjbu87|Variant=1}}===
+
===Regimen {{#subobject:3a3bdf|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 20%"|Study
+
! style="width: 20%" |Study
−
!style="width: 20%"|Years of enrollment
+
! style="width: 20%" |Years of enrollment
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|Comparator
+
! style="width: 20%" |Comparator
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+
! 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<br>Median PFS: NYR vs 22.6 mo<br>(HR 0.20, 95% CI 0.13-0.30)
 
 
|-
 
|-
 +
|[https://doi.org/10.1016/S1470-2045(18)30915-X Primrose et al. 2019 (BILCAP)]
 +
|2006-2014
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[Cholangiocarcinoma_-_null_regimens#Observation|Observation]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<sup>1</sup><br>Median OS: 49.6 vs 36.1 mo<br>(aHR 0.84, 95% CI 0.67-1.06)
 
|}
 
|}
−
''Note: Byrd et al. 2021 reports on a treatment-naive cohort from a trial that mostly enrolled patients in relapse.''
+
''<sup>1</sup>Reported efficacy is based on the 2022 update.''<br>
 +
''Note: Chemotherapy start date 8 to 16 weeks after surgery''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery|Surgical resection]] with macroscopically curative resection
 +
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Targeted therapy====
+
====Chemotherapy====
−
*[[Acalabrutinib (Calquence)]] 100 mg PO twice per day or 200 mg PO once per day
+
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO twice per day on days 1 to 14
−
'''Continued indefinitely'''
+
'''21-day cycle for 8 cycles'''
 
</div></div>
 
</div></div>
 
===References===
 
===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] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/32305093 PubMed] NCT02475681
+
#'''BILCAP:''' Primrose JN, Fox RP, Palmer DH, Malik HZ, Prasad R, Mirza D, Anthony A, Corrie P, Falk S, Finch-Jones M, Wasan H, Ross P, Wall L, Wadsley J, Evans JTR, Stocken D, Praseedom R, Ma YT, Davidson B, Neoptolemos JP, Iveson T, Raftery J, Zhu S, Cunningham D, Garden OJ, Stubbs C, Valle JW, Bridgewater J; BILCAP study group. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol. 2019 May;20(5):663-673. Epub 2019 Mar 25. Erratum in: Lancet Oncol. 2019 Apr 2. [https://doi.org/10.1016/S1470-2045(18)30915-X link to original article] [https://pubmed.ncbi.nlm.nih.gov/30922733 PubMed] NCT00363584
−
# '''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] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/33786588/ PubMed] NCT02029443
+
##'''Update:''' Bridgewater J, Fletcher P, Palmer DH, Malik HZ, Prasad R, Mirza D, Anthony A, Corrie P, Falk S, Finch-Jones M, Wasan H, Ross P, Wall L, Wadsley J, Evans TR, Stocken D, Stubbs C, Praseedom R, Ma YT, Davidson B, Neoptolemos J, Iveson T, Cunningham D, Garden OJ, Valle JW, Primrose J; BILCAP study group. Long-Term Outcomes and Exploratory Analyses of the Randomized Phase III BILCAP Study. J Clin Oncol. 2022 Jun 20;40(18):2048-2057. Epub 2022 Mar 22. [https://doi.org/10.1200/jco.21.02568 link to original article] [https://pubmed.ncbi.nlm.nih.gov/35316080/ PubMed]
−
==Acalabrutinib & Obinutuzumab {{#subobject:85jajb|Regimen=1}}==
+
==Capecitabine & Gemcitabine {{#subobject:17f9f2|Regimen=1}}==
 +
GemCap: '''<u>Gem</u>'''citabine & '''<u>Cap</u>'''ecitabine
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:cjb857|Variant=1}}===
+
===Regimen {{#subobject:e6a3e3|Variant=1}}===
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
!style="width: 20%"|Study
+
!style="width: 33%"|Study
−
!style="width: 20%"|Years of enrollment
+
!style="width: 33%"|Years of enrollment
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 33%"|[[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)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4534524/ Ben-Josef et al. 2015 (SWOG S0809)]
−
|rowspan=2|2015-2017
+
|2008-2012
−
|rowspan=2 style="background-color:#1a9851"|Phase 3 (E-RT-switch-ooc)
+
| style="background-color:#91cf61" |Phase 2
−
|1. [[#Acalabrutinib_monotherapy|Acalabrutinib]]
 
−
|style="background-color:#d3d3d3"|Not reported
 
−
|-
 
−
|2. [[#Chlorambucil_.26_Obinutuzumab_.28GClb.29|Chlorambucil & Obinutuzumab]]
 
−
|style="background-color:#1a9850"|Superior PFS<br>Median PFS: NYR vs 22.6 mo<br>(HR 0.10, 95% CI 0.06-0.17)
 
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Surgical_resection|Surgical resection]]
 +
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Targeted therapy====
+
====Chemotherapy====
−
*[[Acalabrutinib (Calquence)]] 100 mg PO twice per day
+
*[[Capecitabine (Xeloda)]] 750 mg/m<sup>2</sup>/day PO twice per day on days 1 to 14
−
*[[Obinutuzumab (Gazyva)]] as follows:
+
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8
−
**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
+
'''21-day cycle for 4 cycles'''
−
**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] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/32305093 PubMed] NCT02475681
 
−
==Alemtuzumab monotherapy {{#subobject:9ca7b3|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:54cc87|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years 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.2007.12.9098 Hillmen et al. 2007 (CAM 307)]
 
−
|2001-2004
 
−
|style="background-color:#1a9851"|Phase 3 (E-RT-switch-ooc)
 
−
|[[Chronic_lymphocytic_leukemia_-_historical#Chlorambucil_monotherapy|Chlorambucil]]
 
−
|style="background-color:#1a9850"|Superior PFS<sup>1</sup><br>Median PFS: 15 vs 12 mo<br>(aHR 0.58, 95% CI 0.43-0.77)
 
−
|-
 
−
|}
 
−
''<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>
−
<div class="toccolours" style="background-color:#b3e2cd">
+
<div class="toccolours" style="background-color:#cbd5e7">
−
====Targeted therapy====
+
====Subsequent treatment====
−
*[[Alemtuzumab (Campath)]] by the following criteria:
+
*[[#Capecitabine_.26_RT_88|Capecitabine & RT]]
−
**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====
 
−
*''See references for details, as they differ by paper.''
 
−
*[[Diphenhydramine (Benadryl)]] 50 mg PO once per infusion, 30 minutes prior to [[Alemtuzumab (Campath)]]
 
−
*[[Acetaminophen (Tylenol)]] 650 mg PO once per infusion, 30 minutes prior to [[Alemtuzumab (Campath)]]
 
−
*[[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'''
 
 
</div></div>
 
</div></div>
 
===References===
 
===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. [https://doi.org/10.1200/jco.2007.12.9098 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/17984186 PubMed] NCT00046683
+
#'''SWOG S0809:''' Ben-Josef E, Guthrie KA, El-Khoueiry AB, Corless CL, Zalupski MM, Lowy AM, Thomas CR Jr, Alberts SR, Dawson LA, Micetich KC, Thomas MB, Siegel AB, Blanke CD. SWOG S0809: A phase II intergroup trial of adjuvant capecitabine and gemcitabine followed by radiotherapy and concurrent capecitabine in extrahepatic cholangiocarcinoma and gallbladder carcinoma. J Clin Oncol. 2015 Aug 20;33(24):2617-22. Epub 2015 May 11. [https://doi.org/10.1200/JCO.2014.60.2219 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4534524/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25964250 PubMed] NCT00789958
−
==Bendamustine monotherapy {{#subobject:694d2f|Regimen=1}}==
+
==Gemcitabine monotherapy {{#subobject:f8c8d9|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:a166c6|Variant=1}}===
+
===Regimen {{#subobject:4c4adf|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 20%"|Study
+
! style="width: 20%" |Study
−
!style="width: 20%"|Years of enrollment
+
! style="width: 20%" |Years of enrollment
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|Comparator
+
! style="width: 20%" |Comparator
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+
! 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<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)]
 
−
|2009-2016
 
−
|style="background-color:#1a9851"|Phase 3 (E-switch-ic)
 
−
|[[Chronic_lymphocytic_leukemia_-_historical#Chlorambucil_monotherapy|Chlorambucil]]
 
−
|style="background-color:#1a9850"|Superior PFS<br>Median PFS: 16.5 vs 9.6 mo
 
 
|-
 
|-
 +
|[https://doi.org/full/10.1002/bjs.10776 Ebata et al. 2018 (BCAT)]
 +
|2007-2011
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[Cholangiocarcinoma_-_null_regimens#Observation|Observation]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 
|}
 
|}
−
<div class="toccolours" style="background-color:#fdcdac">
+
<div class="toccolours" style="background-color:#cbd5e8">
−
====Eligibility criteria====
+
====Preceding treatment====
−
*This regimen was intended for previously untreated CLL patients up to 75 years of age 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]].''
+
*[[Surgery|Surgical resection]] with macroscopically curative resection
 
</div>
 
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Bendamustine]] 100 mg/m<sup>2</sup> IV once per day on days 1 & 2
+
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
 
'''28-day cycle for 6 cycles'''
 
'''28-day cycle for 6 cycles'''
 
</div></div>
 
</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. -->
+
#'''BCAT:''' Ebata T, Hirano S, Konishi M, Uesaka K, Tsuchiya Y, Ohtsuka M, Kaneoka Y, Yamamoto M, Ambo Y, Shimizu Y, Ozawa F, Fukutomi A, Ando M, Nimura Y, Nagino M; Bile Duct Cancer Adjuvant Trial (BCAT) Study Group. Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer. Br J Surg. 2018 Feb;105(3):192-202. [https://doi.org/full/10.1002/bjs.10776 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29405274 PubMed] UMIN000000820
−
# 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] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19652068 PubMed]
+
==Gemcitabine/Fluorouracil & RT {{#subobject:f8c8d9|Regimen=1}}==
−
## '''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]
+
Gemcitabine/Fluorouracil & RT: Gemcitabine alternating with Fluorouracil & '''<u>R</u>'''adiation '''<u>T</u>'''herapy
−
# '''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] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/35031896/ PubMed] NCT01109264
 
−
==Bendamustine & Rituximab (BR) {{#subobject:7542a2|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">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #1, 6 cycles {{#subobject:da5692|Variant=1}}===
+
===Protocol {{#subobject:3fef3f|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
!style="width: 20%"|Study
 
!style="width: 20%"|Study
Line 194: Line 118:
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
!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)]
+
|[http://jama.ama-assn.org/content/299/9/1019.long Regine et al. 2008 (RTOG 9704)]
−
|2007-2008
+
|1998-2002
−
|style="background-color:#91cf61"|Phase 2
+
| style="background-color:#1a9851" |Phase 3 (E-esc)
−
|style="background-color:#d3d3d3"|
+
|[[#Fluorouracil_.26_RT|Fluorouracil & RT]]
−
|style="background-color:#d3d3d3"|
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<sup>1</sup>
−
|-
 
−
|[https://doi.org/10.1016/S1470-2045(16)30051-1 Eichhorst et al. 2016 (GCLLSG CLL10)]
 
−
|2008-2011
 
−
|style="background-color:#1a9851"|Phase 3 (E-switch-ic)
 
−
|[[#FCR|FCR]]
 
−
|style="background-color:#fc8d59"|Seems to have inferior PFS
 
−
|-
 
−
|[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<br>Median PFS: 39.6 vs 29.9 mo<br>(HR 0.52, 95% CI 0.34-0.81)
 
−
|-
 
−
|[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">
+
''<sup>1</sup>Reported efficacy is based on the 2011 update.''<br>
−
====Biomarker eligibility criteria====
+
''Note: this study was in pancreatic cancer but in practice it is extrapolated to cholangiocarcinoma.''
−
*SEQUOIA<sub>CLL</sub>: No 17p deletion
+
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Surgical_resection|Surgical resection]]
 
</div>
 
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Chemotherapy, part 1====
−
*[[Bendamustine]] 90 mg/m<sup>2</sup> IV once per day on days 1 & 2
+
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15
−
====Targeted therapy====
+
'''21-day course, followed in 1 to 2 weeks by:'''
−
*[[Rituximab (Rituxan)]] as follows:
+
====Chemotherapy, part 2====
−
**Cycle 1: 375 mg/m<sup>2</sup> IV once on day 0 or 1
+
*[[Fluorouracil (5-FU)]] 250 mg/m<sup>2</sup>/day IV continuous infusion throughout radiation therapy
−
**Cycle 2 onwards: 500 mg/m<sup>2</sup> IV once on day 1
+
====Radiotherapy====
−
'''28-day cycle for up to 6 cycles'''
+
*Concurrent [[External_beam_radiotherapy|radiation therapy]], 1.8 Gy fractions x 28 fractions given 5 days per week, for a total dose of 50.4 Gy. The last 5.4 Gy of the 50.4 Gy is limited to the tumor bed.
−
</div></div><br>
+
'''6-week course, followed in 3 to 5 weeks by:'''
−
<div class="toccolours" style="background-color:#eeeeee">
+
====Chemotherapy, part 3====
−
===Regimen variant #2, 6 cycles with maintenance rituximab {{#subobject:da5ii2|Variant=1}}===
+
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
+
'''28-day cycle for 3 cycles'''
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years 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)]
 
−
|2013-2014
 
−
|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:#b3e2cd">
 
−
====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)]] 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>
 
</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] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22869884 PubMed] NCT00274989
+
#'''RTOG 9704:''' Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Kudrimoti MR, Fromm ML, Haddock MG, Schaefer P, Willett CG, Rich TA. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008 Mar 5;299(9):1019-26. [http://jama.ama-assn.org/content/299/9/1019.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18319412 PubMed] NCT00003216
−
# '''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]
+
##'''Update:''' Regine WF, Winter KA, Abrams R, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Rich TA, Willett CG. Fluorouracil-based chemoradiation with either gemcitabine or fluorouracil chemotherapy after resection of pancreatic adenocarcinoma: 5-year analysis of the US Intergroup/RTOG 9704 phase III trial. Ann Surg Oncol. 2011 May;18(5):1319-26. Epub 2011 Mar 10. [https://link.springer.com/article/10.1245/s10434-011-1630-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3548408/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21499862 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 [http://www.bloodjournal.org/content/122/21/526 link to abstract] -->
+
==GemOx {{#subobject:f8c8d9|Regimen=1}}==
−
# '''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] [https://pubmed.ncbi.nlm.nih.gov/27216274 PubMed] NCT000769522
+
GemOx: '''<u>Gem</u>'''citabine & '''<u>Ox</u>'''aliplatin
−
# '''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. [http://www.haematologica.org/content/103/4/698 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865431/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29419437 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. [https://doi.org/10.1056/NEJMoa1812836 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6325637/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30501481 PubMed] NCT01886872
 
−
# '''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] [https://pubmed.ncbi.nlm.nih.gov/35657079/ PubMed] 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] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/35810754/ PubMed] NCT03336333
 
−
# '''ACE-CL-311:''' NCT03836261
 
−
# '''BRUIN CLL-313:''' NCT05023980
 
−
# '''CRISTALLO:''' NCT04285567
 
−
# '''GAIA:''' NCT02950051
 
−
==Bendamustine & Rituximab (BR) & Ibrutinib {{#subobject:98jg89|Regimen=1}}==
 
−
BR & Ibrutinib: '''<u>B</u>'''endamustine, '''<u>R</u>'''ituximab, Ibrutinib
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:adhgg4|Variant=1}}===
+
===Regimen {{#subobject:3ghg3f|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 20%"|Study
+
! style="width: 20%" |Study
−
!style="width: 20%"|Years of enrollment
+
! style="width: 20%" |Years of enrollment
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|Comparator
+
! style="width: 20%" |Comparator
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
|-
 
−
|[https://doi.org/10.1056/nejmoa2201817 Wang et al. 2022 (SHINE)]
 
−
|2013-2014
 
−
|style="background-color:#1a9851"|Phase 3 (E-esc)
 
−
|[[#Bendamustine_.26_Rituximab_.28BR.29|BR]]
 
−
| style="background-color:#91cf60" |Seems to have superior PFS<br>Median PFS: 80.6 vs 52.9 mo<br>(HR 0.75, 95% CI 0.59-0.96)
 
 
|-
 
|-
 +
|[https://doi.org/10.1200/JCO.18.00050 Edeline et al. 2019 (PRODIGE 12-ACCORD 18-UNICANCER GI)]
 +
|2009-2014
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[Cholangiocarcinoma_-_null_regimens#Observation|Observation]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of RFS
 
|}
 
|}
−
''Note: the cycle timing changes during rituximab maintenance; the dosing does not change.''
+
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery|Surgical resection]] with macroscopically curative resection
 +
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Bendamustine]] as follows:
+
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once on day 1
−
**Cycles 1 to 6: 90 mg/m<sup>2</sup> IV once per day on days 1 & 2
+
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV once on day 2
−
====Targeted therapy====
+
'''14-day cycle for 12 cycles'''
−
*[[Rituximab (Rituxan)]] as follows:
 
−
**Cycles 1 to 18: 375 mg/m<sup>2</sup> IV once on day 1
 
−
*[[Ibrutinib (Imbruvica)]] 560 mg PO once per day
 
−
'''28-day cycle for 6 cycles, then 8-week cycles'''
 
 
</div></div>
 
</div></div>
 
===References===
 
===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] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/35657079/ PubMed] NCT01776840
+
#'''PRODIGE 12-ACCORD 18-UNICANCER GI:''' Edeline J, Benabdelghani M, Bertaut A, Watelet J, Hammel P, Joly JP, Boudjema K, Fartoux L, Bouhier-Leporrier K, Jouve JL, Faroux R, Guerin-Meyer V, Kurtz JE, Assénat E, Seitz JF, Baumgaertner I, Tougeron D, de la Fouchardière C, Lombard-Bohas C, Boucher E, Stanbury T, Louvet C, Malka D, Phelip JM. Gemcitabine and Oxaliplatin Chemotherapy or Surveillance in Resected Biliary Tract Cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): A Randomized Phase III Study. J Clin Oncol. 2019 Mar 10;37(8):658-667. Epub 2019 Feb 1. [https://doi.org/10.1200/JCO.18.00050 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30707660 PubMed] NCT01313377
−
==Cladribine & Cyclophosphamide (CC) {{#subobject:719404|Regimen=1}}==
+
=Metastatic, first-line therapy=
−
CC: '''<u>C</u>'''ladribine, '''<u>C</u>'''yclophosphamide
+
==CapeOx {{#subobject:cf9acc|Regimen=1}}==
 +
CapeOx: '''<u>Cape</u>'''citabine & '''<u>Ox</u>'''aliplatin
 +
<br>XELOX: '''<u>XEL</u>'''oda (Capecitabine) & '''<u>OX</u>'''aliplatin
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #1, 0.36/650 {{#subobject:add51b|Variant=1}}===
+
===Regimen {{#subobject:1ef938|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 20%"|Study
+
! style="width: 20%" |Study
−
!style="width: 20%"|Years of enrollment
+
! style="width: 20%" |Years of enrollment
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|Comparator
+
! style="width: 20%" |Comparator
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|rowspan=2|[http://www.bloodjournal.org/content/108/2/473.long Robak et al. 2006 (PALG CLL2)]
+
|[https://doi.org/10.1093/annonc/mdz058 Kim et al. 2019 (SMC 2011-05-070)]
−
|rowspan=2|1998-2003
+
|2011-2016
−
|rowspan=2 style="background-color:#1a9851"|Phase 3 (E-esc)
+
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
−
|1. [[#Cladribine_monotherapy|Cladribine]]
+
|[[#GemOx_2|GEMOX]]
−
|style="background-color:#d9ef8b"|Might have superior CR rate
+
| style="background-color:#eeee01" |Non-inferior PFS
−
|-
 
−
|2. [[Chronic_lymphocytic_leukemia_-_historical#CMC|CMC]]
 
−
|style="background-color:#fc8d59"|Seems to have inferior CR rate
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[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
 
−
====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>
 
−
<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%"|Years 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.2009.25.9630 Robak et al. 2010 (PALG-CLL3)]
 
−
|2004-2007
 
−
|style="background-color:#1a9851"|Phase 3 (E-switch-ic)
 
−
|[[Chronic_lymphocytic_leukemia_-_historical#FC|FC]]
 
−
|style="background-color:#ffffbf"|Did not meet primary endpoint of CR rate
 
 
|-
 
|-
 
|}
 
|}
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Cladribine (Leustatin)]] 0.12 mg/kg IV over 30 minutes once per day on days 1 to 3
+
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
−
*[[Cyclophosphamide (Cytoxan)]] 250 mg/m<sup>2</sup> IV over 30 to 60 minutes once per day on days 1 to 3
+
*[[Oxaliplatin (Eloxatin)]] 130 mg/m<sup>2</sup> IV once on day 1
−
====Supportive therapy====
+
'''21-day cycle for 8 cycles'''
−
*"No routine prophylaxis with antibiotics, antiviral agents, or growth factors."
 
−
'''28-day cycle for up to 6 cycles'''
 
 
</div></div>
 
</div></div>
 
===References===
 
===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. [http://www.bloodjournal.org/content/108/2/473.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16551966 PubMed]
+
#'''SMC 2011-05-070:''' Kim ST, Kang JH, Lee J, Lee HW, Oh SY, Jang JS, Lee MA, Sohn BS, Yoon SY, Choi HJ, Hong JH, Kim MJ, Kim S, Park YS, Park JO, Lim HY. Capecitabine plus oxaliplatin versus gemcitabine plus oxaliplatin as first-line therapy for advanced biliary tract cancers: a multicenter, open-label, randomized, phase III, noninferiority trial. Ann Oncol. 2019 May 1;30(5):788-795. [https://doi.org/10.1093/annonc/mdz058 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/30785198 PubMed] NCT01470443
−
## '''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]
+
==Cisplatin & Gemcitabine (GC) {{#subobject:8ug357|Regimen=1}}==
−
<!-- 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. -->
+
GC: '''<u>G</u>'''emcitabine & '''<u>C</u>'''isplatin
−
# '''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] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20212251 PubMed]
 
−
==Chlorambucil & Obinutuzumab (GClb) {{#subobject:50878e|Regimen=1}}==
 
−
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">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #1, 6 cycles {{#subobject:9c3473|Variant=1}}===
+
===Regimen {{#subobject:cb3ttq|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 20%"|Study
+
! style="width: 20%" |Study
−
!style="width: 20%"|Years of enrollment
+
! style="width: 20%" |Years of enrollment
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|Comparator
+
! style="width: 20%" |Comparator
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|rowspan = "2" |[https://doi.org/10.1056/NEJMoa1313984 Goede et al. 2014 (GCLLSG CLL11)]
+
|Awaiting publication (TOPAZ-1)
−
|rowspan=2|2010-2012
+
|2019-2021
−
|rowspan = "2" style="background-color:#1a9851"|Phase 3 (E-RT-esc)
+
| style="background-color:#1a9851" |Phase 3 (C)
−
|1. [[Chronic_lymphocytic_leukemia_-_historical#Chlorambucil_monotherapy|Chlorambucil]]
+
|[[#Cisplatin_.26Gemcitabine_.28GC.29_.26_Durvalumab|GC & Durvalumab]]
−
|style="background-color:#1a9850"|Superior OS<br>Median OS: NYR vs NYR<br>(HR 0.41, 95% CI 0.23-0.74)
+
| style="background-color:#fc8d59" |Seems to have inferior OS
−
|-
 
−
|2. [[#Chlorambucil_.26_Rituximab_.28RClb.29|Chlorambucil & Rituximab]]
 
−
|style="background-color:#1a9850"|Superior PFS
 
−
|-
 
−
|[https://doi.org/10.1016/S1470-2045(18)30788-5 Moreno et al. 2018 (iLLUMINATE)]
 
−
|2014-2015
 
−
| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
 
−
|[[#Ibrutinib_.26_Obinutuzumab|Ibrutinib & Obinutuzumab]]
 
−
| style="background-color:#d73027" |Inferior PFS
 
 
|-
 
|-
 
|}
 
|}
 +
''Note: dosing information is from the FDA approval announcement.''
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Chlorambucil (Leukeran)]] 0.5 mg/kg PO once per day on days 1 & 15
+
*[[Cisplatin (Platinol)]] 25 mg/m<sup>2</sup> IV once per day on days 1 & 8
−
====Targeted therapy====
+
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8
−
*[[Obinutuzumab (Gazyva)]] as follows:
+
'''21-day cycle for up to 8 cycles'''
−
**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'''
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #2, 12 cycles {{#subobject:9c6233|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years 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)]
 
−
|2015-2016
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[#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:#b3e2cd">
 
−
====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'''
 
 
</div></div>
 
</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) [http://meetinglibrary.asco.org/content/116249-132 link to abstract] -->
+
#'''TOPAZ-1:''' NCT03875235
−
# '''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] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/24401022 PubMed] NCT01010061
+
==Cisplatin & Gemcitabine (GC) & Durvalumab {{#subobject:dub057|Regimen=1}}==
−
## '''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]
+
GC & Durvalumab: '''<u>G</u>'''emcitabine, '''<u>C</u>'''isplatin, Durvalumab
−
# '''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] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/30522969 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. [https://doi.org/10.1056/NEJMoa1815281 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31166681 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. [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]
 
−
# '''CR108428:''' NCT03462719
 
−
# '''UNITY-CLL:''' NCT02612311
 
−
==Chlorambucil & Ofatumumab {{#subobject:c168f0|Regimen=1}}==
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:c88f0b|Variant=1}}===
+
===Regimen {{#subobject:cb6g11|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 20%"|Study
+
! style="width: 20%" |Study
−
!style="width: 20%"|Years of enrollment
+
! style="width: 20%" |Years of enrollment
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|Comparator
+
! style="width: 20%" |Comparator
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+
! 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)]
+
|Awaiting publication (TOPAZ-1)
−
|2008-2011
+
|2019-2021
−
|style="background-color:#1a9851"|Phase 3 (E-RT-esc)
+
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
−
|[[Chronic_lymphocytic_leukemia_-_historical#Chlorambucil_monotherapy|Chlorambucil]]
+
|[[#Cisplatin_.26Gemcitabine_.28GC.29|GC]]
−
|style="background-color:#1a9850"|Superior PFS<br>Median PFS: 22.4 vs 13.1 mo<br>(HR 0.57, 95% CI 0.45-0.72)
+
| style="background-color:#91cf60" |Seems to have superior OS<br>Median OS: 12.8 vs 11.5 mo<br>(HR 0.80, 95% CI 0.66-0.97)
 
|-
 
|-
 
|}
 
|}
 +
''Note: efficacy and dosing information are from the FDA approval announcement.''
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Chlorambucil (Leukeran)]] 10 mg/m<sup>2</sup> PO once per day on days 1 to 7
+
*[[Cisplatin (Platinol)]] as follows:
−
====Targeted therapy====
+
**Cycles 1 up to 8: 25 mg/m<sup>2</sup> IV once per day on days 1 & 8
−
*[[Ofatumumab (Arzerra)]] as follows:
+
*[[Gemcitabine (Gemzar)]] as follows:
−
**Cycle 1: 300 mg IV once on day 1, then 1000 mg IV once on day 8
+
**Cycles 1 up to 8: 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8
−
**Cycle 2 onwards: 1000 mg IV once on day 1
+
====Immunotherapy====
−
====Supportive therapy====  
+
*[[Durvalumab (Imfinzi)]] 1500 mg IV once on day 1
−
*Premedication for [[Ofatumumab (Arzerra)]] included [[Acetaminophen (Tylenol)]], [[:Category:Antihistamines|antihistamines]], and [[:Category:Steroids|glucocorticoids]] (no doses or further information provided)
+
'''21-day cycle for up to 8 cycles, then 28-day cycles'''
−
'''28-day cycle for a minimum of 3 cycles, and then given until best response up to a maximum of 12 cycles'''
 
 
</div></div>
 
</div></div>
 
===References===
 
===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. [https://ash.confex.com/ash/2013/webprogram/Paper58498.html link to abstract] -->
+
#'''TOPAZ-1:''' NCT03875235
−
# '''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] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/25882396 PubMed] NCT00748189
+
==ECF {{#subobject:57bd6d|Regimen=1}}==
−
## '''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]
+
ECF: '''<u>E</u>'''pirubicin, '''<u>C</u>'''isplatin, '''<u>F</u>'''luorouracil
−
==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
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #1, Clb 0.5 mg/kg q2wk {{#subobject:bdacc9|Variant=1}}===
+
===Regimen {{#subobject:f87869|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
!style="width: 20%"|Study
 
!style="width: 20%"|Study
Line 475: Line 273:
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|rowspan = "2" |[https://doi.org/10.1056/NEJMoa1313984 Goede et al. 2014 (GCLLSG CLL11)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2362051/ Rao et al. 2005]
−
|rowspan=2|2010-2012
+
|1997-2003
−
|rowspan = "2" style="background-color:#1a9851"|Phase 3 (E-esc)
+
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
−
|1. [[Chronic_lymphocytic_leukemia_-_historical#Chlorambucil_monotherapy|Chlorambucil]]
+
|[[#FELV|FELV]]
−
|style="background-color:#1a9850"|Superior PFS<br>Median PFS: 16.3 vs 11.1 mo<br>(HR 0.44, 95% CI 0.34-0.57)
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
−
|-
 
−
|2. [[#Chlorambucil_.26_Obinutuzumab_.28GClb.29|Chlorambucil & Obinutuzumab]]
 
−
|style="background-color:#d73027"|Inferior PFS
 
−
|-
 
−
|Awaiting publication (D822BC00001)
 
−
|2020-2024
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[#Acalabrutinib_monotherapy|Acalabrutinib]]
 
−
|style="background-color:#d3d3d3"|TBD
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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/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 #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%"|Years 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 portion of phase 2 RCT
 
 
|-
 
|-
 
|}
 
|}
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Chlorambucil (Leukeran)]] 8 mg/m<sup>2</sup>/day PO once per day on days 1 to 7
+
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once on day 1
−
====Targeted therapy====
+
*[[Cisplatin (Platinol)]] 60 mg/m<sup>2</sup> IV once on day 1
−
*[[Rituximab (Rituxan)]] as follows:
+
*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup>/day IV continuous infusion over 21 days, started on day 1 (total dose per cycle: 4200 mg/m<sup>2</sup>)
−
**Cycle 3: 375 mg/m<sup>2</sup> IV once on day 1
+
'''21-day cycles'''
−
**Cycle 4 onwards: 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">
 
−
====Subsequent treatment====
 
−
*Responders (PR or better): [[#Observation_2|Observation]] versus [[#Rituximab_monotherapy_2|Rituximab]] maintenance
 
−
</div></div><br>
 
−
<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}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years 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:#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)
 
−
|[[#Bendamustine_.26_Rituximab_.28BR.29|BR]]
 
−
| style="background-color:#d73027" |Inferior PFS
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Chlorambucil (Leukeran)]] 10 mg/m<sup>2</sup> PO once per day on days 1 to 7
 
−
====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 class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*NCRI CLL208; Patients not achieving CR: Optional [[Chronic_lymphocytic_leukemia_-_historical#Chlorambucil_monotherapy|chlorambucil]] x up to 6 cycles
 
−
*MABLE; Patients not achieving CR: Optional [[Chronic_lymphocytic_leukemia_-_historical#Chlorambucil_monotherapy|chlorambucil]] x up to 6 cycles or until CR
 
 
</div></div>
 
</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) [http://meetinglibrary.asco.org/content/116249-132 link to abstract] -->
+
#Rao S, Cunningham D, Hawkins RE, Hill ME, Smith D, Daniel F, Ross PJ, Oates J, Norman AR. Phase III study of 5FU, etoposide and leucovorin (FELV) compared to epirubicin, cisplatin and 5FU (ECF) in previously untreated patients with advanced biliary cancer. Br J Cancer. 2005 May 9;92(9):1650-4. [https://doi.org/10.1038/sj.bjc.6602576 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2362051/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/15856037 PubMed]
−
# '''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] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/24401022 PubMed] NCT01010061
+
==FELV {{#subobject:ut11a8|Regimen=1}}==
−
## '''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]
+
FELV: '''<u>F</u>'''luorouracil , '''<u>E</u>'''toposide & '''<u>L</u>'''euco'''<u>V</u>'''orin (Folinic acid)
−
<!-- # '''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 [http://www.ehaweb.org/congress-and-events/20th-congress/previous-congresses-2/abstract-book link to abstract book] -->
 
−
# '''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] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/24415640 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. [https://doi.org/10.1200/jco.2013.49.6547 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4876343/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24638012 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. [http://www.haematologica.org/content/103/4/698 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865431/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29419437 PubMed] NCT01056510
 
−
#'''D822BC00001:''' '''contains dosing details on CT.gov''' NCT04075292
 
−
==Cladribine monotherapy {{#subobject:3ae1a1|Regimen=1}}==
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #1, 0.6 mg/kg {{#subobject:8cab02|Variant=1}}===
+
===Regimen {{#subobject:8e152d|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
!style="width: 20%"|Study
 
!style="width: 20%"|Study
Line 580: Line 300:
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://doi.org/10.3109/10428194.2014.893306 Mulligan et al. 2014]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2362051/ Rao et al. 2005]
−
|1997-2004
+
|1997-2003
−
|style="background-color:#1a9851"|Phase 3 (E-switch-ic)
+
| style="background-color:#1a9851" |Phase 3 (C)
−
|1. [[Chronic_lymphocytic_leukemia_-_historical#Chlorambucil_monotherapy|Chlorambucil]]<br> 2. [[Chronic_lymphocytic_leukemia_-_historical#Fludarabine_monotherapy|Fludarabine]]
+
|[[#ECF|ECF]]
−
| style="background-color:#1a9850" |Superior PFS
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
−
|-
 
−
|rowspan=2|[http://www.bloodjournal.org/content/108/2/473.long 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
 
−
|-
 
−
|}
 
−
''Note: Dosing details for Mulligan et al. 2014 were not available in the abstract.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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>
 
−
<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;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years 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
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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>
 
−
===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] '''contains dosing details in abstract''' [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. [http://www.bloodjournal.org/content/108/2/473.long link to original article] '''contains dosing details in manuscript''' [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] [https://pubmed.ncbi.nlm.nih.gov/24524339 PubMed]
 
−
==FCA {{#subobject:68d031|Regimen=1}}==
 
−
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 {{#subobject:218cde|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/123/21/3255.long Geisler et al. 2014 (HOVON-68)]
 
−
|2006-2010
 
−
|style="background-color:#1a9851"|Phase 3 (E-esc)
 
−
|[[Chronic_lymphocytic_leukemia_-_historical#FC|FC]]
 
−
|style="background-color:#1a9850"|Superior PFS<br>PFS36: 53% vs 37%
 
−
|-
 
−
|[http://www.bloodjournal.org/content/119/22/5104.long 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
 
 
|-
 
|-
 
|}
 
|}
−
''Note: GOELAMS CLL2007FMP was halted prematurely due to excess mortality.''
 
−
<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 of age, 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:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Fludarabine (Fludara)]] 40 mg/m<sup>2</sup> PO once per day on days 1 to 3
+
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV bolus once per day on days 1 to 3, '''given first'''
−
*[[Cyclophosphamide (Cytoxan)]] 250 mg/m<sup>2</sup> PO once per day on days 1 to 3
+
*[[Etoposide (Vepesid)]] 120 mg/m<sup>2</sup> IV over 40 minutes once per day on days 1 to 3, '''given second'''
−
====Targeted therapy====
+
*[[Folinic acid (Leucovorin)]] 60 mg/m<sup>2</sup> IV bolus once per day on days 1 to 3, '''given third'''
−
*[[Alemtuzumab (Campath)]] as follows:
+
'''21-day cycles'''
−
**Cycle 1: 30 mg SC once per day on days -1, 0, and 1
 
−
**Cycle 2 onwards: 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'''
 
 
</div></div>
 
</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. [http://abstracts.hematologylibrary.org/cgi/content/abstract/114/22/538?maxtoshow=&hits=10&RESULTFORMAT=&fulltext=CLL2007FMP&searchid=1&FIRSTINDEX=0&volume=114&issue=22&resourcetype=HWCIT link to abstract] -->
+
#Rao S, Cunningham D, Hawkins RE, Hill ME, Smith D, Daniel F, Ross PJ, Oates J, Norman AR. Phase III study of 5FU, etoposide and leucovorin (FELV) compared to epirubicin, cisplatin and 5FU (ECF) in previously untreated patients with advanced biliary cancer. Br J Cancer. 2005 May 9;92(9):1650-4. [https://doi.org/10.1038/sj.bjc.6602576 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2362051/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/15856037 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. [http://www.bloodjournal.org/content/119/22/5104.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/22337714 PubMed] NCT00564512
+
==Gemcitabine & nab-Paclitaxel {{#subobject:fbd698|Regimen=1}}==
−
<!-- 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. -->
+
NG: '''<u>N</u>'''ab-Paclitaxel & '''<u>G</u>'''emcitabine
−
# '''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. [http://www.bloodjournal.org/content/123/21/3255.long link to original article] '''contains dosing details in manuscript''' [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, 25/250/375-500 {{#subobject:17f90c|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 17%"|Study
 
−
!style="width: 15%"|Years 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#FC|FC]]
 
−
|style="background-color:#1a9850"|Superior OS<sup>1</sup><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)
 
−
|[[#Observation|Observation]]
 
−
|style="background-color:#1a9850"|Superior EFS<br>Median EFS: NYR vs 18.5 mo<br>(HR 0.22, 95% CI 0.15-0.33)
 
−
|
 
−
|-
 
−
|[http://www.bloodjournal.org/content/119/22/5104.long Lepretre et al. 2012 (GOELAMS CLL2007FMP)]
 
−
|2007-2009
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[#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://www.ncbi.nlm.nih.gov/pmc/articles/pmc6908306/ Shanafelt et al. 2019 (ECOG E1912)]
 
−
|2014-2016
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[#Ibrutinib_.26_Rituximab|Ibrutinib & Rituximab]]
 
−
| style="background-color:#d73027" |Inferior OS
 
−
|
 
−
|-
 
−
|}
 
−
''<sup>1</sup>Reported efficacy for GCLLSG CLL8 is based on the 2016 update.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[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
 
−
====Targeted therapy====
 
−
*[[Rituximab (Rituxan)]] as follows:
 
−
**Cycle 1: 375 mg/m<sup>2</sup> IV once on day 0
 
−
***Alternate dosing in ECOG E1912: 50 mg/m<sup>2</sup> IV once on day 1, then 325 mg/m<sup>2</sup> IV once on day 2
 
−
**Cycles 2 to 6: 500 mg/m<sup>2</sup> 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 (Rituxan)]]
 
−
*[[Acetaminophen (Tylenol)]] 650 mg PO once per infusion, 30 minutes prior to [[Rituximab (Rituxan)]]
 
−
*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
 
−
*[[: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">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #2, 25/250/500 {{#subobject:dg134c|Variant=1}}===
+
===Regimen {{#subobject:ecc1c9|Variant=1}}===
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years 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-NR
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[#FCR_.26_Lumiliximab_77|FCR+L]]
 
−
|style="background-color:#ffffbf"|Did not meet primary endpoint of CR rate
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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
 
−
**Cycle 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
 
−
**Cycle 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>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #3, 20/150/375-500 ("FCR-Lite") {{#subobject:44cd18|Variant=1}}===
 
 
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 
!style="width: 33%"|Study
 
!style="width: 33%"|Study
Line 795: Line 325:
 
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://doi.org/10.1200/jco.2008.17.2619 Foon et al. 2009]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6440720/ Sahai et al. 2018 (PrE0204)]
−
|2003-2007
+
|2014-2016
−
|style="background-color:#91cf61"|Phase 2
+
| style="background-color:#91cf61" |Phase 2
 
|-
 
|-
 
|}
 
|}
 +
''Note: this regimen was intended for ECOG PS 0 to 2, and Child-Pugh score less than 8.''
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Fludarabine (Fludara)]] as follows:
+
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
−
**Cycle 1: 20 mg/m<sup>2</sup> IV over 30 minutes once per day on days 2 to 4
+
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 125 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
−
**Cycles 2 to 6: 20 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 3
+
'''28-day cycles'''
−
*[[Cyclophosphamide (Cytoxan)]] as follows:
 
−
**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 (Rituxan)]]
 
−
*[[Acetaminophen (Tylenol)]] 650 mg PO once per day on days 1 & 14, prior to [[Rituximab (Rituxan)]]
 
−
*[[Dexamethasone (Decadron)]] 10 mg IV or PO once per day on days 1 & 14, prior to [[Rituximab (Rituxan)]]
 
−
*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 #4, 40/250/375-500, oral FC {{#subobject:e5ab00|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years 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 portion of RCT
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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====
 
−
*[[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 [[#Observation_2|observation]]
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #5, 25/250/375 {{#subobject:6dc0af|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years 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:#b3e2cd">
 
−
====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><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #6, 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%"|Years 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)
 
−
|[[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>)]
 
−
|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
 
−
|-
 
−
|}
 
−
''Note: in contrast to other variants, FC is given over 5 days not 3. ARCTIC should not be confused with the trial by the same name in NSCLC.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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>
 
</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] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15767648 PubMed]
+
#'''PrE0204:''' Sahai V, Catalano PJ, Zalupski MM, Lubner SJ, Menge MR, Nimeiri HS, Munshi HG, Benson AB 3rd, O'Dwyer PJ. nab-Paclitaxel and gemcitabine as first-line treatment of advanced or metastatic cholangiocarcinoma: a phase 2 clinical trial. JAMA Oncol. 2018 Dec 1;4(12):1707-1712. [https://jamanetwork.com/journals/jamaoncology/article-abstract/2698042 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6440720/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30178032 PubMed] NCT02181634
−
## '''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. [http://www.bloodjournal.org/content/112/4/975.long 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]
+
==GemOx {{#subobject:a99e6e|Regimen=1}}==
−
## '''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. [http://www.bloodjournal.org/content/127/3/303.long 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]
+
GemOx: '''<u>Gem</u>'''citabine & '''<u>Ox</u>'''aliplatin
−
# 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] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16649223 PubMed]
+
<br>GEMOX: '''<u>GEM</u>'''citabine & '''<u>OX</u>'''aliplatin
−
# 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] '''contains dosing details in manuscript''' [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. [http://www.bloodjournal.org/content/119/13/3184.long 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
 
−
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 [http://abstracts.hematologylibrary.org/cgi/content/abstract/114/22/535 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] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20888994 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. [http://www.bloodjournal.org/content/127/2/208.long 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. [http://abstracts.hematologylibrary.org/cgi/content/abstract/114/22/538?maxtoshow=&hits=10&RESULTFORMAT=&fulltext=CLL2007FMP&searchid=1&FIRSTINDEX=0&volume=114&issue=22&resourcetype=HWCIT 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. [http://www.bloodjournal.org/content/119/22/5104.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/22337714 PubMed] 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 [http://www.bloodjournal.org/content/122/21/524 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] 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] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25130401 PubMed] NCT00391066
 
−
<!-- # '''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 [http://www.bloodjournal.org/content/122/21/526 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] [https://pubmed.ncbi.nlm.nih.gov/27216274 PubMed] NCT000769522
 
−
# '''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] '''contains dosing details in manuscript''' [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] '''contains dosing details in supplement''' [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] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/29275118 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. [https://doi.org/10.1056/NEJMoa1817073 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31365801 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. [https://doi.org/10.1182/blood.2021014960 link to original article] [https://pubmed.ncbi.nlm.nih.gov/35427411/ PubMed]
 
−
# '''ACE-CL-311:''' NCT03836261
 
−
# '''CRISTALLO:''' NCT04285567
 
−
# '''GAIA:''' NCT02950051
 
−
==FCR (Rituximab and hyaluronidase) {{#subobject:1dc25c|Regimen=1}}==
 
−
FCR: '''<u>F</u>'''ludarabine, '''<u>C</u>'''yclophosphamide, '''<u>R</u>'''ituximab hyaluronidase
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:dcbn4c|Variant=1}}===
+
===Regimen {{#subobject:a6c33cb|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 20%"|Study
+
! style="width: 20%" |Study
−
!style="width: 20%"|Years of enrollment
+
! style="width: 20%" |Years of enrollment
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|Comparator
+
! style="width: 20%" |Comparator
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+
! 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)]
+
|[https://doi.org/10.1093/annonc/mdz058 Kim et al. 2019 (SMC 2011-05-070)]
−
|2012-2013
+
|2011-2016
−
|style="background-color:#1a9851"|Randomized Phase 1b (E-RT-switch-ic)
+
| style="background-color:#1a9851" |Phase 3 (C)
−
|[[#FCR|FCR]]
+
|[[#CapeOx|XELOX]]
−
|style="background-color:#d3d3d3"|Not reported
+
| style="background-color:#eeee01" |Non-inferior PFS
 
|-
 
|-
 
|}
 
|}
−
''Note: other variants include oral fludarabine and/or cyclophosphamide; to be completed.''
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Fludarabine (Fludara)]] 25 mg/m<sup>2</sup> IV once per day on days 1 to 3
+
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8
−
*[[Cyclophosphamide (Cytoxan)]] 250 mg/m<sup>2</sup> IV once per day on days 1 to 3
+
*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV once on day 1
−
====Targeted therapy====
+
'''21-day cycle for 8 cycles'''
−
*[[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>
 
</div></div>
 
===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] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26947201 PubMed] NCT01292603
+
#'''SMC 2011-05-070:''' Kim ST, Kang JH, Lee J, Lee HW, Oh SY, Jang JS, Lee MA, Sohn BS, Yoon SY, Choi HJ, Hong JH, Kim MJ, Kim S, Park YS, Park JO, Lim HY. Capecitabine plus oxaliplatin versus gemcitabine plus oxaliplatin as first-line therapy for advanced biliary tract cancers: a multicenter, open-label, randomized, phase III, noninferiority trial. Ann Oncol. 2019 May 1;30(5):788-795. [https://doi.org/10.1093/annonc/mdz058 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/30785198 PubMed] NCT01470443
−
==Fludarabine & Alemtuzumab {{#subobject:29bf48|Regimen=1}}==
+
=Metastatic disease, all lines of therapy=
 +
==Capecitabine monotherapy {{#subobject:c7cfeb|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:201b46|Variant=1}}===
+
===Regimen {{#subobject:b34ea|Variant=1}}===
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
+
{| class="wikitable" style="width: 40%; text-align:center;"  
−
!style="width: 20%"|Study
+
! style="width: 50%" |Study
−
!style="width: 20%"|Years of enrollment
+
! style="width: 50%" |[[Levels_of_Evidence#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/10.1016/S1470-2045(11)70242-X Elter et al. 2011 (CAM 314)]
+
|[https://doi.org/10.1002/cncr.20368 Patt et al. 2004]
−
|2004-2008
+
| style="background-color:#ffffbe" |Retrospective
−
|style="background-color:#1a9851"|Phase 3 (E-esc)
 
−
|[[Chronic_lymphocytic_leukemia_-_historical#Fludarabine_monotherapy|Fludarabine]]
 
−
| style="background-color:#1a9850" |Superior OS<br>Median OS: NYR vs 52.9 mo<br>(HR 0.65, 95% CI 0.45-0.94)
 
 
|-
 
|-
 
|}
 
|}
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV once per day on days 1 to 3
+
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
−
====Targeted therapy====
+
'''21-day cycles'''
−
*[[Alemtuzumab (Campath)]] 30 mg IV once per day on days 1 to 3
 
−
'''28-day cycle for up to 6 cycles'''
 
 
</div></div>
 
</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] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/21992852 PubMed] NCT00086580
+
#'''Retrospective:''' Patt YZ, Hassan MM, Aguayo A, Nooka AK, Lozano RD, Curley SA, Vauthey JN, Ellis LM, Schnirer II, Wolff RA, Charnsangavej C, Brown TD. Oral capecitabine for the treatment of hepatocellular carcinoma, cholangiocarcinoma, and gallbladder carcinoma. Cancer. 2004 Aug 1;101(3):578-86. [https://doi.org/10.1002/cncr.20368 link to original article] [https://pubmed.ncbi.nlm.nih.gov/15274071 PubMed]
−
==Ibrutinib monotherapy {{#subobject:8c370d|Regimen=1}}==
+
==Capecitabine & Mitomycin {{#subobject:6a9270|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:9887c1|Variant=1}}===
+
===Regimen {{#subobject:a46bbd|Variant=1}}===
−
{| class="wikitable" style="color:white; background-color:#404040"
 
−
|<small>'''FDA-recommended dose'''</small>
 
−
|-
 
−
|}
 
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
!style="width: 20%"|Study
 
!style="width: 20%"|Study
Line 1,008: Line 395:
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://doi.org/10.1016/S1470-2045(13)70513-8 O'Brien et al. 2013 (PCYC-1102 untreated)]
+
|[https://doi.org/10.1093/annonc/mdh096 Kornek et al. 2004]
−
|2010-2012
+
|2000-2001
−
|style="background-color:#91cf61"|Phase 1b/2
+
| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ic)
−
|style="background-color:#d3d3d3"|
+
|[[#Gemcitabine_.26_Mitomycin|Gemcitabine & Mitomycin]]
−
|style="background-color:#d3d3d3"|
+
| style="background-color:#d9ef8b" |Might have superior ORR
−
|-
 
−
|[https://doi.org/10.1016/S1470-2045(14)71182-9 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-NR
 
−
|style="background-color:#1a9851"|Phase 3 (E-RT-switch-ooc)
 
−
|[[Chronic_lymphocytic_leukemia_-_historical#Chlorambucil_monotherapy|Chlorambucil]]
 
−
| style="background-color:#1a9850" |Superior OS<sup>1</sup><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)
 
−
|[[#Bendamustine_.26_Rituximab_.28BR.29|BR]]
 
−
| style="background-color:#1a9850" |Superior PFS<br>PFS24: 87% vs 74%<br>(HR 0.39, 95% CI 0.26-0.58)
 
−
|-
 
−
|[[#Ibrutinib_.26_Rituximab|Ibrutinib & Rituximab]]
 
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br>(HR 1.00, 95% CI 0.62-1.62)
 
−
|-
 
−
|[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)]
 
−
|2014-2019
 
−
|style="background-color:#1a9851"|Phase 3 (E-esc)
 
−
|[[#Observation|Placebo]]
 
−
| style="background-color:#1a9850" |Superior EFS<br>Median EFS: NYR vs 47.8 mo<br>(HR 0.25, 95% CI 0.14-0.43)
 
−
|-
 
−
|Awaiting publication (SYMPATICO)
 
−
|2017-2023
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[#Ibrutinib_.26_Venetoclax_.28VI.29|VI]]
 
−
| style="background-color:#d3d3d3" |TBD
 
−
|-
 
−
|Awaiting publication (GCLLSG CLL17)
 
−
|2021-2027
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|1. [[#Venetoclax_.26_Obinutuzumab|VG]]<br>2. [[#Ibrutinib_.26_Venetoclax_.28VI.29|VI]]
 
−
| style="background-color:#d3d3d3" |TBD
 
−
|-
 
−
|Awaiting publication (BRUIN CLL-314)
 
−
|2022-2028
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[#Pirtobrutinib_monotherapy_77|Pirtobrutinib]]
 
−
| style="background-color:#d3d3d3" |TBD
 
 
|-
 
|-
 
|}
 
|}
−
''<sup>1</sup>Reported efficacy for RESONATE-2 is based on the 2019 update.''<br>
 
−
''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:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Targeted therapy====
+
====Chemotherapy====
−
*[[Ibrutinib (Imbruvica)]] 420 mg PO once per day
+
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
−
'''28-day cycles'''
+
*[[Mitomycin (Mutamycin)]] 8 mg/m<sup>2</sup> IV bolus once on day 1
−
</div></div>
+
====Supportive therapy====
−
===References===
+
*[[Dexamethasone (Decadron)]] and [[:Category:Serotonin_5-HT3_antagonists|5-HT3 antagonists]] on the day of IV chemotherapy
−
# '''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] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4134524/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24332241 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. [http://www.bloodjournal.org/content/125/16/2497 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. [http://www.bloodjournal.org/content/131/17/1910.long 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] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342187/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25555420 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. [https://doi.org/10.1056/NEJMoa1509388 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4722809/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26639149 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. [http://www.haematologica.org/content/103/9/1502 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] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6325637/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30501481 PubMed] NCT01886872
 
−
# '''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. [http://www.bloodjournal.org/content/133/10/1011.long link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405333/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30530801 PubMed] 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. [http://www.bloodjournal.org/content/126/23/2934 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] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/34758069/ PubMed] NCT02863718
 
−
#'''BRUIN CLL-314:''' NCT05254743
 
−
# '''GCLLSG CLL17:''' NCT04608318
 
−
# '''SYMPATICO:''' 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;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years 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(18)30788-5 Moreno et al. 2018 (iLLUMINATE)]
 
−
|2014-2015
 
−
| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
 
−
|[[#Chlorambucil_.26_Obinutuzumab_.28GClb.29|G-Clb]]
 
−
| style="background-color:#1a9850" |Superior PFS<br>Median PFS: NYR vs 19 mo<br>(HR 0.23, 95% CI 0.15-0.37)
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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'''
 
'''28-day cycles'''
 
</div></div>
 
</div></div>
 
===References===
 
===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] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/30522969 PubMed] NCT02264574
+
#Kornek GV, Schuell B, Laengle F, Gruenberger T, Penz M, Karall K, Depisch D, Lang F, Scheithauer W. Mitomycin C in combination with capecitabine or biweekly high-dose gemcitabine in patients with advanced biliary tract cancer: a randomised phase II trial. Ann Oncol. 2004 Mar;15(3):478-83. [https://doi.org/10.1093/annonc/mdh096 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/14998852 PubMed]
−
# '''ECOG-ACRIN EA9161:''' NCT03701282
+
==Cisplatin & Gemcitabine (GC) {{#subobject:af0357|Regimen=1}}==
−
# '''Alliance A041702:''' NCT03737981
+
GC: '''<u>G</u>'''emcitabine & '''<u>C</u>'''isplatin
−
==Ibrutinib & Rituximab {{#subobject:7ccq6f|Regimen=1}}==
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:ec91tb|Variant=1}}===
+
===Regimen {{#subobject:cb3c9d|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 20%"|Study
+
! style="width: 20%" |Study
−
!style="width: 20%"|Years of enrollment
+
! style="width: 20%" |Years of enrollment
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|Comparator
+
! style="width: 20%" |Comparator
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+
! 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)]
+
|[https://doi.org/10.1056/NEJMoa0908721 Valle et al. 2010 (ABC-02)]
−
|2014-2016
+
|2002-2008
−
| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
+
| style="background-color:#1a9851" |Phase 3 (E-esc)
−
|[[#FCR|FCR]]
+
|[[#Gemcitabine_monotherapy_2|Gemcitabine]]
−
| style="background-color:#1a9850" |Superior OS<sup>1</sup><br>OS60: 95% vs 89%<br>(HR 0.47, 95% CI 0.25-0.89)
+
| style="background-color:#1a9850" |Superior OS<br>Median OS: 11.7 vs 8.1 mo<br>(HR 0.64, 95% CI 0.52-0.80)
 
|-
 
|-
−
|}
+
|[https://doi.org/10.1093/annonc/mdz402 Morizane et al. 2019 (FUGA-BT)]
−
''<sup>1</sup>Reported efficacy is based on the 2022 update.''
+
|2013-2016
−
<div class="toccolours" style="background-color:#b3e2cd">
+
| style="background-color:#1a9851" |Phase 3 (C)
−
====Targeted therapy====
+
|[[#Gemcitabine_.26_S-1|Gemcitabine & S-1]]
−
*[[Ibrutinib (Imbruvica)]] 420 mg PO once per day
+
| style="background-color:#eeee01" |Seems to have non-inferior OS
−
*[[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===
 
−
# '''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] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6908306/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31365801 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. [https://doi.org/10.1182/blood.2021014960 link to original article] [https://pubmed.ncbi.nlm.nih.gov/35427411/ PubMed]
 
−
==Obinutuzumab monotherapy {{#subobject:f0a8d4|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #1, standard-dose (1000 mg) {{#subobject:f89f3a|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years 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-NR
 
−
|style="background-color:#1a9851"|Randomized Phase 2 (C)
 
−
|[[#Obinutuzumab_monotherapy|Obinutuzumab]]; high-dose
 
−
|style="background-color:#fee08b"|Might have inferior ORR rate
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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
 
−
**Cycle 2 onwards: 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 (Gazyva)]]
 
−
*[[:Category:Antihistamines|Antihistamine]] "such as" [[Diphenhydramine (Benadryl)]] 50 to 100 mg PO once per infusion, 30 to 60 minutes prior to [[Obinutuzumab (Gazyva)]]
 
−
*[[Prednisolone (Millipred)]] (or equivalent) 100 mg IV once per infusion, prior to each of the first three doses of [[Obinutuzumab (Gazyva)]], afterwards at the discretion of treating physician
 
−
'''21-day cycle up to 8 cycles'''
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #2, high-dose (2000 mg) {{#subobject:6ca538|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years 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-NR
 
−
|style="background-color:#1a9851"|Randomized Phase 2 (E-esc)
 
−
|[[#Obinutuzumab_monotherapy|Obinutuzumab]]; standard-dose
 
−
|style="background-color:#d9ef8b"|Might have superior ORR rate
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Targeted therapy====
 
−
*[[Obinutuzumab (Gazyva)]] as follows:
 
−
**Cycle 1, option A: 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
 
−
**Cycle 1, option B: 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
 
−
**Cycle 2 onwards: 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 (Gazyva)]]
 
−
*[[:Category:Antihistamines|Antihistamine]] "such as" [[Diphenhydramine (Benadryl)]] 50 to 100 mg PO once per infusion, 30 to 60 minutes prior to [[Obinutuzumab (Gazyva)]]
 
−
*[[Prednisolone (Millipred)]] (or equivalent) 100 mg IV once per infusion, prior to each of the first three doses of [[Obinutuzumab (Gazyva)]], afterwards at the discretion of treating physician
 
−
'''21-day cycle up to 8 cycles'''
 
−
</div></div>
 
−
===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. [http://www.bloodjournal.org/content/127/1/79.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4705612/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26472752 PubMed] NCT01414205
 
−
==Observation==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years 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/10.1056/NEJM199805213382104 Dighiero et al. 1998 (FRE-CLL-85)]
 
−
|rowspan=2|1985-1990
 
−
|rowspan=2 style="background-color:#1a9851"|Phase 3 (C)
 
−
|1. [[Chronic_lymphocytic_leukemia_-_historical#Chlorambucil_monotherapy|Chlorambucil]]
 
−
|style="background-color:#fc8d59"|Seems to have inferior PFS
 
−
|-
 
−
|2. [[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
 
−
|-
 
−
|Awaiting publication (GLLC-EARLY)
 
−
|2019-2024
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[#Acalabrutinib_monotherapy|Acalabrutinib]]
 
−
| style="background-color:#d3d3d3" |TBD
 
−
|-
 
−
|}
 
−
''No active treatment, also known as "watchful waiting".''
 
−
</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. Chlorambucil in indolent chronic lymphocytic leukemia: French Cooperative Group on Chronic Lymphocytic Leukemia. N Engl J Med. 1998 May 21;338(21):1506-14. [https://doi.org/10.1056/NEJM199805213382104 link to original article] '''contains dosing details in manuscript''' [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 [http://www.bloodjournal.org/content/122/21/524 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] 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. [http://www.bloodjournal.org/content/122/21/4127 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] 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. [http://www.bloodjournal.org/content/126/23/2934 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] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/34758069/ PubMed] NCT02863718
 
−
#'''GLLC-EARLY:''' NCT04178798
 
−
==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 sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years 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)]
 
−
|2015-2016
 
−
|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><br>Median PFS: NYR vs 36.4 mo<br>(HR 0.33, 95% CI 0.25-0.45)
 
−
|-
 
−
|Awaiting publication (GCLLSG CLL16)
 
−
|2022-2026
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[#GAVE_66|GAVE]]
 
−
|style="background-color:#d3d3d3"|TBD
 
−
|-
 
−
|Awaiting publication (MAJIC)
 
−
|2022-2029
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[#Acalabrutinib_.26_Venetoclax_66|Acalabrutinib & Venetoclax]]
 
−
|style="background-color:#d3d3d3"|TBD
 
−
|-
 
−
|}
 
−
''<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:#b3e2cd">
 
−
====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'''
 
−
</div></div>
 
−
===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. [https://doi.org/10.1056/NEJMoa1815281 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31166681 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. [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]
 
−
#'''EVOLVE CLL/SLL:''' NCT04269902
 
−
#'''GCLLSG CLL16:''' NCT05197192
 
−
#'''MAJIC:''' NCT05057494
 
−
==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%"|Years 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-switch-ooc)
 
−
|[[#Bendamustine_.26_Rituximab_.28BR.29|BR]]
 
−
| style="background-color:#1a9850" |Superior PFS<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:#b3e2cd">
 
−
====Targeted therapy====
 
−
*[[Zanubrutinib (Brukinsa)]] 160 mg PO twice per day
 
−
'''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] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/35810754/ PubMed] 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%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#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
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#fdcdac">
 
−
====Biomarker eligibility criteria====
 
−
*TP53 deletion
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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===
 
−
# '''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] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22493413 PubMed] NCT00292760
 
−
==AVO {{#subobject:78g7gg|Regimen=1}}==
 
−
AVO: '''<u>A</u>'''calabrutinib, '''<u>V</u>'''enetoclax, '''<u>O</u>'''binutuzumab
 
−
<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%"|Years 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
 
−
|-
 
−
|}
 
−
''Note: detailed venetoclax dosing was not available in the abstract.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Targeted therapy====
 
−
*[[Acalabrutinib (Calquence)]] 100 mg PO twice per day
 
−
*[[Venetoclax (Venclexta)]]
 
−
*[[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] [https://pubmed.ncbi.nlm.nih.gov/34534514/ PubMed] NCT03580928
 
−
==Bendamustine & Obinutuzumab {{#subobject:e26569|Regimen=1}}==
 
−
G-B: '''<u>G</u>'''azyva (Obinutuzumab), '''<u>B</u>'''endamustine
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:c1bbd2|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 80%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|Years 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-NR
 
−
|style="background-color:#91cf61"|Phase 1b, 20 pts
 
−
| 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%
 
 
|-
 
|-
 
|}
 
|}
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Bendamustine]] as follows:
+
*[[Cisplatin (Platinol)]] 25 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 8, '''given first'''
−
**Cycle 1: 90 mg/m<sup>2</sup> IV once per day on days 2 & 3
+
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8, '''given second'''
−
**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====
 
====Supportive therapy====
−
*[[Acetaminophen (Tylenol)]] (dose not specified) once per infusion, prior to [[Obinutuzumab (Gazyva)]]
+
*Cisplatin is mixed in a solution of 1 liter of normal saline with 20 mmol potassium chloride, 8 mmol magnesium sulfate
−
*[[:Category:Antihistamines|Antihistamine]] e.g. [[Diphenhydramine (Benadryl)]] once per infusion, prior to [[Obinutuzumab (Gazyva)]]
+
*After cisplatin, 500 mL normal saline given over 30 minutes
−
*[[:Category:Steroids|Highly potent corticosteroid]] (e.g. [[Prednisolone (Millipred)]] 100 mg IV) once, prior to first dose of [[Obinutuzumab (Gazyva)]]
+
'''21-day cycle for 4 to 8 cycles depending on response'''
−
*[[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===
 
−
<!-- 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. [http://www.bloodjournal.org/content/125/18/2779.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4416529/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25769620 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. [https://doi.org/10.1080/10428194.2020.1850719 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/33243049/ PubMed] 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;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|Years 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%
 
−
|-
 
−
|}
 
−
''Note: the doses of cyclophosphamide and fludarabine are lower than in the r/r CFAR regimen.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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:
 
−
**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====
 
−
*[[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 (Rituxan)]]/[[Alemtuzumab (Campath)]]
 
−
*[[Diphenhydramine (Benadryl)]] 25 to 50 mg IV or PO once per day on days 1, 2, 3, 5, prior to [[Rituximab (Rituxan)]]/[[Alemtuzumab (Campath)]]
 
−
*[[Hydrocortisone (Cortef)]] 100 mg IV once per day on days 1, 2, 3, 5, prior to [[Rituximab (Rituxan)]]/[[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>
 
</div></div>
 
===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. [http://www.bloodjournal.org/content/118/8/2062.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081295/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21750315 PubMed]
+
#'''ABC-02:''' Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, Madhusudan S, Iveson T, Hughes S, Pereira SP, Roughton M, Bridgewater J; ABC-02 Trial Investigators. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010 Apr 8;362(14):1273-81. [https://doi.org/10.1056/NEJMoa0908721 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20375404 PubMed] NCT00262769
−
==G-FC {{#subobject:b5592a|Regimen=1}}==
+
#'''FUGA-BT:''' Morizane C, Okusaka T, Mizusawa J, Katayama H, Ueno M, Ikeda M, Ozaka M, Okano N, Sugimori K, Fukutomi A, Hara H, Mizuno N, Yanagimoto H, Wada K, Tobimatsu K, Yane K, Nakamori S, Yamaguchi H, Asagi A, Yukisawa S, Kojima Y, Kawabe K, Kawamoto Y, Sugimoto R, Iwai T, Nakamura K, Miyakawa H, Yamashita T, Hosokawa A, Ioka T, Kato N, Shioji K, Shimizu K, Nakagohri T, Kamata K, Ishii H, Furuse J; JCOG. Combination gemcitabine plus S-1 versus gemcitabine plus cisplatin for advanced/recurrent biliary tract cancer: the FUGA-BT (JCOG1113) randomized phase III clinical trial. Ann Oncol. 2019 Dec 1;30(12):1950-1958. [https://doi.org/10.1093/annonc/mdz402 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31566666 PubMed] UMIN000010667
−
G-FC: '''<u>G</u>'''azyva (Obinutuzumab), '''<u>F</u>'''ludarabine, '''<u>C</u>'''yclophosphamide
+
#'''FIGHT-302:''' NCT03656536
 +
#'''FOENIX-CCA3:''' NCT04093362
 +
#'''KEYNOTE-966:''' NCT04003636
 +
#'''NuTide:121:''' NCT04163900
 +
#'''PROOF 301:''' NCT03773302
 +
#'''SWOG S1815:''' NCT03768414
 +
==Cisplatin & Gemcitabine (GC) & nab-Paclitaxel {{#subobject:17f9f2|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:8a0232|Variant=1}}===
+
===Regimen {{#subobject:e6a3e3|Variant=1}}===
 
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 
!style="width: 33%"|Study
 
!style="width: 33%"|Study
Line 1,491: Line 462:
 
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4416529/ Brown et al. 2015 (GALTON)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6567834/ Shroff et al. 2019 (MDACC 2014-0524)]
−
|2011-NR
+
|2015-2017
−
|style="background-color:#91cf61"|Non-randomized
+
| style="background-color:#91cf61" |Phase 2
−
|-
 
 
|}
 
|}
−
<div class="toccolours" style="background-color:#b3e2cd">
+
''Prolonged median PFS and OS vs reported for historical controls treated with gemcitabine-cisplatin alone. This is the dose after a mid-protocol amendment for hematologic toxicity.''
−
====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:
+
*[[Cisplatin (Platinol)]] 25 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 8
−
**Cycle 1: 25 mg/m<sup>2</sup> IV once per day on days 2 to 4
+
*[[Gemcitabine (Gemzar)]] 800 mg/m<sup>2</sup> IV once per day on days 1 & 8
−
**Cycles 2 to 6: 25 mg/m<sup>2</sup> IV once per day on days 1 to 3
+
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 mg/m<sup>2</sup> IV once per day on days 1 & 8
−
*[[Cyclophosphamide (Cytoxan)]] as follows:
+
'''21-day cycles'''
−
**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 (Gazyva)]]
 
−
*[[:Category:Antihistamines|Antihistamine]] e.g. [[Diphenhydramine (Benadryl)]] once per infusion, prior to [[Obinutuzumab (Gazyva)]]
 
−
*[[:Category:Steroids|Highly potent corticosteroid]] (e.g. [[Prednisolone (Millipred)]] 100 mg IV) once, prior to first dose of [[Obinutuzumab (Gazyva)]]
 
−
*[[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>
 
</div></div>
 
===References===
 
===References===
−
<!-- Presented at the 55th annual meeting of the American Society of Hematology, New Orleans, LA, December 9, 2013. -->
+
#'''MDACC 2014-0524:''' Shroff RT, Javle MM, Xiao L, Kaseb AO, Varadhachary GR, Wolff RA, Raghav KPS, Iwasaki M, Masci P, Ramanathan RK, Ahn DH, Bekaii-Saab TS, Borad MJ. Gemcitabine, cisplatin, and nab-paclitaxel for the treatment of advanced biliary tract cancers: a phase 2 clinical trial. JAMA Oncol. 2019 Jun 1;5(6):824-830. Epub 2019 Apr 18. [https://jamanetwork.com/journals/jamaoncology/article-abstract/2730639 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6567834/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30998813 PubMed] NCT02392637
−
# '''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. [http://www.bloodjournal.org/content/125/18/2779.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4416529/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25769620 PubMed] NCT01300247
+
==Erlotinib & Bevacizumab {{#subobject:CMR1|Regimen=1}}==
−
==HDMP-R {{#subobject:1c202|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">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:38a97d|Variant=1}}===
+
===Regimen {{#subobject:CMV1|Variant=1}}===
 
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 
!style="width: 33%"|Study
 
!style="width: 33%"|Study
Line 1,529: Line 483:
 
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2761991/ Castro et al. 2009]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917213/ Lubner et al. 2010 (MC044G)]
−
|NR
+
|2006-2008
−
|style="background-color:#91cf61"|Phase 2
+
| style="background-color:#91cf61" |Phase 2
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Glucocorticoid therapy====
 
−
*[[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:
 
−
**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 (Solumedrol)]]
 
−
*[[Acetaminophen (Tylenol)]] as premedication for [[Rituximab (Rituxan)]]
 
−
*[[Diphenhydramine (Benadryl)]] as premedication for [[Rituximab (Rituxan)]]
 
−
*[[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] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2761991/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19693094 PubMed]
 
−
==Ibrutinib & Venetoclax {{#subobject:7c8bdd|Regimen=1}}==
 
−
VI: '''<u>V</u>'''entoclax & '''<u>I</u>'''brutinib
 
−
<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%"|Years 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
 
−
|-
 
−
|}
 
−
''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:#b3e2cd">
 
−
====Targeted therapy====
 
−
*[[Ibrutinib (Imbruvica)]] 420 mg PO once per day
 
−
*[[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
 
−
**Cycle 5 onwards: 400 mg PO once per day
 
−
'''28-day cycle for up to 24 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] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/31141631 PubMed] NCT02756897
 
−
==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%"|Years 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
 
 
|-
 
|-
 
|}
 
|}
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Targeted therapy====
 
====Targeted therapy====
−
*[[Ibrutinib (Imbruvica)]] as follows:
+
*[[Erlotinib (Tarceva)]] 150 mg PO once per day
−
**Cycle 2 onwards: 420 mg PO once per day
+
*[[Bevacizumab (Avastin)]] 5 mg/kg IV once per day on days 1 & 15
−
*[[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'''
 
'''28-day cycles'''
 
</div></div>
 
</div></div>
 
===References===
 
===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] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/32795224/ PubMed] NCT02427451
+
#'''MC044G:''' Lubner SJ, Mahoney MR, Kolesar JL, Loconte NK, Kim GP, Pitot HC, Philip PA, Picus J, Yong WP, Horvath L, Van Hazel G, Erlichman CE, Holen KD. Report of a multicenter phase II trial testing a combination of biweekly bevacizumab and daily erlotinib in patients with unresectable biliary cancer: a phase II Consortium study. J Clin Oncol. 2010 Jul 20;28(21):3491-7. Epub 2010 Jun 7. [https://doi.org/10.1200/jco.2010.28.4075 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917213/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20530271 PubMed] NCT00356889
−
==iFCR {{#subobject:7c8bdd|Regimen=1}}==
+
==FELV {{#subobject:3658a8|Regimen=1}}==
−
iFCR: '''<u>i</u>'''brutinib, '''<u>F</u>'''ludarabine, '''<u>C</u>'''yclophosphamide, '''<u>R</u>'''ituximab
+
FELV: '''<u>F</u>'''luorouracil , '''<u>E</u>'''toposide & '''<u>L</u>'''euco'''<u>V</u>'''orin (Folinic acid)
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:44ddcc|Variant=1}}===
+
===Regimen {{#subobject:beef1c|Variant=1}}===
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 33%"|Study
+
! style="width: 20%" |Study
−
!style="width: 33%"|Years of enrollment
+
! style="width: 20%" |Years of enrollment
−
!style="width: 33%"|[[Levels_of_Evidence#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://www.ncbi.nlm.nih.gov/pmc/articles/pmc7036668/ Davids et al. 2019 (DFCI 14-296)]
+
|[https://doi.org/10.1093/oxfordjournals.annonc.a010676 Glimelius et al. 1996]
−
|2014-2018
+
|1991-1995
−
|style="background-color:#91cf61"|Phase 2
+
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[Cholangiocarcinoma_-_null_regimens#Best_supportive_care|Best supportive care]]
 +
| style="background-color:#1a9850" |Superior OS
 
|-
 
|-
 
|}
 
|}
−
''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:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Targeted therapy====
 
−
*[[Ibrutinib (Imbruvica)]] as follows:
 
−
**Cycle 0 (pre-phase): 420 mg PO once per day on days 1 to 7
 
−
**Cycle 1 onwards: 420 mg PO once per day
 
−
*[[Rituximab (Rituxan)]]
 
−
**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:
+
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV bolus once per day on days 1 to 3, '''given first'''
−
**Cycles 1 to 6: 25 mg/m<sup>2</sup> IV once per day on days 1 to 3
+
*[[Etoposide (Vepesid)]] 120 mg/m<sup>2</sup> IV over 40 minutes once per day on days 1 to 3, '''given second'''
−
*[[Cyclophosphamide (Cytoxan)]] as follows:
+
*[[Folinic acid (Leucovorin)]] 60 mg/m<sup>2</sup> IV bolus once per day on days 1 to 3, '''given third'''
−
**Cycles 1 to 6: 250 mg/m<sup>2</sup> IV once per day on days 1 to 3
+
'''21-day cycles'''
−
'''28-day cycles (see note)'''
 
 
</div></div>
 
</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] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31208944/ PubMed] NCT02251548
+
#Glimelius B, Hoffman K, Sjödén PO, Jacobsson G, Sellström H, Enander LK, Linné T, Svensson C. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol. 1996 Aug;7(6):593-600. [https://doi.org/10.1093/oxfordjournals.annonc.a010676 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/8879373 PubMed] content property of [http://hemonc.org HemOnc.org]
−
==Lenalidomide & Rituximab (R<sup>2</sup>) {{#subobject:d71dfb|Regimen=1}}==
+
==FULV {{#subobject:7bfb92|Regimen=1}}==
 +
FULV: 5-'''<u>FU</u>''' & '''<u>L</u>'''euco'''<u>V</u>'''orin (Folinic acid)
 +
<br>FUFA: 5-'''<u>FU</u>''' (Fluorouracil) & '''<u>F</u>'''olinic '''<u>A</u>'''cid
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #1 {{#subobject:5d17e2|Variant=1}}===
+
===Regimen {{#subobject:38dd78|Variant=1}}===
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 33%"|Study
+
! style="width: 20%" |Study
−
!style="width: 33%"|Years of enrollment
+
! style="width: 20%" |Years of enrollment
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
|-
+
! style="width: 20%" |Comparator
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4067945/ James et al. 2014 (CRC014)]
+
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
|2008-NR
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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
 
−
**Subsequent cycles: 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
 
−
**Subsequent cycles: 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 cycle for 1 cycle, 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%"|Years 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)]
 
−
|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:#b3e2cd">
 
−
====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>
 
−
===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] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4067945/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24868031 PubMed] 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. [http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview==abst_detail_view&confID==74&abstractID==53803 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. [http://abstracts.hematologylibrary.org/cgi/content/abstract/120/21/901 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] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4370362/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25439689 PubMed] NCT00695786
 
−
==O-FC {{#subobject:a1a5f0|Regimen=1}}==
 
−
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%"|Years 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-NR
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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/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
 
−
**Cycle 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 (Arzerra)]]
 
−
*[[Cetirizine (Zyrtec)]] 10 mg (or equivalent) PO once on day 1, prior to [[Ofatumumab (Arzerra)]]
 
−
*[[Prednisolone (Millipred)]] 100 mg ([[Steroid conversions|or equivalent]]) PO once on day 1, prior to doses 1 & 2 of [[Ofatumumab (Arzerra)]], 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. [http://www.bloodjournal.org/content/117/24/6450.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916561/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21498674 PubMed] 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%"|Years 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]
+
|[https://doi.org/10.1093/oxfordjournals.annonc.a010676 Glimelius et al. 1996]
−
|2011-2013
+
|1991-1995
−
|style="background-color:#91cf61"|Phase 2
+
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[Cholangiocarcinoma_-_null_regimens#Best_supportive_care|Best supportive care]]
 +
| style="background-color:#1a9850" |Superior OS
 
|-
 
|-
 
|}
 
|}
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Pentostatin (Nipent)]] 2 mg/m<sup>2</sup> IV once on day 1
+
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, '''given first'''
−
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
+
*[[Folinic acid (Leucovorin)]] 60 mg/m<sup>2</sup> IV bolus once per day on days 1 & 2, '''given second, 40 minutes after Fluorouracil (5-FU)'''
−
====Targeted therapy====
+
'''14-day cycles'''
−
*[[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 (Arzerra)]]
 
−
*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'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*MC0983 arm 2: [[#Ofatumumab_monotherapy|Ofatumumab]] consolidation
 
 
</div></div>
 
</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/full/10.1002/cncr.28292 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3894149/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23922059 PubMed] NCT01024010
+
#Glimelius B, Hoffman K, Sjödén PO, Jacobsson G, Sellström H, Enander LK, Linné T, Svensson C. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol. 1996 Aug;7(6):593-600. [https://doi.org/10.1093/oxfordjournals.annonc.a010676 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/8879373 PubMed]
−
# 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. [http://www.haematologica.org/content/100/12/e501.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4666341/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26294723 PubMed] NCT01681563
+
==FULV & Gemcitabine {{#subobject:eb427f|Regimen=1}}==
−
# '''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] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/27570087 PubMed] NCT01024010
+
FULV & Gemcitabine: 5-'''<u>FU</u>''', '''<u>L</u>'''euco'''<u>V</u>'''orin (Folinic acid), Gemcitabine
−
==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">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #1, 2/600/100->375 {{#subobject:90f7f6|Variant=1}}===
+
===Regimen {{#subobject:85fb7b|Variant=1}}===
 
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 
!style="width: 33%"|Study
 
!style="width: 33%"|Study
Line 1,787: Line 559:
 
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1785105/ Kay et al. 2007]
+
|[https://doi.org/10.1200/jco.2001.19.20.4089 Gebbia et al. 2001]
−
|2002-2005
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|-
 
−
|[https://doi.org/10.1002/cncr.22662 Shanafelt et al. 2007]
 
 
|NR
 
|NR
−
|style="background-color:#91cf61"|Phase 2
+
| style="background-color:#91cf61" |Phase 2
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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====
 
−
*[[Rituximab (Rituxan)]] as follows:
 
−
**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: 375 mg/m<sup>2</sup> 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/uL 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'''
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #2, 4/600/375 {{#subobject:90f7f7|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5278955/ Samaniego et al. 2015 (MDACC 2004-0818)]
 
−
|2005-NR
 
−
|style="background-color:#91cf61"|Phase 2
 
 
|-
 
|-
 
|}
 
|}
−
''Note: this regimen was specifically studied in SLL, not CLL.''
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Pentostatin (Nipent)]] 4 mg/m<sup>2</sup> IV once on day 1
+
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 600 mg/m<sup>2</sup> IV continuous infusion over 22 hours (total dose per cycle: 1000 mg/m<sup>2</sup>)
−
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
+
*[[Folinic acid (Leucovorin)]] 100 mg/m<sup>2</sup> IV over 2 hours once on day 1
−
====Targeted therapy====
+
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8
−
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once on day 1
+
'''21-day cycles'''
−
====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 (Nipent)]] 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'''
 
 
</div></div>
 
</div></div>
 
===References===
 
===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. [http://www.bloodjournal.org/content/109/2/405.long link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1785105/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/17008537 PubMed]
+
#Gebbia V, Giuliani F, Maiello E, Colucci G, Verderame F, Borsellino N, Mauceri G, Caruso M, Tirrito ML, Valdesi M. Treatment of inoperable and/or metastatic biliary tree carcinomas with single-agent gemcitabine or in combination with levofolinic acid and infusional fluorouracil: results of a multicenter phase II study. J Clin Oncol. 2001 Oct 15;19(20):4089-91. [https://doi.org/10.1200/jco.2001.19.20.4089 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11600613 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]
+
==Gemcitabine monotherapy {{#subobject:1129f1|Regimen=1}}==
−
# '''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] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5278955/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25828695 PubMed] 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">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:81c7f7|Variant=1}}===
+
===Regimen variant #1 {{#subobject:b0f450|Variant=1}}===
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1111/ejh.13042 Robak et al. 2018 (PALG CLL4)]
 
−
|2009-2011
 
−
|style="background-color:#91cf61"|Non-randomized portion of RCT
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Targeted therapy====
 
−
*[[Rituximab (Rituxan)]]
 
−
====Chemotherapy====
 
−
*[[Cladribine (Leustatin)]]
 
−
*[[Cyclophosphamide (Cytoxan)]]
 
−
'''28-day cycle for 6 cycles'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*[[#Observation_2|Observation]] versus [[#Rituximab_monotherapy_2|Rituximab]] maintenance
 
−
</div></div>
 
−
===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] [https://pubmed.ncbi.nlm.nih.gov/29427355 PubMed] NCT00718549
 
−
==Rituximab monotherapy {{#subobject:9f1176|Regimen=1}}==
 
−
<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%"|Years 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 portion of RCT
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Targeted therapy====
 
−
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 
−
**In Hainsworth et al. 2003, optional alternate initial dosing for patients with WBC count greater 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 per day on days 1, 8, 15, 22; 30 minutes prior to [[Rituximab (Rituxan)]]
 
−
*[[Diphenhydramine (Benadryl)]] 50 mg PO or IV once per day on days 1, 8, 15, 22; 30 minutes prior to [[Rituximab (Rituxan)]]
 
−
*In Hainsworth et al. 2003, if WBC count greater 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 (Rituxan)]]
 
−
*In Hainsworth et al. 2003, one of the following:
 
−
**[[Cimetidine (Tagamet)]] 300 mg IV once per day on days 1, 8, 15, 22; 30 minutes prior to [[Rituximab (Rituxan)]]
 
−
**[[Ranitidine (Zantac)]] 50 mg IV once per day on days 1, 8, 15, 22; 30 minutes prior to [[Rituximab (Rituxan)]]
 
−
'''4-week course'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Hainsworth et al. 2003 patients with SD or better: [[#Rituximab_monotherapy_2|Rituximab]] maintenance
 
−
*RESORT substudy patients with PR/CR: [[#Rituximab_monotherapy_2|Indefinite rituximab]] 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] [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] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4900920/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26970533 PubMed] 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%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1016/S2352-3026(16)30194-6 Jain et al. 2017 (MDACC 2013-0044)]
 
−
|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:#b3e2cd">
 
−
====Targeted therapy====
 
−
*[[Ruxolitinib (Jakafi)]] 10 mg PO twice per day
 
−
</div></div>
 
−
===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] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356368/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28089238 PubMed] NCT02131584
 
−
==Zanubrutinib & Obinutuzumab {{#subobject:7ygqqd |Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:it81db |Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7556127/ Tam et al. 2020]
 
−
|2016-NR
 
−
|style="background-color:#91cf61"|Phase 1b, >20 pts in this subgroup
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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'''
 
−
</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] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33022066/ PubMed] NCT02569476
 
−
=Consolidation and/or maintenance after first-line therapy=
 
−
==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%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/full/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====
 
−
*[[Regimen_classes#Chemotherapy|Chemotherapy]] (details not specified)
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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'''
 
−
</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;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
!style="width: 20%"|Study
 
!style="width: 20%"|Study
Line 1,987: Line 583:
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://www.nature.com/articles/2403354 Wendtner et al. 2004 (GCLLSG CLL4B)]
+
|[https://doi.org/10.1056/NEJMoa0908721 Valle et al. 2010 (ABC-02)]
−
|NR
+
|2002-2008
−
|style="background-color:#1a9851"|Phase 3 (E-esc)
+
| style="background-color:#1a9851" |Phase 3 (E-de-esc)
−
|[[#Observation_2|Observation]]
+
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_2|Cisplatin & Gemcitabine]]
−
| style="background-color:#1a9850" |Superior PFS<sup>1</sup>
+
| style="background-color:#d73027" |Inferior OS
−
|-
 
−
|}
 
−
''<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.''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[Chronic_lymphocytic_leukemia_-_historical#Fludarabine_monotherapy|F]] x 6 or [[Chronic_lymphocytic_leukemia_-_historical#FC|FC]] x 6
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Targeted therapy====
 
−
*[[Alemtuzumab (Campath)]] as follows:
 
−
**Day 1: 3 mg SC once
 
−
**Day 2, if 3 mg dose is well tolerated: 10 mg SC once
 
−
**Day 3 onwards, if 10 mg dose is well tolerated: 30 mg SC once on day 3, then SC 3 times per week
 
−
'''12-week course'''
 
−
</div></div>
 
−
===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://www.nature.com/articles/2403354 link to original article] '''contains dosing details in manuscript''' [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/full/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/full/10.1111/bjh.14342 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/28032335 PubMed]
 
−
==Lenalidomide monotherapy {{#subobject:7210a7|Regimen=1}}==
 
−
<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%"|Years 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)
 
−
|[[#Observation_2|Observation]]
 
−
|style="background-color:#1a9850"|Superior PFS<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/show/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".''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*GCLLSG CLLM1: "Chemoimmunotherapy"
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Targeted therapy====
 
−
*[[Lenalidomide (Revlimid)]] as follows:
 
−
**Cycle 1: 5 mg PO once per day
 
−
**If tolerated, Cycles 2 to 6: 10 mg PO once per day
 
−
**If tolerated, Cycle 7 onwards: 15 mg PO once per day
 
−
'''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] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/28916311 PubMed] NCT01556776
 
−
==Observation==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years 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.nature.com/articles/2403354 Wendtner et al. 2004 (GCLLSG CLL4B)]
 
−
|NR
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[#Alemtuzumab_monotherapy_2|Alemtuzumab]]
 
−
|style="background-color:#d73027"|Inferior PFS<sup>1</sup>
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2668968/ Hochster et al. 2009 (ECOG E1496)]
 
−
|NR
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[#Rituximab_monotherapy_2|Rituximab]]
 
−
|style="background-color:#d73027"|Inferior PFS
 
−
|-
 
−
|[http://www.bloodjournal.org/content/117/5/1516.long Michallet et al. 2010]
 
−
|2001-2007
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|1. [[#Cyclophosphamide_.26_TBI.2C_then_auto_HSCT_88|Cy/TBI, then auto HSCT]]<br> 2. [[#BEAM.2C_then_auto_HSCT_88|BEAM, then auto HSCT]]
 
−
|style="background-color:#d73027"|Inferior EFS
 
−
|-
 
−
|[http://www.bloodjournal.org/content/117/23/6109 Sutton et al. 2011 (Auto-LLC 2001)]
 
−
|2001-2007
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[#Cyclophosphamide_.26_TBI.2C_then_auto_HSCT_88|Cy/TBI, then auto HSCT]]
 
−
|style="background-color:#d73027"|Inferior EFS
 
−
|-
 
−
|[https://doi.org/10.1002/ajh.23668 Foà et al. 2014 (ML21445)]
 
−
|2008-2013
 
−
|style="background-color:#1a9851"|Randomized Phase 2 (C)
 
−
|[[#Rituximab_monotherapy_2|Rituximab]]
 
−
|style="background-color:#fee08b"|Might have inferior 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 (C)
 
−
|[[#Rituximab_monotherapy_2|Rituximab]]
 
−
|style="background-color:#d73027"|Inferior PFS
 
−
|-
 
−
|[https://doi.org/10.1016/S2352-3026(17)30171-0 Fink et al. 2017 (GCLLSG CLLM1)]
 
−
|2012-2016
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[#Lenalidomide_monotherapy_2|Lenalidomide]]
 
−
|style="background-color:#d73027"|Inferior PFS
 
−
|-
 
−
|[https://doi.org/10.1016/S2352-3026(17)30235-1 Dartigeas et al. 2017 (CLL 2007 SA)]
 
−
|2007-2014
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[#Rituximab_monotherapy_2|Rituximab]]
 
−
|style="background-color:#d73027"|Inferior PFS
 
−
|-
 
−
|}
 
−
''<sup>1</sup>Reported efficacy for GCLLSG CLL4B is based on the 2009 update.''<br>
 
−
''No further treatment; used as a comparator arm. GCLLSG CLL4B closed early due to high rates of infections in the experimental arm''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*GCLLSG CLL4B: [[Chronic_lymphocytic_leukemia_-_historical#Fludarabine_monotherapy|F]] x 6 versus [[Chronic_lymphocytic_leukemia_-_historical#FC|FC]] x 6
 
−
*ECOG E1496: [[Chronic_lymphocytic_leukemia_-_historical#CVP|CVP]]
 
−
*Auto-LLC 2001: [[#mini_CHOP_88|mini-CHOP]] x 3, then [[Chronic_lymphocytic_leukemia_-_historical#Fludarabine_monotherapy|F]] x 3
 
−
*ML21445: [[#Chlorambucil_.26_Rituximab_.28RClb.29|Clb-R]]
 
−
*AGMT CLL-8a: [[Regimen_classes#Rituximab-containing_regimen|Rituximab-containing chemoimmunotherapy]]
 
−
*GCLLSG CLLM1: "Chemoimmunotherapy"
 
−
*CLL 2007 SA: [[#FCR|FCR]] x 4
 
−
</div></div>
 
−
===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://www.nature.com/articles/2403354 link to original article] [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/full/10.1111/j.1365-2141.2008.07394.x link to original article] [https://pubmed.ncbi.nlm.nih.gov/19016732 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. [https://doi.org/10.1200/jco.2008.17.1561 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2668968/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19255334 PubMed] NCT00003204
 
−
# Michallet M, Dreger P, Sutton L, Brand R, Richards S, van Os M, Sobh M, Choquet S, Corront B, Dearden C, Gratwohl A, Herr W, Catovsky D, Hallek M, de Witte T, Niederwieser D, Leporrier M, Milligan D; EBMT Chronic Leukemia Working Party. Autologous hematopoietic stem cell transplantation in chronic lymphocytic leukemia: results of European intergroup randomized trial comparing autografting versus observation. Blood. 2011 Feb 3;117(5):1516-21. Epub 2010 Nov 24. [http://www.bloodjournal.org/content/117/5/1516.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/21106985 PubMed]
 
−
# '''Auto-LLC 2001:''' Sutton L, Chevret S, Tournilhac O, Diviné M, Leblond V, Corront B, Leprêtre S, Eghbali H, Van Den Neste E, Michallet M, Maloisel F, Bouabdallah K, Decaudin D, Berthou C, Brice P, Gonzalez H, Chapiro E, Radford-Weiss I, Leporrier N, Maloum K, Nguyen-Khac F, Davi F, Lejeune J, Merle-Béral H, Leporrier M; Société Française de Greffe de Moelle et de Thérapie Cellulaire; Groupe Français d'étude de la Leucémie Lymphoïde Chronique. Autologous stem cell transplantation as a first-line treatment strategy for chronic lymphocytic leukemia: a multicenter, randomized, controlled trial from the SFGM-TC and GFLLC. Blood. 2011 Jun 9;117(23):6109-19. Epub 2011 Mar 15. [http://www.bloodjournal.org/content/117/23/6109 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21406717 PubMed] NCT00931645
 
−
<!-- # '''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 [http://www.ehaweb.org/congress-and-events/20th-congress/previous-congresses-2/abstract-book link to abstract book] -->
 
−
# '''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] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/24415640 PubMed] EudraCT 2008-001612-20
 
−
# '''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] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/27374465 PubMed] NCT01118234
 
−
# '''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] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/28916311 PubMed] NCT01556776
 
−
# '''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] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/29275118 PubMed] NCT00645606
 
−
==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%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[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
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Preceding treatment====
 
−
*[[#PCO|PCO]] x 6
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Targeted therapy====
 
−
*[[Ofatumumab (Arzerra)]] 1000 mg IV once on day 1
 
−
'''28-day cycle for 6 cycles'''
 
−
</div></div>
 
−
===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] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/27570087 PubMed] NCT01024010
 
−
==Rituximab monotherapy {{#subobject:726c55|Regimen=1}}==
 
−
<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%"|Years 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)
 
−
|[[#Observation_2|Observation]]
 
−
|style="background-color:#d9ef8b"|Might have superior PFS
 
−
|-
 
−
|[https://doi.org/10.1111/ejh.13042 Robak et al. 2018 (PALG CLL4)]
 
−
|2009-2011
 
−
|style="background-color:#1a9851"|Phase 3b (E-esc)
 
−
|[[#Observation_2|Observation]]
 
−
|style="background-color:#91cf60"|Seems to have superior PFS
 
−
|-
 
−
|}
 
−
''Note: dosing details for PALG CLL4 were not available in the abstract.''
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*ML21445: [[#Chlorambucil_.26_Rituximab_.28RClb.29|Clb-R]]
 
−
*PALG CLL4: [[#RCC|RCC]] x 6
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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%"|Years 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]
 
−
|2005-2007
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|style="background-color:#d3d3d3"|
 
−
|style="background-color:#d3d3d3"|
 
−
|-
 
−
|[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)
 
−
|[[#Observation_2|Observation]]
 
−
|style="background-color:#1a9850"|Superior PFS<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">
 
−
====Preceding treatment====
 
−
*Bosch et al. 2009: [[Chronic_lymphocytic_leukemia_-_historical#R-FCM|R-FCM]]
 
−
*AGMT CLL-8a: [[Regimen_classes#Rituximab-containing_regimen|Rituximab-containing chemoimmunotherapy]]
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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%"|Years 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)]
 
−
|2007-2014
 
−
|style="background-color:#1a9851"|Phase 3 (E-esc)
 
−
|[[#Observation_2|Observation]]
 
−
|style="background-color:#1a9850"|Superior PFS<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====
 
−
*[[#FCR|FCR]] x 4
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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%"|Years 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)]
 
−
|NR
 
−
|style="background-color:#1a9851"|Phase 3 (E-esc)
 
−
|[[#Observation_2|Observation]]
 
−
|style="background-color:#1a9850"|Superior PFS
 
−
|-
 
−
|}
 
−
''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: [[#Rituximab_monotherapy|Rituximab]] induction
 
−
*ECOG E1496: [[Chronic_lymphocytic_leukemia_-_historical#CVP|CVP]]
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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 (Rituxan)]]
 
−
*[[Diphenhydramine (Benadryl)]] 50 mg IV once per day on days 1, 8, 15, 22; 30 minutes prior to [[Rituximab (Rituxan)]]
 
−
*One of the following:
 
−
**[[Cimetidine (Tagamet)]] 300 mg IV once per day on days 1, 8, 15, 22; 30 minutes prior to [[Rituximab (Rituxan)]]
 
−
**[[Ranitidine (Zantac)]] 50 mg IV once per day on days 1, 8, 15, 22; 30 minutes prior to [[Rituximab (Rituxan)]]
 
−
'''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;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years 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/PMC4900920/ Williams et al. 2016 (RESORT substudy)]
 
−
|2003-2008
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[#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====
 
−
*[[#Rituximab_monotherapy|Rituximab]]
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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%"|Years 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:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[#FCR|FCR-Lite]] x 6
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Targeted therapy====
 
−
*[[Rituximab (Rituxan)]] 500 mg/m<sup>2</sup> IV once on day 1
 
−
'''3-month cycles'''
 
−
</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] [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] '''contains dosing details in manuscript''' [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. [http://www.bloodjournal.org/content/119/13/3184.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/22461474 PubMed]
 
−
<!-- 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] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2668968/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19255334 PubMed] 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] '''contains dosing details in manuscript''' [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. [http://www.bloodjournal.org/content/122/24/3951.long link to original article] '''contains dosing details in manuscript''' [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 [http://www.ehaweb.org/congress-and-events/20th-congress/previous-congresses-2/abstract-book link to abstract book] -->
 
−
# '''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] '''contains dosing details in manuscript''' [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] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4900920/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26970533 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. [https://doi.org/10.1016/s2352-3026(16)30045-x link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/27374465 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. [https://doi.org/10.1016/S2352-3026(17)30235-1 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/29275118 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. [https://doi.org/10.1111/ejh.13042 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29427355 PubMed] NCT00718549
 
−
=Relapsed or refractory, randomized data=
 
−
==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%"|Years 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/PMC4862586/ Byrd et al. 2015 (ACE-CL-001 r/r)]
 
−
|2014-NR
 
−
|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<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)]
 
−
|2017-2018
 
−
| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
 
−
|Investigator's choice of:<br>1. [[#Bendamustine_.26_Rituximab_.28BR.29_2|BR]]<br>2. [[#Idelalisib_.26_Rituximab|Idelalisib & Rituximab]]
 
−
| style="background-color:#1a9850" |Superior PFS<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:#b3e2cd">
 
−
====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] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26641137 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. [https://doi.org/10.1200/jco.19.03355 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/32459600 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. [https://doi.org/10.1200/jco.21.01210 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8547923/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34310172/ PubMed] NCT02477696
 
−
 
 
−
==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}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years 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)]
 
−
|2011-2013
 
−
|style="background-color:#1a9851"|Randomized Phase 2 (C)
 
−
|[[#Bendamustine_.26_Otlertuzumab_77|Bendamustine & Otlertuzumab]]
 
−
|style="background-color:#fc8d59"|Seems to have inferior PFS
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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>
 
−
<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%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[http://link.springer.com/article/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
 
 
|-
 
|-
 
|}
 
|}
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Bendamustine]] 100 mg/m<sup>2</sup> IV once per day on days 1 & 2
+
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15
−
'''28-day cycle for up to 8 cycles'''
+
'''28-day cycle for 3 to 6 cycles depending on response'''
 
</div></div><br>
 
</div></div><br>
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #3, 120 mg/m<sup>2</sup> {{#subobject:3f29c2|Variant=1}}===
+
===Regimen variant #2 {{#subobject:fcd6f1|Variant=1}}===
 
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 
!style="width: 33%"|Study
 
!style="width: 33%"|Study
Line 2,446: Line 602:
 
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://doi.org/10.1200/jco.2007.12.5070 Friedberg et al. 2008]
+
|[https://doi.org/10.1200/jco.2001.19.20.4089 Gebbia et al. 2001]
−
|2003-2005
+
|NR
−
|style="background-color:#91cf61"|Phase 2
+
| style="background-color:#91cf61" |Phase 2
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2916680/ Kahl et al. 2010]
 
−
|2005-2007
 
−
|style="background-color:#91cf61"|Phase 2
 
 
|-
 
|-
 
|}
 
|}
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Bendamustine]] 120 mg/m<sup>2</sup> IV once per day on days 1 & 2
+
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15
−
'''21-day cycle for 6 to 8 (Kahl et al. 2010) or up to 12 (Friedberg et al. 2008) cycles'''
+
'''30-day cycles'''
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
<!-- Presented in part at the 48th Annual Meeting of the American Society of Hematology, December 9-12, 2006, Orlando, Florida -->
+
#Gebbia V, Giuliani F, Maiello E, Colucci G, Verderame F, Borsellino N, Mauceri G, Caruso M, Tirrito ML, Valdesi M. Treatment of inoperable and/or metastatic biliary tree carcinomas with single-agent gemcitabine or in combination with levofolinic acid and infusional fluorouracil: results of a multicenter phase II study. J Clin Oncol. 2001 Oct 15;19(20):4089-91. [https://doi.org/10.1200/jco.2001.19.20.4089 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11600613 PubMed]
−
# 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] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18182663 PubMed]
+
#'''ABC-02:''' Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, Madhusudan S, Iveson T, Hughes S, Pereira SP, Roughton M, Bridgewater J; ABC-02 Trial Investigators. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010 Apr 8;362(14):1273-81. [https://doi.org/10.1056/NEJMoa0908721 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20375404 PubMed] NCT00262769
−
<!-- 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. -->
+
==Gemcitabine, Cisplatin, S-1 {{#subobject:e0d17a|Regimen=1}}==
−
# 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] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2916680/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19890959 PubMed]
+
GCS: '''<u>G</u>'''emcitabine, '''<u>C</u>'''isplatin, '''<u>S</u>'''-1
−
# '''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. [http://link.springer.com/article/10.1007/s00277-012-1660-6 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23340738 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. [https://doi.org/10.1111/bjh.14464 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5324531/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27977057 PubMed] 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">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:39f839|Variant=1}}===
+
===Regimen {{#subobject:87f9c7|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
!style="width: 20%"|Study
 
!style="width: 20%"|Study
Line 2,480: Line 626:
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://doi.org/10.1200/jco.2010.33.8061g Fischer et al. 2011 (GCLLSG CLL2M r/r)]
+
|[https://academic.oup.com/annonc/article/29/suppl_8/mdy282/5140253 Sakai et al. 2018 (KHBO1401-MITSUBA)]
−
|2006-2007
+
|2014-NR
−
|style="background-color:#91cf61"|Phase 2
+
| style="background-color:#1a9851" |Phase 3 (E-esc)
−
|style="background-color:#d3d3d3"|
+
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_2|Cisplatin & Gemcitabine]]
−
|style="background-color:#d3d3d3"|
+
| style="background-color:#d9ef8b" |Seems to have superior OS
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865431/ Michallet et al. 2018 (MABLE)]
 
−
|2010-2014
 
−
| style="background-color:#1a9851"|Phase 3 (E-switch-ic)
 
−
|[[#Chlorambucil_.26_Rituximab_.28RClb.29_88|R-Clb]]
 
−
| style="background-color:#1a9850" |Superior CR rate<sup>1</sup>
 
−
|-
 
−
|[https://doi.org/10.1016/S1470-2045(15)00465-9 Chanan-Khan et al. 2015 (HELIOS)]
 
−
|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)]
 
−
|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)]
 
−
|2014-2015
 
−
|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)]
 
−
|2017-2018
 
−
| style="background-color:#1a9851" |Phase 3 (C)
 
−
|[[#Acalabrutinib_monotherapy_2|Acalabrutinib]]
 
−
|style="background-color:#d73027"|Inferior PFS
 
−
|-
 
−
|Awaiting publication (BRUIN CLL-321)
 
−
|2021-2024
 
−
| style="background-color:#1a9851" |Phase 3 (C)
 
−
|[[#Pirtobrutinib_monotherapy_77|Pirtobrutinib]]
 
−
|style="background-color:#d3d3d3"|TBD
 
−
|-
 
 
|}
 
|}
−
''<sup>1</sup>Reported efficacy 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:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Bendamustine]] 70 mg/m<sup>2</sup> IV once per day on days 1 & 2
+
*[[Cisplatin (Platinol)]] 25 mg/m<sup>2</sup> IV once on day 1
−
**HELIOS gave 1st cycle on days 2 & 3
+
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once on day 1
−
====Targeted therapy====
+
*[[Tegafur, gimeracil, oteracil (S-1)]] 80 mg/m<sup>2</sup> PO once per day on days 1 to 7
−
*[[Rituximab (Rituxan)]] as follows:
+
'''14-day cycles'''
−
**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>
 
</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. -->
+
#'''Abstract:''' Sakai D, Kanai M , Kobayashi S, Eguchi H, Baba H, Seo S, Taketomi A, Takayama T, Yamaue H, Ishioka C, Sho M, Takeyama Y, Fujimoto J, Toyoda M, Shimizu J, Goto T, Yoshimura K, Hatano E, Nagano H, Ioka T. Randomized phase III study of gemcitabine, cisplatin plus S-1 (GCS) versus gemcitabine, cisplatin (GC) for advanced biliary tract cancer (KHBO1401-MITSUBA). Annals of Oncology 29 (Supplement 8): viii205–viii270, 2018 [https://academic.oup.com/annonc/article/29/suppl_8/mdy282/5140253 link to abstract] NCT02182778
−
# '''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.2010.33.8061g link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21844497 PubMed] NCT00274989
+
==Gemcitabine & Mitomycin {{#subobject:5dad3c|Regimen=1}}==
−
# '''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] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/26655421 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. [https://www.nature.com/articles/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 [https://ash.confex.com/ash/2015/webprogram/Paper87420.html link to abstract] -->
 
−
# '''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] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/28139405 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. [http://www.haematologica.org/content/103/4/698 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865431/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29419437 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. [https://doi.org/10.1056/NEJMoa1713976 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/29562156 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. [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://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] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/32459600 PubMed] NCT02970318
 
−
#'''BRUIN CLL-321:''' NCT04666038
 
−
==Bendamustine & Rituximab (BR) & Ibrutinib {{#subobject:9861f9|Regimen=1}}==
 
−
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">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:ad1034|Variant=1}}===
+
===Regimen {{#subobject:42a188|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
!style="width: 20%"|Study
 
!style="width: 20%"|Study
Line 2,569: Line 651:
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
!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)]
+
|[https://doi.org/10.1093/annonc/mdh096 Kornek et al. 2004]
−
|2011-NR
+
|2000-2001
−
|style="background-color:#91cf61"|Phase 2
+
| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ic)
−
|style="background-color:#d3d3d3"|
+
|[[#Capecitabine_.26_Mitomycin|Capecitabine & Mitomycin]]
−
|style="background-color:#d3d3d3"|
+
| style="background-color:#fee08b" |Might have inferior ORR
−
|-
 
−
|[https://doi.org/10.1016/S1470-2045(15)00465-9 Chanan-Khan et al. 2015 (HELIOS)]
 
−
|2012-2014
 
−
|style="background-color:#1a9851"|Phase 3 (E-RT-esc)
 
−
|[[#Bendamustine_.26_Rituximab_.28BR.29_2|BR]]
 
−
| style="background-color:#1a9850" |Superior OS<sup>1</sup><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:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Bendamustine]] as follows:
+
*[[Gemcitabine (Gemzar)]] 2000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 15
−
**Cycles 1 to 6: 70 mg/m<sup>2</sup> IV once per day on days 1 & 2
+
*[[Mitomycin (Mutamycin)]] 8 mg/m<sup>2</sup> IV bolus once on day 1
−
***HELIOS gave 1st cycle on days 2 & 3
+
====Supportive therapy====
−
====Targeted therapy====
+
*[[Dexamethasone (Decadron)]] and [[:Category:Serotonin_5-HT3_antagonists|5-HT3 antagonists]] on the day of IV chemotherapy
−
*[[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
 
 
'''28-day cycles'''
 
'''28-day cycles'''
 
</div></div>
 
</div></div>
 
===References===
 
===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. [http://www.bloodjournal.org/content/125/19/2915.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4424415/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25755291 PubMed] NCT01292135
+
#Kornek GV, Schuell B, Laengle F, Gruenberger T, Penz M, Karall K, Depisch D, Lang F, Scheithauer W. Mitomycin C in combination with capecitabine or biweekly high-dose gemcitabine in patients with advanced biliary tract cancer: a randomised phase II trial. Ann Oncol. 2004 Mar;15(3):478-83. [https://doi.org/10.1093/annonc/mdh096 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/14998852 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] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/26655421 PubMed] NCT01611090
+
==Gemcitabine & S-1 {{#subobject:afbc17|Regimen=1}}==
−
## '''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://www.nature.com/articles/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]
+
GS: '''<u>G</u>'''emcitabine & '''<u>S</u>'''-1
−
## '''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
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:5c2b6f|Variant=1}}===
+
===Regimen {{#subobject:cb3b9cd|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 20%"|Study
+
! style="width: 20%" |Study
−
!style="width: 20%"|Years of enrollment
+
! style="width: 20%" |Years of enrollment
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|Comparator
+
! style="width: 20%" |Comparator
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5589180/ Zelenetz et al. 2017 (Tugela)]
+
|[https://doi.org/10.1093/annonc/mdz402 Morizane et al. 2019 (FUGA-BT)]
−
|2012-2014
+
|2013-2016
−
|style="background-color:#1a9851"|Phase 3 (E-esc)
+
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
−
|[[#Bendamustine_.26_Rituximab_.28BR.29_2|BR]]
+
|[[#Cisplatin_.26_Gemcitabine_.28GC.29_2|Gemcitabine & Cisplatin]]
−
|style="background-color:#1a9850"|Superior PFS<br>Median PFS: 20.8 vs 11.1 mo<br>(HR 0.33, 95% CI 0.25-0.44)
+
| style="background-color:#eeee01" |Seems to have non-inferior OS
 
|-
 
|-
 
|}
 
|}
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Bendamustine]] as follows:
+
*[[Gemcitabine (Gemzar)]]
−
**Cycles 1 to 6: 70 mg/m<sup>2</sup> IV once per day on days 1 & 2
+
*[[Tegafur, gimeracil, oteracil (S-1)]]
−
====Targeted therapy====
 
−
*[[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
 
−
*[[Idelalisib (Zydelig)]] 150 mg PO twice per day
 
−
'''28-day cycles'''
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
<!--
+
#'''FUGA-BT:''' Morizane C, Okusaka T, Mizusawa J, Katayama H, Ueno M, Ikeda M, Ozaka M, Okano N, Sugimori K, Fukutomi A, Hara H, Mizuno N, Yanagimoto H, Wada K, Tobimatsu K, Yane K, Nakamori S, Yamaguchi H, Asagi A, Yukisawa S, Kojima Y, Kawabe K, Kawamoto Y, Sugimoto R, Iwai T, Nakamura K, Miyakawa H, Yamashita T, Hosokawa A, Ioka T, Kato N, Shioji K, Shimizu K, Nakagohri T, Kamata K, Ishii H, Furuse J; JCOG. Combination gemcitabine plus S-1 versus gemcitabine plus cisplatin for advanced/recurrent biliary tract cancer: the FUGA-BT (JCOG1113) randomized phase III clinical trial. Ann Oncol. 2019 Dec 1;30(12):1950-1958. [https://doi.org/10.1093/annonc/mdz402 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31566666 PubMed] UMIN000010667
−
# '''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 [https://ash.confex.com/ash/2015/webprogram/Paper87420.html link to abstract] -->
+
==GemOx {{#subobject:a99e6e|Regimen=1}}==
−
# '''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] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5589180/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28139405 PubMed] NCT01569295
+
GemOx: '''<u>Gem</u>'''citabine & '''<u>Ox</u>'''aliplatin
−
==Duvelisib monotherapy {{#subobject:4a9cdb|Regimen=1}}==
+
<br>GEMOX: '''<u>GEM</u>'''citabine & '''<u>OX</u>'''aliplatin
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:8e168d|Variant=1}}===
+
===Regimen variant #1, 1000/85, bi-weekly {{#subobject:508f1b|Variant=1}}===
−
{| class="wikitable" style="color:white; background-color:#404040"
+
{| class="wikitable sortable" style="width: 80%; text-align:center;"
−
|<small>'''FDA-recommended dose'''</small>
+
!style="width: 25%"|Study
 +
!style="width: 25%"|Years of enrollment
 +
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
|-
 
|-
−
|}
+
|[https://academic.oup.com/jjco/article/41/2/217/875887 Halim et al. 2011]
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
+
|2005-2009
−
!style="width: 20%"|Study
+
| style="background-color:#91cf61" |Phase 2
−
!style="width: 20%"|Years of enrollment
+
|ORR: 27.5%
−
!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/PMC6284216/ Flinn et al. 2018 (DUO)]
 
−
|2014-2015
 
−
|style="background-color:#1a9851"|Phase 3 (E-RT-switch-ooc)
 
−
|[[#Ofatumumab_monotherapy_2|Ofatumumab]]
 
−
|style="background-color:#1a9850" |Superior PFS<br>Median PFS: 13.3 vs 9.9 mo<br>(HR 0.52)
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Targeted therapy====
 
−
*[[Duvelisib (Copiktra)]] 25 mg PO twice per day
 
−
'''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. [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] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/30287523 PubMed] 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}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years 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-NR
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[#FCR_.26_Lumiliximab_77|FCR+L]]
 
−
|style="background-color:#ffffbf"|Did not meet primary endpoint of CR rate
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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 an equivalent
 
−
'''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%"|Years 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.2009.26.4556 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<br>Median PFS: 30.6 vs 20.6 mo<br>(HR 0.65)
 
 
|-
 
|-
 
|}
 
|}
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Fludarabine (Fludara)]] as follows:
+
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once on day 1, '''given first'''
−
**Cycle 1: 25 mg/m<sup>2</sup> IV once per day on days 2 to 4
+
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1, '''given second'''
−
**Cycles 2 to 6: 25 mg/m<sup>2</sup> IV once per day on days 1 to 3
+
'''14-day cycles'''
−
*[[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 (Rituxan)]]
 
−
*[[Acetaminophen (Tylenol)]] 650 mg PO once on day 1; 30 minutes prior to [[Rituximab (Rituxan)]]
 
−
*[[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></div><br>
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #3 {{#subobject:fb9678|Variant=1}}===
+
===Regimen variant #2, 1000/100, bi-weekly {{#subobject:a8fecb|Variant=1}}===
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years 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
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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 (Rituxan)]]
 
−
*[[Acetaminophen (Tylenol)]] 650 mg PO once on day 1, prior to [[Rituximab (Rituxan)]]
 
−
*[[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%"|Years 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:#b3e2cd">
 
−
====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===
 
−
# 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] '''contains dosing details in manuscript''' [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. [http://www.bloodjournal.org/content/117/11/3016.long 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] '''contains dosing details in manuscript''' [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] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20194844 PubMed] content property of [http://hemonc.org 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. [https://doi.org/10.1111/bjh.13061 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25130401 PubMed] 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;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
!style="width: 20%"|Study
 
!style="width: 20%"|Study
Line 2,805: Line 725:
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://doi.org/10.1016/S0140-6736(96)91681-5 Johnson et al. 1996]
+
|[https://doi.org/10.1016/S1470-2045(11)70301-1 Lee et al. 2011 (SMC 2008-12-024)]
−
|1990-1992
+
|2009-2010
−
|style="background-color:#1a9851"|Phase 3 (E-de-esc)
 
−
|[[Chronic_lymphocytic_leukemia_-_historical#CAP|CAP]]
 
−
| style="background-color:#91cf60" |Seems to have superior ORR
 
−
|-
 
−
|[http://link.springer.com/article/10.1007/s00277-012-1660-6 Niederle et al. 2013 (WiSP RI05)]
 
−
|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 is 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:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Fludarabine (Fludara)]] 25 mg/m<sup>2</sup> IV once per day on days 1 to 5
 
−
'''28-day cycle for up to 6 to 12 cycles'''
 
−
</div></div>
 
−
===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] '''contains dosing details in abstract''' [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. [http://link.springer.com/article/10.1007/s00277-012-1660-6 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23340738 PubMed] NCT01423032
 
−
==Ibrutinib monotherapy {{#subobject:29205a|Regimen=1}}==
 
−
<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%"|Years 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/PMC3772525/ Byrd et al. 2013 (PCYC-1102 relapsed)]
 
−
|2010-2011
 
−
|style="background-color:#91cf61"|Phase 2 (RT)
 
−
|style="background-color:#d3d3d3"|
 
−
|style="background-color:#d3d3d3"|
 
−
|-
 
−
|[https://doi.org/10.1016/S1470-2045(14)71182-9 Farooqui et al. 2014 (NHLBI 12-H-0035)]
 
−
|2011-2014
 
−
|style="background-color:#ffffbe"|Phase 2, <20 pts
 
−
|style="background-color:#d3d3d3"|
 
−
|style="background-color:#d3d3d3"|
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4134521/ Byrd et al. 2014 (RESONATE)]
 
−
|2012-2013
 
−
|style="background-color:#1a9851"|Phase 3 (E-RT-switch-ooc)
 
−
|[[#Ofatumumab_monotherapy_2|Ofatumumab]]
 
−
| style="background-color:#1a9850" |Superior PFS<sup>1</sup><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 OS<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)]
 
−
|2015-2016
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[Stub#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)]
 
−
|2015-2017
 
 
| style="background-color:#1a9851" |Phase 3 (C)
 
| style="background-color:#1a9851" |Phase 3 (C)
−
|[[#Acalabrutinib_monotherapy_2|Acalabrutinib]]
+
|[[#GemOx_.26_Erlotinib_88|GEMOX & Erlotinib]]
−
| style="background-color:#eeee01" |Non-inferior PFS
+
| style="background-color:#fee08b" |Might have inferior PFS
−
|-
 
−
|[https://doi.org/10.1016/s2152-2650(22)01324-6 Brown et al. 2022 (ALPINE)]
 
−
|2018-2019
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[#Zanubrutinib_monotherapy_2|Zanubrutinib]]
 
−
| style="background-color:#d73027" |Inferior ORR
 
 
|-
 
|-
 
|}
 
|}
−
''<sup>1</sup>Reported efficacy for RESONATE is based on the second 2019 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:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Targeted therapy====
 
−
*[[Ibrutinib (Imbruvica)]] 420 mg PO once per day
 
−
'''Continued indefinitely'''
 
−
</div></div>
 
−
===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. [https://doi.org/10.1056/NEJMoa1215637 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772525/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23782158 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. [http://www.bloodjournal.org/content/125/16/2497 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. [http://www.bloodjournal.org/content/131/17/1910.long 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) [http://abstracts.asco.org/144/AbstView_144_129571.html 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] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4134521/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24881631 PubMed] 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] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342187/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25555420 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. [https://doi.org/10.1016/S1470-2045(16)30212-1 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/27637985 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. [http://www.bloodjournal.org/content/128/25/2899 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/full/10.1002/cam4.1337 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5911578/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29533000 PubMed] 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] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/33631112/ 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. [https://doi.org/10.1200/jco.21.01210 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8547923/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34310172/ PubMed] 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 article] [https://pubmed.ncbi.nlm.nih.gov/36163869/ PubMed] NCT03734016
 
−
 
−
==Idelalisib & Ofatumumab {{#subobject:c4f11b|Regimen=1}}==
 
−
<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%"|Years 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<br>Median PFS: 16.3 vs 8 mo<br>(HR 0.27, 95% CI 0.19-0.39)
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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'''
 
−
</div></div>
 
−
===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] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/28257752 PubMed] NCT01659021
 
−
==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%"|Years 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)]
 
−
|2012-2013
 
−
|style="background-color:#1a9851"|Phase 3 (E-RT-esc)
 
−
|[[#Rituximab_monotherapy_3|Rituximab]]
 
−
| style="background-color:#1a9850" |Superior PFS<br>PFS6: 93% vs 46%<br>(aHR 0.15, 95% CI 0.08-0.28)
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Targeted therapy====
 
−
*[[Idelalisib (Zydelig)]] 150 mg PO twice per day
 
−
*[[Rituximab (Rituxan)]] as follows:
 
−
**Week 1: 375 mg/m<sup>2</sup> IV once
 
−
**Weeks 3, 5, 7, 9, 13, 17, 21: 500 mg/m<sup>2</sup> IV once
 
−
'''21-day cycle for 1 cycle, then 28-day cycle for up to 17 cycles (18 cycles total)'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Upon progression: Idelalisib can be increased to 300 mg PO twice per day
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #2, indefinite {{#subobject:2fu7bz|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years 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)]
 
−
|2017-2018
 
−
| style="background-color:#1a9851" |Phase 3 (C)
 
−
|[[#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:#b3e2cd">
 
−
====Targeted therapy====
 
−
*[[Idelalisib (Zydelig)]] 150 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 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
 
−
'''14-day cycle for 1 cycle, then 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] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161365/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24450857 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. [https://doi.org/10.1200/JCO.18.01460 link to original 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] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/32459600 PubMed] NCT02970318
 
−
#'''BRUIN CLL-321:''' 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%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1111/bjh.13380 Österborg et al. 2015 (GEN416)]
 
−
|2009-2011
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|-
 
−
|}
 
−
''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:#b3e2cd">
 
−
====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 (Arzerra)]]
 
−
*[[Cetirizine (Zyrtec)]] (or equivalent) 10 mg PO once per day on days 1, 8, 15, 22, prior to [[Ofatumumab (Arzerra)]]
 
−
*[[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====
 
−
*Patients with SD or better could proceed to [[#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%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/111/3/1094.long 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-NR
 
−
|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-NR
 
−
|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)]
 
−
|2012-2013
 
−
|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)]
 
−
|2014-2015
 
−
|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:#b3e2cd">
 
−
====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 [[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%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/129/13/1876.long Ghia et al. 2017 (P07714)]
 
−
|2012-NR
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[#Dinaciclib_monotherapy_77|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:#b3e2cd">
 
−
====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===
 
−
# 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. [http://www.bloodjournal.org/content/111/3/1094.long 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] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979101/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20194866 PubMed] 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. [http://www.bloodjournal.org/content/118/19/5126.long 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. [http://www.haematologica.org/content/100/8/e311.long 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) [http://abstracts.asco.org/144/AbstView_144_129571.html 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] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4134521/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24881631 PubMed] 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]
 
−
# '''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. [http://www.haematologica.org/content/100/4/511 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] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25825041 PubMed] NCT00802737
 
−
# '''Novartis 114242:''' Österborg A, Udvardy M, Zaritskey A, Andersson PO, Grosicki S, Mazur G, Kaplan P, Steurer M, Schuh A, Montillo M, Kryachok 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] NCT01313689
 
−
##'''Update:''' Miklos U, Strugov V, Lewerin C, Grosicki S, Mazur G, Steurer M, Montillo M, Kryachok 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] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/28257752 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. [http://www.bloodjournal.org/content/129/13/1876.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/28126927 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. [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] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/30287523 PubMed] 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">
 
−
===Regimen {{#subobject:f8f0ee|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years 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-NR
 
−
|style="background-color:#1a9851"|Phase 3 (E-RT-esc)
 
−
|[[Chronic_lymphocytic_leukemia_-_historical#FC_2|FC]]
 
−
|style="background-color:#1a9850"|Superior PFS<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:#b3e2cd">
 
−
====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====
 
====Chemotherapy====
−
*[[Fludarabine (Fludara)]] 25 mg/m<sup>2</sup> IV once per day on days 1 to 3
+
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once on day 1
−
*[[Cyclophosphamide (Cytoxan)]] 250 mg/m<sup>2</sup> IV once per day on days 1 to 3
+
*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV once on day 2
−
====Supportive therapy====
+
'''14-day cycles'''
−
*[[Acetaminophen (Tylenol)]] 1000 mg PO once on day 1, prior to [[Ofatumumab (Arzerra)]]
 
−
*[[Cetirizine (Zyrtec)]] 10 mg (or equivalent) PO once on day 1, prior to [[Ofatumumab (Arzerra)]]
 
−
*[[Prednisolone (Millipred)]] 100 mg ([[Steroid conversions|or equivalent]]) PO once on day 1, prior to doses 1 & 2 of [[Ofatumumab (Arzerra)]], 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, Kryachok 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] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/27731748 PubMed] 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%"|Years 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)]
 
−
|2003-2008
 
−
|style="background-color:#1a9851"|Phase 3 (E-de-esc)
 
−
|[[#Rituximab_monotherapy_2|Rituximab]] maintenance
 
−
|style="background-color:#fc8d59"|Seems to have inferior TTTF
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*RESORT substudy: [[#Rituximab_monotherapy|Rituximab]], with progression
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Targeted therapy====
 
−
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 
−
'''4-week course'''
 
 
</div></div><br>
 
</div></div><br>
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #2, 8 doses {{#subobject:5ed834|Variant=1}}===
+
===Regimen variant #3, 1000/100 ("GEMOX-3") {{#subobject:a8fefg|Variant=1}}===
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years 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)]
 
−
|2012-2013
 
−
|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:#b3e2cd">
 
−
====Targeted therapy====
 
−
*[[Rituximab (Rituxan)]] as follows:
 
−
**Cycle 1: 375 mg/m<sup>2</sup> IV once on day 1
 
−
**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'''
 
−
</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%"|Years 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
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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 15
 
−
**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 6 cycles'''
 
−
</div></div>
 
−
===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] '''contains dosing details in manuscript''' [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] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161365/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24450857 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. [https://doi.org/10.1200/JCO.18.01460 link to original 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] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4900920/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26970533 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. [https://doi.org/full/10.1002/cam4.1337 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5911578/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29533000 PubMed] NCT01973387
 
−
==Venetoclax & Rituximab {{#subobject:68691a|Regimen=1}}==
 
−
VenR: '''<u>Ven</u>'''etoclax & '''<u>R</u>'''ituximab
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===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%"|Years 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/NEJMoa1713976 Seymour et al. 2018 (MURANO)]
 
−
|2014-2015
 
−
|style="background-color:#1a9851"|Phase 3 (E-RT-switch-ooc)
 
−
|[[#Bendamustine_.26_Rituximab_.28BR.29_2|BR]]
 
−
| style="background-color:#1a9850" |Superior OS<sup>1</sup><br>OS48: 85.3% vs 66.8%<br>(HR 0.41, 95% CI 0.26-0.65)
 
−
|-
 
−
|Awaiting publication (BRUIN CLL-322)
 
−
|2021-2025
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[#Pirtobrutinib.2C_Venetoclax.2C_Rituximab|Pirtobrutinib, Venetoclax, Rituximab]]
 
−
| style="background-color:#d3d3d3" |TBD
 
−
|-
 
−
|}
 
−
''<sup>1</sup>Reported efficacy is based on the 2020 update.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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
 
−
**Week 5 onwards: 400 mg PO once per day
 
−
*[[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===
 
−
# '''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] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/29562156 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. [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://pubmed.ncbi.nlm.nih.gov/35605176/ PubMed]
 
−
# '''BRUIN CLL-322:''' 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%"|Years 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/s2152-2650(22)01324-6 Brown et al. 2022 (ALPINE)]
 
−
|2018-2019
 
−
|style="background-color:#1a9851"|Phase 3 (E-switch-ic)
 
−
|[[#Ibrutinib_monotherapy_2|Ibrutinib]]
 
−
| style="background-color:#1a9850" |Superior ORR<br>ORR: 78.3% vs 62.5%
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#fdcdac">
 
−
====Prior treatment criteria====
 
−
*ALPINE: At least 1 prior systemic therapy
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Targeted therapy====
 
−
*[[Zanubrutinib (Brukinsa)]] 160 mg PO twice per day
 
−
'''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 article] [https://pubmed.ncbi.nlm.nih.gov/36163869/ PubMed] NCT03734016
 
−
=Relapsed or refractory, non-randomized or retrospective data=
 
−
==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%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/99/10/3554.full 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]
 
−
|NR-1994
 
−
|style="background-color:#91cf61"|Phase 2 (RT)
 
−
|-
 
−
|}
 
−
''Note: total course varies depending on reference.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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 (Campath)]]
 
−
*[[Acetaminophen (Tylenol)]] 650 mg PO once per infusion; 30 minutes prior to [[Alemtuzumab (Campath)]]
 
−
*[[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%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/103/9/3278.long Lozanski et al. 2004]
 
−
|NR
 
−
|style="background-color:#91cf61"|Phase 2 (RT)
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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===
 
−
# 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. [http://www.bloodjournal.org/content/99/10/3554.full link to original article] '''contains dosing details in abstract''' [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] '''contains dosing details in abstract''' [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. [http://www.bloodjournal.org/content/103/9/3278.long link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/14726385 PubMed]
 
−
==Alemtuzumab & Rituximab {{#subobject:b3ab64|Regimen=1}}==
 
−
<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%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/101/9/3413.long Faderl et al. 2003]
 
−
|NR
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 
−
**For patients with WBC count greater 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
 
−
====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'''
 
−
</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. [http://www.bloodjournal.org/content/101/9/3413.long link to original article] '''contains dosing details in abstract''' [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;"  
 
{| class="wikitable sortable" style="width: 80%; text-align:center;"  
 
!style="width: 25%"|Study
 
!style="width: 25%"|Study
Line 3,448: Line 746:
 
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
|-
 
|-
−
|[https://doi.org/10.1038/leu.2013.334 Cortelezzi et al. 2013 (GIMEMA CLL0809)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2360533/ Harder et al. 2006]
−
|2010-2011
+
|2002-2005
−
|style="background-color:#91cf61"|Phase 2
+
| style="background-color:#91cf61" |Phase 2
−
| style="background-color:#bfd3e6" |ORR: 72% (95% CI, 57–84%)
+
|ORR: 26% (95% CI 14–44)
 
|-
 
|-
 
|}
 
|}
−
<div class="toccolours" style="background-color:#b3e2cd">
+
GEMOX-3: '''<u>GEM</u>'''citabine & '''<u>OX</u>'''aliplatin, 3 visits per month
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Bendamustine]] 70 mg/m<sup>2</sup> IV once per day on days 1 & 2
+
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15, '''given first'''
−
====Targeted therapy====
+
*[[Oxaliplatin (Eloxatin)]] 100 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 15, '''given second'''
−
*[[Ofatumumab (Arzerra)]] as follows:
+
'''28-day cycles'''
−
**Cycle 1: 300 mg IV once on day 1, then 1000 mg IV once on day 7
 
−
**Cycle 2 onwards: 1000 mg IV once on day 1
 
−
====Supportive therapy====
 
−
*[[Acetaminophen (Tylenol)]] 1000 mg PO once per infusion, prior to [[Ofatumumab (Arzerra)]]
 
−
*[[Diphenhydramine (Benadryl)]] 50 mg PO once per infusion, prior to [[Ofatumumab (Arzerra)]]
 
−
*[[Methylprednisolone (Solumedrol)]] 40 mg IV once per infusion, prior to [[Ofatumumab (Arzerra)]]
 
−
*[[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 up to 6 cycles'''
 
 
</div></div>
 
</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] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/24220274 PubMed] NCT01244451
+
#Harder J, Riecken B, Kummer O, Lohrmann C, Otto F, Usadel H, Geissler M, Opitz O, Henss H. Outpatient chemotherapy with gemcitabine and oxaliplatin in patients with biliary tract cancer. Br J Cancer. 2006 Oct 9;95(7):848-52. [https://doi.org/10.1038/sj.bjc.6603334 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2360533/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16969352 PubMed]
−
==CFAR {{#subobject:6cf406|Regimen=1}}==
+
#Halim A, Ebrahim MA, Saleh Y. A phase II study of outpatient biweekly gemcitabine-oxaliplatin in advanced biliary tract carcinomas. Jpn J Clin Oncol. 2011 Feb;41(2):217-24. [https://academic.oup.com/jjco/article/41/2/217/875887 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21062755 PubMed]
−
CFAR: '''<u>C</u>'''yclophosphamide, '''<u>F</u>'''ludarabine, '''<u>A</u>'''lemtuzumab, '''<u>R</u>'''ituximab
+
#'''SMC 2008-12-024:''' Lee J, Park SH, Chang HM, Kim JS, Choi HJ, Lee MA, Jang JS, Jeung HC, Kang JH, Lee HW, Shin DB, Kang HJ, Sun JM, Park JO, Park YS, Kang WK, Lim HY. Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary-tract cancer: a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2012 Feb;13(2):181-8. Epub 2011 Dec 20. [https://doi.org/10.1016/S1470-2045(11)70301-1 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/22192731 PubMed] NCT01149122
 +
#'''KN035-BTC:''' NCT03478488
 +
==GEMOX-B {{#subobject:119bb0|Regimen=1}}==
 +
GEMOX-B: '''<u>GEM</u>'''citabine, '''<u>OX</u>'''aliplatin, '''<u>B</u>'''evacizumab
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:40c38d|Variant=1}}===
+
===Regimen {{#subobject:3748a1|Variant=1}}===
−
{| class="wikitable sortable" style="width: 80%; text-align:center;"
 
−
!style="width: 25%"|Study
 
−
!style="width: 25%"|Years 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:#b3e2cd">
 
−
====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:
 
−
**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 (Rituxan)]]/[[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 (Rituxan)]]/[[Alemtuzumab (Campath)]]
 
−
**[[Hydrocortisone (Cortef)]] 100 mg IV once per day on days 1, 2, 3, 5; 30 minutes prior to [[Alemtuzumab (Campath)]]
 
−
'''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. [http://www.bloodjournal.org/content/118/8/2085.long link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123326/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21670470 PubMed] 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;"  
 
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 
!style="width: 33%"|Study
 
!style="width: 33%"|Study
Line 3,522: Line 772:
 
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7895867/ Davids et al. 2020 (DFCI 14-193)]
+
|[https://doi.org/10.1016/S1470-2045%2809%2970333-X Zhu et al. 2009 (MGH 05-349)]
−
|2014-2016
+
|2006-2007
−
|style="background-color:#91cf61"|Phase 1b/2
+
| style="background-color:#91cf61" |Phase 2
−
|-
 
−
|}
 
−
''Note: This is the phase 2 dosing.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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====
 
−
*[[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
 
−
'''28-day cycle for up to 26 cycles (2 years)
 
−
</div></div>
 
−
===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] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/32820271/ PubMed] 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%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1200/jco.2005.01.9950 Elter et al. 2005]
 
−
|NR
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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
 
−
**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 (Campath)]], then with subsequent doses if clinically indicated
 
−
*[[Clemastine (Tavist)]] 2 mg IV once on day 1, prior to first dose of [[Alemtuzumab (Campath)]], then with subsequent doses if clinically indicated
 
−
*[[Prednisone (Sterapred)]] 100 mg IV once on day 1, prior to first dose of [[Alemtuzumab (Campath)]], then with subsequent doses if clinically indicated
 
−
*For patients with WBC count greater 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 (Campath)]], and used later if clinically indicated
 
−
'''28-day cycle for 6 cycles'''
 
−
</div></div>
 
−
===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] '''contains dosing details in abstract''' [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 sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years 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
 
 
|-
 
|-
 
|}
 
|}
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Fludarabine (Fludara)]] as follows:
+
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 100 minutes once per day on days 1 & 15, '''given second'''
−
**Cycles 3 & 4: 25 mg/m<sup>2</sup> IV once per day on days 1 to 5
+
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 & 15, '''given third'''
 
====Targeted therapy====
 
====Targeted therapy====
−
*[[Ibrutinib (Imbruvica)]] 420 mg PO once per day
+
*[[Bevacizumab (Avastin)]] 10 mg/kg IV once per day on days 1 & 15, '''given first'''
 
'''28-day cycles'''
 
'''28-day cycles'''
 
</div></div>
 
</div></div>
 
===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] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8932338/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32808680/ PubMed] NCT02514083
+
#'''MGH 05-349:''' Zhu AX, Meyerhardt JA, Blaszkowsky LS, Kambadakone AR, Muzikansky A, Zheng H, Clark JW, Abrams TA, Chan JA, Enzinger PC, Bhargava P, Kwak EL, Allen JN, Jain SR, Stuart K, Horgan K, Sheehan S, Fuchs CS, Ryan DP, Sahani DV. Efficacy and safety of gemcitabine, oxaliplatin, and bevacizumab in advanced biliary-tract cancers and correlation of changes in 18-fluorodeoxyglucose PET with clinical outcome: a phase 2 study. Lancet Oncol. 2010 Jan;11(1):48-54. Epub 2009 Nov 20. [https://doi.org/10.1016/S1470-2045%2809%2970333-X link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19932054 PubMed] NCT00361231
−
==Fludarabine & Prednisone {{#subobject:a00ad0|Regimen=1}}==
+
==Nivolumab monotherapy {{#subobject:gh317a|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:b907b6|Variant=1}}===
+
===Regimen {{#subobject:8ghb87|Variant=1}}===
 
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 
!style="width: 33%"|Study
 
!style="width: 33%"|Study
Line 3,608: Line 795:
 
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://www.bloodjournal.org/content/82/6/1695.long O'Brien et al. 1993]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7193528/ Kim et al. 2020 (MCC-18684)]
−
|1988-1991
+
|2016-2018
−
|style="background-color:#91cf61"|Phase 2
+
| style="background-color:#91cf61" |Phase 2
 
|-
 
|-
 
|}
 
|}
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Immunotherapy====
−
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5
+
*[[Nivolumab (Opdivo)]] as follows:
−
====Glucocorticoid therapy====
+
**Cycles 1 to 8: 240 mg IV once on day 1
−
*[[Prednisone (Sterapred)]] 30 mg/m<sup>2</sup> PO once per day on days 1 to 5
+
**Cycle 9 onwards: 480 mg IV once on day 1
−
'''28-day cycles'''
+
'''14-day cycle for 8 cycles, then 28-day cycles'''
 
</div></div>
 
</div></div>
 
===References===
 
===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. [http://www.bloodjournal.org/content/82/6/1695.long link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/8400226 PubMed]
+
#'''MCC-18684:''' Kim RD, Chung V, Alese OB, El-Rayes BF, Li D, Al-Toubah TE, Schell MJ, Zhou JM, Mahipal A, Kim BH, Kim DW. A Phase 2 Multi-institutional Study of Nivolumab for Patients With Advanced Refractory Biliary Tract Cancer. JAMA Oncol. 2020 Jun 1;6(6):888-894. [https://doi.org/10.1001/jamaoncol.2020.0930 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7193528/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/32352498/ PubMed] NCT02829918
−
## '''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. [http://www.bloodjournal.org/content/92/4/1165.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/9694704 PubMed]
+
==Pembrolizumab monotherapy {{#subobject:e0d17a|Regimen=1}}==
−
==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">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #1, 3 cycles {{#subobject:89350e|Variant=1}}===
+
===Regimen {{#subobject:87f9c7|Variant=1}}===
 
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 
!style="width: 33%"|Study
 
!style="width: 33%"|Study
Line 3,632: Line 817:
 
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5289283/ Castro et al. 2008]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4481136/ Le et al. 2015 (KEYNOTE-016)]
−
|NR
+
|2013-2016
−
| style="background-color:#ffffbe" |Phase 2, <20 pts
+
| style="background-color:#ffffbe" |Phase 2, <20 pts of this subtype
 
|-
 
|-
 
|}
 
|}
 +
''Note: KEYNOTE-016 was an expansion to a CRC-specific trial.''
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Glucocorticoid therapy====
+
====Immunotherapy====
−
*[[Methylprednisolone (Solumedrol)]] 1000 mg/m<sup>2</sup> IV over 90 minutes once per day on days 1 to 5
+
*[[Pembrolizumab (Keytruda)]] 10 mg/kg IV once on day 1
−
====Targeted therapy====
+
'''14-day cycle for up to 52 cycles (2 years)'''
−
*[[Rituximab (Rituxan)]] as follows:
 
−
**Cycle 1: 375 mg/m<sup>2</sup> IV once per day on days 1, 3, 5, 8, 17, 22
 
−
**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%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.3109/10428194.2011.562572 Pileckyte et al. 2011]
 
−
|NR in abstract
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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:
 
−
**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 per day on days 1 & 5
 
−
====Supportive therapy====
 
−
*[[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>
 
</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://www.nature.com/articles/leu2008214 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5289283/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18754025 PubMed]
+
# '''KEYNOTE-016:''' Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, Biedrzycki B, Donehower RC, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Duffy SM, Goldberg RM, de la Chapelle A, Koshiji M, Bhaijee F, Huebner T, Hruban RH, Wood LD, Cuka N, Pardoll DM, Papadopoulos N, Kinzler KW, Zhou S, Cornish TC, Taube JM, Anders RA, Eshleman JR, Vogelstein B, Diaz LA Jr. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015 Jun 25;372(26):2509-20. Epub 2015 May 30. [https://doi.org/10.1056/NEJMoa1500596 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4481136/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26028255 PubMed] NCT01876511
−
# 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] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/21599591 PubMed]
+
## '''Update:''' Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, Lu S, Kemberling H, Wilt C, Luber BS, Wong F, Azad NS, Rucki AA, Laheru D, Donehower R, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Greten TF, Duffy AG, Ciombor KK, Eyring AD, Lam BH, Joe A, Kang SP, Holdhoff M, Danilova L, Cope L, Meyer C, Zhou S, Goldberg RM, Armstrong DK, Bever KM, Fader AN, Taube J, Housseau F, Spetzler D, Xiao N, Pardoll DM, Papadopoulos N, Kinzler KW, Eshleman JR, Vogelstein B, Anders RA, Diaz LA Jr. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017 Jul 28;357(6349):409-413. Epub 2017 Jun 8. [http://science.sciencemag.org/content/357/6349/409.long link to original article]  [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576142/ link to PMC article] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/28596308 PubMed]
−
==Ibrutinib & Ofatumumab {{#subobject:2a71b9|Regimen=1}}==
+
==Pemigatinib monotherapy ==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #1, concurrent ibrutinib and ofatumumab {{#subobject:e85085|Variant=1}}===
+
===Regimen ===
 
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 
!style="width: 33%"|Study
 
!style="width: 33%"|Study
Line 3,680: Line 839:
 
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536539/ Jaglowski et al. 2015 (PCYC-1109-CA)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8461541/ Abou-Alfa et al. 2020 (FIGHT-202)]
−
|2011-2012
+
|2017-2019
−
|style="background-color:#91cf61"|Phase 2
+
| style="background-color:#91cf61" |Phase 2 (RT)
 
|-
 
|-
 
|}
 
|}
 +
''Note: Patients with previously treated unresectable or metastatic disease.''
 
<div class="toccolours" style="background-color:#fdcdac">
 
<div class="toccolours" style="background-color:#fdcdac">
−
====Prior treatment criteria====
+
====Biomarker eligibility criteria====
−
*Failure of two or more prior therapies, or Richter transformation
+
*Fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Targeted therapy====
 
−
*[[Ibrutinib (Imbruvica)]] 420 mg PO once per day
 
−
*[[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%"|Years 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>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Targeted therapy====
 
====Targeted therapy====
−
*[[Ibrutinib (Imbruvica)]] 420 mg PO once per day
+
*[[Pemigatinib (Pemazyre)]] 13.5 mg PO once per day on days 1 to 14
−
*[[Ofatumumab (Arzerra)]] as follows:
+
'''21-day cycles'''
−
**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%"|Years 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:#b3e2cd">
 
−
====Targeted therapy====
 
−
*[[Ibrutinib (Imbruvica)]] as follows:
 
−
**Cycle 3 onwards: 420 mg PO once per day
 
−
*[[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>
 
</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. -->
+
#'''FIGHT-202:''' Abou-Alfa GK, Sahai V, Hollebecque A, Vaccaro G, Melisi D, Al-Rajabi R, Paulson AS, Borad MJ, Gallinson D, Murphy AG, Oh DY, Dotan E, Catenacci DV, Van Cutsem E, Ji T, Lihou CF, Zhen H, Féliz L, Vogel A. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol. 2020 May;21(5):671-684. Epub 2020 Mar 20 [https://doi.org/10.1016/S1470-2045(20)30109-1 link to original article] '''contains dosing details in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8461541/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32203698 PubMed] NCT02924376
−
# '''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. [http://www.bloodjournal.org/content/126/7/842.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4536539/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26116658 PubMed] NCT01217749
+
=Metastatic disease, subsequent lines of therapy=
−
==Ibrutinib & Rituximab {{#subobject:503e48|Regimen=1}}==
+
==mFOLFOX6 {{#subobject:32d6c5|Regimen=1}}==
 +
mFOLFOX6: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:673f95|Variant=1}}===
+
===Regimen {{#subobject:205ad6|Variant=1}}===
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 33%"|Study
+
!style="width: 20%"|Study
−
!style="width: 33%"|Years of enrollment
+
!style="width: 20%"|Years of enrollment
−
!style="width: 33%"|[[Levels_of_Evidence#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/10.1016/S1470-2045(14)70335-3 Burger et al. 2014 (MDACC 2011-0785)]
+
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc8082275/ Lamarca et al. 2021 (ABC-06)]
−
|2012
+
|2014-2018
−
|style="background-color:#91cf61"|Phase 2
+
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[Cholangiocarcinoma_-_null_regimens#Best_supportive_care|Active symptom control]]
 +
| style="background-color:#91cf60" |Seems to have superior OS<br>Median OS: 6.2 vs 5.3 mo<br>(HR 0.69, 95% CI 0.50-0.97)
 
|-
 
|-
 
|}
 
|}
−
''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:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Targeted therapy====
+
====Chemotherapy====
−
*[[Ibrutinib (Imbruvica)]] 420 mg PO once per day
+
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
−
*[[Rituximab (Rituxan)]] as follows:
+
*[[Folinic acid (Leucovorin)]] 350 mg/m<sup>2</sup> IV once on day 1
−
**Cycle 1: 375 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
+
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1
−
**Cycles 2 to 6: 375 mg/m<sup>2</sup> IV once on day 1
+
'''14-day cycle for up to 12 cycles'''
−
'''28-day cycles'''
 
 
</div></div>
 
</div></div>
 
===References===
 
===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. [http://www.bloodjournal.org/content/122/21/675 link to original abstract] -->
+
#'''ABC-06:''' Lamarca A, Palmer DH, Wasan HS, Ross PJ, Ma YT, Arora A, Falk S, Gillmore R, Wadsley J, Patel K, Anthoney A, Maraveyas A, Iveson T, Waters JS, Hobbs C, Barber S, Ryder WD, Ramage J, Davies LM, Bridgewater JA, Valle JW; Advanced Biliary Cancer Working Group. Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2021 May;22(5):690-701. Epub 2021 Mar 30. [https://doi.org/10.1016/s1470-2045(21)00027-9 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc8082275/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/33798493/ PubMed] NCT01926236
−
# '''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] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4174348/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25150798 PubMed] NCT01520519
+
==mFOLFOX6 (L-Leucovorin) {{#subobject:yg1tz5|Regimen=1}}==
−
## '''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. [http://clincancerres.aacrjournals.org/content/23/9/2154 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]
+
mFOLFOX6: '''<u>m</u>'''odified '''<u>FOL</u>'''inic acid, '''<u>F</u>'''luorouracil, '''<u>OX</u>'''aliplatin
−
==Ibrutinib, Venetoclax, Obinutuzumab {{#subobject:78gu1g|Regimen=1}}==
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:52rgcc|Variant=1}}===
+
===Regimen {{#subobject:583ad6|Variant=1}}===
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 33%"|Study
+
!style="width: 20%"|Study
−
!style="width: 33%"|Years of enrollment
+
!style="width: 20%"|Years of enrollment
−
!style="width: 33%"|[[Levels_of_Evidence#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://www.ncbi.nlm.nih.gov/pmc/articles/pmc7605394/ Rogers et al. 2020 (OSU-14266)]
+
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc8082275/ Lamarca et al. 2021 (ABC-06)]
−
|2015-2017
+
|2014-2018
−
|style="background-color:#91cf61"|Phase 2
+
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[Cholangiocarcinoma_-_null_regimens#Best_supportive_care|Active symptom control]]
 +
| style="background-color:#91cf60" |Seems to have superior OS<br>Median OS: 6.2 vs 5.3 mo<br>(HR 0.69, 95% CI 0.50-0.97)
 
|-
 
|-
 
|}
 
|}
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Targeted therapy====
+
====Chemotherapy====
−
*[[Ibrutinib (Imbruvica)]] as follows:
+
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV bolus once on day 1, then 2400 mg/m<sup>2</sup> IV continuous infusion over 46 hours (total dose per cycle: 2800 mg/m<sup>2</sup>)
−
**Cycle 2 onwards: 420 mg PO once per day
+
*[[Levoleucovorin (Fusilev)]] 175 mg/m<sup>2</sup> IV once on day 1
−
*[[Venetoclax (Venclexta)]] as follows:
+
*[[Oxaliplatin (Eloxatin)]] 85 mg/m<sup>2</sup> IV over 2 hours once on day 1
−
**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
+
'''14-day cycle for up to 12 cycles'''
−
**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>
 
</div></div>
 
===References===
 
===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] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/32795224/ PubMed] NCT02427451
+
#'''ABC-06:''' Lamarca A, Palmer DH, Wasan HS, Ross PJ, Ma YT, Arora A, Falk S, Gillmore R, Wadsley J, Patel K, Anthoney A, Maraveyas A, Iveson T, Waters JS, Hobbs C, Barber S, Ryder WD, Ramage J, Davies LM, Bridgewater JA, Valle JW; Advanced Biliary Cancer Working Group. Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2021 May;22(5):690-701. Epub 2021 Mar 30. [https://doi.org/10.1016/s1470-2045(21)00027-9 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc8082275/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/33798493/ PubMed] NCT01926236
−
==Idelalisib monotherapy {{#subobject:b872c5|Regimen=1}}==
+
==Futibatinib monotherapy {{#subobject:ahcx1g|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:5cabd0|Variant=1}}===
+
===Regimen {{#subobject:2tty9d|Variant=1}}===
−
{| class="wikitable" style="width: 60%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 
!style="width: 33%"|Study
 
!style="width: 33%"|Study
 
!style="width: 33%"|Years of enrollment
 
!style="width: 33%"|Years of enrollment
 
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123414/ Brown et al. 2014 (Gilead 101-02)]
+
|Awaiting publication (TAS-120-101)
−
|2008-2011
+
|2014-2021
−
|style="background-color:#91cf61"|Phase 1, >20 pts
+
| style="background-color:#91cf61" |Phase 1/2 (RT)
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4039496/ Gopal et al. 2014 (DELTA)]
 
−
|2011-2012
 
−
|style="background-color:#91cf61"|Phase 2 (RT)
 
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#fdcdac">
 +
====Biomarker eligibility criteria====
 +
*Fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement
 +
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Targeted therapy====
 
====Targeted therapy====
−
*[[Idelalisib (Zydelig)]] 150 mg PO twice per day
+
*[[Futibatinib (Lytgobi)]] 20 mg PO once per day
 
'''Continued indefinitely'''
 
'''Continued indefinitely'''
 
</div></div>
 
</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] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4039496/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24450858 PubMed] NCT01282424
+
#'''TAS-120-101:''' NCT02052778
−
## '''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 [https://ash.confex.com/ash/2014/webprogram/Paper74940.html link to abstract]
+
==Infigratinib monotherapy {{#subobject:afgh1g|Regimen=1}}==
−
# '''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. [http://www.bloodjournal.org/content/123/22/3390 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] NCT00710528
 
−
==Lenalidomide monotherapy {{#subobject:a19994|Regimen=1}}==
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #1 {{#subobject:5e49d5|Variant=1}}===
+
===Regimen {{#subobject:yt719d|Variant=1}}===
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
+
{| class="wikitable sortable" style="color:white; background-color:#404040"
−
!style="width: 33%"|Study
+
|<small>'''FDA-recommended dose'''</small>
−
!style="width: 33%"|Years 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:#91cf61"|Phase 2
 
 
|-
 
|-
 
|}
 
|}
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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 (Revlimid)]], 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:787570|Variant=1}}===
 
 
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 
!style="width: 33%"|Study
 
!style="width: 33%"|Study
Line 3,862: Line 947:
 
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4082321/ Ferrajoli et al. 2008 (MDACC 2005-0175)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6075847/ Javle et al. 2017 (CBGJ398X2204)]
−
|2005-2007
+
|2014-2020
−
|style="background-color:#91cf61"|Phase 2
+
| style="background-color:#91cf61" |Phase 2 (RT)
−
|-
 
 
|}
 
|}
−
<div class="toccolours" style="background-color:#b3e2cd">
+
<div class="toccolours" style="background-color:#fdcdac">
−
====Targeted therapy====
+
====Biomarker eligibility criteria====
−
*[[Lenalidomide (Revlimid)]] as follows:
+
*FGFR2 gene fusions or translocations or other FGFR genetic alterations
−
**Cycle 1: 10 mg PO once per day
 
−
**Cycle 2: 15 mg PO once per day
 
−
**Cycle 3: 20 mg PO once per day
 
−
**Cycle 4 onwards: 25 mg PO once per day
 
−
'''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%"|Years 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, <20 patients in this subgroup
 
−
|-
 
−
|}
 
−
''Note: Patients studied in this trial and in this subgroup had a diagnosis of SLL.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Targeted therapy====
 
−
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21
 
−
'''28-day cycles'''
 
−
</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] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/17088571 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. [http://www.bloodjournal.org/content/111/11/5291.long 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] NCT00267059
 
−
<!-- 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] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19805688 PubMed] NCT00179673
 
−
==Lenalidomide & Ofatumumab {{#subobject:2f1b19|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #1 {{#subobject:fe2be4|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years 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
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Targeted therapy====
 
−
*[[Lenalidomide (Revlimid)]] as follows:
 
−
**Cycle 1: 10 mg PO once per day on days 9 to 28
 
−
**Cycle 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>
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Patients with a sustained PR or CR were allowed to continue treatment with lenalidomide monotherapy indefinitely
 
−
</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. [http://clincancerres.aacrjournals.org/content/22/10/2359.full link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5118034/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26733610 PubMed] 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%"|Years 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:#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.''
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Targeted therapy====
 
====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
+
*[[Infigratinib (Truseltiq)]] 125 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'''
 
'''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%"|Years 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
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Targeted therapy====
 
−
*[[Lenalidomide (Revlimid)]] as follows:
 
−
**Cycle 1: 10 mg PO once per day on days 9 to 28
 
−
**Cycle 2 onwards: 10 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
 
−
**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====
 
−
*Responders: Lenalidomide could continue indefinitely
 
 
</div></div>
 
</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. -->
+
#'''CBGJ398X2204:''' Javle M, Lowery M, Shroff RT, Weiss KH, Springfeld C, Borad MJ, Ramanathan RK, Goyal L, Sadeghi S, Macarulla T, El-Khoueiry A, Kelley RK, Borbath I, Choo SP, Oh DY, Philip PA, Chen LT, Reungwetwattana T, Van Cutsem E, Yeh KH, Ciombor K, Finn RS, Patel A, Sen S, Porter D, Isaacs R, Zhu AX, Abou-Alfa GK, Bekaii-Saab T. Phase II study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma. J Clin Oncol. 2018 Jan 20;36(3):276-282. Epub 2017 Nov 28. [https://doi.org/10.1200/JCO.2017.75.5009 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6075847/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/29182496 PubMed] NCT02150967
−
# 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] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17088571 PubMed]
+
##'''Update:''' Javle M, Roychowdhury S, Kelley RK, Sadeghi S, Macarulla T, Weiss KH, Waldschmidt DT, Goyal L, Borbath I, El-Khoueiry A, Borad MJ, Yong WP, Philip PA, Bitzer M, Tanasanvimon S, Li A, Pande A, Soifer HS, Shepherd SP, Moran S, Zhu AX, Bekaii-Saab TS, Abou-Alfa GK. Infigratinib (BGJ398) in previously treated patients with advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements: mature results from a multicentre, open-label, single-arm, phase 2 study. Lancet Gastroenterol Hepatol. 2021 Oct;6(10):803-815. Epub 2021 Aug 3. [https://doi.org/10.1016/s2468-1253(21)00196-5 link to original article] [https://pubmed.ncbi.nlm.nih.gov/34358484/ 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. -->
+
==Ivosidenib monotherapy {{#subobject:af0357|Regimen=1}}==
−
# '''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] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878047/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23270003 PubMed] NCT00759603
 
−
==Obinutuzumab monotherapy {{#subobject:97dd49|Regimen=1}}==
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:a20fcb|Variant=1}}===
+
===Regimen {{#subobject:cb3c9d|Variant=1}}===
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/119/22/5126.long 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:#b3e2cd">
 
−
====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 (Gazyva)]], 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 (Gazyva)]], 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 (Gazyva)]]
 
−
'''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. [http://www.bloodjournal.org/content/119/22/5126.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/22431570 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. [https://doi.org/10.1200/jco.2012.46.9585 link to original article] '''contains dosing details in manuscript''' [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] '''contains dosing details in manuscript''' [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. [http://www.bloodjournal.org/content/124/14/2196 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25143487 PubMed]
 
−
==OFAR {{#subobject:6c2942|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:776e7d|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1200/jco.2007.11.8513 Tsimberidou et al. 2008]
 
−
|2004-2006
 
−
|style="background-color:#91cf61"|Phase 1/2
 
−
|-
 
−
|}
 
−
''Note: this is the dosing used in the phase II portion.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Oxaliplatin (Eloxatin)]] 25 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 4
 
−
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV once per day on days 2 & 3, '''administered within 30 minutes of completion of oxaliplatin'''
 
−
*[[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV over 2 hours once per day on days 2 & 3, '''4 hours after fludarabine started'''
 
−
====Targeted therapy====
 
−
*[[Rituximab (Rituxan)]] as follows:
 
−
**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===
 
−
<!-- Presented in part at the 48th Annual Meeting of the American Society of Hematology, December 9-12, 2006, Orlando, FL, and at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA. -->
 
−
# 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] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18182662 PubMed]
 
−
==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">
 
−
===Regimen {{#subobject:ebf988|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years 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
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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 (Kytril)]] 2 mg (route not specified) once on day 1
 
−
*[[Filgrastim (Neupogen)]] by the following criteria:
 
−
**Patients weighing up to 70 kg: 300 mcg SC once per day from day 3 until ANC greater than 5000/uL once or 1500/uL for 2 days
 
−
**Patients weighing more than 70 kg: 480 mcg SC once per day from day 3 until ANC greater than 5000/uL once or 1500/uL 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===
 
−
# 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] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16520464 PubMed]
 
−
==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%"|Years 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, <20 patients reported
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Targeted therapy====
 
−
*[[Rituximab (Rituxan)]] as follows:
 
−
**Cycle 1: 375 mg/m<sup>2</sup> IV once on day 1
 
−
**Cycle 2 onwards: 500 mg/m<sup>2</sup> IV once on day 1
 
−
====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] '''contains dosing details in manuscript''' [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%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1016/S2352-3026(16)30194-6 Jain et al. 2017 (MDACC 2013-0044)]
 
−
|2014-2015
 
−
|style="background-color:#ffffbe"|Phase 2, <20 pts in this subgroup
 
−
|-
 
−
|}
 
−
''Note: this was a trial focused on symptom control, not efficacy.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Targeted therapy====
 
−
*[[Ruxolitinib (Jakafi)]] 10 mg PO twice per day
 
−
</div></div>
 
−
===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] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356368/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28089238 PubMed] 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"
 
{| class="wikitable" style="color:white; background-color:#404040"
 
|<small>'''FDA-recommended dose'''</small>
 
|<small>'''FDA-recommended dose'''</small>
 
|-
 
|-
 
|}
 
|}
−
{| class="wikitable" style="width: 80%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 25%"|Study
+
!style="width: 20%"|Study
−
!style="width: 25%"|Years of enrollment
+
!style="width: 20%"|Years of enrollment
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
+
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7107002/ Roberts et al. 2015 (M12-175)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7523268/ Abou-Alfa et al. 2020 (ClarIDHy)]
−
|2011-2014
+
|2017-2019
−
|style="background-color:#91cf61"|Phase 1/2 (RT)
+
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
−
| style="background-color:#e0ecf4" |ORR: 79%
+
|[[Cholangiocarcinoma_-_null_regimens#Placebo|Placebo]]
−
|-
+
| style="background-color:#1a9850" |Superior PFS<br>Median PFS: 2.7 vs 1.4 mo<br>(HR 0.37, 95% CI 0.25-0.54)
−
|[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)]
 
−
|2014-NR
 
−
|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.''
+
''Note: Patients with unresectable or metastatic disease with IDH1 mutation with progression after at least one prior systemic therapy.''
 
<div class="toccolours" style="background-color:#fdcdac">
 
<div class="toccolours" style="background-color:#fdcdac">
 
====Biomarker eligibility criteria====
 
====Biomarker eligibility criteria====
−
*M13-982: 17p deletion
+
*IDH1 mutation
 
</div>
 
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Targeted therapy====
 
====Targeted therapy====
−
*[[Venetoclax (Venclexta)]] as follows:
+
*[[Ivosidenib (Tibsovo)]] 500 mg PO once per day
−
**Week 1: 20 mg PO once per day
+
'''28-day cycles'''
−
**Week 2: 50 mg PO once per day
 
−
**Week 3: 100 mg PO once per day
 
−
**Week 4: 200 mg PO once per day
 
−
**Week 5 onwards: 400 mg PO once per day
 
−
'''Continued indefinitely'''
 
−
</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%"|Years 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-NR
 
−
|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:#b3e2cd">
 
−
====Targeted therapy====
 
−
*[[Venetoclax (Venclexta)]] as follows:
 
−
**Day 1: 20 mg PO once per day
 
−
**Days 2 & 3: 50 mg PO once per day
 
−
**Days 4 to 7: 100 mg PO once per day
 
−
**Week 2: 200 mg PO once per day
 
−
**Week 3 onwards: 400 mg PO once per day
 
−
'''Continued indefinitely'''
 
 
</div></div>
 
</div></div>
 
===References===
 
===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) [http://meetinglibrary.asco.org/content/132375-144 link to abstract] -->
+
<!-- #'''Abstract:''' GK Abou-Alfa, T Macarulla Mercade, M Javle, RK Kelley, S Lubner, J Adeva, JM Cleary, DV Catenacci, MJ Borad, JA Bridgewater, WP Harris, AG Murphy, D-Y Oh, J Whisenant, B Wu, L Jiang, C Gliser, SS Pandya, JW Valle, AX Zhu. ClarIDHy: A global, phase III, randomized, double-blind study of ivosidenib (IVO) vs placebo in pateints with advanced cholangiocarcinoma (CC) with an isocitrate dehydrogenase 1 (IDH1) mutation. Annals of Oncology, Volume 30, Issue Supplement-5, October 2019, mdz394.027. [https://doi.org/10.1093/annonc/mdz394.027 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] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7107002/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26639348 PubMed] NCT01328626
+
#'''ClarIDHy:''' Abou-Alfa GK, Macarulla T, Javle MM, Kelley RK, Lubner SJ, Adeva J, Cleary JM, Catenacci DV, Borad MJ, Bridgewater J, Harris WP, Murphy AG, Oh DY, Whisenant J, Lowery MA, Goyal L, Shroff RT, El-Khoueiry AB, Fan B, Wu B, Chamberlain CX, Jiang L, Gliser C, Pandya SS, Valle JW, Zhu AX. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020 Jun;21(6):796-807. Epub 2020 May 13. Erratum in: Lancet Oncol. 2020 Oct;21(10):e462. [https://doi.org/10.1016/s1470-2045(20)30157-1 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7523268/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32416072 PubMed] NCT02989857
−
<!-- 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 -->
+
##'''Update:''' Zhu AX, Macarulla T, Javle MM, Kelley RK, Lubner SJ, Adeva J, Cleary JM, Catenacci DVT, Borad MJ, Bridgewater JA, Harris WP, Murphy AG, Oh DY, Whisenant JR, Lowery MA, Goyal L, Shroff RT, El-Khoueiry AB, Chamberlain CX, Aguado-Fraile E, Choe S, Wu B, Liu H, Gliser C, Pandya SS, Valle JW, Abou-Alfa GK. Final Overall Survival Efficacy Results of Ivosidenib for Patients With Advanced Cholangiocarcinoma With IDH1 Mutation: The Phase 3 Randomized Clinical ClarIDHy Trial. JAMA Oncol. 2021 Nov 1;7(11):1669-1677. [https://doi.org/10.1001/jamaoncol.2021.3836 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8461552/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34554208/ PubMed]
−
# '''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] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/27178240 PubMed] NCT01889186
+
==Lenvatinib & Pembrolizumab {{#subobject:17f8ug|Regimen=1}}==
−
## '''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] 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. [http://www.bloodjournal.org/content/131/15/1704.long link to original article] '''contains dosing details in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5922273/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29305552 PubMed] NCT02141282
 
−
 
 
−
==Zanubrutinib & Obinutuzumab {{#subobject:7ygqqd |Regimen=1}}==
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:it81db |Variant=1}}===
+
===Regimen {{#subobject:egh1e3|Variant=1}}===
 
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 
!style="width: 33%"|Study
 
!style="width: 33%"|Study
Line 4,228: Line 1,006:
 
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7556127/ Tam et al. 2020]
+
|Awaiting publication (LEAP-005)
−
|2016-NR
+
|2019-ongoing
−
|style="background-color:#91cf61"|Phase 1b, >20 pts in this subgroup
+
| style="background-color:#91cf61" |Phase 2
−
|-
 
 
|}
 
|}
 +
''Note: Dosing details are from ASCO abstract #321 (2021).''
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Targeted therapy====
 
====Targeted therapy====
−
*[[Zanubrutinib (Brukinsa)]] 160 mg PO twice per day or 320 mg PO once per day
+
*[[Lenvatinib (Lenvima)]] 20 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===
 
−
#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] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33022066/ PubMed] NCT02569476
 
−
=Consolidation and/or maintenance after subsequent lines of therapy=
 
−
==FC, then allo HSCT {{#subobject:1a1ed9|Regimen=1}}==
 
−
FC: '''<u>F</u>'''ludarabine & '''<u>C</u>'''yclophosphamide
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:886e40|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/116/14/2438 Dreger et al. 2010 (GCLLSG CLL3X)]
 
−
|2001-2007
 
−
| style="background-color:#91cf61" |Phase 2
 
−
|-
 
−
|}
 
−
{{#lst:Allogeneic HSCT|886e40}}
 
−
====Immunotherapy====
 
−
*[[Allogeneic stem cells]]
 
−
'''Stem cells transfused on day 0'''
 
−
</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. [http://www.bloodjournal.org/content/116/14/2438 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20595516 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. [http://www.bloodjournal.org/content/121/16/3284.long 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. [http://www.bloodjournal.org/content/130/12/1477.long 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
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1200/jco.2005.04.569 Sorror et al. 2005]
 
−
|1997-2003
 
−
| style="background-color:#91cf61" |Phase 2
 
−
|-
 
−
|}
 
−
{{#lst:Allogeneic HSCT|7fa6ce}}
 
−
====Immunotherapy====
 
−
*[[Allogeneic stem cells]]
 
−
'''Stem cells transfused on day 0'''
 
−
</div></div>
 
−
===References===
 
−
<!-- 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. [https://doi.org/10.1200/jco.2005.04.569 link to original article] [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. [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]
 
−
==Fludarabine, Busulfan, ATG, 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
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[http://www.bloodjournal.org/content/91/3/756.full Slavin et al. 1998]
 
−
|NR
 
−
| style="background-color:#91cf61" |Phase 2
 
−
|-
 
−
|[https://doi.org/10.1200/jco.2003.12.011 Schetelig et al. 2003]
 
−
|1998-2001
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|-
 
−
|}
 
−
{{#lst:Allogeneic HSCT|e2c4bf}}
 
 
====Immunotherapy====
 
====Immunotherapy====
−
*[[Allogeneic stem cells]]
+
*[[Pembrolizumab (Keytruda)]] as follows:
−
'''Stem cells transfused on day 0'''
+
**Cycles 1 to 35: 200 mg IV once on day 1
 +
'''35-day cycles'''
 
</div></div>
 
</div></div>
 
===References===
 
===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. [http://www.bloodjournal.org/content/91/3/756.full link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/9446633 PubMed]
+
*'''LEAP-005:''' NCT03797326
−
# 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]
+
==Regorafenib monotherapy {{#subobject:17f9f2|Regimen=1}}==
−
==Fludarabine, Cyclophosphamide, ATG, then allo HSCT {{#subobject:f2ce14|Regimen=1}}==
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:3e71d0|Variant=1}}===
+
===Regimen {{#subobject:e6a3e3|Variant=1}}===
 
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 
!style="width: 33%"|Study
 
!style="width: 33%"|Study
Line 4,323: Line 1,029:
 
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://www.bloodjournal.org/content/116/14/2438 Dreger et al. 2010 (GCLLSG CLL3X)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402964/ Sun et al. 2019 (UPMC 13-100)]
−
|2001-2007
+
|2014-2017
 
| style="background-color:#91cf61" |Phase 2
 
| style="background-color:#91cf61" |Phase 2
−
|-
 
 
|}
 
|}
−
{{#lst:Allogeneic HSCT|3e71d0}}
+
''Only studied in patients with advanced biliary cancer who failed at least 1 line of systemic therapy.''  
−
====Immunotherapy====
 
−
*[[Allogeneic stem cells]]
 
−
'''Stem cells transfused on day 0'''
 
−
</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. [http://www.bloodjournal.org/content/116/14/2438 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20595516 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. [http://www.bloodjournal.org/content/121/16/3284.long 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. [http://www.bloodjournal.org/content/130/12/1477.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/28716861 PubMed]
 
−
==Observation==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years 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 (C)
 
−
|[[#Rituximab_monotherapy_4|Rituximab]]
 
−
|style="background-color:#d73027"|Inferior PFS
 
−
|-
 
−
|[https://doi.org/10.1016/S1470-2045(15)00143-6 van Oers et al. 2015 (PROLONG)]
 
−
|2010-2014
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[#Ofatumumab_monotherapy_3|Ofatumumab]]
 
−
|style="background-color:#d73027"|Inferior PFS
 
−
|-
 
−
|}
 
−
''No further treatment offered to patients in their second or third CR or PR; prior treatment was not specified in PROLONG.
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*AGMT CLL-8a: [[Regimen_classes#Rituximab-containing_regimen|Rituximab-containing chemoimmunotherapy]]
 
−
</div></div>
 
−
===References===
 
−
# '''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] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26377300 PubMed] NCT00802737
 
−
## '''Update:''' van Oers M, Smolej L, Petrini M, Offner F, Grosicki S, Levin MD, Davis J, Banerjee H, Stefanelli T, Hoever P, Geisler C. Ofatumumab maintenance prolongs progression-free survival in relapsed chronic lymphocytic leukemia: final analysis of the PROLONG study. Blood Cancer J. 2019 Dec 4;9(12):98. [https://doi.org/10.1038/s41408-019-0260-2 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6893027/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31801940 PubMed]
 
−
# '''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] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/27374465 PubMed] NCT01118234
 
−
==Ofatumumab monotherapy {{#subobject:9a07b6|Regimen=1}}==
 
−
<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%"|Years 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)
 
−
|[[#Observation_3|Observation]]
 
−
|style="background-color:#1a9850"|Superior PFS<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>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
 
====Targeted therapy====
 
====Targeted therapy====
−
*[[Ofatumumab (Arzerra)]] as follows:
+
*[[Regorafenib (Stivarga)]] 120 mg PO once per day on days 1 to 21
−
**Cycle 1: 300 mg IV once on day 1, then 1000 mg IV once on day 7
+
'''28-day cycles'''
−
**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 (Arzerra)]]
 
−
*[[Diphenhydramine (Benadryl)]] (or equivalent [[:Category:Antihistamines|antihistamine]]) 50 mg IV or PO once per infusion, 30 to 120 minutes prior to [[Ofatumumab (Arzerra)]]
 
−
*[[Prednisolone (Millipred)]] (or equivalent [[:Category:Steroids|glucocorticoid]]) 50 mg IV once per infusion, 30 to 120 minutes prior to [[Ofatumumab (Arzerra)]]
 
−
'''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%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1111/bjh.13380 Österborg et al. 2015 (GEN416)]
 
−
|2009-2011
 
−
|style="background-color:#91cf61"|Phase 2
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[#Ofatumumab_monotherapy_3|Ofatumumab]] x 8
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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 (Arzerra)]]
 
−
*[[Cetirizine (Zyrtec)]] (or equivalent [[:Category:Antihistamines|antihistamine]]) 10 mg PO once on day 1, prior to [[Ofatumumab (Arzerra)]]
 
−
'''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] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25825041 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. [https://doi.org/10.1016/S1470-2045(15)00143-6 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26377300 PubMed] NCT00802737
 
−
==Placebo==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years 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)30168-0 Chanan-Khan et al. 2017 (CONTINUUM)]
 
−
|2009-2015
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[#Lenalidomide_monotherapy_99|Lenalidomide]]
 
−
|style="background-color:#ffffbf"|Did not meet primary endpoint of OS
 
−
|-
 
−
|}
 
−
''No active antineoplastic treatment offered to patients with at least partial response to second-line therapy.''
 
−
</div></div>
 
−
===References===
 
−
# '''CONTINUUM:''' Chanan-Khan AA, Zaritskey A, Egyed M, Vokurka S, Semochkin S, Schuh A, Kassis J, Simpson D, Zhang J, Purse B, Foà R. Lenalidomide maintenance therapy in previously treated chronic lymphocytic leukaemia (CONTINUUM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Haematol. 2017 Nov;4(11):e534-e543. Epub 2017 Sep 25. [https://doi.org/10.1016/S2352-3026(17)30168-0 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28958469 PubMed] NCT00774345
 
−
==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%"|Years 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)
 
−
|[[#Observation_3|Observation]]
 
−
|style="background-color:#1a9850"|Superior PFS<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">
 
−
====Preceding treatment====
 
−
*[[Regimen_classes#Rituximab-containing_regimen|Rituximab-containing chemoimmunotherapy]]
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====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>
 
</div></div>
 
===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] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/27374465 PubMed] NCT01118234
+
#'''UPMC 13-100:''' Sun W, Patel A, Normolle A, Patel K, Ohr J, Lee JJ, Bahary N, Chu E, Streeter N, Drummond S. A phase 2 trial of regorafenib as a single agent in patients with chemotherapy-refractory, advanced, and metastatic biliary tract adenocarcinoma. Cancer. 2019 Mar 15;125(6):902-909. Epub 2018 Dec 18. [https://doi.org/10.1002/cncr.31872 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402964/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30561756 PubMed] NCT02053376
−
=Prognosis=
+
[[Category:Cholangiocarcinoma regimens]]
−
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. [http://www.bloodjournal.org/content/46/2/219.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/8652811 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 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. [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==
 
−
*''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. [http://www.bloodjournal.org/content/133/11/1205.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/30602617 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. [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. [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]
 
−
==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. [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:''
 
−
# 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 [http://www.bloodjournal.org/content/120/21/3892 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==
 
−
# 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. [http://www.bloodjournal.org/content/94/6/1840 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. [http://www.bloodjournal.org/content/118/13/3470 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]
 
−
==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]
 
−
==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. [http://www.bloodjournal.org/content/121/8/1403.long 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]
 
−
==CLL-IPI (2016)==
 
−
*[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. [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]
 
−
=Investigational agents=
 
−
*[[Otlertuzumab (TRU-016)]]
 
−
[[Category:Chronic lymphocytic leukemia regimens]]
 
 
[[Category:Disease-specific pages]]
 
[[Category:Disease-specific pages]]
−
[[Category:Indolent lymphomas]]
+
[[Category:Hepatobiliary cancers]]

Revision as of 16:27, 9 October 2022

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Section editor transclusions

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Note: there is some overlap, especially in the earlier literature, between treatment regimens for cholangiocarcinoma and those for pancreatic adenocarcinoma, periampullary adenocarcinoma, and gallbladder cancer; please see those pages for additional regimens.
Are you looking for a regimen but can't find it here? For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!


Guidelines

ASCO

ESMO

NCCN

Adjuvant therapy

Capecitabine monotherapy

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Primrose et al. 2019 (BILCAP) 2006-2014 Phase 3 (E-esc) Observation Did not meet primary endpoint of OS1
Median OS: 49.6 vs 36.1 mo
(aHR 0.84, 95% CI 0.67-1.06)

1Reported efficacy is based on the 2022 update.
Note: Chemotherapy start date 8 to 16 weeks after surgery

Preceding treatment

Chemotherapy

21-day cycle for 8 cycles

References

  1. BILCAP: Primrose JN, Fox RP, Palmer DH, Malik HZ, Prasad R, Mirza D, Anthony A, Corrie P, Falk S, Finch-Jones M, Wasan H, Ross P, Wall L, Wadsley J, Evans JTR, Stocken D, Praseedom R, Ma YT, Davidson B, Neoptolemos JP, Iveson T, Raftery J, Zhu S, Cunningham D, Garden OJ, Stubbs C, Valle JW, Bridgewater J; BILCAP study group. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol. 2019 May;20(5):663-673. Epub 2019 Mar 25. Erratum in: Lancet Oncol. 2019 Apr 2. link to original article PubMed NCT00363584
    1. Update: Bridgewater J, Fletcher P, Palmer DH, Malik HZ, Prasad R, Mirza D, Anthony A, Corrie P, Falk S, Finch-Jones M, Wasan H, Ross P, Wall L, Wadsley J, Evans TR, Stocken D, Stubbs C, Praseedom R, Ma YT, Davidson B, Neoptolemos J, Iveson T, Cunningham D, Garden OJ, Valle JW, Primrose J; BILCAP study group. Long-Term Outcomes and Exploratory Analyses of the Randomized Phase III BILCAP Study. J Clin Oncol. 2022 Jun 20;40(18):2048-2057. Epub 2022 Mar 22. link to original article PubMed

Capecitabine & Gemcitabine

GemCap: Gemcitabine & Capecitabine

Regimen

Study Years of enrollment Evidence
Ben-Josef et al. 2015 (SWOG S0809) 2008-2012 Phase 2

Preceding treatment

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment

References

  1. SWOG S0809: Ben-Josef E, Guthrie KA, El-Khoueiry AB, Corless CL, Zalupski MM, Lowy AM, Thomas CR Jr, Alberts SR, Dawson LA, Micetich KC, Thomas MB, Siegel AB, Blanke CD. SWOG S0809: A phase II intergroup trial of adjuvant capecitabine and gemcitabine followed by radiotherapy and concurrent capecitabine in extrahepatic cholangiocarcinoma and gallbladder carcinoma. J Clin Oncol. 2015 Aug 20;33(24):2617-22. Epub 2015 May 11. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00789958

Gemcitabine monotherapy

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Ebata et al. 2018 (BCAT) 2007-2011 Phase 3 (E-esc) Observation Did not meet primary endpoint of OS

Preceding treatment

Chemotherapy

28-day cycle for 6 cycles

References

  1. BCAT: Ebata T, Hirano S, Konishi M, Uesaka K, Tsuchiya Y, Ohtsuka M, Kaneoka Y, Yamamoto M, Ambo Y, Shimizu Y, Ozawa F, Fukutomi A, Ando M, Nimura Y, Nagino M; Bile Duct Cancer Adjuvant Trial (BCAT) Study Group. Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer. Br J Surg. 2018 Feb;105(3):192-202. link to original article PubMed UMIN000000820

Gemcitabine/Fluorouracil & RT

Gemcitabine/Fluorouracil & RT: Gemcitabine alternating with Fluorouracil & Radiation Therapy

Protocol

Study Years of enrollment Evidence Comparator Comparative Efficacy
Regine et al. 2008 (RTOG 9704) 1998-2002 Phase 3 (E-esc) Fluorouracil & RT Did not meet primary endpoint of OS1

1Reported efficacy is based on the 2011 update.
Note: this study was in pancreatic cancer but in practice it is extrapolated to cholangiocarcinoma.

Preceding treatment

Chemotherapy, part 1

21-day course, followed in 1 to 2 weeks by:

Chemotherapy, part 2

Radiotherapy

  • Concurrent radiation therapy, 1.8 Gy fractions x 28 fractions given 5 days per week, for a total dose of 50.4 Gy. The last 5.4 Gy of the 50.4 Gy is limited to the tumor bed.

6-week course, followed in 3 to 5 weeks by:

Chemotherapy, part 3

28-day cycle for 3 cycles

References

  1. RTOG 9704: Regine WF, Winter KA, Abrams RA, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Kudrimoti MR, Fromm ML, Haddock MG, Schaefer P, Willett CG, Rich TA. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008 Mar 5;299(9):1019-26. link to original article contains dosing details in manuscript PubMed NCT00003216
    1. Update: Regine WF, Winter KA, Abrams R, Safran H, Hoffman JP, Konski A, Benson AB, Macdonald JS, Rich TA, Willett CG. Fluorouracil-based chemoradiation with either gemcitabine or fluorouracil chemotherapy after resection of pancreatic adenocarcinoma: 5-year analysis of the US Intergroup/RTOG 9704 phase III trial. Ann Surg Oncol. 2011 May;18(5):1319-26. Epub 2011 Mar 10. link to original article link to PMC article PubMed

GemOx

GemOx: Gemcitabine & Oxaliplatin

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Edeline et al. 2019 (PRODIGE 12-ACCORD 18-UNICANCER GI) 2009-2014 Phase 3 (E-esc) Observation Did not meet primary endpoint of RFS

Preceding treatment

Chemotherapy

14-day cycle for 12 cycles

References

  1. PRODIGE 12-ACCORD 18-UNICANCER GI: Edeline J, Benabdelghani M, Bertaut A, Watelet J, Hammel P, Joly JP, Boudjema K, Fartoux L, Bouhier-Leporrier K, Jouve JL, Faroux R, Guerin-Meyer V, Kurtz JE, Assénat E, Seitz JF, Baumgaertner I, Tougeron D, de la Fouchardière C, Lombard-Bohas C, Boucher E, Stanbury T, Louvet C, Malka D, Phelip JM. Gemcitabine and Oxaliplatin Chemotherapy or Surveillance in Resected Biliary Tract Cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): A Randomized Phase III Study. J Clin Oncol. 2019 Mar 10;37(8):658-667. Epub 2019 Feb 1. link to original article PubMed NCT01313377

Metastatic, first-line therapy

CapeOx

CapeOx: Capecitabine & Oxaliplatin
XELOX: XELoda (Capecitabine) & OXaliplatin

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Kim et al. 2019 (SMC 2011-05-070) 2011-2016 Phase 3 (E-switch-ic) GEMOX Non-inferior PFS

Chemotherapy

21-day cycle for 8 cycles

References

  1. SMC 2011-05-070: Kim ST, Kang JH, Lee J, Lee HW, Oh SY, Jang JS, Lee MA, Sohn BS, Yoon SY, Choi HJ, Hong JH, Kim MJ, Kim S, Park YS, Park JO, Lim HY. Capecitabine plus oxaliplatin versus gemcitabine plus oxaliplatin as first-line therapy for advanced biliary tract cancers: a multicenter, open-label, randomized, phase III, noninferiority trial. Ann Oncol. 2019 May 1;30(5):788-795. link to original article contains dosing details in abstract PubMed NCT01470443

Cisplatin & Gemcitabine (GC)

GC: Gemcitabine & Cisplatin

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Awaiting publication (TOPAZ-1) 2019-2021 Phase 3 (C) GC & Durvalumab Seems to have inferior OS

Note: dosing information is from the FDA approval announcement.

Chemotherapy

21-day cycle for up to 8 cycles

References

  1. TOPAZ-1: NCT03875235

Cisplatin & Gemcitabine (GC) & Durvalumab

GC & Durvalumab: Gemcitabine, Cisplatin, Durvalumab

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Awaiting publication (TOPAZ-1) 2019-2021 Phase 3 (E-RT-esc) GC Seems to have superior OS
Median OS: 12.8 vs 11.5 mo
(HR 0.80, 95% CI 0.66-0.97)

Note: efficacy and dosing information are from the FDA approval announcement.

Chemotherapy

Immunotherapy

21-day cycle for up to 8 cycles, then 28-day cycles

References

  1. TOPAZ-1: NCT03875235

ECF

ECF: Epirubicin, Cisplatin, Fluorouracil

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Rao et al. 2005 1997-2003 Phase 3 (E-switch-ic) FELV Did not meet primary endpoint of OS

Chemotherapy

21-day cycles

References

  1. Rao S, Cunningham D, Hawkins RE, Hill ME, Smith D, Daniel F, Ross PJ, Oates J, Norman AR. Phase III study of 5FU, etoposide and leucovorin (FELV) compared to epirubicin, cisplatin and 5FU (ECF) in previously untreated patients with advanced biliary cancer. Br J Cancer. 2005 May 9;92(9):1650-4. link to original article contains dosing details in manuscript link to PMC article PubMed

FELV

FELV: Fluorouracil , Etoposide & LeucoVorin (Folinic acid)

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Rao et al. 2005 1997-2003 Phase 3 (C) ECF Did not meet primary endpoint of OS

Chemotherapy

21-day cycles

References

  1. Rao S, Cunningham D, Hawkins RE, Hill ME, Smith D, Daniel F, Ross PJ, Oates J, Norman AR. Phase III study of 5FU, etoposide and leucovorin (FELV) compared to epirubicin, cisplatin and 5FU (ECF) in previously untreated patients with advanced biliary cancer. Br J Cancer. 2005 May 9;92(9):1650-4. link to original article contains dosing details in manuscript link to PMC article PubMed

Gemcitabine & nab-Paclitaxel

NG: Nab-Paclitaxel & Gemcitabine

Regimen

Study Years of enrollment Evidence
Sahai et al. 2018 (PrE0204) 2014-2016 Phase 2

Note: this regimen was intended for ECOG PS 0 to 2, and Child-Pugh score less than 8.

Chemotherapy

28-day cycles

References

  1. PrE0204: Sahai V, Catalano PJ, Zalupski MM, Lubner SJ, Menge MR, Nimeiri HS, Munshi HG, Benson AB 3rd, O'Dwyer PJ. nab-Paclitaxel and gemcitabine as first-line treatment of advanced or metastatic cholangiocarcinoma: a phase 2 clinical trial. JAMA Oncol. 2018 Dec 1;4(12):1707-1712. link to original article contains dosing details in abstract link to PMC article PubMed NCT02181634

GemOx

GemOx: Gemcitabine & Oxaliplatin
GEMOX: GEMcitabine & OXaliplatin

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Kim et al. 2019 (SMC 2011-05-070) 2011-2016 Phase 3 (C) XELOX Non-inferior PFS

Chemotherapy

21-day cycle for 8 cycles

References

  1. SMC 2011-05-070: Kim ST, Kang JH, Lee J, Lee HW, Oh SY, Jang JS, Lee MA, Sohn BS, Yoon SY, Choi HJ, Hong JH, Kim MJ, Kim S, Park YS, Park JO, Lim HY. Capecitabine plus oxaliplatin versus gemcitabine plus oxaliplatin as first-line therapy for advanced biliary tract cancers: a multicenter, open-label, randomized, phase III, noninferiority trial. Ann Oncol. 2019 May 1;30(5):788-795. link to original article contains dosing details in abstract PubMed NCT01470443

Metastatic disease, all lines of therapy

Capecitabine monotherapy

Regimen

Study Evidence
Patt et al. 2004 Retrospective

Chemotherapy

21-day cycles

References

  1. Retrospective: Patt YZ, Hassan MM, Aguayo A, Nooka AK, Lozano RD, Curley SA, Vauthey JN, Ellis LM, Schnirer II, Wolff RA, Charnsangavej C, Brown TD. Oral capecitabine for the treatment of hepatocellular carcinoma, cholangiocarcinoma, and gallbladder carcinoma. Cancer. 2004 Aug 1;101(3):578-86. link to original article PubMed

Capecitabine & Mitomycin

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Kornek et al. 2004 2000-2001 Randomized Phase 2 (E-switch-ic) Gemcitabine & Mitomycin Might have superior ORR

Chemotherapy

Supportive therapy

28-day cycles

References

  1. Kornek GV, Schuell B, Laengle F, Gruenberger T, Penz M, Karall K, Depisch D, Lang F, Scheithauer W. Mitomycin C in combination with capecitabine or biweekly high-dose gemcitabine in patients with advanced biliary tract cancer: a randomised phase II trial. Ann Oncol. 2004 Mar;15(3):478-83. link to original article contains dosing details in manuscript PubMed

Cisplatin & Gemcitabine (GC)

GC: Gemcitabine & Cisplatin

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Valle et al. 2010 (ABC-02) 2002-2008 Phase 3 (E-esc) Gemcitabine Superior OS
Median OS: 11.7 vs 8.1 mo
(HR 0.64, 95% CI 0.52-0.80)
Morizane et al. 2019 (FUGA-BT) 2013-2016 Phase 3 (C) Gemcitabine & S-1 Seems to have non-inferior OS

Chemotherapy

Supportive therapy

  • Cisplatin is mixed in a solution of 1 liter of normal saline with 20 mmol potassium chloride, 8 mmol magnesium sulfate
  • After cisplatin, 500 mL normal saline given over 30 minutes

21-day cycle for 4 to 8 cycles depending on response

References

  1. ABC-02: Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, Madhusudan S, Iveson T, Hughes S, Pereira SP, Roughton M, Bridgewater J; ABC-02 Trial Investigators. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010 Apr 8;362(14):1273-81. link to original article contains dosing details in manuscript PubMed NCT00262769
  2. FUGA-BT: Morizane C, Okusaka T, Mizusawa J, Katayama H, Ueno M, Ikeda M, Ozaka M, Okano N, Sugimori K, Fukutomi A, Hara H, Mizuno N, Yanagimoto H, Wada K, Tobimatsu K, Yane K, Nakamori S, Yamaguchi H, Asagi A, Yukisawa S, Kojima Y, Kawabe K, Kawamoto Y, Sugimoto R, Iwai T, Nakamura K, Miyakawa H, Yamashita T, Hosokawa A, Ioka T, Kato N, Shioji K, Shimizu K, Nakagohri T, Kamata K, Ishii H, Furuse J; JCOG. Combination gemcitabine plus S-1 versus gemcitabine plus cisplatin for advanced/recurrent biliary tract cancer: the FUGA-BT (JCOG1113) randomized phase III clinical trial. Ann Oncol. 2019 Dec 1;30(12):1950-1958. link to original article PubMed UMIN000010667
  3. FIGHT-302: NCT03656536
  4. FOENIX-CCA3: NCT04093362
  5. KEYNOTE-966: NCT04003636
  6. NuTide:121: NCT04163900
  7. PROOF 301: NCT03773302
  8. SWOG S1815: NCT03768414

Cisplatin & Gemcitabine (GC) & nab-Paclitaxel

Regimen

Study Years of enrollment Evidence
Shroff et al. 2019 (MDACC 2014-0524) 2015-2017 Phase 2

Prolonged median PFS and OS vs reported for historical controls treated with gemcitabine-cisplatin alone. This is the dose after a mid-protocol amendment for hematologic toxicity.

Chemotherapy

21-day cycles

References

  1. MDACC 2014-0524: Shroff RT, Javle MM, Xiao L, Kaseb AO, Varadhachary GR, Wolff RA, Raghav KPS, Iwasaki M, Masci P, Ramanathan RK, Ahn DH, Bekaii-Saab TS, Borad MJ. Gemcitabine, cisplatin, and nab-paclitaxel for the treatment of advanced biliary tract cancers: a phase 2 clinical trial. JAMA Oncol. 2019 Jun 1;5(6):824-830. Epub 2019 Apr 18. link to original article contains dosing details in abstract link to PMC article PubMed NCT02392637

Erlotinib & Bevacizumab

Regimen

Study Years of enrollment Evidence
Lubner et al. 2010 (MC044G) 2006-2008 Phase 2

Targeted therapy

28-day cycles

References

  1. MC044G: Lubner SJ, Mahoney MR, Kolesar JL, Loconte NK, Kim GP, Pitot HC, Philip PA, Picus J, Yong WP, Horvath L, Van Hazel G, Erlichman CE, Holen KD. Report of a multicenter phase II trial testing a combination of biweekly bevacizumab and daily erlotinib in patients with unresectable biliary cancer: a phase II Consortium study. J Clin Oncol. 2010 Jul 20;28(21):3491-7. Epub 2010 Jun 7. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00356889

FELV

FELV: Fluorouracil , Etoposide & LeucoVorin (Folinic acid)

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Glimelius et al. 1996 1991-1995 Phase 3 (E-esc) Best supportive care Superior OS

Chemotherapy

21-day cycles

References

  1. Glimelius B, Hoffman K, Sjödén PO, Jacobsson G, Sellström H, Enander LK, Linné T, Svensson C. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol. 1996 Aug;7(6):593-600. link to original article contains dosing details in manuscript PubMed content property of HemOnc.org

FULV

FULV: 5-FU & LeucoVorin (Folinic acid)
FUFA: 5-FU (Fluorouracil) & Folinic Acid

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Glimelius et al. 1996 1991-1995 Phase 3 (E-esc) Best supportive care Superior OS

Chemotherapy

14-day cycles

References

  1. Glimelius B, Hoffman K, Sjödén PO, Jacobsson G, Sellström H, Enander LK, Linné T, Svensson C. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol. 1996 Aug;7(6):593-600. link to original article contains dosing details in manuscript PubMed

FULV & Gemcitabine

FULV & Gemcitabine: 5-FU, LeucoVorin (Folinic acid), Gemcitabine

Regimen

Study Years of enrollment Evidence
Gebbia et al. 2001 NR Phase 2

Chemotherapy

21-day cycles

References

  1. Gebbia V, Giuliani F, Maiello E, Colucci G, Verderame F, Borsellino N, Mauceri G, Caruso M, Tirrito ML, Valdesi M. Treatment of inoperable and/or metastatic biliary tree carcinomas with single-agent gemcitabine or in combination with levofolinic acid and infusional fluorouracil: results of a multicenter phase II study. J Clin Oncol. 2001 Oct 15;19(20):4089-91. link to original article contains dosing details in manuscript PubMed

Gemcitabine monotherapy

Regimen variant #1

Study Years of enrollment Evidence Comparator Comparative Efficacy
Valle et al. 2010 (ABC-02) 2002-2008 Phase 3 (E-de-esc) Cisplatin & Gemcitabine Inferior OS

Chemotherapy

28-day cycle for 3 to 6 cycles depending on response


Regimen variant #2

Study Years of enrollment Evidence
Gebbia et al. 2001 NR Phase 2

Chemotherapy

30-day cycles

References

  1. Gebbia V, Giuliani F, Maiello E, Colucci G, Verderame F, Borsellino N, Mauceri G, Caruso M, Tirrito ML, Valdesi M. Treatment of inoperable and/or metastatic biliary tree carcinomas with single-agent gemcitabine or in combination with levofolinic acid and infusional fluorouracil: results of a multicenter phase II study. J Clin Oncol. 2001 Oct 15;19(20):4089-91. link to original article contains dosing details in manuscript PubMed
  2. ABC-02: Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, Madhusudan S, Iveson T, Hughes S, Pereira SP, Roughton M, Bridgewater J; ABC-02 Trial Investigators. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010 Apr 8;362(14):1273-81. link to original article contains dosing details in manuscript PubMed NCT00262769

Gemcitabine, Cisplatin, S-1

GCS: Gemcitabine, Cisplatin, S-1

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Sakai et al. 2018 (KHBO1401-MITSUBA) 2014-NR Phase 3 (E-esc) Cisplatin & Gemcitabine Seems to have superior OS

Chemotherapy

14-day cycles

References

  1. Abstract: Sakai D, Kanai M , Kobayashi S, Eguchi H, Baba H, Seo S, Taketomi A, Takayama T, Yamaue H, Ishioka C, Sho M, Takeyama Y, Fujimoto J, Toyoda M, Shimizu J, Goto T, Yoshimura K, Hatano E, Nagano H, Ioka T. Randomized phase III study of gemcitabine, cisplatin plus S-1 (GCS) versus gemcitabine, cisplatin (GC) for advanced biliary tract cancer (KHBO1401-MITSUBA). Annals of Oncology 29 (Supplement 8): viii205–viii270, 2018 link to abstract NCT02182778

Gemcitabine & Mitomycin

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Kornek et al. 2004 2000-2001 Randomized Phase 2 (E-switch-ic) Capecitabine & Mitomycin Might have inferior ORR

Chemotherapy

Supportive therapy

28-day cycles

References

  1. Kornek GV, Schuell B, Laengle F, Gruenberger T, Penz M, Karall K, Depisch D, Lang F, Scheithauer W. Mitomycin C in combination with capecitabine or biweekly high-dose gemcitabine in patients with advanced biliary tract cancer: a randomised phase II trial. Ann Oncol. 2004 Mar;15(3):478-83. link to original article contains dosing details in manuscript PubMed

Gemcitabine & S-1

GS: Gemcitabine & S-1

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Morizane et al. 2019 (FUGA-BT) 2013-2016 Phase 3 (E-switch-ic) Gemcitabine & Cisplatin Seems to have non-inferior OS

Chemotherapy

References

  1. FUGA-BT: Morizane C, Okusaka T, Mizusawa J, Katayama H, Ueno M, Ikeda M, Ozaka M, Okano N, Sugimori K, Fukutomi A, Hara H, Mizuno N, Yanagimoto H, Wada K, Tobimatsu K, Yane K, Nakamori S, Yamaguchi H, Asagi A, Yukisawa S, Kojima Y, Kawabe K, Kawamoto Y, Sugimoto R, Iwai T, Nakamura K, Miyakawa H, Yamashita T, Hosokawa A, Ioka T, Kato N, Shioji K, Shimizu K, Nakagohri T, Kamata K, Ishii H, Furuse J; JCOG. Combination gemcitabine plus S-1 versus gemcitabine plus cisplatin for advanced/recurrent biliary tract cancer: the FUGA-BT (JCOG1113) randomized phase III clinical trial. Ann Oncol. 2019 Dec 1;30(12):1950-1958. link to original article PubMed UMIN000010667

GemOx

GemOx: Gemcitabine & Oxaliplatin
GEMOX: GEMcitabine & OXaliplatin

Regimen variant #1, 1000/85, bi-weekly

Study Years of enrollment Evidence Efficacy
Halim et al. 2011 2005-2009 Phase 2 ORR: 27.5%

Chemotherapy

14-day cycles


Regimen variant #2, 1000/100, bi-weekly

Study Years of enrollment Evidence Comparator Comparative Efficacy
Lee et al. 2011 (SMC 2008-12-024) 2009-2010 Phase 3 (C) GEMOX & Erlotinib Might have inferior PFS

Chemotherapy

14-day cycles


Regimen variant #3, 1000/100 ("GEMOX-3")

Study Years of enrollment Evidence Efficacy
Harder et al. 2006 2002-2005 Phase 2 ORR: 26% (95% CI 14–44)

GEMOX-3: GEMcitabine & OXaliplatin, 3 visits per month

Chemotherapy

28-day cycles

References

  1. Harder J, Riecken B, Kummer O, Lohrmann C, Otto F, Usadel H, Geissler M, Opitz O, Henss H. Outpatient chemotherapy with gemcitabine and oxaliplatin in patients with biliary tract cancer. Br J Cancer. 2006 Oct 9;95(7):848-52. link to original article link to PMC article contains dosing details in manuscript PubMed
  2. Halim A, Ebrahim MA, Saleh Y. A phase II study of outpatient biweekly gemcitabine-oxaliplatin in advanced biliary tract carcinomas. Jpn J Clin Oncol. 2011 Feb;41(2):217-24. link to original article contains dosing details in manuscript PubMed
  3. SMC 2008-12-024: Lee J, Park SH, Chang HM, Kim JS, Choi HJ, Lee MA, Jang JS, Jeung HC, Kang JH, Lee HW, Shin DB, Kang HJ, Sun JM, Park JO, Park YS, Kang WK, Lim HY. Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary-tract cancer: a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2012 Feb;13(2):181-8. Epub 2011 Dec 20. link to original article contains dosing details in abstract PubMed NCT01149122
  4. KN035-BTC: NCT03478488

GEMOX-B

GEMOX-B: GEMcitabine, OXaliplatin, Bevacizumab

Regimen

Study Years of enrollment Evidence
Zhu et al. 2009 (MGH 05-349) 2006-2007 Phase 2

Chemotherapy

Targeted therapy

28-day cycles

References

  1. MGH 05-349: Zhu AX, Meyerhardt JA, Blaszkowsky LS, Kambadakone AR, Muzikansky A, Zheng H, Clark JW, Abrams TA, Chan JA, Enzinger PC, Bhargava P, Kwak EL, Allen JN, Jain SR, Stuart K, Horgan K, Sheehan S, Fuchs CS, Ryan DP, Sahani DV. Efficacy and safety of gemcitabine, oxaliplatin, and bevacizumab in advanced biliary-tract cancers and correlation of changes in 18-fluorodeoxyglucose PET with clinical outcome: a phase 2 study. Lancet Oncol. 2010 Jan;11(1):48-54. Epub 2009 Nov 20. link to original article contains dosing details in manuscript PubMed NCT00361231

Nivolumab monotherapy

Regimen

Study Years of enrollment Evidence
Kim et al. 2020 (MCC-18684) 2016-2018 Phase 2

Immunotherapy

  • Nivolumab (Opdivo) as follows:
    • Cycles 1 to 8: 240 mg IV once on day 1
    • Cycle 9 onwards: 480 mg IV once on day 1

14-day cycle for 8 cycles, then 28-day cycles

References

  1. MCC-18684: Kim RD, Chung V, Alese OB, El-Rayes BF, Li D, Al-Toubah TE, Schell MJ, Zhou JM, Mahipal A, Kim BH, Kim DW. A Phase 2 Multi-institutional Study of Nivolumab for Patients With Advanced Refractory Biliary Tract Cancer. JAMA Oncol. 2020 Jun 1;6(6):888-894. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02829918

Pembrolizumab monotherapy

Regimen

Study Years of enrollment Evidence
Le et al. 2015 (KEYNOTE-016) 2013-2016 Phase 2, <20 pts of this subtype

Note: KEYNOTE-016 was an expansion to a CRC-specific trial.

Immunotherapy

14-day cycle for up to 52 cycles (2 years)

References

  1. KEYNOTE-016: Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, Biedrzycki B, Donehower RC, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Duffy SM, Goldberg RM, de la Chapelle A, Koshiji M, Bhaijee F, Huebner T, Hruban RH, Wood LD, Cuka N, Pardoll DM, Papadopoulos N, Kinzler KW, Zhou S, Cornish TC, Taube JM, Anders RA, Eshleman JR, Vogelstein B, Diaz LA Jr. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015 Jun 25;372(26):2509-20. Epub 2015 May 30. link to original article contains dosing details in abstract link to PMC article PubMed NCT01876511
    1. Update: Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, Lu S, Kemberling H, Wilt C, Luber BS, Wong F, Azad NS, Rucki AA, Laheru D, Donehower R, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Greten TF, Duffy AG, Ciombor KK, Eyring AD, Lam BH, Joe A, Kang SP, Holdhoff M, Danilova L, Cope L, Meyer C, Zhou S, Goldberg RM, Armstrong DK, Bever KM, Fader AN, Taube J, Housseau F, Spetzler D, Xiao N, Pardoll DM, Papadopoulos N, Kinzler KW, Eshleman JR, Vogelstein B, Anders RA, Diaz LA Jr. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017 Jul 28;357(6349):409-413. Epub 2017 Jun 8. link to original article link to PMC article contains dosing details in supplement PubMed

Pemigatinib monotherapy

Regimen

Study Years of enrollment Evidence
Abou-Alfa et al. 2020 (FIGHT-202) 2017-2019 Phase 2 (RT)

Note: Patients with previously treated unresectable or metastatic disease.

Biomarker eligibility criteria

  • Fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement

Targeted therapy

21-day cycles

References

  1. FIGHT-202: Abou-Alfa GK, Sahai V, Hollebecque A, Vaccaro G, Melisi D, Al-Rajabi R, Paulson AS, Borad MJ, Gallinson D, Murphy AG, Oh DY, Dotan E, Catenacci DV, Van Cutsem E, Ji T, Lihou CF, Zhen H, Féliz L, Vogel A. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. Lancet Oncol. 2020 May;21(5):671-684. Epub 2020 Mar 20 link to original article contains dosing details in supplement link to PMC article PubMed NCT02924376

Metastatic disease, subsequent lines of therapy

mFOLFOX6

mFOLFOX6: modified FOLinic acid, Fluorouracil, OXaliplatin

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Lamarca et al. 2021 (ABC-06) 2014-2018 Phase 3 (E-esc) Active symptom control Seems to have superior OS
Median OS: 6.2 vs 5.3 mo
(HR 0.69, 95% CI 0.50-0.97)

Chemotherapy

14-day cycle for up to 12 cycles

References

  1. ABC-06: Lamarca A, Palmer DH, Wasan HS, Ross PJ, Ma YT, Arora A, Falk S, Gillmore R, Wadsley J, Patel K, Anthoney A, Maraveyas A, Iveson T, Waters JS, Hobbs C, Barber S, Ryder WD, Ramage J, Davies LM, Bridgewater JA, Valle JW; Advanced Biliary Cancer Working Group. Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2021 May;22(5):690-701. Epub 2021 Mar 30. link to original article link to PMC article contains dosing details in abstract PubMed NCT01926236

mFOLFOX6 (L-Leucovorin)

mFOLFOX6: modified FOLinic acid, Fluorouracil, OXaliplatin

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Lamarca et al. 2021 (ABC-06) 2014-2018 Phase 3 (E-esc) Active symptom control Seems to have superior OS
Median OS: 6.2 vs 5.3 mo
(HR 0.69, 95% CI 0.50-0.97)

Chemotherapy

14-day cycle for up to 12 cycles

References

  1. ABC-06: Lamarca A, Palmer DH, Wasan HS, Ross PJ, Ma YT, Arora A, Falk S, Gillmore R, Wadsley J, Patel K, Anthoney A, Maraveyas A, Iveson T, Waters JS, Hobbs C, Barber S, Ryder WD, Ramage J, Davies LM, Bridgewater JA, Valle JW; Advanced Biliary Cancer Working Group. Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2021 May;22(5):690-701. Epub 2021 Mar 30. link to original article link to PMC article contains dosing details in abstract PubMed NCT01926236

Futibatinib monotherapy

Regimen

Study Years of enrollment Evidence
Awaiting publication (TAS-120-101) 2014-2021 Phase 1/2 (RT)

Biomarker eligibility criteria

  • Fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement

Targeted therapy

Continued indefinitely

References

  1. TAS-120-101: NCT02052778

Infigratinib monotherapy

Regimen

FDA-recommended dose
Study Years of enrollment Evidence
Javle et al. 2017 (CBGJ398X2204) 2014-2020 Phase 2 (RT)

Biomarker eligibility criteria

  • FGFR2 gene fusions or translocations or other FGFR genetic alterations

Targeted therapy

28-day cycles

References

  1. CBGJ398X2204: Javle M, Lowery M, Shroff RT, Weiss KH, Springfeld C, Borad MJ, Ramanathan RK, Goyal L, Sadeghi S, Macarulla T, El-Khoueiry A, Kelley RK, Borbath I, Choo SP, Oh DY, Philip PA, Chen LT, Reungwetwattana T, Van Cutsem E, Yeh KH, Ciombor K, Finn RS, Patel A, Sen S, Porter D, Isaacs R, Zhu AX, Abou-Alfa GK, Bekaii-Saab T. Phase II study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma. J Clin Oncol. 2018 Jan 20;36(3):276-282. Epub 2017 Nov 28. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02150967
    1. Update: Javle M, Roychowdhury S, Kelley RK, Sadeghi S, Macarulla T, Weiss KH, Waldschmidt DT, Goyal L, Borbath I, El-Khoueiry A, Borad MJ, Yong WP, Philip PA, Bitzer M, Tanasanvimon S, Li A, Pande A, Soifer HS, Shepherd SP, Moran S, Zhu AX, Bekaii-Saab TS, Abou-Alfa GK. Infigratinib (BGJ398) in previously treated patients with advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements: mature results from a multicentre, open-label, single-arm, phase 2 study. Lancet Gastroenterol Hepatol. 2021 Oct;6(10):803-815. Epub 2021 Aug 3. link to original article PubMed

Ivosidenib monotherapy

Regimen

FDA-recommended dose
Study Years of enrollment Evidence Comparator Comparative Efficacy
Abou-Alfa et al. 2020 (ClarIDHy) 2017-2019 Phase 3 (E-RT-esc) Placebo Superior PFS
Median PFS: 2.7 vs 1.4 mo
(HR 0.37, 95% CI 0.25-0.54)

Note: Patients with unresectable or metastatic disease with IDH1 mutation with progression after at least one prior systemic therapy.

Biomarker eligibility criteria

  • IDH1 mutation

Targeted therapy

28-day cycles

References

  1. ClarIDHy: Abou-Alfa GK, Macarulla T, Javle MM, Kelley RK, Lubner SJ, Adeva J, Cleary JM, Catenacci DV, Borad MJ, Bridgewater J, Harris WP, Murphy AG, Oh DY, Whisenant J, Lowery MA, Goyal L, Shroff RT, El-Khoueiry AB, Fan B, Wu B, Chamberlain CX, Jiang L, Gliser C, Pandya SS, Valle JW, Zhu AX. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020 Jun;21(6):796-807. Epub 2020 May 13. Erratum in: Lancet Oncol. 2020 Oct;21(10):e462. link to original article contains dosing details in abstract link to PMC article PubMed NCT02989857
    1. Update: Zhu AX, Macarulla T, Javle MM, Kelley RK, Lubner SJ, Adeva J, Cleary JM, Catenacci DVT, Borad MJ, Bridgewater JA, Harris WP, Murphy AG, Oh DY, Whisenant JR, Lowery MA, Goyal L, Shroff RT, El-Khoueiry AB, Chamberlain CX, Aguado-Fraile E, Choe S, Wu B, Liu H, Gliser C, Pandya SS, Valle JW, Abou-Alfa GK. Final Overall Survival Efficacy Results of Ivosidenib for Patients With Advanced Cholangiocarcinoma With IDH1 Mutation: The Phase 3 Randomized Clinical ClarIDHy Trial. JAMA Oncol. 2021 Nov 1;7(11):1669-1677. link to original article link to PMC article PubMed

Lenvatinib & Pembrolizumab

Regimen

Study Years of enrollment Evidence
Awaiting publication (LEAP-005) 2019-ongoing Phase 2

Note: Dosing details are from ASCO abstract #321 (2021).

Targeted therapy

Immunotherapy

35-day cycles

References

  • LEAP-005: NCT03797326

Regorafenib monotherapy

Regimen

Study Years of enrollment Evidence
Sun et al. 2019 (UPMC 13-100) 2014-2017 Phase 2

Only studied in patients with advanced biliary cancer who failed at least 1 line of systemic therapy.

Targeted therapy

28-day cycles

References

  1. UPMC 13-100: Sun W, Patel A, Normolle A, Patel K, Ohr J, Lee JJ, Bahary N, Chu E, Streeter N, Drummond S. A phase 2 trial of regorafenib as a single agent in patients with chemotherapy-refractory, advanced, and metastatic biliary tract adenocarcinoma. Cancer. 2019 Mar 15;125(6):902-909. Epub 2018 Dec 18. link to original article link to PMC article PubMed NCT02053376
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