Difference between revisions of "Chronic lymphocytic leukemia - historical"

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The purpose of this page is to provide references to regimens that are obsolete, outdated, or of historical interest only. As a general rule, this includes the inferior arm(s) of a randomized study, unless said regimens continue to be recommended by trustworthy sources such as the [http://www.nccn.org/professionals/physician_gls/f_guidelines.asp NCCN Guidelines]. Is there a regimen missing from this list? Please go to the [[Chronic_lymphocytic_leukemia|main CLL/SLL regimen page]] to find other regimens.
 
The purpose of this page is to provide references to regimens that are obsolete, outdated, or of historical interest only. As a general rule, this includes the inferior arm(s) of a randomized study, unless said regimens continue to be recommended by trustworthy sources such as the [http://www.nccn.org/professionals/physician_gls/f_guidelines.asp NCCN Guidelines]. Is there a regimen missing from this list? Please go to the [[Chronic_lymphocytic_leukemia|main CLL/SLL regimen page]] to find other regimens.
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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>
 
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=First-line therapy=
 
=First-line therapy=
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==CAP {{#subobject:6a668f|Regimen=1}}==
 
==CAP {{#subobject:6a668f|Regimen=1}}==
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CAP: '''<u>C</u>'''yclophosphamide, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>P</u>'''rednisone
 
CAP: '''<u>C</u>'''yclophosphamide, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>P</u>'''rednisone
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen {{#subobject:e29575|Variant=1}}===
 
===Regimen {{#subobject:e29575|Variant=1}}===
 
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''<sup>1</sup>The inferior endpoint in Johnson et al. 1996 was only observed in this subgroup, not pretreated patients.''<br>
 
''<sup>1</sup>The inferior endpoint in Johnson et al. 1996 was only observed in this subgroup, not pretreated patients.''<br>
 
''Note: To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''
 
''Note: 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">
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Cyclophosphamide (Cytoxan)]] 750 mg/m<sup>2</sup> IV once on day 1
 
*[[Cyclophosphamide (Cytoxan)]] 750 mg/m<sup>2</sup> IV once on day 1
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====Glucocorticoid therapy====
 
====Glucocorticoid therapy====
 
*[[Prednisone (Sterapred)]] 40 mg/m<sup>2</sup> PO once per day on days 1 to 5
 
*[[Prednisone (Sterapred)]] 40 mg/m<sup>2</sup> PO once per day on days 1 to 5
−
 
 
'''1-month cycle for 6 cycles'''
 
'''1-month cycle for 6 cycles'''
−
 
+
</div></div>
 
===References===
 
===References===
 
# '''SWOG-7410:''' Keating MJ, Hester JP, McCredie KB, Burgess MA, Murphy WK, Freireich EJ. Long-term results of CAP therapy in chronic lymphocytic leukemia. Leuk Lymphoma. 1990;2(6):391-7. [https://doi.org/10.3109/10428199009069292 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27457043 PubMed]
 
# '''SWOG-7410:''' Keating MJ, Hester JP, McCredie KB, Burgess MA, Murphy WK, Freireich EJ. Long-term results of CAP therapy in chronic lymphocytic leukemia. Leuk Lymphoma. 1990;2(6):391-7. [https://doi.org/10.3109/10428199009069292 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27457043 PubMed]
 
# Johnson S, Smith AG, Löffler H, Osby E, Juliusson G, Emmerich B, Wyld PJ, Hiddemann W; French Cooperative Group on 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]
 
# Johnson S, Smith AG, Löffler H, Osby E, Juliusson G, Emmerich B, Wyld PJ, Hiddemann W; French Cooperative Group on 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]
 
# '''FCGCLL 1996:''' Leporrier M, Chevret S, Cazin B, Boudjerra N, Feugier P, Desablens B, Rapp MJ, Jaubert J, Autrand C, Divine M, Dreyfus B, Maloum K, Travade P, Dighiero G, Binet JL, Chastang C; French Cooperative Group on Chronic Lymphocytic Leukemia. Randomized comparison of fludarabine, CAP, and ChOP in 938 previously untreated stage B and C chronic lymphocytic leukemia patients. Blood. 2001 Oct 15;98(8):2319-25. [http://www.bloodjournal.org/content/98/8/2319.long link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/11588025 PubMed]
 
# '''FCGCLL 1996:''' Leporrier M, Chevret S, Cazin B, Boudjerra N, Feugier P, Desablens B, Rapp MJ, Jaubert J, Autrand C, Divine M, Dreyfus B, Maloum K, Travade P, Dighiero G, Binet JL, Chastang C; French Cooperative Group on Chronic Lymphocytic Leukemia. Randomized comparison of fludarabine, CAP, and ChOP in 938 previously untreated stage B and C chronic lymphocytic leukemia patients. Blood. 2001 Oct 15;98(8):2319-25. [http://www.bloodjournal.org/content/98/8/2319.long link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/11588025 PubMed]
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==Chlorambucil monotherapy {{#subobject:69ac3|Regimen=1}}==
 
==Chlorambucil monotherapy {{#subobject:69ac3|Regimen=1}}==
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<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen variant #1, 0.1 mg/kg {{#subobject:512687|Variant=1}}===
 
===Regimen variant #1, 0.1 mg/kg {{#subobject:512687|Variant=1}}===
 
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''<sup>1</sup>In FRE-CLL-80, this was the experimental arm for Binet Stage A and the control arm for Binet Stage B.''<br>
 
''<sup>1</sup>In FRE-CLL-80, this was the experimental arm for Binet Stage A and the control arm for Binet Stage B.''<br>
 
''Note: FRE-CLL-85 is one of two trials reported in Dighiero et al. 1998; the other was comparing chlorambucil & prednisone vs. observation.''
 
''Note: FRE-CLL-85 is one of two trials reported in Dighiero et al. 1998; the other was comparing chlorambucil & prednisone vs. observation.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Chlorambucil (Leukeran)]] 0.1 mg/kg PO once per day
 
*[[Chlorambucil (Leukeran)]] 0.1 mg/kg PO once per day
−
 
 
'''Continued indefinitely'''
 
'''Continued indefinitely'''
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</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen variant #2, 0.4 mg/kg {{#subobject:ca331d|Variant=1}}===
 
===Regimen variant #2, 0.4 mg/kg {{#subobject:ca331d|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
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|-
 
|-
 
|}
 
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''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]].''
+
''Note: 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]].''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Chlorambucil (Leukeran)]] 0.4 mg/kg PO once per day on days 1 to 2, 15 to 16
 
*[[Chlorambucil (Leukeran)]] 0.4 mg/kg PO once per day on days 1 to 2, 15 to 16
−
 
 
'''28-day cycle for up to 6 cycles'''
 
'''28-day cycle for up to 6 cycles'''
−
 
+
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen variant #3, 0.4 mg/kg, with dose escalation {{#subobject:1ac4ad|Variant=1}}===
 
===Regimen variant #3, 0.4 mg/kg, with dose escalation {{#subobject:1ac4ad|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
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|-
 
|-
 
|}
 
|}
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''This regimen was intended for untreated patients between 65 and 80 years with [[#Binet_staging_.281981.29|Binet stage]] C, or [[#Binet_staging_.281981.29|Binet stage]] B or A if they had rapid disease progression (lymphocyte doubling time less than 3 months) or symptoms from enlarged lymph nodes and organs, or if they had severe B symptoms.''
+
''Note: This regimen was intended for untreated patients between 65 and 80 years with [[#Binet_staging_.281981.29|Binet stage]] C, or [[#Binet_staging_.281981.29|Binet stage]] B or A if they had rapid disease progression (lymphocyte doubling time less than 3 months) or symptoms from enlarged lymph nodes and organs, or if they had severe B symptoms.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Chlorambucil (Leukeran)]] as follows:
 
*[[Chlorambucil (Leukeran)]] as follows:
 
**Cycle 1: 0.4 mg/kg PO once on day 1
 
**Cycle 1: 0.4 mg/kg PO once on day 1
 
**To be increased as tolerated by 0.1 mg/kg each cycle, up to a maximum of 0.8 mg/kg PO once on day 1
 
**To be increased as tolerated by 0.1 mg/kg each cycle, up to a maximum of 0.8 mg/kg PO once on day 1
−
 
 
'''14-day cycle for up to 24 cycles'''
 
'''14-day cycle for up to 24 cycles'''
−
 
+
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen variant #4, 0.5 mg/kg {{#subobject:ad0508|Variant=1}}===
 
===Regimen variant #4, 0.5 mg/kg {{#subobject:ad0508|Variant=1}}===
 
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''<sup>1</sup>Reported efficacy for RESONATE-2 is based on the 2019 update.''<br>
 
''<sup>1</sup>Reported efficacy for RESONATE-2 is based on the 2019 update.''<br>
 
''Note: Patients enrolled on RESONATE-2 were allowed to increase the dose up to 0.8 mg/kg if "there was not an unacceptable level of toxic effects."''
 
''Note: Patients enrolled on RESONATE-2 were allowed to increase the dose up to 0.8 mg/kg if "there was not an unacceptable level of toxic effects."''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Chlorambucil (Leukeran)]] 0.5 mg/kg PO once per day on days 1 & 15
 
*[[Chlorambucil (Leukeran)]] 0.5 mg/kg PO once per day on days 1 & 15
−
 
 
'''28-day cycle for 6 to 12 cycles'''
 
'''28-day cycle for 6 to 12 cycles'''
−
 
+
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen variant #5, 0.8 mg/kg {{#subobject:cea31d|Variant=1}}===
 
===Regimen variant #5, 0.8 mg/kg {{#subobject:cea31d|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
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|-
 
|-
 
|}
 
|}
−
''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]].''
+
''Note: 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]].''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Chlorambucil (Leukeran)]] 0.8 mg/kg PO once per day on days 1 & 15
 
*[[Chlorambucil (Leukeran)]] 0.8 mg/kg PO once per day on days 1 & 15
−
 
 
'''28-day cycle for up to 6 cycles (Knauf et al. 2009) or indefinitely (ORIGIN)'''
 
'''28-day cycle for up to 6 cycles (Knauf et al. 2009) or indefinitely (ORIGIN)'''
−
 
+
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen variant #6, 10 mg/m<sup>2</sup> {{#subobject:ec8dfe|Variant=1}}===
 
===Regimen variant #6, 10 mg/m<sup>2</sup> {{#subobject:ec8dfe|Variant=1}}===
 
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|-
 
|-
 
|}
 
|}
 +
<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
 
*[[Chlorambucil (Leukeran)]] 10 mg/m<sup>2</sup> PO once per day on days 1 to 7
−
 
 
====Supportive therapy====
 
====Supportive therapy====
 
*Per '''Catovsky et al. 2007''': Patients with stage C disease (hemoglobin less than 10 g/dL or platelet count less than 100 x 10<sup>9</sup>/L) received [[Prednisolone (Millipred)]] 30 mg/m<sup>2</sup> PO once per day for 3 weeks, then 1 week taper before starting [[Chlorambucil (Leukeran)]] to reduce its myelotoxicity
 
*Per '''Catovsky et al. 2007''': Patients with stage C disease (hemoglobin less than 10 g/dL or platelet count less than 100 x 10<sup>9</sup>/L) received [[Prednisolone (Millipred)]] 30 mg/m<sup>2</sup> PO once per day for 3 weeks, then 1 week taper before starting [[Chlorambucil (Leukeran)]] to reduce its myelotoxicity
−
 
 
'''28-day cycle for up to 12 cycles'''
 
'''28-day cycle for up to 12 cycles'''
−
 
+
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen variant #7, 40 mg/m<sup>2</sup> {{#subobject:e1b84b|Variant=1}}===
 
===Regimen variant #7, 40 mg/m<sup>2</sup> {{#subobject:e1b84b|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
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|-
 
|-
 
|}
 
|}
−
''In CALGB 9011, this regimen was intended for previously untreated patients with CLL who were high-risk ([[#Original_Rai_staging_.281975.29|Rai stage]] III or IV) or intermediate-risk ([[#Original_Rai_staging_.281975.29|Rai stage]] I or II) if they had at least one of the following: disease-related symptoms such as weight loss, extreme fatigue, night sweats, or fever without evidence of infection; massive or progressive splenomegaly or lymphadenopathy, or more than a 50 percent increase in the number of peripheral-blood lymphocytes over a 2-month period or an anticipated doubling of these cells within less than 12 months. In CAM 307, this regimen was intended for patients who were at least 18 years old with flow cytometry–confirmed diagnosis of B-cell CLL, [[#Original_Rai_staging_.281975.29|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.''
+
''Note: In CALGB 9011, this regimen was intended for previously untreated patients with CLL who were high-risk ([[#Original_Rai_staging_.281975.29|Rai stage]] III or IV) or intermediate-risk ([[#Original_Rai_staging_.281975.29|Rai stage]] I or II) if they had at least one of the following: disease-related symptoms such as weight loss, extreme fatigue, night sweats, or fever without evidence of infection; massive or progressive splenomegaly or lymphadenopathy, or more than a 50 percent increase in the number of peripheral-blood lymphocytes over a 2-month period or an anticipated doubling of these cells within less than 12 months. In CAM 307, this regimen was intended for patients who were at least 18 years old with flow cytometry–confirmed diagnosis of B-cell CLL, [[#Original_Rai_staging_.281975.29|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 class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Chlorambucil (Leukeran)]] 40 mg/m<sup>2</sup> PO once on day 1
 
*[[Chlorambucil (Leukeran)]] 40 mg/m<sup>2</sup> PO once on day 1
−
 
 
'''28-day cycle for up to 12 cycles'''
 
'''28-day cycle for up to 12 cycles'''
 +
</div></div>
  
 
===References===
 
===References===
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## '''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://pubmed.ncbi.nlm.nih.gov/31628428 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://pubmed.ncbi.nlm.nih.gov/31628428 PubMed]
 
# '''ORIGIN:''' Chanan-Khan A, Egyed M, Robak T, Martinelli de Oliveira FA, Echeveste MA, Dolan S, Desjardins P, Blonski JZ, Mei J, Golany N, Zhang J, Gribben JG. Randomized phase 3 study of lenalidomide versus chlorambucil as first-line therapy for older patients with chronic lymphocytic leukemia (the ORIGIN trial). Leukemia. 2017 May;31(5):1240-1243. Epub 2017 Jan 31. [https://www.nature.com/articles/leu201747 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5420789/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28140392 PubMed] NCT00910910
 
# '''ORIGIN:''' Chanan-Khan A, Egyed M, Robak T, Martinelli de Oliveira FA, Echeveste MA, Dolan S, Desjardins P, Blonski JZ, Mei J, Golany N, Zhang J, Gribben JG. Randomized phase 3 study of lenalidomide versus chlorambucil as first-line therapy for older patients with chronic lymphocytic leukemia (the ORIGIN trial). Leukemia. 2017 May;31(5):1240-1243. Epub 2017 Jan 31. [https://www.nature.com/articles/leu201747 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5420789/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28140392 PubMed] NCT00910910
−
 
 
==Chlorambucil & Prednisone {{#subobject:f03d93|Regimen=1}}==
 
==Chlorambucil & Prednisone {{#subobject:f03d93|Regimen=1}}==
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen variant #1, 0.3/40 {{#subobject:157c8a|Variant=1}}===
 
===Regimen variant #1, 0.3/40 {{#subobject:157c8a|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
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|-
 
|-
 
|}
 
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<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Chlorambucil (Leukeran)]] 0.3 mg/kg PO once per day on days 1 to 5
 
*[[Chlorambucil (Leukeran)]] 0.3 mg/kg PO once per day on days 1 to 5
 
====Glucocorticoid therapy====
 
====Glucocorticoid therapy====
 
*[[Prednisone (Sterapred)]] 40 mg/m<sup>2</sup> PO once per day on days 1 to 5
 
*[[Prednisone (Sterapred)]] 40 mg/m<sup>2</sup> PO once per day on days 1 to 5
−
 
 
'''1-month cycle for up to 36 cycles (3 years)'''
 
'''1-month cycle for up to 36 cycles (3 years)'''
−
 
+
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen variant #2, 12/30 {{#subobject:6ce9db|Variant=1}}===
 
===Regimen variant #2, 12/30 {{#subobject:6ce9db|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
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|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Chlorambucil (Leukeran)]] 12 mg/m<sup>2</sup> PO once per day on days 1 to 7
 
*[[Chlorambucil (Leukeran)]] 12 mg/m<sup>2</sup> PO once per day on days 1 to 7
 
====Glucocorticoid therapy====
 
====Glucocorticoid therapy====
 
*[[Prednisone (Sterapred)]] 30 mg/m<sup>2</sup> PO once per day on days 1 to 7
 
*[[Prednisone (Sterapred)]] 30 mg/m<sup>2</sup> PO once per day on days 1 to 7
−
 
 
'''28-day cycles, continued until CR'''
 
'''28-day cycles, continued until CR'''
−
 
+
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen variant #3, 30/80 {{#subobject:213140|Variant=1}}===
 
===Regimen variant #3, 30/80 {{#subobject:213140|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
Line 348: Line 350:
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Chlorambucil (Leukeran)]] 30 mg/m<sup>2</sup> PO once on day 1
 
*[[Chlorambucil (Leukeran)]] 30 mg/m<sup>2</sup> PO once on day 1
 
====Glucocorticoid therapy====
 
====Glucocorticoid therapy====
 
*[[Prednisone (Sterapred)]] 80 mg PO once per day on days 1 to 5
 
*[[Prednisone (Sterapred)]] 80 mg PO once per day on days 1 to 5
−
 
 
'''14-day cycle for up to 39 cycles (18 months)'''
 
'''14-day cycle for up to 39 cycles (18 months)'''
−
 
+
</div></div>
 
===References===
 
===References===
 
<!-- Raphael BG, Silber R, Moore DF, et al: Survival duration and complete remission (CR) incidence in advanced chronic lymphocytic leukemia (CLL). Blood 67: 229A, 1986 -->
 
<!-- Raphael BG, Silber R, Moore DF, et al: Survival duration and complete remission (CR) incidence in advanced chronic lymphocytic leukemia (CLL). Blood 67: 229A, 1986 -->
Line 360: Line 362:
 
# '''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]
 
# '''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]
 
# '''PALG CLL1:''' Robak T, Bloński JZ, Kasznicki M, Blasińska-Morawiec M, Krykowski E, Dmoszyńska A, Mrugala-Spiewak H, Skotnicki AB, Nowak W, Konopka L, Ceglarek B, Maj S, Dwilewicz-Trojaczek J, Hellmann A, Urasiński I, Zdziarska B, Kotlarek-Haus S, Potoczek S, Grieb P. Cladribine with prednisone versus chlorambucil with prednisone as first-line therapy in chronic lymphocytic leukemia: report of a prospective, randomized, multicenter trial. Blood. 2000 Oct 15;96(8):2723-9. [http://www.bloodjournal.org/content/96/8/2723 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/11023504 PubMed]
 
# '''PALG CLL1:''' Robak T, Bloński JZ, Kasznicki M, Blasińska-Morawiec M, Krykowski E, Dmoszyńska A, Mrugala-Spiewak H, Skotnicki AB, Nowak W, Konopka L, Ceglarek B, Maj S, Dwilewicz-Trojaczek J, Hellmann A, Urasiński I, Zdziarska B, Kotlarek-Haus S, Potoczek S, Grieb P. Cladribine with prednisone versus chlorambucil with prednisone as first-line therapy in chronic lymphocytic leukemia: report of a prospective, randomized, multicenter trial. Blood. 2000 Oct 15;96(8):2723-9. [http://www.bloodjournal.org/content/96/8/2723 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/11023504 PubMed]
−
 
 
==CHOP {{#subobject:3b1abe|Regimen=1}}==
 
==CHOP {{#subobject:3b1abe|Regimen=1}}==
−
 
 
CHOP: '''<u>C</u>'''yclophosphamide, '''<u>H</u>'''ydroxydaunorubicin (Doxorubicin), '''<u>O</u>'''ncovin (Vincristine), '''<u>P</u>'''rednisone
 
CHOP: '''<u>C</u>'''yclophosphamide, '''<u>H</u>'''ydroxydaunorubicin (Doxorubicin), '''<u>O</u>'''ncovin (Vincristine), '''<u>P</u>'''rednisone
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen {{#subobject:557db6|Variant=1}}===
 
===Regimen {{#subobject:557db6|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
Line 389: Line 389:
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1 to 5
 
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1 to 5
Line 395: Line 396:
 
====Glucocorticoid therapy====
 
====Glucocorticoid therapy====
 
*[[Prednisone (Sterapred)]] 40 mg/m<sup>2</sup> PO once per day on days 1 to 5
 
*[[Prednisone (Sterapred)]] 40 mg/m<sup>2</sup> PO once per day on days 1 to 5
−
 
 
'''28-day cycle for 6 cycles'''
 
'''28-day cycle for 6 cycles'''
−
 
+
</div></div>
 
===References===
 
===References===
 
# '''FRE-CLL-80:''' Binet JL, Chastang C, Dighiero G, Travad P; French Cooperative Group on Chronic Lymphocytic Leukaemia. Effectiveness of "CHOP" regimen in advanced untreated chronic lymphocytic leukaemia. Lancet. 1986 Jun 14;1(8494):1346-9. [https://doi.org/10.1016/S0140-6736(86)91663-6 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/2872470 PubMed]
 
# '''FRE-CLL-80:''' Binet JL, Chastang C, Dighiero G, Travad P; French Cooperative Group on Chronic Lymphocytic Leukaemia. Effectiveness of "CHOP" regimen in advanced untreated chronic lymphocytic leukaemia. Lancet. 1986 Jun 14;1(8494):1346-9. [https://doi.org/10.1016/S0140-6736(86)91663-6 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/2872470 PubMed]
 
## '''Update:''' Benichou J, Binet JL, Chastang C, Chevret S, Dighiero G, Travade P; French Cooperative Group on Chronic Lymphocytic Leukaemia. Long-term results of the CHOP regimen in stage C chronic lymphocytic leukaemia. Br J Haematol. 1989 Nov;73(3):334-40. [https://doi.org/10.1111/j.1365-2141.1989.tb07749.x link to original article] [https://pubmed.ncbi.nlm.nih.gov/2690923 PubMed]
 
## '''Update:''' Benichou J, Binet JL, Chastang C, Chevret S, Dighiero G, Travade P; French Cooperative Group on Chronic Lymphocytic Leukaemia. Long-term results of the CHOP regimen in stage C chronic lymphocytic leukaemia. Br J Haematol. 1989 Nov;73(3):334-40. [https://doi.org/10.1111/j.1365-2141.1989.tb07749.x link to original article] [https://pubmed.ncbi.nlm.nih.gov/2690923 PubMed]
 
# '''FCGCLL 1996:''' Leporrier M, Chevret S, Cazin B, Boudjerra N, Feugier P, Desablens B, Rapp MJ, Jaubert J, Autrand C, Divine M, Dreyfus B, Maloum K, Travade P, Dighiero G, Binet JL, Chastang C; French Cooperative Group on Chronic Lymphocytic Leukemia. Randomized comparison of fludarabine, CAP, and ChOP in 938 previously untreated stage B and C chronic lymphocytic leukemia patients. Blood. 2001 Oct 15;98(8):2319-25. [http://www.bloodjournal.org/content/98/8/2319.long link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/11588025 PubMed]
 
# '''FCGCLL 1996:''' Leporrier M, Chevret S, Cazin B, Boudjerra N, Feugier P, Desablens B, Rapp MJ, Jaubert J, Autrand C, Divine M, Dreyfus B, Maloum K, Travade P, Dighiero G, Binet JL, Chastang C; French Cooperative Group on Chronic Lymphocytic Leukemia. Randomized comparison of fludarabine, CAP, and ChOP in 938 previously untreated stage B and C chronic lymphocytic leukemia patients. Blood. 2001 Oct 15;98(8):2319-25. [http://www.bloodjournal.org/content/98/8/2319.long link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/11588025 PubMed]
−
 
 
==CMC {{#subobject:25f5b2|Regimen=1}}==
 
==CMC {{#subobject:25f5b2|Regimen=1}}==
−
 
 
CMC: '''<u>C</u>'''ladribine, '''<u>M</u>'''itoxantrone, '''<u>C</u>'''yclophosphamide
 
CMC: '''<u>C</u>'''ladribine, '''<u>M</u>'''itoxantrone, '''<u>C</u>'''yclophosphamide
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen {{#subobject:c2431|Variant=1}}===
 
===Regimen {{#subobject:c2431|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
Line 425: Line 423:
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Cladribine (Leustatin)]] 0.12 mg/kg IV over 2 hours once per day on days 1 to 3
 
*[[Cladribine (Leustatin)]] 0.12 mg/kg IV over 2 hours once per day on days 1 to 3
 
*[[Mitoxantrone (Novantrone)]] 10 mg/m<sup>2</sup> IV once on day 1
 
*[[Mitoxantrone (Novantrone)]] 10 mg/m<sup>2</sup> IV once on day 1
 
*[[Cyclophosphamide (Cytoxan)]] 650 mg/m<sup>2</sup> IV once on day 1
 
*[[Cyclophosphamide (Cytoxan)]] 650 mg/m<sup>2</sup> IV once on day 1
−
 
 
'''28-day cycle for up to 6 cycles'''
 
'''28-day cycle for up to 6 cycles'''
−
 
+
</div></div>
 
===References===
 
===References===
 
<!-- Preliminary results of this study were presented at the 44th Annual Meeting of the American Society of Hematology, Philadelphia, PA, December 6-10, 2002; and at the 10th International Workshop on CLL, Stresa, Lake Maggiore, Italy, October 10-12, 2003; and at the 46th Annual Meeting of the American Society of Hematology, San Diego, CA, December 4-7, 2004; and at the 11th International Workshop on CLL, New York, NY, September 16-18, 2005. -->
 
<!-- Preliminary results of this study were presented at the 44th Annual Meeting of the American Society of Hematology, Philadelphia, PA, December 6-10, 2002; and at the 10th International Workshop on CLL, Stresa, Lake Maggiore, Italy, October 10-12, 2003; and at the 46th Annual Meeting of the American Society of Hematology, San Diego, CA, December 4-7, 2004; and at the 11th International Workshop on CLL, New York, NY, September 16-18, 2005. -->
 
# '''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 abstract''' [https://pubmed.ncbi.nlm.nih.gov/16551966 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 abstract''' [https://pubmed.ncbi.nlm.nih.gov/16551966 PubMed]
−
 
 
==CVP {{#subobject:c1b3ad|Regimen=1}}==
 
==CVP {{#subobject:c1b3ad|Regimen=1}}==
−
 
 
CVP: '''<u>C</u>'''yclophosphamide, '''<u>V</u>'''incristine, '''<u>P</u>'''rednisone
 
CVP: '''<u>C</u>'''yclophosphamide, '''<u>V</u>'''incristine, '''<u>P</u>'''rednisone
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen variant #1, PO cyclophosphamide; uncapped vincristine {{#subobject:88f0a5|Variant=1}}===
 
===Regimen variant #1, PO cyclophosphamide; uncapped vincristine {{#subobject:88f0a5|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
Line 455: Line 451:
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1 to 5
 
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1 to 5
Line 460: Line 457:
 
====Glucocorticoid therapy====
 
====Glucocorticoid therapy====
 
*[[Prednisone (Sterapred)]] 100 mg/m<sup>2</sup> PO once per day on days 1 to 5
 
*[[Prednisone (Sterapred)]] 100 mg/m<sup>2</sup> PO once per day on days 1 to 5
−
 
 
'''21-day cycle for up to 26 cycles (18 months)'''
 
'''21-day cycle for up to 26 cycles (18 months)'''
−
 
+
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen variant #2, capped vincristine {{#subobject:14a751|Variant=1}}===
 
===Regimen variant #2, capped vincristine {{#subobject:14a751|Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
!style="width: 25%"|Study
+
!style="width: 33%"|Study
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 33%"|Years of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
 
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2668968/ Hochster et al. 2009 (ECOG E1496)]
 
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2668968/ Hochster et al. 2009 (ECOG E1496)]
−
|style="background-color:#91cf61"|Non-randomized portion of RCT
+
|NR
 +
|style="background-color:#91cf61"|Non-randomized portion of phase 3 RCT
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV once on day 1
 
*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV once on day 1
Line 477: Line 477:
 
====Glucocorticoid therapy====
 
====Glucocorticoid therapy====
 
*[[Prednisone (Sterapred)]] 100 mg/m<sup>2</sup> PO once per day on days 1 to 5
 
*[[Prednisone (Sterapred)]] 100 mg/m<sup>2</sup> PO once per day on days 1 to 5
−
 
 
'''21-day cycle for 6 to 8 cycles'''
 
'''21-day cycle for 6 to 8 cycles'''
−
 
+
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 
====Subsequent treatment====
 
====Subsequent treatment====
 
*[[#Rituximab_monotherapy_2|Rituximab]] maintenance versus [[#Observation_2|observation]]
 
*[[#Rituximab_monotherapy_2|Rituximab]] maintenance versus [[#Observation_2|observation]]
−
 
+
</div></div>
 
===References===
 
===References===
 
<!-- Raphael BG, Silber R, Moore DF, et al: Survival duration and complete remission (CR) incidence in advanced chronic lymphocytic leukemia (CLL). Blood 67: 229A, 1986 -->
 
<!-- Raphael BG, Silber R, Moore DF, et al: Survival duration and complete remission (CR) incidence in advanced chronic lymphocytic leukemia (CLL). Blood 67: 229A, 1986 -->
 
# '''ECOG E2480:''' Raphael B, Andersen JW, Silber R, Oken M, Moore D, Bennett J, Bonner H, Hahn R, Knospe WH, Mazza J, Glick J. Comparison of chlorambucil and prednisone versus cyclophosphamide, vincristine, and prednisone as initial treatment for chronic lymphocytic leukemia: long-term follow-up of an Eastern Cooperative Oncology Group randomized clinical trial. J Clin Oncol. 1991 May;9(5):770-6. [https://doi.org/10.1200/jco.1991.9.5.770 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/2016618 PubMed]
 
# '''ECOG E2480:''' Raphael B, Andersen JW, Silber R, Oken M, Moore D, Bennett J, Bonner H, Hahn R, Knospe WH, Mazza J, Glick J. Comparison of chlorambucil and prednisone versus cyclophosphamide, vincristine, and prednisone as initial treatment for chronic lymphocytic leukemia: long-term follow-up of an Eastern Cooperative Oncology Group randomized clinical trial. J Clin Oncol. 1991 May;9(5):770-6. [https://doi.org/10.1200/jco.1991.9.5.770 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/2016618 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
 
# '''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
−
 
 
==FC {{#subobject:42f3ac|Regimen=1}}==
 
==FC {{#subobject:42f3ac|Regimen=1}}==
−
 
 
FC: '''<u>F</u>'''ludarabine, '''<u>C</u>'''yclophosphamide
 
FC: '''<u>F</u>'''ludarabine, '''<u>C</u>'''yclophosphamide
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen variant #1, 75/750 (IV fludarabine) {{#subobject:ad1330|Variant=1}}===
 
===Regimen variant #1, 75/750 (IV fludarabine) {{#subobject:ad1330|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
Line 522: Line 521:
 
|}
 
|}
 
''<sup>1</sup>Reported efficacy for GCLLSG CLL8 is based on the updated 2016 results.''
 
''<sup>1</sup>Reported efficacy for GCLLSG CLL8 is based on the updated 2016 results.''
 +
<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
 
*[[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 over 30 to 60 minutes once per day on days 1 to 3
 
*[[Cyclophosphamide (Cytoxan)]] 250 mg/m<sup>2</sup> IV over 30 to 60 minutes once per day on days 1 to 3
−
 
 
====Supportive therapy====
 
====Supportive therapy====
 
*Per '''Robak et al. 2010''': "No routine prophylaxis with antibiotics, antiviral agents, or growth factors."
 
*Per '''Robak et al. 2010''': "No routine prophylaxis with antibiotics, antiviral agents, or growth factors."
−
 
 
'''28-day cycle for up to 6 cycles'''
 
'''28-day cycle for up to 6 cycles'''
−
 
+
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen variant #2, 90/750 {{#subobject:c2ddf9|Variant=1}}===
 
===Regimen variant #2, 90/750 {{#subobject:c2ddf9|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
Line 548: Line 547:
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 3
 
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 3
 
*[[Cyclophosphamide (Cytoxan)]] 250 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 3
 
*[[Cyclophosphamide (Cytoxan)]] 250 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 3
−
 
 
====Supportive therapy====
 
====Supportive therapy====
 
*No routine antibiotic, antiviral, or growth factor use
 
*No routine antibiotic, antiviral, or growth factor use
−
 
 
'''28-day cycle for up to 6 cycles'''
 
'''28-day cycle for up to 6 cycles'''
−
 
+
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen variant #3, 100/600 {{#subobject:447aa0|Variant=1}}===
 
===Regimen variant #3, 100/600 {{#subobject:447aa0|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
Line 572: Line 571:
 
|-
 
|-
 
|}
 
|}
−
''This regimen was intended for untreated patients greater than or equal to 18 years with a diagnosis of progressive CLL using the [[#NCI_Sponsored_Working_Group_Criteria_.281996.29|National Cancer Institute criteria]].''
+
''Note: This regimen was intended for untreated patients greater than or equal to 18 years with a diagnosis of progressive CLL using the [[#NCI_Sponsored_Working_Group_Criteria_.281996.29|National Cancer Institute criteria]].''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Fludarabine (Fludara)]] 20 mg/m<sup>2</sup> IV once per day on days 1 to 5
 
*[[Fludarabine (Fludara)]] 20 mg/m<sup>2</sup> IV once per day on days 1 to 5
 
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
−
 
 
'''28-day cycle for up to 6 cycles'''
 
'''28-day cycle for up to 6 cycles'''
−
 
+
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen variant #4, 120/750 (PO fludarabine) {{#subobject:20616|Variant=1}}===
 
===Regimen variant #4, 120/750 (PO fludarabine) {{#subobject:20616|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
Line 594: Line 594:
 
|-
 
|-
 
|}
 
|}
−
''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]].''
+
''Note: 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 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
 
*[[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
 
*[[Cyclophosphamide (Cytoxan)]] 250 mg/m<sup>2</sup> PO once per day on days 1 to 3
−
 
 
====Supportive therapy====
 
====Supportive therapy====
 
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS) | Cotrimoxazole]] 400/80 mg PO once per day until 6 months after end of treatment
 
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS) | Cotrimoxazole]] 400/80 mg PO once per day until 6 months after end of treatment
Line 604: Line 604:
 
**[[Acyclovir (Zovirax)]] 400 mg PO three times per day until 3 months after end of treatment
 
**[[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
 
**[[Valacyclovir (Valtrex)]] 500 mg PO twice per day until 3 months after end of treatment
−
 
 
'''28-day cycle for 6 cycles'''
 
'''28-day cycle for 6 cycles'''
−
 
+
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen variant #5, 120/750 (all PO) {{#subobject:470e55|Variant=1}}===
 
===Regimen variant #5, 120/750 (all PO) {{#subobject:470e55|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
Line 625: Line 625:
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Fludarabine (Fludara)]] 24 mg/m<sup>2</sup> PO once per day on days 1 to 5
 
*[[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> PO once per day on days 1 to 5
 
*[[Cyclophosphamide (Cytoxan)]] 150 mg/m<sup>2</sup> PO once per day on days 1 to 5
−
 
 
'''28-day cycle for up to 6 cycles'''
 
'''28-day cycle for up to 6 cycles'''
−
 
+
</div></div>
 
===References===
 
===References===
 
# '''GCLLSG CLL4:''' Eichhorst BF, Busch R, Hopfinger G, Pasold R, Hensel M, Steinbrecher C, Siehl S, Jäger U, Bergmann M, Stilgenbauer S, Schweighofer C, Wendtner CM, Döhner H, Brittinger G, Emmerich B, Hallek M; German CLL Study Group. Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood. 2006 Feb 1;107(3):885-91. Epub 2005 Oct 11. [http://www.bloodjournal.org/content/107/3/885.long link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/16219797 PubMed] NCT00276848
 
# '''GCLLSG CLL4:''' Eichhorst BF, Busch R, Hopfinger G, Pasold R, Hensel M, Steinbrecher C, Siehl S, Jäger U, Bergmann M, Stilgenbauer S, Schweighofer C, Wendtner CM, Döhner H, Brittinger G, Emmerich B, Hallek M; German CLL Study Group. Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood. 2006 Feb 1;107(3):885-91. Epub 2005 Oct 11. [http://www.bloodjournal.org/content/107/3/885.long link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/16219797 PubMed] NCT00276848
Line 646: Line 646:
 
<!-- 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. -->
 
<!-- 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. -->
 
# '''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
 
# '''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
−
 
 
==FCM {{#subobject:f6adfc|Regimen=1}}==
 
==FCM {{#subobject:f6adfc|Regimen=1}}==
−
 
 
FCM: '''<u>F</u>'''ludarabine, '''<u>C</u>'''yclophosphamide, '''<u>M</u>'''itoxantrone
 
FCM: '''<u>F</u>'''ludarabine, '''<u>C</u>'''yclophosphamide, '''<u>M</u>'''itoxantrone
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen variant #1 {{#subobject:e76bd1|Variant=1}}===
 
===Regimen variant #1 {{#subobject:e76bd1|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
Line 667: Line 665:
 
|}
 
|}
 
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
 
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Fludarabine (Fludara)]] 24 mg/m<sup>2</sup> PO once per day on days 1 to 5
 
*[[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> PO once per day on days 1 to 5
 
*[[Cyclophosphamide (Cytoxan)]] 150 mg/m<sup>2</sup> PO once per day on days 1 to 5
 
*[[Mitoxantrone (Novantrone)]] 6 mg/m<sup>2</sup> IV once on day 1
 
*[[Mitoxantrone (Novantrone)]] 6 mg/m<sup>2</sup> IV once on day 1
−
 
 
'''28-day cycle for 6 cycles'''
 
'''28-day cycle for 6 cycles'''
−
 
+
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen variant #2 {{#subobject:455511|Variant=1}}===
 
===Regimen variant #2 {{#subobject:455511|Variant=1}}===
 
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
Line 685: Line 684:
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Fludarabine (Fludara)]] 25 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 3
 
*[[Fludarabine (Fludara)]] 25 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 3
 
*[[Cyclophosphamide (Cytoxan)]] 200 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 3
 
*[[Cyclophosphamide (Cytoxan)]] 200 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 3
 
*[[Mitoxantrone (Novantrone)]] 6 mg/m<sup>2</sup> IV over 30 minutes once on day 1
 
*[[Mitoxantrone (Novantrone)]] 6 mg/m<sup>2</sup> IV over 30 minutes once on day 1
−
 
 
====Supportive therapy====
 
====Supportive therapy====
 
*[[:Category:Granulocyte_colony-stimulating_factors|Granulocyte colony-stimulating factor]] (type not specified) 300 mcg SC once per day on days 1 to 7
 
*[[:Category:Granulocyte_colony-stimulating_factors|Granulocyte colony-stimulating factor]] (type not specified) 300 mcg SC once per day on days 1 to 7
 
*[[Allopurinol (Zyloprim)]] 300 mg PO once per day on days 1 to 5
 
*[[Allopurinol (Zyloprim)]] 300 mg PO once per day on days 1 to 5
−
 
 
'''28-day cycle for 6 cycles'''
 
'''28-day cycle for 6 cycles'''
−
 
+
</div></div>
 
===References===
 
===References===
 
# Bosch F, Ferrer A, Villamor N, González M, Briones J, González-Barca E, Abella E, Gardella S, Escoda L, Pérez-Ceballos E, Asensi A, Sayas MJ, Font L, Altés A, Muntañola A, Bertazzoni P, Rozman M, Aymerich M, Giné E, Montserrat E. Fludarabine, cyclophosphamide, and mitoxantrone as initial therapy of chronic lymphocytic leukemia: high response rate and disease eradication. Clin Cancer Res. 2008 Jan 1;14(1):155-61. [https://doi.org/10.1158/1078-0432.CCR-07-1371 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18172266 PubMed]
 
# Bosch F, Ferrer A, Villamor N, González M, Briones J, González-Barca E, Abella E, Gardella S, Escoda L, Pérez-Ceballos E, Asensi A, Sayas MJ, Font L, Altés A, Muntañola A, Bertazzoni P, Rozman M, Aymerich M, Giné E, Montserrat E. Fludarabine, cyclophosphamide, and mitoxantrone as initial therapy of chronic lymphocytic leukemia: high response rate and disease eradication. Clin Cancer Res. 2008 Jan 1;14(1):155-61. [https://doi.org/10.1158/1078-0432.CCR-07-1371 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18172266 PubMed]
Line 703: Line 701:
 
-->
 
-->
 
# Hillmen P, Cohen DR, Cocks K, Pettitt A, Sayala HA, Rawstron AC, Kennedy DB, Fegan C, Milligan DW, Radford J, Mercieca J, Dearden C, Ezekwisili R, Smith AF, Brown J, Booth GA, Varghese AM, Pocock C; NCRI CLL Sub-Group. A randomized phase II trial of fludarabine, cyclophosphamide and mitoxantrone (FCM) with or without rituximab in previously treated chronic lymphocytic leukaemia. Br J Haematol. 2011 Mar;152(5):570-8. Epub 2011 Jan 14. [https://doi.org/10.1111/j.1365-2141.2010.08317.x link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21231927 PubMed]
 
# Hillmen P, Cohen DR, Cocks K, Pettitt A, Sayala HA, Rawstron AC, Kennedy DB, Fegan C, Milligan DW, Radford J, Mercieca J, Dearden C, Ezekwisili R, Smith AF, Brown J, Booth GA, Varghese AM, Pocock C; NCRI CLL Sub-Group. A randomized phase II trial of fludarabine, cyclophosphamide and mitoxantrone (FCM) with or without rituximab in previously treated chronic lymphocytic leukaemia. Br J Haematol. 2011 Mar;152(5):570-8. Epub 2011 Jan 14. [https://doi.org/10.1111/j.1365-2141.2010.08317.x link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21231927 PubMed]
−
 
 
==Fludarabine monotherapy {{#subobject:aaed0b|Regimen=1}}==
 
==Fludarabine monotherapy {{#subobject:aaed0b|Regimen=1}}==
−
 
 
F: '''<u>F</u>'''ludarabine
 
F: '''<u>F</u>'''ludarabine
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen variant #1, IV {{#subobject:63d019|Variant=1}}===
 
===Regimen variant #1, IV {{#subobject:63d019|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
Line 793: Line 790:
 
|}
 
|}
 
''<sup>1</sup>The superior endpoint in Johnson et al. 1996 was only observed in this subgroup, not pretreated patients.''<br>
 
''<sup>1</sup>The superior endpoint in Johnson et al. 1996 was only observed in this subgroup, not pretreated patients.''<br>
 +
<div class="toccolours" style="background-color:#fdcdac">
 
====Eligibility criteria====
 
====Eligibility criteria====
 
*CALGB 9011: intended for previously untreated patients with CLL who were high-risk ([[#Original_Rai_staging_.281975.29|Rai stage]] III or IV) or intermediate-risk ([[#Original_Rai_staging_.281975.29|Rai stage]] I or II) if they had at least one of the following: disease-related symptoms such as weight loss, extreme fatigue, night sweats, or fever without evidence of infection; massive or progressive splenomegaly or lymphadenopathy, or more than a 50 percent increase in the number of peripheral-blood lymphocytes over a 2-month period or an anticipated doubling of these cells within less than 12 months.  
 
*CALGB 9011: intended for previously untreated patients with CLL who were high-risk ([[#Original_Rai_staging_.281975.29|Rai stage]] III or IV) or intermediate-risk ([[#Original_Rai_staging_.281975.29|Rai stage]] I or II) if they had at least one of the following: disease-related symptoms such as weight loss, extreme fatigue, night sweats, or fever without evidence of infection; massive or progressive splenomegaly or lymphadenopathy, or more than a 50 percent increase in the number of peripheral-blood lymphocytes over a 2-month period or an anticipated doubling of these cells within less than 12 months.  
 
*ECOG E2997: intended for untreated patients greater than or equal to 18 years with a diagnosis of progressive CLL using the [[#NCI_Sponsored_Working_Group_Criteria_.281996.29|National Cancer Institute criteria]].''
 
*ECOG E2997: intended for untreated patients greater than or equal to 18 years with a diagnosis of progressive CLL using the [[#NCI_Sponsored_Working_Group_Criteria_.281996.29|National Cancer Institute criteria]].''
 
*GCLLSG CLL5: intended for untreated patients between 65 and 80 years with [[#Binet_staging_.281981.29|Binet stage]] C, or [[#Binet_staging_.281981.29|Binet stage]] B or A if they had rapid disease progression (lymphocyte doubling time less than 3 months) or symptoms from enlarged lymph nodes and organs, or if they had severe B symptoms.''
 
*GCLLSG CLL5: intended for untreated patients between 65 and 80 years with [[#Binet_staging_.281981.29|Binet stage]] C, or [[#Binet_staging_.281981.29|Binet stage]] B or A if they had rapid disease progression (lymphocyte doubling time less than 3 months) or symptoms from enlarged lymph nodes and organs, or if they had severe B symptoms.''
 +
</div>
 +
<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 5
 
*[[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'''
 
'''28-day cycle for up to 6 to 12 cycles'''
−
 
+
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen variant #2, PO {{#subobject:d44d0d|Variant=1}}===
 
===Regimen variant #2, PO {{#subobject:d44d0d|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
Line 820: Line 820:
 
|-
 
|-
 
|}
 
|}
 +
<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 5
 
*[[Fludarabine (Fludara)]] 40 mg/m<sup>2</sup> PO once per day on days 1 to 5
−
 
 
'''28-day cycle for up to 6 to 12 cycles'''
 
'''28-day cycle for up to 6 to 12 cycles'''
−
 
+
</div></div>
 
===References===
 
===References===
 
# Johnson S, Smith AG, Löffler H, Osby E, Juliusson G, Emmerich B, Wyld PJ, Hiddemann W; French Cooperative Group on 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]
 
# Johnson S, Smith AG, Löffler H, Osby E, Juliusson G, Emmerich B, Wyld PJ, Hiddemann W; French Cooperative Group on 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]
Line 841: Line 841:
 
<!-- # '''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] -->
 
<!-- # '''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
 
#'''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
−
 
 
==Fludarabine & Prednisone {{#subobject:d4f71b|Regimen=1}}==
 
==Fludarabine & Prednisone {{#subobject:d4f71b|Regimen=1}}==
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen {{#subobject:408021|Variant=1}}===
 
===Regimen {{#subobject:408021|Variant=1}}===
 
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
Line 855: Line 854:
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5
 
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5
 
====Glucocorticoid therapy====
 
====Glucocorticoid therapy====
 
*[[Prednisone (Sterapred)]] 30 mg/m<sup>2</sup> PO once per day on days 1 to 5
 
*[[Prednisone (Sterapred)]] 30 mg/m<sup>2</sup> PO once per day on days 1 to 5
−
 
 
'''28-day cycles'''
 
'''28-day cycles'''
−
 
+
</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]
 
# 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]
 
## '''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]
 
## '''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]
−
 
 
==Fludarabine & Rituximab (FR) {{#subobject:94f00c|Regimen=1}}==
 
==Fludarabine & Rituximab (FR) {{#subobject:94f00c|Regimen=1}}==
−
 
 
FR: '''<u>F</u>'''ludarabine, '''<u>R</u>'''ituximab
 
FR: '''<u>F</u>'''ludarabine, '''<u>R</u>'''ituximab
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen {{#subobject:4ee0e6|Variant=1}}===
 
===Regimen {{#subobject:4ee0e6|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
Line 885: Line 882:
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Fludarabine (Fludara)]] 25 mg/m<sup>2</sup> IV over 20 to 30 minutes once per day on days 1 to 5
 
*[[Fludarabine (Fludara)]] 25 mg/m<sup>2</sup> IV over 20 to 30 minutes once per day on days 1 to 5
Line 891: Line 889:
 
**Cycle 1: 375 mg/m<sup>2</sup> IV once per day on days 1 & 4  
 
**Cycle 1: 375 mg/m<sup>2</sup> IV once per day on days 1 & 4  
 
**Cycles 2 to 6: 375 mg/m<sup>2</sup> IV once on day 1
 
**Cycles 2 to 6: 375 mg/m<sup>2</sup> IV once on day 1
−
 
 
====Supportive therapy====
 
====Supportive therapy====
 
*Cycle 1: [[Allopurinol (Zyloprim)]] 300 mg PO once per day on days 1 to 14
 
*Cycle 1: [[Allopurinol (Zyloprim)]] 300 mg PO once per day on days 1 to 14
 
*[[Diphenhydramine (Benadryl)]] 50 mg IV once per infusion, 30 minutes prior to [[Rituximab (Rituxan)]]
 
*[[Diphenhydramine (Benadryl)]] 50 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)]]  
 
*[[Acetaminophen (Tylenol)]] 650 mg PO once per infusion, 30 minutes prior to [[Rituximab (Rituxan)]]  
−
 
 
'''28-day cycle for 6 cycles'''
 
'''28-day cycle for 6 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 
====Subsequent treatment====
 
====Subsequent treatment====
 
*If restaging done 2 months after 6 cycles of therapy shows SD or better: [[Chronic_lymphocytic_leukemia#Rituximab_monotherapy_2|Rituximab]] consolidation
 
*If restaging done 2 months after 6 cycles of therapy shows SD or better: [[Chronic_lymphocytic_leukemia#Rituximab_monotherapy_2|Rituximab]] consolidation
−
 
+
</div></div>
 
===References===
 
===References===
 
<!-- Byrd JC, Peterson B, Park K, Morrison V, Vardiman JW, Jacobson RJ, et al. Rituximab added to fludarabine improves response in previously untreated chronic lymphocytic leukemia: preliminary results from CALGB 9712. Journal of Clinical Oncology 2001;20 (Pt 1):280a. -->
 
<!-- Byrd JC, Peterson B, Park K, Morrison V, Vardiman JW, Jacobson RJ, et al. Rituximab added to fludarabine improves response in previously untreated chronic lymphocytic leukemia: preliminary results from CALGB 9712. Journal of Clinical Oncology 2001;20 (Pt 1):280a. -->
Line 907: Line 905:
 
## '''Update:''' Byrd JC, Rai K, Peterson BL, Appelbaum FR, Morrison VA, Kolitz JE, Shepherd L, Hines JD, Schiffer CA, Larson RA. Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and CALGB 9011. Blood. 2005 Jan 1;105(1):49-53. Epub 2004 May 11. [http://www.bloodjournal.org/content/105/1/49.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/15138165 PubMed]
 
## '''Update:''' Byrd JC, Rai K, Peterson BL, Appelbaum FR, Morrison VA, Kolitz JE, Shepherd L, Hines JD, Schiffer CA, Larson RA. Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and CALGB 9011. Blood. 2005 Jan 1;105(1):49-53. Epub 2004 May 11. [http://www.bloodjournal.org/content/105/1/49.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/15138165 PubMed]
 
## '''Update:''' Woyach JA, Ruppert AS, Heerema NA, Peterson BL, Gribben JG, Morrison VA, Rai KR, Larson RA, Byrd JC. Chemoimmunotherapy with fludarabine and rituximab produces extended overall survival and progression-free survival in chronic lymphocytic leukemia: long-term follow-up of CALGB study 9712. J Clin Oncol. 2011 Apr 1;29(10):1349-55. Epub 2011 Feb 14. [https://doi.org/10.1200/jco.2010.31.1811 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3084002/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21321292 PubMed]
 
## '''Update:''' Woyach JA, Ruppert AS, Heerema NA, Peterson BL, Gribben JG, Morrison VA, Rai KR, Larson RA, Byrd JC. Chemoimmunotherapy with fludarabine and rituximab produces extended overall survival and progression-free survival in chronic lymphocytic leukemia: long-term follow-up of CALGB study 9712. J Clin Oncol. 2011 Apr 1;29(10):1349-55. Epub 2011 Feb 14. [https://doi.org/10.1200/jco.2010.31.1811 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3084002/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21321292 PubMed]
−
 
 
==Idelalisib & Rituximab {{#subobject:7bacdd|Regimen=1}}==
 
==Idelalisib & Rituximab {{#subobject:7bacdd|Regimen=1}}==
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen {{#subobject:33cbcc|Variant=1}}===
 
===Regimen {{#subobject:33cbcc|Variant=1}}===
 
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
Line 922: Line 919:
 
|}
 
|}
 
''Note: In a letter dated 3/21/2016, Gilead states that idelalisib should '''not''' be used for first line treatment of CLL.''
 
''Note: In a letter dated 3/21/2016, Gilead states that idelalisib should '''not''' be used for first line treatment of CLL.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Targeted therapy====
 
====Targeted therapy====
 
*[[Idelalisib (Zydelig)]] 150 mg PO twice per day
 
*[[Idelalisib (Zydelig)]] 150 mg PO twice per day
 
*[[Rituximab (Rituxan)]] as follows:
 
*[[Rituximab (Rituxan)]] as follows:
 
**Cycles 1 & 2: 375 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 
**Cycles 1 & 2: 375 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
−
 
 
'''28-day cycle for 12 cycles'''
 
'''28-day cycle for 12 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 
====Subsequent treatment====
 
====Subsequent treatment====
 
*Patients who had not progressed could continue on an extension study
 
*Patients who had not progressed could continue on an extension study
−
 
+
</div></div>
 
===References===
 
===References===
 
<!-- # '''Abstract:''' Susan Mary O'Brien, Nicole Lamanna, Thomas J. Kipps, Ian Flinn, Andrew David Zelenetz, Jan Andreas Burger, Leanne Holes, David Michael Johnson, Jessie Gu, Roger D. Dansey, Ronald L. Dubowy, Steven E. Coutre. A phase II study of the selective phosphatidylinositol 3-kinase delta (PI3Kd) inhibitor idelalisib (GS-1101) in combination with rituximab (R) in treatment-naive patients (pts) ≥65 years with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). J Clin Oncol 31, 2013 (suppl; abstr 7005) [http://meetinglibrary.asco.org/content/117245-132 link to abstract] -->
 
<!-- # '''Abstract:''' Susan Mary O'Brien, Nicole Lamanna, Thomas J. Kipps, Ian Flinn, Andrew David Zelenetz, Jan Andreas Burger, Leanne Holes, David Michael Johnson, Jessie Gu, Roger D. Dansey, Ronald L. Dubowy, Steven E. Coutre. A phase II study of the selective phosphatidylinositol 3-kinase delta (PI3Kd) inhibitor idelalisib (GS-1101) in combination with rituximab (R) in treatment-naive patients (pts) ≥65 years with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). J Clin Oncol 31, 2013 (suppl; abstr 7005) [http://meetinglibrary.asco.org/content/117245-132 link to abstract] -->
 
# '''Study 101-08:''' O'Brien SM, Lamanna N, Kipps TJ, Flinn I, Zelenetz AD, Burger JA, Keating M, Mitra S, Holes L, Yu AS, Johnson DM, Miller LL, Kim Y, Dansey RD, Dubowy RL, Coutre SE. A phase 2 study of idelalisib plus rituximab in treatment-naïve older patients with chronic lymphocytic leukemia. Blood. 2015 Dec 17;126(25):2686-94. Epub 2015 Oct 15. [http://www.bloodjournal.org/content/126/25/2686.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4732760/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26472751 PubMed] NCT01203930
 
# '''Study 101-08:''' O'Brien SM, Lamanna N, Kipps TJ, Flinn I, Zelenetz AD, Burger JA, Keating M, Mitra S, Holes L, Yu AS, Johnson DM, Miller LL, Kim Y, Dansey RD, Dubowy RL, Coutre SE. A phase 2 study of idelalisib plus rituximab in treatment-naïve older patients with chronic lymphocytic leukemia. Blood. 2015 Dec 17;126(25):2686-94. Epub 2015 Oct 15. [http://www.bloodjournal.org/content/126/25/2686.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4732760/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26472751 PubMed] NCT01203930
−
 
 
==Lenalidomide monotherapy {{#subobject:9820ba|Regimen=1}}==
 
==Lenalidomide monotherapy {{#subobject:9820ba|Regimen=1}}==
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen variant #1, target 10 mg/day {{#subobject:2c7fe5|Variant=1}}===
 
===Regimen variant #1, target 10 mg/day {{#subobject:2c7fe5|Variant=1}}===
 
{| class="wikitable" style="width: 60%; text-align:center;"  
 
{| class="wikitable" style="width: 60%; text-align:center;"  
Line 948: Line 946:
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Targeted therapy====
 
====Targeted therapy====
 
*[[Lenalidomide (Revlimid)]] as follows:
 
*[[Lenalidomide (Revlimid)]] as follows:
Line 953: Line 952:
 
**Cycle 2: Increased if tolerated to 5 mg PO once per day on days 1 to 21  
 
**Cycle 2: Increased if tolerated to 5 mg PO once per day on days 1 to 21  
 
**Cycle 3 onwards: Increased if tolerated to 10 mg PO once per day on days 1 to 21
 
**Cycle 3 onwards: Increased if tolerated to 10 mg PO once per day on days 1 to 21
−
 
 
====Supportive therapy====
 
====Supportive therapy====
 
*[[Aspirin]] 81 mg PO once per day
 
*[[Aspirin]] 81 mg PO once per day
−
 
 
'''28-day cycles'''
 
'''28-day cycles'''
−
 
+
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen variant #2, target 15 mg/day {{#subobject:a6761e|Variant=1}}===
 
===Regimen variant #2, target 15 mg/day {{#subobject:a6761e|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"
Line 975: Line 973:
 
|}
 
|}
 
''Note: this is an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have been previously published with encouraging non-randomized results.''
 
''Note: this is an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have been previously published with encouraging non-randomized results.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Targeted therapy====
 
====Targeted therapy====
 
*[[Lenalidomide (Revlimid)]] 5 mg PO once per day, increased to a target dose of 15 mg PO once per day  
 
*[[Lenalidomide (Revlimid)]] 5 mg PO once per day, increased to a target dose of 15 mg PO once per day  
−
 
 
'''Continued indefinitely'''
 
'''Continued indefinitely'''
−
 
+
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen variant #3, target 25 mg/day {{#subobject:3acdbb|Variant=1}}===
 
===Regimen variant #3, target 25 mg/day {{#subobject:3acdbb|Variant=1}}===
 
{| class="wikitable" style="width: 60%; text-align:center;"  
 
{| class="wikitable" style="width: 60%; text-align:center;"  
Line 991: Line 990:
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Targeted therapy====
 
====Targeted therapy====
 
*[[Lenalidomide (Revlimid)]] 5 mg PO once per day on days 1 to 56, then increased to a target dose of 25 mg PO once per day  
 
*[[Lenalidomide (Revlimid)]] 5 mg PO once per day on days 1 to 56, then increased to a target dose of 25 mg PO once per day  
−
 
 
'''Continued indefinitely'''
 
'''Continued indefinitely'''
−
 
+
</div></div>
 
===References===
 
===References===
 
<!-- Presented in part at the 49th Annual Meeting of the American Society of Hematology, December 7-11, 2007, Atlanta, GA; at the 50th Annual Meeting of the American Society of Hematology, December 6-9, 2008, San Francisco, CA; and at the International Workshop for CLL October 16-18, 2009, Barcelona, Spain. -->
 
<!-- Presented in part at the 49th Annual Meeting of the American Society of Hematology, December 7-11, 2007, Atlanta, GA; at the 50th Annual Meeting of the American Society of Hematology, December 6-9, 2008, San Francisco, CA; and at the International Workshop for CLL October 16-18, 2009, Barcelona, Spain. -->
Line 1,004: Line 1,003:
 
## '''Update:''' Strati P, Keating MJ, Wierda WG, Badoux XC, Calin S, Reuben JM, O'Brien S, Kornblau SM, Kantarjian HM, Gao H, Ferrajoli A. Lenalidomide induces long-lasting responses in elderly patients with chronic lymphocytic leukemia. Blood. 2013 Aug 1;122(5):734-7. Epub 2013 Jun 25. [http://www.bloodjournal.org/content/122/5/734.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123325/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23801633 PubMed]
 
## '''Update:''' Strati P, Keating MJ, Wierda WG, Badoux XC, Calin S, Reuben JM, O'Brien S, Kornblau SM, Kantarjian HM, Gao H, Ferrajoli A. Lenalidomide induces long-lasting responses in elderly patients with chronic lymphocytic leukemia. Blood. 2013 Aug 1;122(5):734-7. Epub 2013 Jun 25. [http://www.bloodjournal.org/content/122/5/734.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123325/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23801633 PubMed]
 
# '''ORIGIN:''' Chanan-Khan A, Egyed M, Robak T, Martinelli de Oliveira FA, Echeveste MA, Dolan S, Desjardins P, Blonski JZ, Mei J, Golany N, Zhang J, Gribben JG. Randomized phase 3 study of lenalidomide versus chlorambucil as first-line therapy for older patients with chronic lymphocytic leukemia (the ORIGIN trial). Leukemia. 2017 May;31(5):1240-1243. Epub 2017 Jan 31. [https://www.nature.com/articles/leu201747 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5420789/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28140392 PubMed] NCT00910910
 
# '''ORIGIN:''' Chanan-Khan A, Egyed M, Robak T, Martinelli de Oliveira FA, Echeveste MA, Dolan S, Desjardins P, Blonski JZ, Mei J, Golany N, Zhang J, Gribben JG. Randomized phase 3 study of lenalidomide versus chlorambucil as first-line therapy for older patients with chronic lymphocytic leukemia (the ORIGIN trial). Leukemia. 2017 May;31(5):1240-1243. Epub 2017 Jan 31. [https://www.nature.com/articles/leu201747 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5420789/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28140392 PubMed] NCT00910910
−
 
 
==R-FCM {{#subobject:290a43|Regimen=1}}==
 
==R-FCM {{#subobject:290a43|Regimen=1}}==
−
 
 
R-FCM: '''<u>R</u>'''ituximab, '''<u>F</u>'''ludarabine, '''<u>C</u>'''yclophosphamide, '''<u>M</u>'''itoxantrone  
 
R-FCM: '''<u>R</u>'''ituximab, '''<u>F</u>'''ludarabine, '''<u>C</u>'''yclophosphamide, '''<u>M</u>'''itoxantrone  
 
<br>FCM-R: '''<u>F</u>'''ludarabine, '''<u>C</u>'''yclophosphamide, '''<u>M</u>'''itoxantrone, '''<u>R</u>'''ituximab
 
<br>FCM-R: '''<u>F</u>'''ludarabine, '''<u>C</u>'''yclophosphamide, '''<u>M</u>'''itoxantrone, '''<u>R</u>'''ituximab
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen variant #1 {{#subobject:73c565|Variant=1}}===
 
===Regimen variant #1 {{#subobject:73c565|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
Line 1,024: Line 1,022:
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Targeted therapy====
 
====Targeted therapy====
 
*[[Rituximab (Rituxan)]] as follows:
 
*[[Rituximab (Rituxan)]] as follows:
Line 1,032: Line 1,031:
 
*[[Cyclophosphamide (Cytoxan)]] 150 mg/m<sup>2</sup> PO once per day on days 1 to 5
 
*[[Cyclophosphamide (Cytoxan)]] 150 mg/m<sup>2</sup> PO once per day on days 1 to 5
 
*[[Mitoxantrone (Novantrone)]] 6 mg/m<sup>2</sup> IV once on day 1
 
*[[Mitoxantrone (Novantrone)]] 6 mg/m<sup>2</sup> IV once on day 1
−
 
 
'''28-day cycle for 6 cycles'''
 
'''28-day cycle for 6 cycles'''
−
 
+
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen variant #2 {{#subobject:63498|Variant=1}}===
 
===Regimen variant #2 {{#subobject:63498|Variant=1}}===
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
Line 1,044: Line 1,043:
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Targeted therapy====
 
====Targeted therapy====
 
*[[Rituximab (Rituxan)]] as follows:
 
*[[Rituximab (Rituxan)]] as follows:
Line 1,052: Line 1,052:
 
*[[Cyclophosphamide (Cytoxan)]] 200 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 3
 
*[[Cyclophosphamide (Cytoxan)]] 200 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 3
 
*[[Mitoxantrone (Novantrone)]] 6 mg/m<sup>2</sup> IV over 30 minutes once on day 1
 
*[[Mitoxantrone (Novantrone)]] 6 mg/m<sup>2</sup> IV over 30 minutes once on day 1
−
 
 
====Supportive therapy====
 
====Supportive therapy====
 
*[[:Category:Granulocyte_colony-stimulating_factors|Pegylated granulocyte colony-stimulating factor]] once on day 4
 
*[[:Category:Granulocyte_colony-stimulating_factors|Pegylated granulocyte colony-stimulating factor]] once on day 4
 
*[[Allopurinol (Zyloprim)]] 300 mg PO once per day on days 1 to 5
 
*[[Allopurinol (Zyloprim)]] 300 mg PO once per day on days 1 to 5
 
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] (dose not specified) PO twice per week for up to 9 months after completion of therapy
 
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] (dose not specified) PO twice per week for up to 9 months after completion of therapy
−
 
 
'''28-day cycle for 6 cycles'''
 
'''28-day cycle for 6 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 
====Subsequent treatment====
 
====Subsequent treatment====
 
*Patients with a PR or CR at 3 months: [[#Rituximab_monotherapy_2|Rituximab]] maintenance
 
*Patients with a PR or CR at 3 months: [[#Rituximab_monotherapy_2|Rituximab]] maintenance
−
 
+
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen variant #3 {{#subobject:523a98|Variant=1}}===
 
===Regimen variant #3 {{#subobject:523a98|Variant=1}}===
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
Line 1,071: Line 1,072:
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Targeted therapy====
 
====Targeted therapy====
 
*[[Rituximab (Rituxan)]] as follows:
 
*[[Rituximab (Rituxan)]] as follows:
Line 1,085: Line 1,087:
 
**Cycle 1: 6 mg/m<sup>2</sup> IV once on day 2
 
**Cycle 1: 6 mg/m<sup>2</sup> IV once on day 2
 
**Cycles 2 to 6: 6 mg/m<sup>2</sup> IV once on day 2
 
**Cycles 2 to 6: 6 mg/m<sup>2</sup> IV once on day 2
−
 
 
====Supportive therapy====
 
====Supportive therapy====
 
*[[Acetaminophen (Tylenol)]] 650 mg PO once on day 1, prior to [[Rituximab (Rituxan)]]
 
*[[Acetaminophen (Tylenol)]] 650 mg PO once on day 1, prior to [[Rituximab (Rituxan)]]
Line 1,093: Line 1,094:
 
*[[:Category:Antivirals|Antiviral]] prophylaxis was at the physician's discretion
 
*[[:Category:Antivirals|Antiviral]] prophylaxis was at the physician's discretion
 
*[[:Category:PCP prophylaxis|PCP]] prophylaxis was at the physician's discretion
 
*[[:Category:PCP prophylaxis|PCP]] prophylaxis was at the physician's discretion
−
 
 
'''4- to 6-week cycle for up to 6 cycles'''
 
'''4- to 6-week cycle for up to 6 cycles'''
−
 
+
</div></div>
 
===References===
 
===References===
 
<!-- Presented in part at the 43rd Annual Meeting of the American Society of Hematology, December 8-11, 2007, Atlanta, GA. -->
 
<!-- Presented in part at the 43rd Annual Meeting of the American Society of Hematology, December 8-11, 2007, Atlanta, GA. -->
Line 1,107: Line 1,107:
 
# '''NCRI CLL201:''' Hillmen P, Cohen DR, Cocks K, Pettitt A, Sayala HA, Rawstron AC, Kennedy DB, Fegan C, Milligan DW, Radford J, Mercieca J, Dearden C, Ezekwisili R, Smith AF, Brown J, Booth GA, Varghese AM, Pocock C; NCRI CLL Sub-Group. A randomized phase II trial of fludarabine, cyclophosphamide and mitoxantrone (FCM) with or without rituximab in previously treated chronic lymphocytic leukaemia. Br J Haematol. 2011 Mar;152(5):570-8. Epub 2011 Jan 14. [https://doi.org/10.1111/j.1365-2141.2010.08317.x link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21231927 PubMed]
 
# '''NCRI CLL201:''' Hillmen P, Cohen DR, Cocks K, Pettitt A, Sayala HA, Rawstron AC, Kennedy DB, Fegan C, Milligan DW, Radford J, Mercieca J, Dearden C, Ezekwisili R, Smith AF, Brown J, Booth GA, Varghese AM, Pocock C; NCRI CLL Sub-Group. A randomized phase II trial of fludarabine, cyclophosphamide and mitoxantrone (FCM) with or without rituximab in previously treated chronic lymphocytic leukaemia. Br J Haematol. 2011 Mar;152(5):570-8. Epub 2011 Jan 14. [https://doi.org/10.1111/j.1365-2141.2010.08317.x link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21231927 PubMed]
 
# '''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] [https://pubmed.ncbi.nlm.nih.gov/28216660 PubMed] ISRCTN42165735
 
# '''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] [https://pubmed.ncbi.nlm.nih.gov/28216660 PubMed] ISRCTN42165735
−
 
 
==Uracil mustard monotherapy {{#subobject:6440d3|Regimen=1}}==
 
==Uracil mustard monotherapy {{#subobject:6440d3|Regimen=1}}==
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen {{#subobject:969dcc|Variant=1}}===
 
===Regimen {{#subobject:969dcc|Variant=1}}===
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
Line 1,119: Line 1,118:
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Uracil mustard]]
 
*[[Uracil mustard]]
 +
</div></div>
 
===References===
 
===References===
 
# Kennedy BJ, Theologides A. Uracil mustard, a new alkylating agent for oral administration in the management of patients with leukemia and lymphoma. N Engl J Med. 1961 Apr 20;264:790-3. [https://doi.org/10.1056/NEJM196104202641603 link to original article] [https://pubmed.ncbi.nlm.nih.gov/13752496 PubMed]
 
# Kennedy BJ, Theologides A. Uracil mustard, a new alkylating agent for oral administration in the management of patients with leukemia and lymphoma. N Engl J Med. 1961 Apr 20;264:790-3. [https://doi.org/10.1056/NEJM196104202641603 link to original article] [https://pubmed.ncbi.nlm.nih.gov/13752496 PubMed]
−
 
 
=Subsequent lines of therapy=
 
=Subsequent lines of therapy=
 
==CAP {{#subobject:6f74d0|Regimen=1}}==
 
==CAP {{#subobject:6f74d0|Regimen=1}}==
−
 
 
CAP: '''<u>C</u>'''yclophosphamide, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>P</u>'''rednisone
 
CAP: '''<u>C</u>'''yclophosphamide, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>P</u>'''rednisone
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen {{#subobject:e29575|Variant=1}}===
 
===Regimen {{#subobject:e29575|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
Line 1,144: Line 1,144:
 
|}
 
|}
 
''<sup>1</sup>The inferior endpoint in Johnson et al. 1996 was only observed in this subgroup, not untreated patients.''
 
''<sup>1</sup>The inferior endpoint in Johnson et al. 1996 was only observed in this subgroup, not untreated patients.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Cyclophosphamide (Cytoxan)]] 750 mg/m<sup>2</sup> IV once on day 1
 
*[[Cyclophosphamide (Cytoxan)]] 750 mg/m<sup>2</sup> IV once on day 1
Line 1,149: Line 1,150:
 
====Glucocorticoid therapy====
 
====Glucocorticoid therapy====
 
*[[Prednisone (Sterapred)]] 40 mg/m<sup>2</sup> PO once per day on days 1 to 5
 
*[[Prednisone (Sterapred)]] 40 mg/m<sup>2</sup> PO once per day on days 1 to 5
−
 
 
'''1-month cycle for 6 cycles'''
 
'''1-month cycle for 6 cycles'''
−
 
+
</div></div>
 
===References===
 
===References===
 
# Johnson S, Smith AG, Löffler H, Osby E, Juliusson G, Emmerich B, Wyld PJ, Hiddemann W; French Cooperative Group on 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]
 
# Johnson S, Smith AG, Löffler H, Osby E, Juliusson G, Emmerich B, Wyld PJ, Hiddemann W; French Cooperative Group on 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]
−
 
 
==Fludarabine monotherapy {{#subobject:005c85|Regimen=1}}==
 
==Fludarabine monotherapy {{#subobject:005c85|Regimen=1}}==
−
 
 
F: '''<u>F</u>'''ludarabine
 
F: '''<u>F</u>'''ludarabine
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen {{#subobject:f9937b|Variant=1}}===
 
===Regimen {{#subobject:f9937b|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
Line 1,186: Line 1,185:
 
|}
 
|}
 
''<sup>1</sup>The superior endpoint in Johnson et al. 1996 was only observed in this subgroup, not untreated patients.''
 
''<sup>1</sup>The superior endpoint in Johnson et al. 1996 was only observed in this subgroup, not untreated patients.''
 +
<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 5
 
*[[Fludarabine (Fludara)]] 25 mg/m<sup>2</sup> IV once per day on days 1 to 5
−
 
 
'''28-day cycle for 6 cycles'''
 
'''28-day cycle for 6 cycles'''
 +
</div></div>
 
===References===
 
===References===
 
# Keating MJ, Kantarjian H, Talpaz M, Redman J, Koller C, Barlogie B, Velasquez W, Plunkett W, Freireich EJ, McCredie KB. Fludarabine: a new agent with major activity against chronic lymphocytic leukemia. Blood. 1989 Jul;74(1):19-25. [http://www.bloodjournal.org/content/74/1/19.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/2473795 PubMed]
 
# Keating MJ, Kantarjian H, Talpaz M, Redman J, Koller C, Barlogie B, Velasquez W, Plunkett W, Freireich EJ, McCredie KB. Fludarabine: a new agent with major activity against chronic lymphocytic leukemia. Blood. 1989 Jul;74(1):19-25. [http://www.bloodjournal.org/content/74/1/19.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/2473795 PubMed]
 
# Grever M, Leiby J, Kraut E, Metz E, Neidhart J, Balcerzak S, Malspeis L. A comprehensive phase I and II clinical investigation of fludarabine phosphate. Semin Oncol. 1990 Oct;17(5 Suppl 8):39-48. [https://pubmed.ncbi.nlm.nih.gov/1699282 PubMed]
 
# Grever M, Leiby J, Kraut E, Metz E, Neidhart J, Balcerzak S, Malspeis L. A comprehensive phase I and II clinical investigation of fludarabine phosphate. Semin Oncol. 1990 Oct;17(5 Suppl 8):39-48. [https://pubmed.ncbi.nlm.nih.gov/1699282 PubMed]
 
# Johnson S, Smith AG, Löffler H, Osby E, Juliusson G, Emmerich B, Wyld PJ, Hiddemann W; French Cooperative Group on 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]
 
# Johnson S, Smith AG, Löffler H, Osby E, Juliusson G, Emmerich B, Wyld PJ, Hiddemann W; French Cooperative Group on 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]
−
 
 
==FC {{#subobject:dc4000|Regimen=1}}==
 
==FC {{#subobject:dc4000|Regimen=1}}==
−
 
 
FC: '''<u>F</u>'''ludarabine, '''<u>C</u>'''yclophosphamide
 
FC: '''<u>F</u>'''ludarabine, '''<u>C</u>'''yclophosphamide
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen {{#subobject:7baff0|Variant=1}}===
 
===Regimen {{#subobject:7baff0|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
Line 1,227: Line 1,225:
 
|}
 
|}
 
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm '''in this context'''.''
 
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm '''in this context'''.''
 +
<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
 
*[[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
 
*[[Cyclophosphamide (Cytoxan)]] 250 mg/m<sup>2</sup> IV once per day on days 1 to 3
−
 
 
====Supportive therapy====
 
====Supportive therapy====
 
*''Note: varied according to reference.''
 
*''Note: varied according to reference.''
Line 1,237: Line 1,235:
 
**[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] 160/800 mg PO twice per week
 
**[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] 160/800 mg PO twice per week
 
**[[Valacyclovir (Valtrex)]] 500 mg PO once per day
 
**[[Valacyclovir (Valtrex)]] 500 mg PO once per day
−
 
 
'''28-day cycle for 6 cycles'''
 
'''28-day cycle for 6 cycles'''
−
 
+
</div></div>
 
===References===
 
===References===
 
# '''GENTA GL303:''' O'Brien S, Moore JO, Boyd TE, Larratt LM, Skotnicki A, Koziner B, Chanan-Khan AA, Seymour JF, Bociek RG, Pavletic S, Rai KR. Randomized phase III trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2007 Mar 20;25(9):1114-20. Epub 2007 Feb 12. Erratum in: J Clin Oncol. 2008 Feb 10;26(5):820. [https://doi.org/10.1200/JCO.2006.07.1191 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/17296974 PubMed] NCT00024440
 
# '''GENTA GL303:''' O'Brien S, Moore JO, Boyd TE, Larratt LM, Skotnicki A, Koziner B, Chanan-Khan AA, Seymour JF, Bociek RG, Pavletic S, Rai KR. Randomized phase III trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2007 Mar 20;25(9):1114-20. Epub 2007 Feb 12. Erratum in: J Clin Oncol. 2008 Feb 10;26(5):820. [https://doi.org/10.1200/JCO.2006.07.1191 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/17296974 PubMed] NCT00024440
Line 1,246: Line 1,243:
 
# '''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 abstract''' [https://pubmed.ncbi.nlm.nih.gov/20194844 PubMed] content property of [http://hemonc.org HemOnc.org] NCT00090051
 
# '''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 abstract''' [https://pubmed.ncbi.nlm.nih.gov/20194844 PubMed] content property of [http://hemonc.org HemOnc.org] NCT00090051
 
# '''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] [https://pubmed.ncbi.nlm.nih.gov/27731748 PubMed] NCT00824265
 
# '''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] [https://pubmed.ncbi.nlm.nih.gov/27731748 PubMed] NCT00824265
−
 
 
==HDMP {{#subobject:1c202|Regimen=1}}==
 
==HDMP {{#subobject:1c202|Regimen=1}}==
−
 
 
HDMP: '''<u>H</u>'''igh '''<u>D</u>'''ose, '''<u>M</u>'''ethyl'''<u>P</u>'''rednisolone
 
HDMP: '''<u>H</u>'''igh '''<u>D</u>'''ose, '''<u>M</u>'''ethyl'''<u>P</u>'''rednisolone
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen {{#subobject:38a97d|Variant=1}}===
 
===Regimen {{#subobject:38a97d|Variant=1}}===
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
Line 1,259: Line 1,255:
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Glucocorticoid therapy====
 
====Glucocorticoid therapy====
 
*[[Methylprednisolone (Solumedrol)]]
 
*[[Methylprednisolone (Solumedrol)]]
 +
</div></div>
 
===References===
 
===References===
 
# Burningham RA, Restrepo A, Pugh RP, Brown EB, Schlossman SF, Khuri PD, Lessner HE, Harrington WJ. Weekly high-dosage glucocorticosteroid treatment of lymphocytic leukemias and lymphomas. N Engl J Med. 1964 May 28;270:1160-6. [https://doi.org/10.1056/NEJM196405282702205 link to original article] [https://pubmed.ncbi.nlm.nih.gov/14129063 PubMed]
 
# Burningham RA, Restrepo A, Pugh RP, Brown EB, Schlossman SF, Khuri PD, Lessner HE, Harrington WJ. Weekly high-dosage glucocorticosteroid treatment of lymphocytic leukemias and lymphomas. N Engl J Med. 1964 May 28;270:1160-6. [https://doi.org/10.1056/NEJM196405282702205 link to original article] [https://pubmed.ncbi.nlm.nih.gov/14129063 PubMed]
−
 
 
==Tisagenlecleucel monotherapy {{#subobject:d68f14|Regimen=1}}==
 
==Tisagenlecleucel monotherapy {{#subobject:d68f14|Regimen=1}}==
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen {{#subobject:60fc19|Variant=1}}===
 
===Regimen {{#subobject:60fc19|Variant=1}}===
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
Line 1,276: Line 1,273:
 
|}
 
|}
 
''Note: this regimen is of historic interest in this context, this being the first clinical use of CAR-T-cell therapy. It is not FDA approved for this indication.''
 
''Note: this regimen is of historic interest in this context, this being the first clinical use of CAR-T-cell therapy. It is not FDA approved for this indication.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Immunotherapy====
 
====Immunotherapy====
 
*[[Tisagenlecleucel (Kymriah)]]  
 
*[[Tisagenlecleucel (Kymriah)]]  
−
 
+
</div></div>
 
===References===
 
===References===
 
# Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011 Aug 25;365(8):725-33. Epub 2011 Aug 10. Erratum in: N Engl J Med. 2016 Mar 10;374(10):998. [https://doi.org/10.1056/NEJMoa1103849 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3387277/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21830940 PubMed]
 
# Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011 Aug 25;365(8):725-33. Epub 2011 Aug 10. Erratum in: N Engl J Med. 2016 Mar 10;374(10):998. [https://doi.org/10.1056/NEJMoa1103849 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3387277/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21830940 PubMed]
 
## '''Update:''' Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A, June CH. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med. 2011 Aug 10;3(95):95ra73. [http://stm.sciencemag.org/content/3/95/95ra73.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3393096/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21832238 PubMed]
 
## '''Update:''' Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A, June CH. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med. 2011 Aug 10;3(95):95ra73. [http://stm.sciencemag.org/content/3/95/95ra73.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3393096/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21832238 PubMed]
 
## '''Update:''' Porter DL, Hwang WT, Frey NV, Lacey SF, Shaw PA, Loren AW, Bagg A, Marcucci KT, Shen A, Gonzalez V, Ambrose D, Grupp SA, Chew A, Zheng Z, Milone MC, Levine BL, Melenhorst JJ, June CH. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 2015 Sep 2;7(303):303ra139. [http://stm.sciencemag.org/content/7/303/303ra139.short link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5909068/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26333935 PubMed]
 
## '''Update:''' Porter DL, Hwang WT, Frey NV, Lacey SF, Shaw PA, Loren AW, Bagg A, Marcucci KT, Shen A, Gonzalez V, Ambrose D, Grupp SA, Chew A, Zheng Z, Milone MC, Levine BL, Melenhorst JJ, June CH. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 2015 Sep 2;7(303):303ra139. [http://stm.sciencemag.org/content/7/303/303ra139.short link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5909068/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26333935 PubMed]
−
 
 
[[Category:Chronic lymphocytic leukemia regimens]]
 
[[Category:Chronic lymphocytic leukemia regimens]]
 
[[Category:Historical regimens]]
 
[[Category:Historical regimens]]
 
[[Category:Disease-specific pages]]
 
[[Category:Disease-specific pages]]
 
[[Category:Indolent lymphomas]]
 
[[Category:Indolent lymphomas]]

Revision as of 13:24, 22 January 2023

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The purpose of this page is to provide references to regimens that are obsolete, outdated, or of historical interest only. As a general rule, this includes the inferior arm(s) of a randomized study, unless said regimens continue to be recommended by trustworthy sources such as the NCCN Guidelines. Is there a regimen missing from this list? Please go to the main CLL/SLL regimen page to find other regimens.

22 regimens on this page
42 variants on this page


First-line therapy

CAP

CAP: Cyclophosphamide, Adriamycin (Doxorubicin), Prednisone

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Keating et al. 1990 (SWOG-7410) 1974-1979 Phase 2
Johnson et al. 1996 1990-1992 Phase 3 (C) Fludarabine Inferior TTP1
Leporrier et al. 2001 (FCGCLL 1996) 1990-1998 Phase 3 (C) 1. CHOP Did not meet primary endpoint of OS
2. Fludarabine Did not meet primary endpoint of OS

1The inferior endpoint in Johnson et al. 1996 was only observed in this subgroup, not pretreated patients.
Note: To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Chemotherapy

Glucocorticoid therapy

1-month cycle for 6 cycles

References

  1. SWOG-7410: Keating MJ, Hester JP, McCredie KB, Burgess MA, Murphy WK, Freireich EJ. Long-term results of CAP therapy in chronic lymphocytic leukemia. Leuk Lymphoma. 1990;2(6):391-7. link to original article PubMed
  2. Johnson S, Smith AG, Löffler H, Osby E, Juliusson G, Emmerich B, Wyld PJ, Hiddemann W; French Cooperative Group on CLL. Multicentre prospective randomised trial of fludarabine versus cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of advanced-stage chronic lymphocytic leukaemia. Lancet. 1996 May 25;347(9013):1432-8. link to original article contains dosing details in abstract PubMed
  3. FCGCLL 1996: Leporrier M, Chevret S, Cazin B, Boudjerra N, Feugier P, Desablens B, Rapp MJ, Jaubert J, Autrand C, Divine M, Dreyfus B, Maloum K, Travade P, Dighiero G, Binet JL, Chastang C; French Cooperative Group on Chronic Lymphocytic Leukemia. Randomized comparison of fludarabine, CAP, and ChOP in 938 previously untreated stage B and C chronic lymphocytic leukemia patients. Blood. 2001 Oct 15;98(8):2319-25. link to original article contains dosing details in abstract PubMed

Chlorambucil monotherapy

Regimen variant #1, 0.1 mg/kg

Study Years of enrollment Evidence Comparator Comparative Efficacy
Binet et al. 1986 (FRE-CLL-80) 1980-1985 Phase 3 (E-esc) Observation1 Did not meet primary endpoint of OS
Binet et al. 1986 (FRE-CLL-80) 1980-1985 Phase 3 (C) CVP1 Did not meet primary endpoint of OS
Dighiero et al. 1998 (FRE-CLL-85) 1985-1990 Phase 3 (E-esc) Observation Seems to have superior PFS

1In FRE-CLL-80, this was the experimental arm for Binet Stage A and the control arm for Binet Stage B.
Note: FRE-CLL-85 is one of two trials reported in Dighiero et al. 1998; the other was comparing chlorambucil & prednisone vs. observation.

Chemotherapy

Continued indefinitely


Regimen variant #2, 0.4 mg/kg

Study Years of enrollment Evidence Comparator Comparative Efficacy
Knauf et al. 2009 2002-2006 Phase 3 (C) Bendamustine Inferior PFS

Note: This regimen was intended for previously untreated CLL patients up to 75 years of age with Binet stage B or C disease in need for treatment per the NCI-WG guidelines or IWCLL guidelines.

Chemotherapy

28-day cycle for up to 6 cycles


Regimen variant #3, 0.4 mg/kg, with dose escalation

Study Years of enrollment Evidence Comparator Comparative Efficacy
Eichhorst et al. 2009 (GCLLSG CLL5) 1999-2004 Phase 3 (C) Fludarabine Did not meet primary endpoints of PFS/OS

Note: This regimen was intended for untreated patients between 65 and 80 years with Binet stage C, or Binet stage B or A if they had rapid disease progression (lymphocyte doubling time less than 3 months) or symptoms from enlarged lymph nodes and organs, or if they had severe B symptoms.

Chemotherapy

  • Chlorambucil (Leukeran) as follows:
    • Cycle 1: 0.4 mg/kg PO once on day 1
    • To be increased as tolerated by 0.1 mg/kg each cycle, up to a maximum of 0.8 mg/kg PO once on day 1

14-day cycle for up to 24 cycles


Regimen variant #4, 0.5 mg/kg

Study Years of enrollment Evidence Comparator Comparative Efficacy
Goede et al. 2014 (GCLLSG CLL11) 2010-2012 Phase 3 (C) 1. Chlorambucil & Obinutuzumab Inferior OS
2. Chlorambucil & Rituximab Inferior PFS
Burger et al. 2015 (RESONATE-2) 2013-NR Phase 3 (C) Ibrutinib Inferior OS1

1Reported efficacy for RESONATE-2 is based on the 2019 update.
Note: Patients enrolled on RESONATE-2 were allowed to increase the dose up to 0.8 mg/kg if "there was not an unacceptable level of toxic effects."

Chemotherapy

28-day cycle for 6 to 12 cycles


Regimen variant #5, 0.8 mg/kg

Study Years of enrollment Evidence Comparator Comparative Efficacy
Knauf et al. 2009 2002-2006 Phase 3 (C) Bendamustine Inferior PFS
Chanan-Khan et al. 2017 (ORIGIN) 2009-2013 Phase 3 (C) Lenalidomide Did not meet primary endpoint of PFS

Note: This regimen was intended for previously untreated CLL patients up to 75 years of age with Binet stage B or C disease in need for treatment per the NCI-WG guidelines or IWCLL guidelines.

Chemotherapy

28-day cycle for up to 6 cycles (Knauf et al. 2009) or indefinitely (ORIGIN)


Regimen variant #6, 10 mg/m2

Study Years of enrollment Evidence Comparator Comparative Efficacy
Catovsky et al. 2007 (LRF CLL4) 1999-2004 Phase 3 (C) 1. FC Did not meet primary endpoint of OS
2. Fludarabine Did not meet primary endpoint of OS
Hillmen et al. 2015 (COMPLEMENT 1) 2008-2011 Phase 3 (C) Chlorambucil & Ofatumumab Inferior PFS

Chemotherapy

Supportive therapy

  • Per Catovsky et al. 2007: Patients with stage C disease (hemoglobin less than 10 g/dL or platelet count less than 100 x 109/L) received Prednisolone (Millipred) 30 mg/m2 PO once per day for 3 weeks, then 1 week taper before starting Chlorambucil (Leukeran) to reduce its myelotoxicity

28-day cycle for up to 12 cycles


Regimen variant #7, 40 mg/m2

Study Years of enrollment Evidence Comparator Comparative Efficacy
Rai et al. 2000 (CALGB 9011) 1990-1994 Phase 3 (C) 1. Chlorambucil & Fludarabine Not reported
2. Fludarabine Inferior PFS
Hillmen et al. 2007 (CAM 307) 2001-2004 Phase 3 (C) Alemtuzumab Inferior PFS

Note: In CALGB 9011, this regimen was intended for previously untreated patients with CLL who were high-risk (Rai stage III or IV) or intermediate-risk (Rai stage I or II) if they had at least one of the following: disease-related symptoms such as weight loss, extreme fatigue, night sweats, or fever without evidence of infection; massive or progressive splenomegaly or lymphadenopathy, or more than a 50 percent increase in the number of peripheral-blood lymphocytes over a 2-month period or an anticipated doubling of these cells within less than 12 months. In CAM 307, this regimen was intended for patients who were at least 18 years old with flow cytometry–confirmed diagnosis of B-cell CLL, Rai stage I through IV with evidence of progression according to the National Cancer Institute Working Group (NCI-WG) 1996 criteria, no previous chemotherapy for CLL, a life expectancy of at least 12 weeks, WHO performance status of 0 to 2, and adequate renal and liver function.

Chemotherapy

28-day cycle for up to 12 cycles

References

  1. Ezdinli EZ, Stutzman L. Chlorambucil therapy for lymphomas and chronic lymphocytic leukemia. JAMA. 1965 Feb 8;191:444-50. link to original article PubMed
  2. FRE-CLL-80: Binet JL, Chastang C, Dighiero G, Travad P; French Cooperative Group on Chronic Lymphocytic Leukaemia. Effectiveness of "CHOP" regimen in advanced untreated chronic lymphocytic leukaemia. Lancet. 1986 Jun 14;1(8494):1346-9. link to original article contains dosing details in manuscript PubMed
  3. FRE-CLL-85: Dighiero G, Maloum K, Desablens B, Cazin B, Navarro M, Leblay R, Leporrier M, Jaubert J, Lepeu G, Dreyfus B, Binet JL, Travade P; French Cooperative Group on Chronic Lymphocytic Leukemia. Chlorambucil in indolent chronic lymphocytic leukemia. N Engl J Med. 1998 May 21;338(21):1506-14. link to original article contains dosing details in manuscript PubMed
  4. CALGB 9011: Rai KR, Peterson BL, Appelbaum FR, Kolitz J, Elias L, Shepherd L, Hines J, Threatte GA, Larson RA, Cheson BD, Schiffer CA. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med. 2000 Dec 14;343(24):1750-7. link to original article contains dosing details in abstract PubMed
  5. LRF CLL4: Catovsky D, Richards S, Matutes E, Oscier D, Dyer MJ, Bezares RF, Pettitt AR, Hamblin T, Milligan DW, Child JA, Hamilton MS, Dearden CE, Smith AG, Bosanquet AG, Davis Z, Brito-Babapulle V, Else M, Wade R, Hillmen P; UK National Cancer Research Institute Haematological Oncology Clinical Studies Group; NCRI Chronic Lymphocytic Leukaemia Working Group. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet. 2007 Jul 21;370(9583):230-9. link to original article contains dosing details in manuscript PubMed NCT00004218
    1. Update: Else M, Wade R, Oscier D, Catovsky D. The long-term outcome of patients in the LRF CLL4 trial: the effect of salvage treatment and biological markers in those surviving 10 years. Br J Haematol. 2016 Jan;172(2):228-37. Epub 2015 Oct 12. link to original article link to PMC article PubMed
  6. CAM 307: Hillmen P, Skotnicki AB, Robak T, Jaksic B, Dmoszynska A, Wu J, Sirard C, Mayer J. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol. 2007 Dec 10;25(35):5616-23. Epub 2007 Nov 5. link to original article contains dosing details in abstract PubMed NCT00046683
  7. Knauf WU, Lissichkov T, Aldaoud A, Liberati A, Loscertales J, Herbrecht R, Juliusson G, Postner G, Gercheva L, Goranov S, Becker M, Fricke HJ, Huguet F, Del Giudice I, Klein P, Tremmel L, Merkle K, Montillo M. Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009 Sep 10;27(26):4378-84. Epub 2009 Aug 3. link to original article contains dosing details in manuscript PubMed
    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. link to original article contains dosing details in manuscript PubMed
  8. GCLLSG CLL5: Eichhorst BF, Busch R, Stilgenbauer S, Stauch M, Bergmann MA, Ritgen M, Kranzhöfer N, Rohrberg R, Söling U, Burkhard O, Westermann A, Goede V, Schweighofer CD, Fischer K, Fink AM, Wendtner CM, Brittinger G, Döhner H, Emmerich B, Hallek M; German CLL Study Group. First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia. Blood. 2009 Oct 15;114(16):3382-91. Epub 2009 Jul 15. link to original article contains dosing details in abstract PubMed NCT00262795
  9. GCLLSG CLL11: Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, Chagorova T, de la Serna J, Dilhuydy MS, Illmer T, Opat S, Owen CJ, Samoylova O, Kreuzer KA, Stilgenbauer S, Döhner H, Langerak AW, Ritgen M, Kneba M, Asikanius E, Humphrey K, Wenger M, Hallek M. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014 Mar 20;370(12):1101-10. Epub 2014 Jan 8. link to original article contains dosing details in manuscript PubMed NCT01010061
    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. link to original article PubMed
  10. COMPLEMENT 1: Hillmen P, Robak T, Janssens A, Babu KG, Kloczko J, Grosicki S, Doubek M, Panagiotidis P, Kimby E, Schuh A, Pettitt AR, Boyd T, Montillo M, Gupta IV, Wright O, Dixon I, Carey JL, Chang CN, Lisby S, McKeown A, Offner F; COMPLEMENT 1 Study Investigators. Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial. Lancet. 2015 May 9;385(9980):1873-83. Epub 2015 Apr 13. link to original article contains dosing details in abstract PubMed NCT00748189
    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. link to original article PubMed
  11. RESONATE-2: Burger JA, Tedeschi A, Barr PM, Robak T, Owen C, Ghia P, Bairey O, Hillmen P, Bartlett NL, Li J, Simpson D, Grosicki S, Devereux S, McCarthy H, Coutre S, Quach H, Gaidano G, Maslyak Z, Stevens DA, Janssens A, Offner F, Mayer J, O'Dwyer M, Hellmann A, Schuh A, Siddiqi T, Polliack A, Tam CS, Suri D, Cheng M, Clow F, Styles L, James DF, Kipps TJ; RESONATE-2 Investigators. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015 Dec 17;373(25):2425-37. Epub 2015 Dec 6. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01722487
    1. Update: Barr PM, Robak T, Owen C, Tedeschi A, Bairey O, Bartlett NL, Burger JA, Hillmen P, Coutre S, Devereux S, Grosicki S, McCarthy H, Li J, Simpson D, Offner F, Moreno C, Zhou C, Styles L, James D, Kipps TJ, Ghia P. Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: extended phase 3 results from RESONATE-2. Haematologica. 2018 Sep;103(9):1502-1510. Epub 2018 Jun 7. link to original article link to PMC article PubMed
    2. Update: Burger JA, Barr PM, Robak T, Owen C, Ghia P, Tedeschi A, Bairey O, Hillmen P, Coutre SE, Devereux S, Grosicki S, McCarthy H, Simpson D, Offner F, Moreno C, Dai S, Lal I, Dean JP, Kipps TJ. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia. 2020 Mar;34(3):787-798. Epub 2019 Oct 18. link to original article PubMed
  12. ORIGIN: Chanan-Khan A, Egyed M, Robak T, Martinelli de Oliveira FA, Echeveste MA, Dolan S, Desjardins P, Blonski JZ, Mei J, Golany N, Zhang J, Gribben JG. Randomized phase 3 study of lenalidomide versus chlorambucil as first-line therapy for older patients with chronic lymphocytic leukemia (the ORIGIN trial). Leukemia. 2017 May;31(5):1240-1243. Epub 2017 Jan 31. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00910910

Chlorambucil & Prednisone

Regimen variant #1, 0.3/40

Study Years of enrollment Evidence Comparator Comparative Efficacy
Dighiero et al. 1998 (FRE-CLL-85) 1985-1990 Phase 3 (E-esc) Observation Superior PFS

Chemotherapy

Glucocorticoid therapy

1-month cycle for up to 36 cycles (3 years)


Regimen variant #2, 12/30

Study Years of enrollment Evidence Comparator Comparative Efficacy
Robak et al. 2000 (PALG CLL1) 1995-1998 Phase 3 (C) Cladribine & Prednisone Inferior ORR

Chemotherapy

Glucocorticoid therapy

28-day cycles, continued until CR


Regimen variant #3, 30/80

Study Years of enrollment Evidence Comparator Comparative Efficacy
Raphael et al. 1991 (ECOG E2480) NR Phase 3 (C) CVP Did not meet efficacy endpoints

Chemotherapy

Glucocorticoid therapy

14-day cycle for up to 39 cycles (18 months)

References

  1. ECOG E2480: Raphael B, Andersen JW, Silber R, Oken M, Moore D, Bennett J, Bonner H, Hahn R, Knospe WH, Mazza J, Glick J. Comparison of chlorambucil and prednisone versus cyclophosphamide, vincristine, and prednisone as initial treatment for chronic lymphocytic leukemia: long-term follow-up of an Eastern Cooperative Oncology Group randomized clinical trial. J Clin Oncol. 1991 May;9(5):770-6. link to original article contains dosing details in manuscript PubMed
  2. 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. link to original article contains dosing details in manuscript PubMed
  3. PALG CLL1: Robak T, Bloński JZ, Kasznicki M, Blasińska-Morawiec M, Krykowski E, Dmoszyńska A, Mrugala-Spiewak H, Skotnicki AB, Nowak W, Konopka L, Ceglarek B, Maj S, Dwilewicz-Trojaczek J, Hellmann A, Urasiński I, Zdziarska B, Kotlarek-Haus S, Potoczek S, Grieb P. Cladribine with prednisone versus chlorambucil with prednisone as first-line therapy in chronic lymphocytic leukemia: report of a prospective, randomized, multicenter trial. Blood. 2000 Oct 15;96(8):2723-9. link to original article contains dosing details in abstract PubMed

CHOP

CHOP: Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Binet et al. 1986 (FRE-CLL-80) 1980-1985 Phase 3 (E-esc) CVP Superior OS
Leporrier et al. 2001 (FCGCLL 1996) 1990-1998 Phase 3 (C) 1. CAP Did not meet primary endpoint of OS
2. Fludarabine Did not meet primary endpoint of OS

Chemotherapy

Glucocorticoid therapy

28-day cycle for 6 cycles

References

  1. FRE-CLL-80: Binet JL, Chastang C, Dighiero G, Travad P; French Cooperative Group on Chronic Lymphocytic Leukaemia. Effectiveness of "CHOP" regimen in advanced untreated chronic lymphocytic leukaemia. Lancet. 1986 Jun 14;1(8494):1346-9. link to original article contains dosing details in manuscript PubMed
    1. Update: Benichou J, Binet JL, Chastang C, Chevret S, Dighiero G, Travade P; French Cooperative Group on Chronic Lymphocytic Leukaemia. Long-term results of the CHOP regimen in stage C chronic lymphocytic leukaemia. Br J Haematol. 1989 Nov;73(3):334-40. link to original article PubMed
  2. FCGCLL 1996: Leporrier M, Chevret S, Cazin B, Boudjerra N, Feugier P, Desablens B, Rapp MJ, Jaubert J, Autrand C, Divine M, Dreyfus B, Maloum K, Travade P, Dighiero G, Binet JL, Chastang C; French Cooperative Group on Chronic Lymphocytic Leukemia. Randomized comparison of fludarabine, CAP, and ChOP in 938 previously untreated stage B and C chronic lymphocytic leukemia patients. Blood. 2001 Oct 15;98(8):2319-25. link to original article contains dosing details in abstract PubMed

CMC

CMC: Cladribine, Mitoxantrone, Cyclophosphamide

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Robak et al. 2006 (PALG CLL2) 1998-2003 Phase 3 (E-esc) 1. Cladribine Superior CR rate
2. CC Seems to have superior CR rate

Chemotherapy

28-day cycle for up to 6 cycles

References

  1. PALG CLL2: Robak T, Blonski JZ, Gora-Tybor J, Jamroziak K, Dwilewicz-Trojaczek J, Tomaszewska A, Konopka L, Ceglarek B, Dmoszynska A, Kowal M, Kloczko J, Stella-Holowiecka B, Sulek K, Calbecka M, Zawilska K, Kuliczkowski K, Skotnicki AB, Warzocha K, Kasznicki M; Polish Adult Leukemia Group. Cladribine alone and in combination with cyclophosphamide or cyclophosphamide plus mitoxantrone in the treatment of progressive chronic lymphocytic leukemia: report of a prospective, multicenter, randomized trial of the Polish Adult Leukemia Group (PALG CLL2). Blood. 2006 Jul 15;108(2):473-9. Epub 2006 Mar 21. link to original article contains dosing details in abstract PubMed

CVP

CVP: Cyclophosphamide, Vincristine, Prednisone

Regimen variant #1, PO cyclophosphamide; uncapped vincristine

Study Years of enrollment Evidence Comparator Comparative Efficacy
Raphael et al. 1991 (ECOG E2480) NR Phase 3 (E-switch-ic) Chlorambucil & Prednisone Did not meet efficacy endpoints

Chemotherapy

Glucocorticoid therapy

21-day cycle for up to 26 cycles (18 months)


Regimen variant #2, capped vincristine

Study Years of enrollment Evidence
Hochster et al. 2009 (ECOG E1496) NR Non-randomized portion of phase 3 RCT

Chemotherapy

Glucocorticoid therapy

21-day cycle for 6 to 8 cycles

Subsequent treatment

References

  1. ECOG E2480: Raphael B, Andersen JW, Silber R, Oken M, Moore D, Bennett J, Bonner H, Hahn R, Knospe WH, Mazza J, Glick J. Comparison of chlorambucil and prednisone versus cyclophosphamide, vincristine, and prednisone as initial treatment for chronic lymphocytic leukemia: long-term follow-up of an Eastern Cooperative Oncology Group randomized clinical trial. J Clin Oncol. 1991 May;9(5):770-6. link to original article contains dosing details in abstract PubMed
  2. ECOG E1496: Hochster H, Weller E, Gascoyne RD, Habermann TM, Gordon LI, Ryan T, Zhang L, Colocci N, Frankel S, Horning SJ. Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG1496 Study. J Clin Oncol. 2009 Apr 1;27(10):1607-14. Epub 2009 Mar 2. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00003204

FC

FC: Fludarabine, Cyclophosphamide

Regimen variant #1, 75/750 (IV fludarabine)

Study Years of enrollment Evidence Comparator Comparative Efficacy
Catovsky et al. 2007 (LRF CLL4) 1999-2004 Phase 3 (E-esc) 1. Chlorambucil Did not meet primary endpoint of OS
2. Fludarabine Did not meet primary endpoint of OS
Hallek et al. 2010 (GCLLSG CLL8) 2003-2006 Phase 3 (C) FCR Inferior OS1
Robak et al. 2010 (PALG-CLL3) 2004-2007 Phase 3 (E-switch-ic) CC Did not meet primary endpoint of CR rate

1Reported efficacy for GCLLSG CLL8 is based on the updated 2016 results.

Chemotherapy

Supportive therapy

  • Per Robak et al. 2010: "No routine prophylaxis with antibiotics, antiviral agents, or growth factors."

28-day cycle for up to 6 cycles


Regimen variant #2, 90/750

Study Years of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Eichhorst et al. 2005 (GCLLSG CLL4) 1999-2003 Phase 3 (E-esc) Fludarabine Superior PFS No statistical difference in HRQoL

Chemotherapy

Supportive therapy

  • No routine antibiotic, antiviral, or growth factor use

28-day cycle for up to 6 cycles


Regimen variant #3, 100/600

Study Years of enrollment Evidence Comparator Comparative Efficacy
Flinn et al. 2007 (ECOG E2997) 1999-NR Phase 3 (E-esc) Fludarabine Superior PFS

Note: This regimen was intended for untreated patients greater than or equal to 18 years with a diagnosis of progressive CLL using the National Cancer Institute criteria.

Chemotherapy

28-day cycle for up to 6 cycles


Regimen variant #4, 120/750 (PO fludarabine)

Study Years of enrollment Evidence Comparator Comparative Efficacy
Geisler et al. 2014 (HOVON-68) 2006-2010 Phase 3 (C) FCA Inferior PFS

Note: This regimen was intended for patients with previously untreated CLL diagnosed and in need of treatment according to the National Cancer Institute guidelines, 18 to 75 years of age, with WHO performance status less than 3 and no severe comorbidities, with high-risk CLL as defined by the presence of either unmutated IGHV, 17p deletion, 11q deletion, or trisomy 12 by FISH.

Chemotherapy

Supportive therapy

28-day cycle for 6 cycles


Regimen variant #5, 120/750 (all PO)

Study Years of enrollment Evidence Comparator Comparative Efficacy
Catovsky et al. 2007 (LRF CLL4) 1999-2004 Phase 3 (E-esc) 1. Chlorambucil Did not meet primary endpoint of OS
2. Fludarabine Did not meet primary endpoint of OS

Chemotherapy

28-day cycle for up to 6 cycles

References

  1. GCLLSG CLL4: Eichhorst BF, Busch R, Hopfinger G, Pasold R, Hensel M, Steinbrecher C, Siehl S, Jäger U, Bergmann M, Stilgenbauer S, Schweighofer C, Wendtner CM, Döhner H, Brittinger G, Emmerich B, Hallek M; German CLL Study Group. Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood. 2006 Feb 1;107(3):885-91. Epub 2005 Oct 11. link to original article contains dosing details in abstract PubMed NCT00276848
    1. HRQoL analysis: Eichhorst BF, Busch R, Obwandner T, Kuhn-Hallek I, Herschbach P, Hallek M; German CLL Study Group. Health-related quality of life in younger patients with chronic lymphocytic leukemia treated with fludarabine plus cyclophosphamide or fludarabine alone for first-line therapy: a study by the German CLL Study Group. J Clin Oncol. 2007 May 1;25(13):1722-31. Epub 2007 Mar 26. link to original article PubMed
  2. ECOG E2997: Flinn IW, Neuberg DS, Grever MR, Dewald GW, Bennett JM, Paietta EM, Hussein MA, Appelbaum FR, Larson RA, Moore DF Jr, Tallman MS. Phase III trial of fludarabine plus cyclophosphamide compared with fludarabine for patients with previously untreated chronic lymphocytic leukemia: US Intergroup Trial E2997. J Clin Oncol. 2007 Mar 1;25(7):793-8. Epub 2007 Feb 5. link to original article contains dosing details in manuscript PubMed NCT00003764
    1. Update: Lucas DM, Ruppert AS, Lozanski G, Dewald GW, Lozanski A, Claus R, Plass C, Flinn IW, Neuberg DS, Paietta EM, Bennett JM, Jelinek DF, Gribben JG, Hussein MA, Appelbaum FR, Larson RA, Moore DF Jr, Tallman MS, Byrd JC, Grever MR. Cytogenetic prioritization with inclusion of molecular markers predicts outcome in previously untreated patients with chronic lymphocytic leukemia treated with fludarabine or fludarabine plus cyclophosphamide: a long-term follow-up study of the US intergroup phase III trial E2997. Leuk Lymphoma. 2015;56(11):3031-7. Epub 2015 Mar 30. link to original article link to PMC article PubMed
  3. LRF CLL4: Catovsky D, Richards S, Matutes E, Oscier D, Dyer MJ, Bezares RF, Pettitt AR, Hamblin T, Milligan DW, Child JA, Hamilton MS, Dearden CE, Smith AG, Bosanquet AG, Davis Z, Brito-Babapulle V, Else M, Wade R, Hillmen P; UK National Cancer Research Institute Haematological Oncology Clinical Studies Group; NCRI Chronic Lymphocytic Leukaemia Working Group. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet. 2007 Jul 21;370(9583):230-9. link to original article contains dosing details in manuscript PubMed NCT00004218
    1. Update: Else M, Wade R, Oscier D, Catovsky D. The long-term outcome of patients in the LRF CLL4 trial: the effect of salvage treatment and biological markers in those surviving 10 years. Br J Haematol. 2016 Jan;172(2):228-37. Epub 2015 Oct 12. link to original article link to PMC article PubMed
  4. 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; Polish Adult Leukemia Group. Comparison of cladribine plus cyclophosphamide with fludarabine plus cyclophosphamide as first-line therapy for chronic lymphocytic leukemia: a phase III randomized study by the Polish Adult Leukemia Group (PALG-CLL3 Study). J Clin Oncol. 2010 Apr 10;28(11):1863-9. Epub 2010 Mar 8. link to original article contains dosing details in manuscript PubMed
  5. GCLLSG CLL8: Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J, Hensel M, Hopfinger G, Hess G, von Grünhagen U, Bergmann M, Catalano J, Zinzani PL, Caligaris-Cappio F, Seymour JF, Berrebi A, Jäger U, Cazin B, Trneny M, Westermann A, Wendtner CM, Eichhorst BF, Staib P, Bühler A, Winkler D, Zenz T, Böttcher S, Ritgen M, Mendila M, Kneba M, Döhner H, Stilgenbauer S; International Group of Investigators; German Chronic Lymphocytic Leukaemia Study Group. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010 Oct 2;376(9747):1164-74. link to original article contains dosing details in abstract PubMed NCT00281918
    1. Update: Fischer K, Bahlo J, Fink AM, Goede V, Herling CD, Cramer P, Langerbeins P, von Tresckow J, Engelke A, Maurer C, Kovacs G, Herling M, Tausch E, Kreuzer KA, Eichhorst B, Böttcher S, Seymour JF, Ghia P, Marlton P, Kneba M, Wendtner CM, Döhner H, Stilgenbauer S, Hallek M. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016 Jan 14;127(2):208-15. Epub 2015 Oct 20. link to original article PubMed
    2. HRQoL analysis: Kutsch N, Busch R, Bahlo J, Mayer J, Hensel M, Hopfinger G, Hess G, von Grünhagen U, Wendtner CM, Maria Fink A, Fischer K, Hallek M, Eichhorst B. FCR front-line therapy and quality of life in patients with chronic lymphocytic leukemia. Leuk Lymphoma. 2017 Feb;58(2):399-407. Epub 2016 Jun 29. link to original article PubMed
  6. HOVON-68: Geisler CH, van T' Veer MB, Jurlander J, Walewski J, Tjønnfjord G, Itälä Remes M, Kimby E, Kozak T, Polliack A, Wu KL, Wittebol S, Abrahamse-Testroote MC, Doorduijn J, Ghidey Alemayehu W, van Oers MH. Frontline low-dose alemtuzumab with fludarabine and cyclophosphamide prolongs progression-free survival in high-risk CLL. Blood. 2014 May 22;123(21):3255-62. Epub 2014 Apr 15. link to original article contains dosing details in manuscript PubMed NTR529

FCM

FCM: Fludarabine, Cyclophosphamide, Mitoxantrone

Regimen variant #1

Study Years of enrollment Evidence Comparator Comparative Efficacy
Hillmen et al. 2011 (NCRI CLL201) 2005-2007 Randomized Phase 2 (C) FCM-R Did not meet primary endpoint of ORR

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

28-day cycle for 6 cycles


Regimen variant #2

Study Years of enrollment Evidence
Bosch et al. 2008 2001-2004 Phase 2

Chemotherapy

Supportive therapy

28-day cycle for 6 cycles

References

  1. Bosch F, Ferrer A, Villamor N, González M, Briones J, González-Barca E, Abella E, Gardella S, Escoda L, Pérez-Ceballos E, Asensi A, Sayas MJ, Font L, Altés A, Muntañola A, Bertazzoni P, Rozman M, Aymerich M, Giné E, Montserrat E. Fludarabine, cyclophosphamide, and mitoxantrone as initial therapy of chronic lymphocytic leukemia: high response rate and disease eradication. Clin Cancer Res. 2008 Jan 1;14(1):155-61. link to original article contains dosing details in manuscript PubMed
  2. Hillmen P, Cohen DR, Cocks K, Pettitt A, Sayala HA, Rawstron AC, Kennedy DB, Fegan C, Milligan DW, Radford J, Mercieca J, Dearden C, Ezekwisili R, Smith AF, Brown J, Booth GA, Varghese AM, Pocock C; NCRI CLL Sub-Group. A randomized phase II trial of fludarabine, cyclophosphamide and mitoxantrone (FCM) with or without rituximab in previously treated chronic lymphocytic leukaemia. Br J Haematol. 2011 Mar;152(5):570-8. Epub 2011 Jan 14. link to original article contains dosing details in manuscript PubMed

Fludarabine monotherapy

F: Fludarabine

Regimen variant #1, IV

Study Years of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Johnson et al. 1996 1990-1992 Phase 3 (E-de-esc) CAP Superior TTP1
Rai et al. 2000 (CALGB 9011) 1990-1994 Phase 3 (E-switch-ic) 1. Chlorambucil Superior PFS
2. Chlorambucil & Fludarabine Did not meet primary endpoint of CR rate
Leporrier et al. 2001 (FCGCLL 1996) 1990-1998 Phase 3 (E-de-esc) 1. CAP Did not meet primary endpoint of OS
2. CHOP Did not meet primary endpoint of OS
Hoechstetter et al. 2017 (GCLLSG CLL1) 1997-2004 Phase 3 (E-esc) Observation Superior PFS
Median PFS: 30.1 vs 12.9 mo
Eichorst et al. 2005 (GCLLSG CLL4) 1999-2003 Phase 3 (C) FC Inferior PFS No statistical difference in HRQoL
Flinn et al. 2007 (ECOG E2997) 1999-NR Phase 3 (C) FC Inferior PFS
Catovsky et al. 2007 (LRF CLL4) 1999-2004 Phase 3 (C) 1. Chlorambucil Did not meet primary endpoint of OS
2. FC Did not meet primary endpoint of OS
Eichhorst et al. 2009 (GCLLSG CLL5) 1999-2004 Phase 3 (E-switch-ic) Chlorambucil Did not meet primary endpoints of PFS/OS
Elter et al. 2011 (CAM 314) 2004-2008 Phase 3 (C) Fludarabine & Alemtuzumab Seems to have inferior OS

1The superior endpoint in Johnson et al. 1996 was only observed in this subgroup, not pretreated patients.

Eligibility criteria

  • CALGB 9011: intended for previously untreated patients with CLL who were high-risk (Rai stage III or IV) or intermediate-risk (Rai stage I or II) if they had at least one of the following: disease-related symptoms such as weight loss, extreme fatigue, night sweats, or fever without evidence of infection; massive or progressive splenomegaly or lymphadenopathy, or more than a 50 percent increase in the number of peripheral-blood lymphocytes over a 2-month period or an anticipated doubling of these cells within less than 12 months.
  • ECOG E2997: intended for untreated patients greater than or equal to 18 years with a diagnosis of progressive CLL using the National Cancer Institute criteria.
  • GCLLSG CLL5: intended for untreated patients between 65 and 80 years with Binet stage C, or Binet stage B or A if they had rapid disease progression (lymphocyte doubling time less than 3 months) or symptoms from enlarged lymph nodes and organs, or if they had severe B symptoms.

Chemotherapy

28-day cycle for up to 6 to 12 cycles


Regimen variant #2, PO

Study Years of enrollment Evidence Comparator Comparative Efficacy
Catovsky et al. 2007 (LRF CLL4) 1999-2004 Phase 3 (C) 1. Chlorambucil Did not meet primary endpoint of OS
2. FC Did not meet primary endpoint of OS

Chemotherapy

28-day cycle for up to 6 to 12 cycles

References

  1. Johnson S, Smith AG, Löffler H, Osby E, Juliusson G, Emmerich B, Wyld PJ, Hiddemann W; French Cooperative Group on CLL. Multicentre prospective randomised trial of fludarabine versus cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of advanced-stage chronic lymphocytic leukaemia. Lancet. 1996 May 25;347(9013):1432-8. link to original article contains dosing details in abstract PubMed
  2. CALGB 9011: Rai KR, Peterson BL, Appelbaum FR, Kolitz J, Elias L, Shepherd L, Hines J, Threatte GA, Larson RA, Cheson BD, Schiffer CA. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med. 2000 Dec 14;343(24):1750-7. link to original article contains dosing details in abstract PubMed
  3. FCGCLL 1996: Leporrier M, Chevret S, Cazin B, Boudjerra N, Feugier P, Desablens B, Rapp MJ, Jaubert J, Autrand C, Divine M, Dreyfus B, Maloum K, Travade P, Dighiero G, Binet JL, Chastang C; French Cooperative Group on Chronic Lymphocytic Leukemia. Randomized comparison of fludarabine, CAP, and ChOP in 938 previously untreated stage B and C chronic lymphocytic leukemia patients. Blood. 2001 Oct 15;98(8):2319-25. link to original article contains dosing details in abstract PubMed
  4. GCLLSG CLL4: Eichhorst BF, Busch R, Hopfinger G, Pasold R, Hensel M, Steinbrecher C, Siehl S, Jäger U, Bergmann M, Stilgenbauer S, Schweighofer C, Wendtner CM, Döhner H, Brittinger G, Emmerich B, Hallek M; German CLL Study Group. Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood. 2006 Feb 1;107(3):885-91. Epub 2005 Oct 11. link to original article contains dosing details in abstract PubMed NCT00276848
    1. HRQoL analysis: Eichhorst BF, Busch R, Obwandner T, Kuhn-Hallek I, Herschbach P, Hallek M; German CLL Study Group. Health-related quality of life in younger patients with chronic lymphocytic leukemia treated with fludarabine plus cyclophosphamide or fludarabine alone for first-line therapy: a study by the German CLL Study Group. J Clin Oncol. 2007 May 1;25(13):1722-31. Epub 2007 Mar 26. link to original article PubMed
  5. ECOG E2997: Flinn IW, Neuberg DS, Grever MR, Dewald GW, Bennett JM, Paietta EM, Hussein MA, Appelbaum FR, Larson RA, Moore DF Jr, Tallman MS. Phase III trial of fludarabine plus cyclophosphamide compared with fludarabine for patients with previously untreated chronic lymphocytic leukemia: US Intergroup Trial E2997. J Clin Oncol. 2007 Mar 1;25(7):793-8. Epub 2007 Feb 5. link to original article contains dosing details in manuscript PubMed NCT00003764
    1. Update: Lucas DM, Ruppert AS, Lozanski G, Dewald GW, Lozanski A, Claus R, Plass C, Flinn IW, Neuberg DS, Paietta EM, Bennett JM, Jelinek DF, Gribben JG, Hussein MA, Appelbaum FR, Larson RA, Moore DF Jr, Tallman MS, Byrd JC, Grever MR. Cytogenetic prioritization with inclusion of molecular markers predicts outcome in previously untreated patients with chronic lymphocytic leukemia treated with fludarabine or fludarabine plus cyclophosphamide: a long-term follow-up study of the US intergroup phase III trial E2997. Leuk Lymphoma. 2015;56(11):3031-7. Epub 2015 Mar 30. link to original article link to PMC article PubMed
  6. LRF CLL4: Catovsky D, Richards S, Matutes E, Oscier D, Dyer MJ, Bezares RF, Pettitt AR, Hamblin T, Milligan DW, Child JA, Hamilton MS, Dearden CE, Smith AG, Bosanquet AG, Davis Z, Brito-Babapulle V, Else M, Wade R, Hillmen P; UK National Cancer Research Institute Haematological Oncology Clinical Studies Group; NCRI Chronic Lymphocytic Leukaemia Working Group. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet. 2007 Jul 21;370(9583):230-9. link to original article contains dosing details in abstract PubMed NCT00004218
    1. Update: Else M, Wade R, Oscier D, Catovsky D. The long-term outcome of patients in the LRF CLL4 trial: the effect of salvage treatment and biological markers in those surviving 10 years. Br J Haematol. 2016 Jan;172(2):228-37. Epub 2015 Oct 12. link to original article link to PMC article PubMed
  7. GCLLSG CLL5: Eichhorst BF, Busch R, Stilgenbauer S, Stauch M, Bergmann MA, Ritgen M, Kranzhöfer N, Rohrberg R, Söling U, Burkhard O, Westermann A, Goede V, Schweighofer CD, Fischer K, Fink AM, Wendtner CM, Brittinger G, Döhner H, Emmerich B, Hallek M; German CLL Study Group. First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia. Blood. 2009 Oct 15;114(16):3382-91. Epub 2009 Jul 15. link to original article contains dosing details in abstract PubMed NCT00262795
  8. CAM 314: Elter T, Gercheva-Kyuchukova L, Pylylpenko H, Robak T, Jaksic B, Rekhtman G, Kyrcz-Krzemień S, Vatutin M, Wu J, Sirard C, Hallek M, Engert A. Fludarabine plus alemtuzumab versus fludarabine alone in patients with previously treated chronic lymphocytic leukaemia: a randomised phase 3 trial. Lancet Oncol. 2011 Dec;12(13):1204-13. Epub 2011 Oct 10. link to original article PubMed NCT00086580
  9. GCLLSG CLL1: Hoechstetter MA, Busch R, Eichhorst B, Bühler A, Winkler D, Eckart MJ, Vehling-Kaiser U, Schimke H, Jäger U, Hurtz HJ, Hopfinger G, Hartmann F, Fuss H, Abenhardt W, Blau I, Freier W, Müller L, Goebeler M, Wendtner CM, Bahlo J, Fischer K, Bentz M, Emmerich B, Döhner H, Hallek M, Stilgenbauer S. Early, risk-adapted treatment with fludarabine in Binet stage A chronic lymphocytic leukemia patients: results of the CLL1 trial of the German CLL study group. Leukemia. 2017 Dec;31(12):2833-2837. Epub 2017 Aug 14. link to original article PubMed NCT00262782

Fludarabine & Prednisone

Regimen

Study Years of enrollment Evidence
O'Brien et al. 1993 1988-1991 Phase 2

Chemotherapy

Glucocorticoid therapy

28-day cycles

References

  1. O'Brien S, Kantarjian H, Beran M, Smith T, Koller C, Estey E, Robertson LE, Lerner S, Keating M. Results of fludarabine and prednisone therapy in 264 patients with chronic lymphocytic leukemia with multivariate analysis-derived prognostic model for response to treatment. Blood. 1993 Sep 15;82(6):1695-700. link to original article contains dosing details in abstract PubMed
    1. Update: Keating MJ, O'Brien S, Lerner S, Koller C, Beran M, Robertson LE, Freireich EJ, Estey E, Kantarjian H. Long-term follow-up of patients with chronic lymphocytic leukemia (CLL) receiving fludarabine regimens as initial therapy. Blood. 1998 Aug 15;92(4):1165-71. link to original article PubMed

Fludarabine & Rituximab (FR)

FR: Fludarabine, Rituximab

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Byrd et al. 2002 (CALGB 9712) 1998-2000 Randomized Phase 2 (E-switch-ic) F, then R Did not meet primary endpoint of CR rate

Chemotherapy

Targeted therapy

  • Rituximab (Rituxan) as follows:
    • Cycle 1: 375 mg/m2 IV once per day on days 1 & 4
    • Cycles 2 to 6: 375 mg/m2 IV once on day 1

Supportive therapy

28-day cycle for 6 cycles

Subsequent treatment

  • If restaging done 2 months after 6 cycles of therapy shows SD or better: Rituximab consolidation

References

  1. CALGB 9712: Byrd JC, Peterson BL, Morrison VA, Park K, Jacobson R, Hoke E, Vardiman JW, Rai K, Schiffer CA, Larson RA. Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712). Blood. 2003 Jan 1;101(1):6-14. Epub 2002 Jul 5. link to original article contains dosing details in abstract PubMed
    1. Update: Byrd JC, Rai K, Peterson BL, Appelbaum FR, Morrison VA, Kolitz JE, Shepherd L, Hines JD, Schiffer CA, Larson RA. Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and CALGB 9011. Blood. 2005 Jan 1;105(1):49-53. Epub 2004 May 11. link to original article PubMed
    2. Update: Woyach JA, Ruppert AS, Heerema NA, Peterson BL, Gribben JG, Morrison VA, Rai KR, Larson RA, Byrd JC. Chemoimmunotherapy with fludarabine and rituximab produces extended overall survival and progression-free survival in chronic lymphocytic leukemia: long-term follow-up of CALGB study 9712. J Clin Oncol. 2011 Apr 1;29(10):1349-55. Epub 2011 Feb 14. link to original article link to PMC article PubMed

Idelalisib & Rituximab

Regimen

Study Years of enrollment Evidence
O'Brien et al. 2015 (Study 101-08) 2010-NR Phase 2

Note: In a letter dated 3/21/2016, Gilead states that idelalisib should not be used for first line treatment of CLL.

Targeted therapy

28-day cycle for 12 cycles

Subsequent treatment

  • Patients who had not progressed could continue on an extension study

References

  1. Study 101-08: O'Brien SM, Lamanna N, Kipps TJ, Flinn I, Zelenetz AD, Burger JA, Keating M, Mitra S, Holes L, Yu AS, Johnson DM, Miller LL, Kim Y, Dansey RD, Dubowy RL, Coutre SE. A phase 2 study of idelalisib plus rituximab in treatment-naïve older patients with chronic lymphocytic leukemia. Blood. 2015 Dec 17;126(25):2686-94. Epub 2015 Oct 15. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01203930

Lenalidomide monotherapy

Regimen variant #1, target 10 mg/day

Study Evidence Efficacy
Chen et al. 2010 (Rev-CLL) Phase 2 ORR: 56%

Targeted therapy

  • Lenalidomide (Revlimid) as follows:
    • Cycle 1: 2.5 mg PO once per day on days 1 to 21
    • Cycle 2: Increased if tolerated to 5 mg PO once per day on days 1 to 21
    • Cycle 3 onwards: Increased if tolerated to 10 mg PO once per day on days 1 to 21

Supportive therapy

28-day cycles


Regimen variant #2, target 15 mg/day

Study Years of enrollment Evidence Comparator Comparative Efficacy
Chanan-Khan et al. 2017 (ORIGIN) 2009-2013 Phase 3 (E-switch-ooc) Chlorambucil Did not meet primary endpoint of PFS

Note: this is an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have been previously published with encouraging non-randomized results.

Targeted therapy

Continued indefinitely


Regimen variant #3, target 25 mg/day

Study Evidence Efficacy
Badoux et al. 2011 (MDACC 2006-0715) Phase 2 ORR: 65%

Targeted therapy

  • Lenalidomide (Revlimid) 5 mg PO once per day on days 1 to 56, then increased to a target dose of 25 mg PO once per day

Continued indefinitely

References

  1. Rev-CLL: Chen CI, Bergsagel PL, Paul H, Xu W, Lau A, Dave N, Kukreti V, Wei E, Leung-Hagesteijn C, Li ZH, Brandwein J, Pantoja M, Johnston J, Gibson S, Hernandez T, Spaner D, Trudel S. Single-agent lenalidomide in the treatment of previously untreated chronic lymphocytic leukemia. J Clin Oncol. 2011 Mar 20;29(9):1175-81. Epub 2010 Dec 28. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00751296
    1. Update: Chen CI, Paul H, Wang T, Le LW, Dave N, Kukreti V, Nong Wei E, Lau A, Bergsagel PL, Trudel S. Long-term follow-up of a phase 2 trial of single agent lenalidomide in previously untreated patients with chronic lymphocytic leukaemia. Br J Haematol. 2014 Jun;165(5):731-3. Epub 2014 Feb 24. link to original article PubMed
  2. MDACC 2006-0715: Badoux XC, Keating MJ, Wen S, Lee BN, Sivina M, Reuben J, Wierda WG, O'Brien SM, Faderl S, Kornblau SM, Burger JA, Ferrajoli A. Lenalidomide as initial therapy of elderly patients with chronic lymphocytic leukemia. Blood. 2011 Sep 29;118(13):3489-98. Epub 2011 Jul 1. link to original article contains dosing details in abstract link to PMC article PubMed
    1. Update: Strati P, Keating MJ, Wierda WG, Badoux XC, Calin S, Reuben JM, O'Brien S, Kornblau SM, Kantarjian HM, Gao H, Ferrajoli A. Lenalidomide induces long-lasting responses in elderly patients with chronic lymphocytic leukemia. Blood. 2013 Aug 1;122(5):734-7. Epub 2013 Jun 25. link to original article link to PMC article PubMed
  3. ORIGIN: Chanan-Khan A, Egyed M, Robak T, Martinelli de Oliveira FA, Echeveste MA, Dolan S, Desjardins P, Blonski JZ, Mei J, Golany N, Zhang J, Gribben JG. Randomized phase 3 study of lenalidomide versus chlorambucil as first-line therapy for older patients with chronic lymphocytic leukemia (the ORIGIN trial). Leukemia. 2017 May;31(5):1240-1243. Epub 2017 Jan 31. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00910910

R-FCM

R-FCM: Rituximab, Fludarabine, Cyclophosphamide, Mitoxantrone
FCM-R: Fludarabine, Cyclophosphamide, Mitoxantrone, Rituximab

Regimen variant #1

Study Years of enrollment Evidence Comparator Comparative Efficacy
Hillmen et al. 2011 (NCRI CLL201) 2005-2007 Randomized Phase 2 (E-esc) FCM Did not meet primary endpoint of ORR at 2 mo

Targeted therapy

  • Rituximab (Rituxan) as follows:
    • Cycle 1: 375 mg/m2 IV once on day 1
    • Cycles 2 to 6: 500 mg/m2 IV once on day 1

Chemotherapy

28-day cycle for 6 cycles


Regimen variant #2

Study Evidence
Bosch et al. 2009 Phase 2

Targeted therapy

  • Rituximab (Rituxan) as follows:
    • Cycle 1: 375 mg/m2 IV once on day 1
    • Cycles 2 to 6: 500 mg/m2 IV once on day 1

Chemotherapy

Supportive therapy

28-day cycle for 6 cycles

Subsequent treatment

  • Patients with a PR or CR at 3 months: Rituximab maintenance


Regimen variant #3

Study Evidence
Faderl et al. 2009 Phase 2

Targeted therapy

  • Rituximab (Rituxan) as follows:
    • Cycle 1: 375 mg/m2 IV once on day 1
    • Cycles 2 to 6: 500 mg/m2 IV once on day 1

Chemotherapy

  • Fludarabine (Fludara) as follows:
    • Cycle 1: 25 mg/m2/day (route not specified) on days 2 to 4
    • Cycles 2 to 6: 25 mg/m2/day (route not specified) on days 1 to 3
  • Cyclophosphamide (Cytoxan) as follows:
    • Cycle 1: 250 mg/m2/day (route not specified) on days 2 to 4
    • Cycles 2 to 6: 250 mg/m2/day (route not specified) on days 1 to 3
  • Mitoxantrone (Novantrone) as follows:
    • Cycle 1: 6 mg/m2 IV once on day 2
    • Cycles 2 to 6: 6 mg/m2 IV once on day 2

Supportive therapy

4- to 6-week cycle for up to 6 cycles

References

  1. Bosch F, Abrisqueta P, Villamor N, Terol MJ, González-Barca E, Ferra C, González Diaz M, Abella E, Delgado J, Carbonell F, García Marco JA, Escoda L, Ferrer S, Monzó E, González Y, Estany C, Jarque I, Salamero O, Muntañola A, Montserrat E. Rituximab, fludarabine, cyclophosphamide, and mitoxantrone: a new, highly active chemoimmunotherapy regimen for chronic lymphocytic leukemia. J Clin Oncol. 2009 Sep 20;27(27):4578-84. Epub 2009 Aug 24. link to original article contains dosing details in manuscript PubMed EudraCT 2005-001569-33
    1. Update: Abrisqueta P, Villamor N, Terol MJ, González-Barca E, González M, Ferrà C, Abella E, Delgado J, García-Marco JA, González Y, Carbonell F, Ferrer S, Monzó E, Jarque I, Muntañola A, Constants M, Escoda L, Calvo X, Bobillo S, Montoro JB, Montserrat E, Bosch F. Rituximab maintenance after first-line therapy with rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) for chronic lymphocytic leukemia. Blood. 2013 Dec 5;122(24):3951-9. Epub 2013 Oct 11. link to original article contains dosing details in manuscript PubMed
  2. Faderl S, Wierda W, O'Brien S, Ferrajoli A, Lerner S, Keating MJ. Fludarabine, cyclophosphamide, mitoxantrone plus rituximab (FCM-R) in frontline CLL less than 70 Years. Leuk Res. 2010 Mar;34(3):284-8. Epub 2009 Jul 30. link to original article contains dosing details in abstract link to PMC article PubMed
  3. NCRI CLL201: Hillmen P, Cohen DR, Cocks K, Pettitt A, Sayala HA, Rawstron AC, Kennedy DB, Fegan C, Milligan DW, Radford J, Mercieca J, Dearden C, Ezekwisili R, Smith AF, Brown J, Booth GA, Varghese AM, Pocock C; NCRI CLL Sub-Group. A randomized phase II trial of fludarabine, cyclophosphamide and mitoxantrone (FCM) with or without rituximab in previously treated chronic lymphocytic leukaemia. Br J Haematol. 2011 Mar;152(5):570-8. Epub 2011 Jan 14. link to original article contains dosing details in manuscript PubMed
  4. ADMIRE: Munir T, Howard DR, McParland L, Pocock C, Rawstron AC, Hockaday A, Varghese A, Hamblin M, Bloor A, Pettitt A, Fegan C, Blundell J, Gribben JG, Phillips D, Hillmen P. Results of the randomized phase IIB ADMIRE trial of FCR with or without mitoxantrone in previously untreated CLL. Leukemia. 2017 Oct;31(10):2085-2093. Epub 2017 Apr 20. link to original article PubMed ISRCTN42165735

Uracil mustard monotherapy

Regimen

Study Evidence
Kennedy & Theologides 1961 Non-randomized

Chemotherapy

References

  1. Kennedy BJ, Theologides A. Uracil mustard, a new alkylating agent for oral administration in the management of patients with leukemia and lymphoma. N Engl J Med. 1961 Apr 20;264:790-3. link to original article PubMed

Subsequent lines of therapy

CAP

CAP: Cyclophosphamide, Adriamycin (Doxorubicin), Prednisone

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Johnson et al. 1996 1990-1992 Phase 3 (C) Fludarabine Seems to have inferior ORR1

1The inferior endpoint in Johnson et al. 1996 was only observed in this subgroup, not untreated patients.

Chemotherapy

Glucocorticoid therapy

1-month cycle for 6 cycles

References

  1. Johnson S, Smith AG, Löffler H, Osby E, Juliusson G, Emmerich B, Wyld PJ, Hiddemann W; French Cooperative Group on CLL. Multicentre prospective randomised trial of fludarabine versus cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of advanced-stage chronic lymphocytic leukaemia. Lancet. 1996 May 25;347(9013):1432-8. link to original article contains dosing details in abstract PubMed

Fludarabine monotherapy

F: Fludarabine

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Keating et al. 1989 1985-1987 Non-randomized (RT)
Grever et al. 1990 NR in abstract Phase 1/2 (RT)
Johnson et al. 1996 1990-1992 Phase 3 (E-de-esc) CAP Seems to have superior ORR1

1The superior endpoint in Johnson et al. 1996 was only observed in this subgroup, not untreated patients.

Chemotherapy

28-day cycle for 6 cycles

References

  1. Keating MJ, Kantarjian H, Talpaz M, Redman J, Koller C, Barlogie B, Velasquez W, Plunkett W, Freireich EJ, McCredie KB. Fludarabine: a new agent with major activity against chronic lymphocytic leukemia. Blood. 1989 Jul;74(1):19-25. link to original article PubMed
  2. Grever M, Leiby J, Kraut E, Metz E, Neidhart J, Balcerzak S, Malspeis L. A comprehensive phase I and II clinical investigation of fludarabine phosphate. Semin Oncol. 1990 Oct;17(5 Suppl 8):39-48. PubMed
  3. Johnson S, Smith AG, Löffler H, Osby E, Juliusson G, Emmerich B, Wyld PJ, Hiddemann W; French Cooperative Group on CLL. Multicentre prospective randomised trial of fludarabine versus cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of advanced-stage chronic lymphocytic leukaemia. Lancet. 1996 May 25;347(9013):1432-8. link to original article contains dosing details in abstract PubMed

FC

FC: Fludarabine, Cyclophosphamide

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
O'Brien et al. 2007 (GENTA GL303) 2001-2003 Phase 3 (C) OBL-FC Seems to have inferior ORR
Robak et al. 2010 (REACH) 2003-2007 Phase 3 (C) R-FC Inferior PFS
Robak et al. 2016 (COMPLEMENT 2) 2008-NR Phase 3 (C) O-FC Inferior PFS

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm in this context.

Chemotherapy

Supportive therapy

28-day cycle for 6 cycles

References

  1. GENTA GL303: O'Brien S, Moore JO, Boyd TE, Larratt LM, Skotnicki A, Koziner B, Chanan-Khan AA, Seymour JF, Bociek RG, Pavletic S, Rai KR. Randomized phase III trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2007 Mar 20;25(9):1114-20. Epub 2007 Feb 12. Erratum in: J Clin Oncol. 2008 Feb 10;26(5):820. link to original article contains dosing details in abstract PubMed NCT00024440
    1. Update: O'Brien S, Moore JO, Boyd TE, Larratt LM, Skotnicki AB, Koziner B, Chanan-Khan AA, Seymour JF, Gribben J, Itri LM, Rai KR. 5-year survival in patients with relapsed or refractory chronic lymphocytic leukemia in a randomized, phase III trial of fludarabine plus cyclophosphamide with or without oblimersen. J Clin Oncol. 2009 Nov 1;27(31):5208-12. Epub 2009 Sep 8. link to original article link to PMC article PubMed
  2. REACH: Robak T, Dmoszynska A, Solal-Céligny P, Warzocha K, Loscertales J, Catalano J, Afanasiev BV, Larratt L, Geisler CH, Montillo M, Zyuzgin I, Ganly PS, Dartigeas C, Rosta A, Maurer J, Mendila M, Saville MW, Valente N, Wenger MK, Moiseev SI. Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia. J Clin Oncol. 2010 Apr 1;28(10):1756-65. Epub 2010 Mar 1. link to original article contains dosing details in abstract PubMed content property of HemOnc.org NCT00090051
  3. 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. link to original article PubMed NCT00824265

HDMP

HDMP: High Dose, MethylPrednisolone

Regimen

Study Evidence
Burningham et al. 1964 Non-randomized, <20 pts

Glucocorticoid therapy

References

  1. Burningham RA, Restrepo A, Pugh RP, Brown EB, Schlossman SF, Khuri PD, Lessner HE, Harrington WJ. Weekly high-dosage glucocorticosteroid treatment of lymphocytic leukemias and lymphomas. N Engl J Med. 1964 May 28;270:1160-6. link to original article PubMed

Tisagenlecleucel monotherapy

Regimen

Study Evidence
Porter et al. 2011 Pilot

Note: this regimen is of historic interest in this context, this being the first clinical use of CAR-T-cell therapy. It is not FDA approved for this indication.

Immunotherapy

References

  1. Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011 Aug 25;365(8):725-33. Epub 2011 Aug 10. Erratum in: N Engl J Med. 2016 Mar 10;374(10):998. link to original article link to PMC article PubMed
    1. Update: Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A, June CH. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med. 2011 Aug 10;3(95):95ra73. link to original article link to PMC article PubMed
    2. Update: Porter DL, Hwang WT, Frey NV, Lacey SF, Shaw PA, Loren AW, Bagg A, Marcucci KT, Shen A, Gonzalez V, Ambrose D, Grupp SA, Chew A, Zheng Z, Milone MC, Levine BL, Melenhorst JJ, June CH. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 2015 Sep 2;7(303):303ra139. link to original article link to PMC article PubMed
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