Difference between revisions of "Chronic lymphocytic leukemia"

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m (Text replacement - "==Obinutuzumab (Gazyva) {" to "==Obinutuzumab monotherapy {")
m (Text replacement - "#Rituximab_.28Rituxan.29" to "#Rituximab_monotherapy")
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'''28-day cycle for up to 8 cycles'''
 
'''28-day cycle for up to 8 cycles'''
  
−
''Responders (PR or better) were randomized to [[#Observation_2|observation]] versus [[#Rituximab_.28Rituxan.29_2|rituximab maintenance]].''
+
''Responders (PR or better) were randomized to [[#Observation_2|observation]] versus [[#Rituximab_monotherapy_2|rituximab maintenance]].''
  
 
===References===
 
===References===
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'''21-day cycle for 6 to 8 cycles'''
 
'''21-day cycle for 6 to 8 cycles'''
  
−
''Patients were then randomized to [[#Rituximab_.28Rituxan.29_2|maintenance rituximab]] versus [[#Observation_2|observation]].''
+
''Patients were then randomized to [[#Rituximab_monotherapy_2|maintenance rituximab]] versus [[#Observation_2|observation]].''
  
 
===References===
 
===References===
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'''28-day cycle for 6 cycles'''
 
'''28-day cycle for 6 cycles'''
  
−
''Patients with a PR or CR at 3 months were treated with  [[#Rituximab_.28Rituxan.29_2|rituximab maintenance]].''
+
''Patients with a PR or CR at 3 months were treated with  [[#Rituximab_monotherapy_2|rituximab maintenance]].''
  
 
===Regimen #2 {{#subobject:523a98|Variant=1}}===
 
===Regimen #2 {{#subobject:523a98|Variant=1}}===
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'''28-day cycles for 6 cycles'''
 
'''28-day cycles for 6 cycles'''
  
−
''Treatment followed by [[#Rituximab_.28Rituxan.29_2|indefinite rituximab maintenance]].''
+
''Treatment followed by [[#Rituximab_monotherapy_2|indefinite rituximab maintenance]].''
  
 
===Regimen #2 {{#subobject:6dc0af|Variant=1}}===
 
===Regimen #2 {{#subobject:6dc0af|Variant=1}}===
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'''4-week course'''
 
'''4-week course'''
  
−
''Patients with PR/CR were randomized to [[#Rituximab_.28Rituxan.29_2|indefinite rituximab]] versus [[#Rituximab_.28Rituxan.29_3|salvage rituximab at time of progression]].''
+
''Patients with PR/CR were randomized to [[#Rituximab_monotherapy_2|indefinite rituximab]] versus [[#Rituximab_monotherapy_3|salvage rituximab at time of progression]].''
  
 
===Regimen #2 {{#subobject:d28cb1|Variant=1}}===
 
===Regimen #2 {{#subobject:d28cb1|Variant=1}}===
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'''28-day cycle for 6 cycles'''
 
'''28-day cycle for 6 cycles'''
  
−
''Patients with response or stable disease then received [[#Rituximab_.28Rituxan.29_2|maintenance rituximab]].''
+
''Patients with response or stable disease then received [[#Rituximab_monotherapy_2|maintenance rituximab]].''
  
 
===References===
 
===References===
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|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2668968/ Hochster et al. 2009 (ECOG1496)]
 
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2668968/ Hochster et al. 2009 (ECOG1496)]
 
|style="background-color:#00cd00"|Phase III
 
|style="background-color:#00cd00"|Phase III
−
|[[#Rituximab_.28Rituxan.29_2|Rituximab]]
+
|[[#Rituximab_monotherapy_2|Rituximab]]
 
|style="background-color:#ff0000"|Inferior PFS
 
|style="background-color:#ff0000"|Inferior PFS
 
|-
 
|-
 
|[http://onlinelibrary.wiley.com/doi/10.1002/ajh.23668/full Foà et al. 2014]
 
|[http://onlinelibrary.wiley.com/doi/10.1002/ajh.23668/full Foà et al. 2014]
 
|style="background-color:#00cd00"|Phase III
 
|style="background-color:#00cd00"|Phase III
−
|[[#Rituximab_.28Rituxan.29_2|Rituximab]]
+
|[[#Rituximab_monotherapy_2|Rituximab]]
 
|style="background-color:#ff0000"|Might have inferior PFS
 
|style="background-color:#ff0000"|Might have inferior PFS
 
|-
 
|-
 
|[http://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(16)30045-X/fulltext Greil et al. 2016 (AGMT CLL-8a)]
 
|[http://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(16)30045-X/fulltext Greil et al. 2016 (AGMT CLL-8a)]
 
|style="background-color:#00cd00"|Phase III
 
|style="background-color:#00cd00"|Phase III
−
|[[#Rituximab_.28Rituxan.29_2|Rituximab]]
+
|[[#Rituximab_monotherapy_2|Rituximab]]
 
|style="background-color:#ff0000"|Inferior PFS
 
|style="background-color:#ff0000"|Inferior PFS
 
|-
 
|-
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|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4900920/ Williams et al. 2016 (RESORT)]
 
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4900920/ Williams et al. 2016 (RESORT)]
 
|style="background-color:#00cd00"|Phase III
 
|style="background-color:#00cd00"|Phase III
−
|[[#Rituximab_.28Rituxan.29_3|Salvage rituximab]]
+
|[[#Rituximab_monotherapy_3|Salvage rituximab]]
 
|style="background-color:#00cd00"|Seems to have superior TTTF
 
|style="background-color:#00cd00"|Seems to have superior TTTF
 
|-
 
|-
 
|}
 
|}
  
−
''Intended for patients with SLL. Treatment preceded by [[#Rituximab_.28Rituxan.29|rituximab]].''
+
''Intended for patients with SLL. Treatment preceded by [[#Rituximab_monotherapy|rituximab]].''
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once every 13 weeks
 
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once every 13 weeks
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|}
 
|}
  
−
''Treatment preceded by [[#Rituximab_.28Rituxan.29|single-agent rituximab]]''
+
''Treatment preceded by [[#Rituximab_monotherapy|single-agent rituximab]]''
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
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|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161365/ Furman et al. 2014 (Study 116)]
 
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161365/ Furman et al. 2014 (Study 116)]
 
|style="background-color:#00cd00"|Phase III
 
|style="background-color:#00cd00"|Phase III
−
|[[#Rituximab_.28Rituxan.29_3|Rituximab]]
+
|[[#Rituximab_monotherapy_3|Rituximab]]
 
|style="background-color:#00cd00"|Seems to have superior OS
 
|style="background-color:#00cd00"|Seems to have superior OS
 
|-
 
|-
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|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4900920/ Williams et al. 2016 (RESORT)]
 
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4900920/ Williams et al. 2016 (RESORT)]
 
|style="background-color:#00cd00"|Phase III
 
|style="background-color:#00cd00"|Phase III
−
|[[#Rituximab_.28Rituxan.29_2|Maintenance rituximab]]
+
|[[#Rituximab_monotherapy_2|Maintenance rituximab]]
 
|style="background-color:#ff0000"|Seems to have inferior TTTF
 
|style="background-color:#ff0000"|Seems to have inferior TTTF
 
|-
 
|-
 
|}
 
|}
  
−
''Treatment in '''RESORT''' was preceded by [[#Rituximab_.28Rituxan.29|rituximab]] and is given at time of progression.''
+
''Treatment in '''RESORT''' was preceded by [[#Rituximab_monotherapy|rituximab]] and is given at time of progression.''
 
====Chemotherapy====
 
====Chemotherapy====
 
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 
*[[Rituximab (Rituxan)]] 375 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
Line 3,920: Line 3,920:
 
|[http://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(16)30045-X/fulltext Greil et al. 2016 (AGMT CLL-8a)]
 
|[http://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(16)30045-X/fulltext Greil et al. 2016 (AGMT CLL-8a)]
 
|style="background-color:#00cd00"|Phase III
 
|style="background-color:#00cd00"|Phase III
−
|[[#Rituximab_.28Rituxan.29_4|Rituximab]]
+
|[[#Rituximab_monotherapy_4|Rituximab]]
 
|style="background-color:#ff0000"|Inferior PFS
 
|style="background-color:#ff0000"|Inferior PFS
 
|-
 
|-

Revision as of 02:38, 19 August 2017

Use of this site is subject to you reading and agreeing with the terms set forth in the disclaimer.

Is there a regimen missing from this list? Would you like to share a different dosage/schedule or an additional reference for a regimen? Have you noticed an error? Do you have an idea that will help the site grow to better meet your needs and the needs of many others? You are invited to contribute to the site.

86 regimens on this page
131 variants on this page


Guidelines

ESMO

NCCN

Untreated, randomized data

Alemtuzumab (Campath)

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Regimen

Study Evidence Comparator Efficacy
Hillmen et al. 2007 (CAM 307) Phase III Chlorambucil Superior PFS

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

  • Alemtuzumab (Campath) as follows:
    • 3 mg IV once per day, then increased as tolerated in terms of infusion reactions to 10 mg IV once per day, and then to 30 mg IV once per day
    • Once 30 mg dose is tolerated: 30 mg IV over 2 hours, 3 times per week

Supportive medications

Up to 12 to 16 weeks of therapy

Total course varies depending on reference.

References

  1. 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 protocol PubMed

Bendamustine

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Regimen

Study Evidence Comparator Efficacy
Knauf et al. 2009 Phase III Chlorambucil Superior PFS

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

Note: these infusion instructions are for the Treanda formulation, which was discontinued on 3/31/2016.

  • Bendamustine 100 mg/m2 IV over 30 minutes once per day on days 1 & 2

28-day cycle for 6 cycles

References

  1. 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 verified protocol 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 PubMed
  2. Retrospective: Kolibaba KS, Sterchele JA, Joshi AD, Forsyth M, Alwon E, Beygi H, Kennealey GT. Demographics, treatment patterns, safety, and real-world effectiveness in patients aged 70 years and over with chronic lymphocytic leukemia receiving bendamustine with or without rituximab: a retrospective study. Ther Adv Hematol. 2013 Jun;4(3):157-71. link to PMC article PubMed

BR

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BR: Bendamustine, Rituximab

Regimen

Study Evidence Comparator Efficacy
Fischer et al. 2012 Phase II
Eichhorst et al. 2016 (GCLLSG CLL10) Phase III FCR Seems to have inferior PFS

Chemotherapy

  • Bendamustine 90 mg/m2 IV once per day on days 1 & 2
  • Rituximab (Rituxan) as follows:
    • Cycle 1: 375 mg/m2 IV once on day 0
    • Subsequent cycles: 500 mg/m2 IV once on day 1

28-day cycle for up to 6 cycles based on response and toxicity

References

  1. Fischer K, Cramer P, Busch R, Böttcher S, Bahlo J, Schubert J, Pflüger KH, Schott S, Goede V, Isfort S, von Tresckow J, Fink AM, Bühler A, Winkler D, Kreuzer KA, Staib P, Ritgen M, Kneba M, Döhner H, Eichhorst BF, Hallek M, Stilgenbauer S, Wendtner CM. Bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. 2012 Sep 10;30(26):3209-16. Epub 2012 Aug 6. link to original article contains verified protocol PubMed
  2. Retrospective: Kolibaba KS, Sterchele JA, Joshi AD, Forsyth M, Alwon E, Beygi H, Kennealey GT. Demographics, treatment patterns, safety, and real-world effectiveness in patients aged 70 years and over with chronic lymphocytic leukemia receiving bendamustine with or without rituximab: a retrospective study. Ther Adv Hematol. 2013 Jun;4(3):157-71. link to PMC article PubMed
  3. Eichhorst B, Fink AM, Bahlo J, Busch R, Kovacs G, Maurer C, Lange E, Köppler H, Kiehl M, Sökler M, Schlag R, Vehling-Kaiser U, Köchling G, Plöger C, Gregor M, Plesner T, Trneny M, Fischer K, Döhner H, Kneba M, Wendtner CM, Klapper W, Kreuzer KA, Stilgenbauer S, Böttcher S, Hallek M; international group of investigators; German CLL Study Group (GCLLSG). First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016 Jul;17(7):928-42. Epub 2016 May 20. link to original article PubMed

CAP

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CAP: Cyclophosphamide, Adriamycin (Doxorubicin), Prednisone

Regimen

Study Evidence Comparator Efficacy
Leporrier et al. 2001 Phase III CHOP Inferior ORR rate
Fludarabine Inferior ORR rate

Chemotherapy

Monthly cycle for 6 cycles

References

  1. 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 protocol PubMed

CC

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CC: Cladribine, Cyclophosphamide

Regimen #1

Study Evidence Comparator Efficacy
Robak et al. 2010 (PALG-CLL3) Phase III FC Seems not superior

Chemotherapy

Supportive medications

  • "No routine prophylaxis with antibiotics, antiviral agents, or growth factors."

28-day cycle for up to 6 cycles

Regimen #2

Study Evidence Comparator Efficacy
Robak et al. 2006 (PALG CLL2) Phase III Cladribine Might have superior CR rate
CMC Seems to have inferior CR rate

Chemotherapy

Supportive medications

  • No routine prophylactic antibiotics, antiviral agents, or growth factor administration was planned.

28-day cycle for up to 6 cycles

References

  1. 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 Leukemia Group (PALG CLL2). 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 verified protocol PubMed
    1. Update: Robak T, Blonski JZ, Gora-Tybor J, Calbecka M, Dwilewicz-Trojaczek J, Boguradzki P, Dmoszynska A, Kowal M, Kloczko J, Piszcz J, Stella-Holowiecka B, Sulek K, Kuliczkowski K, Potoczek S, Warzocha K, Lech-Maranda E, Skotnicki AB, Piotrowska M, Moskwa A, Zawilska K, Jamroziak K. Long-term results of the Polish Adult Leukemia Group PALG-CLL2 phase III randomized study comparing cladribine-based combinations in chronic lymphocytic leukemia. Leuk Lymphoma. 2014 Mar;55(3):606-10. Epub 2013 Nov 14. link to original article PubMed
  2. Robak T, Jamroziak K, Gora-Tybor J, Stella-Holowiecka B, Konopka L, Ceglarek B, Warzocha K, Seferynska I, Piszcz J, Calbecka M, Kostyra A, Dwilewicz-Trojaczek J, Dmoszyñska A, Zawilska K, Hellmann A, Zdunczyk A, Potoczek S, Piotrowska M, Lewandowski K, Blonski JZ. Comparison of cladribine plus cyclophosphamide with fludarabine plus cyclophosphamide as first-line therapy for chronic lymphocytic leukemia: a phase III randomized study by the Polish Adult Leukemia Group (PALG-CLL3 Study). J Clin Oncol. 2010 Apr 10;28(11):1863-9. Epub 2010 Mar 8. link to original article contains verified protocol PubMed

Chlorambucil (Leukeran)

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Regimen #1

Study Evidence Comparator Efficacy
Catovsky et al. 2007 (LRF CLL4) Phase III FC Inferior PFS
Fludarabine Seems not superior
Hillmen et al. 2015 (COMPLEMENT 1) Phase III Chlorambucil & Ofatumumab Inferior PFS

Chemotherapy

Supportive medications

  • 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 #2

Study Evidence Comparator Efficacy
Goede et al. 2014 (CLL11/BO21004) Phase III Chlorambucil & Obinutuzumab Inferior OS
Chlorambucil & Rituximab Inferior PFS
Burger et al. 2015 (RESONATE-2) Phase III Ibrutinib Inferior OS

Chemotherapy

28-day cycle for 6 to 12 cycles

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."

Regimen #3

Study Evidence Comparator Efficacy
Knauf et al. 2009 Phase III Bendamustine Inferior PFS

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

  • Chlorambucil (Leukeran) 0.8 mg/kg PO once per day on days 1 & 15
    • Alternate schedule: 0.4 mg/kg PO once per day on days 1 to 2, 15 to 16

28-day cycle for up to 6 cycles

Regimen #4

Study Evidence Comparator Efficacy
Eichhorst et al. 2009 (GCLLSG CLL5) Phase III Fludarabine Seems not superior

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 #5

Study Evidence Comparator Efficacy
Rai et al. 2000 (CALGB 9011) Phase III Chlorambucil & Fludarabine Not reported
Fludarabine Inferior PFS
Hillmen et al. 2007 (CAM 307) Phase III Alemtuzumab Inferior PFS

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

Regimen #6

Study Evidence Comparator Efficacy
Dighiero et al. 1998 Phase III Observation Seems to have superior PFS

This is one of two trials reported in the same paper; the other was comparing chlorambucil & prednisone vs. observation.

Chemotherapy

Continued until progression

References

  1. 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 verified protocol PubMed
  2. 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 protocol PubMed
  3. 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 (NCRI) 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 verified protocol PubMed
    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. 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 protocol PubMed
  5. 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 verified protocol 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 verified protocol PubMed
  6. 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 (GCLLSG). 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 protocol PubMed
  7. 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 verified protocol PubMed
    1. Update: Goede V, Fischer K, Engelke A, Schlag R, Lepretre S, Montero LF, Montillo M, Fegan C, Asikanius E, Humphrey K, Fingerle-Rowson G, Hallek M. Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study. Leukemia. 2015 Jul;29(7):1602-4. Epub 2015 Jan 30. link to original article PubMed
  8. 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 protocol PubMed
  9. 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 verified protocol link to PMC article PubMed

Chlorambucil & Obinutuzumab (GClb)

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GClb: GA101 (Obinutuzumab), Chlorambucil

Regimen

Study Evidence Comparator Efficacy
Goede et al. 2014 (CLL11/BO21004) Phase III Chlorambucil Superior OS
Chlorambucil & Rituximab Superior PFS

Chemotherapy

  • Obinutuzumab (Gazyva) as follows:
    • Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15
    • Cycles 2 to 6: 1000 mg IV once on day 1
  • Chlorambucil (Leukeran) 0.5 mg/kg PO once per day on days 1 & 15

28-day cycle for 6 cycles

References

  1. 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 verified protocol PubMed
    1. Update: Goede V, Fischer K, Engelke A, Schlag R, Lepretre S, Montero LF, Montillo M, Fegan C, Asikanius E, Humphrey K, Fingerle-Rowson G, Hallek M. Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study. Leukemia. 2015 Jul;29(7):1602-4. Epub 2015 Jan 30. link to original article PubMed

Chlorambucil & Ofatumumab

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Regimen

Study Evidence Comparator Efficacy
Hillmen et al. 2015 (COMPLEMENT 1) Phase III Chlorambucil Superior PFS

Chemotherapy

Supportive medications

28-day cycle for a minimum of 3 cycles, and then given until best response up to a maximum of 12 cycles

References

  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 protocol PubMed

Chlorambucil & Prednisone

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Regimen #1

Study Evidence Comparator Efficacy
Raphael et al. 1991 Phase III CVP Seems not superior

Chemotherapy

14-day cycle for up to 18 months

Regimen #2

Study Evidence Comparator Efficacy
Dighiero et al. 1998 Phase III Observation Superior PFS

Chemotherapy

1-month cycle for up to 36 months

References

  1. Raphael B, Andersen JW, Silber R, Oken M, Moore D, Bennett J, Bonner H, Hahn R, Knospe WH, Mazza J et al. 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 verified protocol PubMed
  2. 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 verified protocol PubMed

Chlorambucil & Rituximab (RClb, CLB-R)

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RClb: Rituximab, Chlorambucil
CLB-R: ChLoramBucil, Rituximab

Regimen

Study Evidence Comparator Efficacy
Goede et al. 2014 (CLL11/BO21004) Phase III Chlorambucil Superior PFS
Chlorambucil & Obinutuzumab Inferior PFS

Chemotherapy

28-day cycle for 6 cycles

References

  1. 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 verified protocol PubMed
    1. Update: Goede V, Fischer K, Engelke A, Schlag R, Lepretre S, Montero LF, Montillo M, Fegan C, Asikanius E, Humphrey K, Fingerle-Rowson G, Hallek M. Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study. Leukemia. 2015 Jul;29(7):1602-4. Epub 2015 Jan 30. link to original article PubMed

CHOP

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

Regimen

Study Evidence Comparator Efficacy
Leporrier et al. 2001 Phase III CAP Superior ORR rate
Fludarabine Seems not superior

Chemotherapy

28-day cycle for 6 cycles

References

  1. 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 protocol PubMed

Cladribine (Leustatin)

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Regimen

Study Evidence Comparator Efficacy
Robak et al. 2006 (PALG CLL2) Phase III CC Might have inferior CR rate
CMC Inferior CR rate

Chemotherapy

Supportive medications

  • No routine prophylactic antibiotics, antiviral agents, or growth factor administration was planned.

28-day cycle for up to 6 cycles

References

  1. 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 Leukemia Group (PALG CLL2). 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 verified protocol PubMed
    1. Update: Robak T, Blonski JZ, Gora-Tybor J, Calbecka M, Dwilewicz-Trojaczek J, Boguradzki P, Dmoszynska A, Kowal M, Kloczko J, Piszcz J, Stella-Holowiecka B, Sulek K, Kuliczkowski K, Potoczek S, Warzocha K, Lech-Maranda E, Skotnicki AB, Piotrowska M, Moskwa A, Zawilska K, Jamroziak K. Long-term results of the Polish Adult Leukemia Group PALG-CLL2 phase III randomized study comparing cladribine-based combinations in chronic lymphocytic leukemia. Leuk Lymphoma. 2014 Mar;55(3):606-10. Epub 2013 Nov 14. link to original article PubMed

CVP

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CVP: Cyclophosphamide, Vincristine, Prednisone

Regimen

Study Evidence Comparator Efficacy
Raphael et al. 1991 Phase III Chlorambucil & Prednisone Seems not superior

Chemotherapy

21-day cycle for up to 18 months

References

  1. Raphael B, Andersen JW, Silber R, Oken M, Moore D, Bennett J, Bonner H, Hahn R, Knospe WH, Mazza J et al. 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 protocol PubMed

FC

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FC: Fludarabine, Cyclophosphamide

Regimen #1

Study Evidence Comparator Efficacy
Geisler et al. 2014 (HOVON-68) Phase III FCA Inferior PFS

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 medications

OR

28-day cycle for 6 cycles

Regimen #2

Study Evidence Comparator Efficacy
Catovsky et al. 2007 (LRF CLL4) Phase III Chlorambucil Superior PFS
Fludarabine Superior PFS
Robak et al. 2010 (PALG-CLL3) Phase III CC Seems not superior
Hallek et al. 2010 (GCLLSG CLL8) Phase III FCR Inferior OS (*)

Note: efficacy for GCLLSG CLL8 is based on the updated 2016 results.

Chemotherapy

Supportive medications

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

28-day cycle for up to 6 cycles

Regimen #3

Study Evidence Comparator Efficacy
Flinn et al. 2007 (ECOG E2997) Phase III Fludarabine Superior PFS

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 #4, PO regimen

Study Evidence Comparator Efficacy
Catovsky et al. 2007 (LRF CLL4) Phase III Chlorambucil Superior PFS
Fludarabine Superior PFS

Chemotherapy

28-day cycle for up to 6 cycles

Regimen #5

Study Evidence Comparator Efficacy
Eichhorst et al. 2005 (GCLLSG CLL4) Phase III Fludarabine Superior PFS

Chemotherapy

Supportive medications

  • No routine antibiotic, antiviral, or growth factor use

28-day cycle for up to 6 cycles

References

  1. 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 protocol PubMed
  2. 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 verified protocol PubMed
    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. 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 (NCRI) 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 verified protocol PubMed
    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. Robak T, Jamroziak K, Gora-Tybor J, Stella-Holowiecka B, Konopka L, Ceglarek B, Warzocha K, Seferynska I, Piszcz J, Calbecka M, Kostyra A, Dwilewicz-Trojaczek J, Dmoszyñska A, Zawilska K, Hellmann A, Zdunczyk A, Potoczek S, Piotrowska M, Lewandowski K, Blonski JZ. Comparison of cladribine plus cyclophosphamide with fludarabine plus cyclophosphamide as first-line therapy for chronic lymphocytic leukemia: a phase III randomized study by the Polish Adult Leukemia Group (PALG-CLL3 Study). J Clin Oncol. 2010 Apr 10;28(11):1863-9. Epub 2010 Mar 8. link to original article contains verified protocol PubMed
  5. 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 protocol PubMed
    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
  6. 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 verified protocol PubMed

FCA; FCCam

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FCA: Fludarabine, Cyclophosphamide, Alemtuzumab
FCCam: Fludarabine, Cyclophosphamide, Campath (Alemtuzumab)

Regimen

Study Evidence Comparator Efficacy
Lepretre et al. 2012 (GOELAMS CLL2007FMP) Phase III FCR Seems not superior
Geisler et al. 2014 (HOVON-68) Phase III FC Superior PFS

GOELAMS CLL2007FMP was halted prematurely due to excess mortality. In HOVON-68, this regimen was intended for patients with previously untreated CLL diagnosed and in need of treatment according to the National Cancer Institute guidelines, 18 to 75 years 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 medications

OR

28-day cycle for 6 cycles

References

  1. Lepretre S, Aurran T, Mahé B, Cazin B, Tournilhac O, Maisonneuve H, Casasnovas O, Delmer A, Leblond V, Royer B, Corront B, Chevret S, Delépine R, Vaudaux S, Van Den Neste E, Béné MC, Letestu R, Cymbalista F, Feugier P. Excess mortality after treatment with fludarabine and cyclophosphamide in combination with alemtuzumab in previously untreated patients with chronic lymphocytic leukemia in a randomized phase 3 trial. Blood. 2012 May 31;119(22):5104-10. Epub 2012 Feb 14. link to original article PubMed
  2. 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 verified protocol PubMed

FCM

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FCM: Fludarabine, Cyclophosphamide, Mitoxantrone

Regimen

Study Evidence Comparator Efficacy
Hillmen et al. 2011 (NCRI CLL201) Randomized Phase II FCM-R Seems not superior

Chemotherapy

28-day cycle for 6 cycles

References

  1. 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 verified protocol PubMed

FCM-R; R-FCM

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

Regimen

Study Evidence Comparator Efficacy
Hillmen et al. 2011 (NCRI CLL201) Randomized Phase II FCM Seems not superior

Chemotherapy

28-day cycle for 6 cycles

References

  1. 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 verified protocol PubMed

FCR

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FCR: Fludarabine, Cyclophosphamide, Rituximab

Regimen #1

Study Evidence Comparator Efficacy
Hallek et al. 2010 (GCLLSG CLL8) Phase III FC Superior OS
Lepretre et al. 2012 (GOELAMS CLL2007FMP) Phase III FCCam Seems not superior
Schweighofer et al. 2013 (GCLLSG CLL7) Phase III Observation Superior EFS
Eichhorst et al. 2016 (GCLLSG CLL10) Phase III BR Seems to have superior PFS

Note: efficacy for GCLLSG CLL8 is based on the updated 2016 results.

Chemotherapy

Supportive medications

28-day cycle for 6 cycles

Regimen #2

Study Evidence Comparator Efficacy
Awan et al. 2014 (LUCID) Phase III FCR+L Seems not superior

Chemotherapy

  • Fludarabine (Fludara) as follows:
    • Cycle 1: 25 mg/m2 IV over at least 10 to 30 minutes once per day on days 2 to 4
    • Cycle 2 to 6: 25 mg/m2 IV over at least 10 to 30 minutes once per day on days 1 to 3
  • Cyclophosphamide (Cytoxan) as follows:
    • Cycle 1: 250 mg/m2 IV over at least 10 to 30 minutes once per day on days 2 to 4
    • Cycle 2 to 6: 250 mg/m2 IV over at least 10 to 30 minutes once per day on days 1 to 3
  • Rituximab (Rituxan) as follows:
    • Cycle 1: 50 mg/m2 IV over 4 hours once on day 1, then 450 mg/m2 IV once on day 3
    • Cycles 2 to 6: 500 mg/m2 IV once on day 1

Supportive medications

28-day cycle for 6 cycles

References

  1. 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 verified protocol PubMed
    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. Lepretre S, Aurran T, Mahé B, Cazin B, Tournilhac O, Maisonneuve H, Casasnovas O, Delmer A, Leblond V, Royer B, Corront B, Chevret S, Delépine R, Vaudaux S, Van Den Neste E, Béné MC, Letestu R, Cymbalista F, Feugier P. Excess mortality after treatment with fludarabine and cyclophosphamide in combination with alemtuzumab in previously untreated patients with chronic lymphocytic leukemia in a randomized phase 3 trial. Blood. 2012 May 31;119(22):5104-10. Epub 2012 Feb 14. link to original article PubMed
  3. Abstract: Carmen D Schweighofer, MD, Florence Cymbalista, MD, Carolin Müller, MD, Raymonde Busch, PhD, Raphael Porcher, PhD, Petra Langerbeins, MD, Bruno Cazin, MD, Anna-Maria Fink, MD, Brigitte Dreyfus, MD, Stefan Ibach, Stéphane Leprêtre, MD, Kirsten Fischer, MD, Ursula Vehling-Kaiser, MD, Barbara Eichhorst, MD, Manuela A. Bergmann, MD, Stephan Stilgenbauer, MD, Hartmut Döhner, MD, Veronique Leblond, MD, Michael Hallek, MD, and Vincent Levy, MD, PhD. Early Versus Deferred Treatment With Combined Fludarabine, Cyclophosphamide and Rituximab (FCR) Improves Event-Free Survival In Patients With High-Risk Binet Stage A Chronic Lymphocytic Leukemia – First Results Of a Randomized German-French Cooperative Phase III Trial. 2013 ASH Annual Symposium abstract 524 link to abstract
  4. Awan FT, Hillmen P, Hellmann A, Robak T, Hughes SG, Trone D, Shannon M, Flinn IW, Byrd JC; LUCID trial investigators. A randomized, open-label, multicentre, phase 2/3 study to evaluate the safety and efficacy of lumiliximab in combination with fludarabine, cyclophosphamide and rituximab versus fludarabine, cyclophosphamide and rituximab alone in subjects with relapsed chronic lymphocytic leukaemia. Br J Haematol. 2014 Nov;167(4):466-77. Epub 2014 Aug 8. link to original article contains verified protocol PubMed
  5. Eichhorst B, Fink AM, Bahlo J, Busch R, Kovacs G, Maurer C, Lange E, Köppler H, Kiehl M, Sökler M, Schlag R, Vehling-Kaiser U, Köchling G, Plöger C, Gregor M, Plesner T, Trneny M, Fischer K, Döhner H, Kneba M, Wendtner CM, Klapper W, Kreuzer KA, Stilgenbauer S, Böttcher S, Hallek M; international group of investigators; German CLL Study Group (GCLLSG). First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016 Jul;17(7):928-42. Epub 2016 May 20. link to original article PubMed

Fludarabine (Fludara)

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Regimen #1

Study Evidence Comparator Efficacy
Rai et al. 2000 (CALGB 9011) Phase III Chlorambucil Superior PFS
Chlorambucil & Fludarabine Seems not superior
Leporrier et al. 2001 Phase III CAP Superior ORR rate
CHOP Seems not superior
Eichorst et al. 2005 (GCLLSG CLL4) Phase III FC Inferior PFS
Flinn et al. 2007 (ECOG E2997) Phase III FC Inferior PFS
Catovsky et al. 2007 (LRF CLL4) Phase III Chlorambucil Seems not superior
FC Inferior PFS
Eichhorst et al. 2009 (GCLLSG CLL5) Phase III Chlorambucil Seems not superior
Bergmann et al. 2013 (GCLLSG CLL1) Phase III Observation Superior PFS

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 #2

Study Evidence Comparator Efficacy
Catovsky et al. 2007 (LRF CLL4) Phase III Chlorambucil Seems not superior
FC Inferior PFS

Chemotherapy

28-day cycle for up to 6 to 12 cycles

References

  1. 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 protocol PubMed
  2. 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 protocol PubMed
  3. 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 protocol PubMed
  4. 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 verified protocol PubMed
    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
  5. 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 (NCRI) 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 protocol PubMed
    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. 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 (GCLLSG). 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 protocol PubMed
  7. 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. 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. link to abstract

FR

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FR: Fludarabine, Rituximab

Regimen

Study Evidence Comparator Efficacy
Byrd et al. 2002 (CALGB 9712) Randomized Phase II F -> R Seems not superior

Chemotherapy

  • Fludarabine (Fludara) 25 mg/m2 IV over 20 to 30 minutes once per day on days 1 to 5
  • 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 medications

28-day cycle for 6 cycles

If restaging done 2 months after 6 cycles of therapy shows stable disease or better, patient were then treated with:

28-day course

References

  1. 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 protocol 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

Ibrutinib (Imbruvica)

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Regimen

Study Evidence Comparator Efficacy
O'Brien et al. 2013 (PCYC-1102) Phase Ib/II
Farooqui et al. 2014 Phase II
Burger et al. 2015 (RESONATE-2) Phase III Chlorambucil Superior OS
Langerbeins et al. 2015 (CLL12) Phase III Placebo TBD

PCYC-1102 was intended for elderly patients. Although both 420 mg and 840 mg doses were planned, the 840 mg cohort was closed due to findings of comparable efficacy in other studies. Farooqui et al. 2014 was intended for patients with TP53 aberrations. RESONATE-2 was intended for patients older than 65 years. CLL12 was intended for patients with asymptomatic Binet stage A CLL.

Chemotherapy

28-day cycles, given until progression of disease or unacceptable toxicity

References

  1. O'Brien S, Furman RR, Coutre SE, Sharman JP, Burger JA, Blum KA, Grant B, Richards DA, Coleman M, Wierda WG, Jones JA, Zhao W, Heerema NA, Johnson AJ, Izumi R, Hamdy A, Chang BY, Graef T, Clow F, Buggy JJ, James DF, Byrd JC. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol. 2014 Jan;15(1):48-58. Epub 2013 Dec 10. link to original article contains verified protocol link to PMC article PubMed
    1. Update: Byrd JC, Furman RR, Coutre SE, Burger JA, Blum KA, Coleman M, Wierda WG, Jones JA, Zhao W, Heerema NA, Johnson AJ, Shaw Y, Bilotti E, Zhou C, James DF, O'Brien S. Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015 Apr 16;125(16):2497-506. Epub 2015 Feb 19. link to original article link to PMC article PubMed
  2. Farooqui MZ, Valdez J, Martyr S, Aue G, Saba N, Niemann CU, Herman SE, Tian X, Marti G, Soto S, Hughes TE, Jones J, Lipsky A, Pittaluga S, Stetler-Stevenson M, Yuan C, Lee YS, Pedersen LB, Geisler CH, Calvo KR, Arthur DC, Maric I, Childs R, Young NS, Wiestner A. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol. 2015 Feb;16(2):169-76. Epub 2014 Dec 31. link to original article contains protocol link to PMC article PubMed
  3. 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 verified protocol link to PMC article PubMed
  4. Abstract: Petra Langerbeins, MD, Jasmin Bahlo, Christina Rhein, Paula Cramer, MD, Anna-Maria Fink, MD, Natali Pflug, MD, Julia von Tresckow, MD, Stephan Stilgenbauer, MD, Karl-Anton Kreuzer, Michael J. Eckart, MD, Ursula Vehling-Kaiser, MD, Rudolf Schlag, MD, Christina Balser, MD, Lothar Müller, MD, Clemens-Martin Wendtner, MD, Kirsten Fischer, MD, Barbara Eichhorst, MD and Michael Hallek, MD. Ibrutinib in Early Stage CLL: Preliminary Safety Results of a Placebo-Controlled Phase III Study. ASH Annual Meeting 2015 Abstract 2934. link to abstract

Obinutuzumab monotherapy

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Regimen #1, standard-dose (1000 mg)

Study Evidence Comparator Efficacy
Byrd et al. 2015 Randomized Phase II High-dose obinutuzumab Might have inferior ORR rate

Chemotherapy

  • Obinutuzumab (Gazyva) as follows:
    • Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15
    • Cycle 2 onwards: 1000 mg IV once on day 1

Supportive medications

21-day cycle up to 8 cycles

Regimen #2, high-dose (2000 mg)

Study Evidence Comparator Efficacy
Byrd et al. 2015 Randomized Phase II Standard-dose obinutuzumab Might have superior ORR rate

Chemotherapy

  • Obinutuzumab (Gazyva) as follows:
    • Cycle 1: either of the following:
      • 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once on day 3, then 2000 mg IV once per day on days 8 & 15
      • 100 mg IV once on day 1, then 1900 mg IV once on day 2, then 2000 mg IV once per day on days 8 & 15
    • Cycle 2 onwards: 2000 mg IV once on day 1

Supportive medications

21-day cycle up to 8 cycles

References

  1. Byrd JC, Flynn JM, Kipps TJ, Boxer M, Kolibaba KS, Carlile DJ, Fingerle-Rowson G, Tyson N, Hirata J, Sharman JP. Randomized phase 2 study of obinutuzumab monotherapy in symptomatic, previously untreated chronic lymphocytic leukemia. Blood. 2016 Jan 7;127(1):79-86. Epub 2015 Oct 15. link to original article contains verified protocol link to PMC article PubMed

Observation

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Regimen

Study Evidence Comparator Efficacy
Dighiero et al. 1998 Phase III Chlorambucil Seems to have inferior PFS
Chlorambucil & Prednisone Inferior PFS
Bergmann et al. 2013 (GCLLSG CLL1) Phase III Fludarabine Inferior PFS
Schweighofer et al. 2013 (GCLLSG CLL7) Phase III FCR Inferior EFS
Langerbeins et al. 2015 (CLL12) Phase III Ibrutinib TBD

No active treatment, also known as "watchful waiting".

References

  1. 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 verified protocol PubMed
  2. 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. 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. link to abstract
  3. Abstract: Carmen D Schweighofer, MD, Florence Cymbalista, MD, Carolin Müller, MD, Raymonde Busch, PhD, Raphael Porcher, PhD, Petra Langerbeins, MD, Bruno Cazin, MD, Anna-Maria Fink, MD, Brigitte Dreyfus, MD, Stefan Ibach, Stéphane Leprêtre, MD, Kirsten Fischer, MD, Ursula Vehling-Kaiser, MD, Barbara Eichhorst, MD, Manuela A. Bergmann, MD, Stephan Stilgenbauer, MD, Hartmut Döhner, MD, Veronique Leblond, MD, Michael Hallek, MD, and Vincent Levy, MD, PhD. Early Versus Deferred Treatment With Combined Fludarabine, Cyclophosphamide and Rituximab (FCR) Improves Event-Free Survival In Patients With High-Risk Binet Stage A Chronic Lymphocytic Leukemia – First Results Of a Randomized German-French Cooperative Phase III Trial. 2013 ASH Annual Symposium abstract 524 link to abstract
  4. Abstract: Petra Langerbeins, MD, Jasmin Bahlo, Christina Rhein, Paula Cramer, MD, Anna-Maria Fink, MD, Natali Pflug, MD, Julia von Tresckow, MD, Stephan Stilgenbauer, MD, Karl-Anton Kreuzer, Michael J. Eckart, MD, Ursula Vehling-Kaiser, MD, Rudolf Schlag, MD, Christina Balser, MD, Lothar Müller, MD, Clemens-Martin Wendtner, MD, Kirsten Fischer, MD, Barbara Eichhorst, MD and Michael Hallek, MD. Ibrutinib in Early Stage CLL: Preliminary Safety Results of a Placebo-Controlled Phase III Study. ASH Annual Meeting 2015 Abstract 2934. link to abstract

Untreated, non-randomized or retrospective data

Alemtuzumab & Methylprednisolone

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Regimen

Study Evidence
Pettitt et al. 2012 (NCRI CLL206) Phase II

Chemotherapy

16 week course

References

  1. Pettitt AR, Jackson R, Carruthers S, Dodd J, Dodd S, Oates M, Johnson GG, Schuh A, Matutes E, Dearden CE, Catovsky D, Radford JA, Bloor A, Follows GA, Devereux S, Kruger A, Blundell J, Agrawal S, Allsup D, Proctor S, Heartin E, Oscier D, Hamblin TJ, Rawstron A, Hillmen P. Alemtuzumab in combination with methylprednisolone is a highly effective induction regimen for patients with chronic lymphocytic leukemia and deletion of TP53: final results of the national cancer research institute CLL206 trial. J Clin Oncol. 2012 May 10;30(14):1647-55. Epub 2012 Apr 9. link to original article PubMed

Chlorambucil & Rituximab (RClb, CLB-R)

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RClb: Rituximab, Chlorambucil
CLB-R: ChLoramBucil, Rituximab

Regimen #1

Study Evidence
Hillmen et al. 2014 (NCRI CLL208) Phase II

Chemotherapy

28-day cycles for 6 cycles

Patients not achieving CR could have up to 6 more cycles of chlorambucil alone.

Regimen #2

Study Evidence
Foà et al. 2014 Phase II

Chemotherapy

28-day cycle for up to 8 cycles

Responders (PR or better) were randomized to observation versus rituximab maintenance.

References

  1. Foà R, Del Giudice I, Cuneo A, Del Poeta G, Ciolli S, Di Raimondo F, Lauria F, Cencini E, Rigolin GM, Cortelezzi A, Nobile F, Callea V, Brugiatelli M, Massaia M, Molica S, Trentin L, Rizzi R, Specchia G, Di Serio F, Orsucci L, Ambrosetti A, Montillo M, Zinzani PL, Ferrara F, Morabito F, Mura MA, Soriani S, Peragine N, Tavolaro S, Bonina S, Marinelli M, De Propris MS, Starza ID, Piciocchi A, Alietti A, Runggaldier EJ, Gamba E, Mauro FR, Chiaretti S, Guarini A. Chlorambucil plus rituximab with or without maintenance rituximab as first-line treatment for elderly chronic lymphocytic leukemia patients. Am J Hematol. 2014 May;89(5):480-6. Epub 2014 Feb 18. link to original article contains verified protocol PubMed
  2. Hillmen P, Gribben JG, Follows GA, Milligan D, Sayala HA, Moreton P, Oscier DG, Dearden CE, Kennedy DB, Pettitt AR, Nathwani A, Varghese A, Cohen D, Rawstron A, Oertel S, Pocock CF. Rituximab Plus Chlorambucil As First-Line Treatment for Chronic Lymphocytic Leukemia: Final Analysis of an Open-Label Phase II Study. J Clin Oncol. 2014 Apr 20;32(12):1236-41. Epub 2014 Mar 17. link to original article contains verified protocol link to PMC article PubMed

Cladribine (Leustatin)

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Regimen

Study Evidence
Saven et al. 1995 Phase II

Chemotherapy

28 to 35-day cycles, repeated until maximum response or limiting toxicity

References

  1. Saven A, Lemon RH, Kosty M, Beutler E, Piro LD. 2-Chlorodeoxyadenosine activity in patients with untreated chronic lymphocytic leukemia. J Clin Oncol. 1995 Mar;13(3):570-4. link to original article contains protocol PubMed

CVP

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CVP: Cyclophosphamide, Vincristine, Prednisone

Regimen

Study Evidence
Hochster et al. 2009 (ECOG1496) Non-randomized

Chemotherapy

21-day cycle for 6 to 8 cycles

Patients were then randomized to maintenance rituximab versus observation.

References

  1. 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 verified protocol link to PMC article PubMed

FCM

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FCM: Fludarabine, Cyclophosphamide, Mitoxantrone

Regimen

Study Evidence
Bosch et al. 2008 Phase II

Chemotherapy

Supportive medications

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 verified protocol PubMed

FCM-R; R-FCM

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

Regimen #1

Study Evidence
Bosch et al. 2009 Phase II

Chemotherapy

Supportive medications

28-day cycle for 6 cycles

Patients with a PR or CR at 3 months were treated with rituximab maintenance.

Regimen #2

Study Evidence
Faderl et al. 2009 Phase II

Chemotherapy

  • 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
  • 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 medications

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 verified protocol PubMed
    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 verified protocol 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 <70 Years. Leuk Res. 2010 Mar;34(3):284-8. Epub 2009 Jul 30. link to original article contains protocol link to PMC article PubMed

FCR

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FCR: Fludarabine, Cyclophosphamide, Rituximab

Regimen #1, "FCR-Lite"

Study Evidence
Foon et al. 2009 Phase II

Chemotherapy

  • Fludarabine (Fludara) as follows:
    • Cycle 1: 20 mg/m2 IV over 30 minutes once per day on days 2 to 4
    • Cycles 2 to 6: 20 mg/m2 IV over 30 minutes once per day on days 1 to 3
  • Cyclophosphamide (Cytoxan) as follows:
    • Cycle 1: 150 mg/m2 IV over 60 minutes once per day on days 2 to 4
    • Cycles 2 to 6: 150 mg/m2 IV over 60 minutes once per day on days 1 to 3
  • Rituximab (Rituxan) as follows:
    • Cycle 1: 375 mg/m2 IV once on day 1, then 500 mg/m2 IV once on day 14
    • Cycles 2 to 6: 500 mg/m2 IV once per day on days 1 & 14

Supportive medications

28-day cycles for 6 cycles

Treatment followed by indefinite rituximab maintenance.

Regimen #2

Study Evidence
Tam et al. 2006 Phase II

Chemotherapy

28-day cycles for up to 6 cycles or "attainment of maximum response"

Regimen #3

Study Evidence
Keating et al. 2005 Phase II

Chemotherapy

Supportive medications

28-day cycles for 6 cycles

References

  1. Keating MJ, O'Brien S, Albitar M, Lerner S, Plunkett W, Giles F, Andreeff M, Cortes J, Faderl S, Thomas D, Koller C, Wierda W, Detry MA, Lynn A, Kantarjian H. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol. 2005 Jun 20;23(18):4079-88. Epub 2005 Mar 14. link to original article contains verified protocol PubMed
    1. Update: Tam CS, O'Brien S, Wierda W, Kantarjian H, Wen S, Do KA, Thomas DA, Cortes J, Lerner S, Keating MJ. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood. 2008 Aug 15;112(4):975-80. Epub 2008 Apr 14. link to original article link to PMC article PubMed
    2. Update and Subgroup Analysis: Thompson PA, Tam CS, O'Brien SM, Wierda WG, Stingo F, Plunkett W, Smith SC, Kantarjian HM, Freireich EJ, Keating MJ. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood. 2016 Jan 21;127(3):303-9. Epub 2015 Oct 22. link to original article link to PMC article PubMed
  2. Tam CS, Wolf M, Prince HM, Januszewicz EH, Westerman D, Lin KI, Carney D, Seymour JF. Fludarabine, cyclophosphamide, and rituximab for the treatment of patients with chronic lymphocytic leukemia or indolent non-Hodgkin lymphoma. Cancer. 2006 Jun 1;106(11):2412-20. link to original article contains verified protocol PubMed
  3. Foon KA, Boyiadzis M, Land SR, Marks S, Raptis A, Pietragallo L, Meisner D, Laman A, Sulecki M, Butchko A, Schaefer P, Lenzer D, Tarhini A. Chemoimmunotherapy with low-dose fludarabine and cyclophosphamide and high dose rituximab in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009 Feb 1;27(4):498-503. Epub 2008 Dec 15. link to original article contains verified protocol PubMed
    1. Update: Foon KA, Mehta D, Lentzsch S, Kropf P, Marks S, Lenzner D, Pietragallo L, Sulecki M, Tarhini A, Boyiadzis M. Long-term results of chemoimmunotherapy with low-dose fludarabine, cyclophosphamide and high-dose rituximab as initial treatment for patients with chronic lymphocytic leukemia. Blood. 2012 Mar 29;119(13):3184-5. link to original article PubMed

Fludarabine & Prednisone

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Regimen

Study Evidence
O'Brien et al. 1993 Phase II

Chemotherapy

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 protocol 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

G-B

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G-B: Gazyva (Obinutuzumab), Bendamustine

Regimen

Study Evidence
Brown et al. 2015 (GALTON) Non-randomized

Chemotherapy

  • Obinutuzumab (Gazyva) as follows:
    • Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once on days 8 & 15
    • Cycles 2 to 6: 1000 mg IV once on day 1
  • Bendamustine as follows:
    • Cycle 1: 90 mg/m2 IV once per day on days 2 & 3
    • Cycles 2 to 6: 90 mg/m2 IV once per day on days 1 &2

Supportive medications

28-day cycle for 6 cycles

References

  1. Brown JR, O'Brien S, Kingsley CD, Eradat H, Pagel JM, Lymp J, Hirata J, Kipps TJ. Obinutuzumab plus fludarabine/cyclophosphamide or bendamustine in the initial therapy of CLL patients: the phase 1b GALTON trial. Blood. 2015 Apr 30;125(18):2779-85. Epub 2015 Mar 13. link to original article contains verified protocol link to PMC article PubMed

G-FC

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G-FC: Gazyva (Obinutuzumab), Fludarabine, Cyclophosphamide

Regimen

Study Evidence
Brown et al. 2015 (GALTON) Non-randomized

Chemotherapy

  • Obinutuzumab (Gazyva) as follows:
    • Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once on days 8 & 15
    • Cycles 2 to 6: 1000 mg IV once on day 1
  • Fludarabine (Fludara) as follows:
    • Cycle 1: 25 mg/m2 IV once per day on days 2 to 4
    • Cycles 2 to 6: 25 mg/m2 IV once per day on days 1 to 3
  • Cyclophosphamide (Cytoxan) as follows:
    • Cycle 1: 250 mg/m2 IV once per day on days 2 to 4
    • Cycles 2 to 6: 250 mg/m2 IV once per day on days 1 to 3

Supportive medications

28-day cycle for 6 cycles

References

  1. Brown JR, O'Brien S, Kingsley CD, Eradat H, Pagel JM, Lymp J, Hirata J, Kipps TJ. Obinutuzumab plus fludarabine/cyclophosphamide or bendamustine in the initial therapy of CLL patients: the phase 1b GALTON trial. Blood. 2015 Apr 30;125(18):2779-85. Epub 2015 Mar 13. link to original article contains verified protocol link to PMC article PubMed

HDMP-R

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HDMP-R: High Dose, MethylPrednisolone, Rituximab

Regimen

Study Evidence
Castro et al. 2009 Phase II

Chemotherapy

  • Methylprednisolone (Solumedrol) 1000 mg/m2 IV over 90 minutes once per day on days 1 to 3
  • Rituximab (Rituxan) as follows:
    • Cycle 1: 375 mg/m2 total divided over 2 days IV once on days 1 & 2, then 375 mg/m2 IV once per day on days 8, 15, 22
    • Cycles 2 & 3: 375 mg/m2 IV once per day on days 1, 8, 15, 22

Supportive medications

28-day cycles for 3 cycles

References

  1. Castro JE, James DF, Sandoval-Sus JD, Jain S, Bole J, Rassenti L, Kipps TJ. Rituximab in combination with high-dose methylprednisolone for the treatment of chronic lymphocytic leukemia. Leukemia. 2009 Oct;23(10):1779-89. Epub 2009 Aug 20. contains protocol link to PMC article PubMed

Idelalisib & Rituximab

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Regimen

Study Evidence
O'Brien et al. 2015 Phase II

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

Chemotherapy

48-week treatment; patients who had not progressed could continue on an extension study

References

  1. 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 verified protocol link to PMC article PubMed

Lenalidomide monotherapy

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Regimen #1

Study Evidence
Badoux et al. 2011 Phase II

Chemotherapy

  • 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

Continue until progression

Regimen #2

Study Evidence
Chen et al. 2010 Phase II

Chemotherapy

  • 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
    • Subsequent cycles: Increased if tolerated to 10 mg PO once per day on days 1 to 21

Supportive medications

28-day cycles

References

  1. 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 verified protocol link to PMC article PubMed
    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. 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 protocol 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

Lenalidomide & Rituximab

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Regimen #1

Study Evidence
James et al. 2014 Phase II

Chemotherapy

  • Lenalidomide (Revlimid) with escalation in the absence of grade 2 or higher toxicities as follows:
    • Cycle 1: 2.5 mg PO once per day on days 1 to 7, then 5 mg PO once per day on days 8 to 21
    • Cycle 2: 5 mg PO once per day on days 1 to 21
    • Subsequent cycles: 10 mg PO once per day on days 1 to 21
  • Rituximab (Rituxan) as follows:
    • Cycle 1: 375 mg/m2 IV once on days 31 & 33
    • Cycle 2: 375 mg/m2 IV once per week on weeks 1 to 4
    • Subsequent cycles: 375 mg/m2 IV once on day 1

Supportive medications

Cycle 1 is 35 days, then 28-day cycle up to 7 total cycles

Regimen #2

Study Evidence
Fowler et al. 2014 Phase II

This combination was only studied in SLL (as opposed to CLL). Lenalidomide is dose-escalated to avoid tumor flare.

Chemotherapy

28-day cycle for up to 12 cycles

References

  1. James DF, Werner L, Brown JR, Wierda WG, Barrientos JC, Castro JE, Greaves A, Johnson AJ, Rassenti LZ, Rai KR, Neuberg D, Kipps TJ. Lenalidomide and Rituximab for the Initial Treatment of Patients With Chronic Lymphocytic Leukemia: A Multicenter Clinical-Translational Study From the Chronic Lymphocytic Leukemia Research Consortium. J Clin Oncol. 2014 Jul 1;32(19):2067-73. Epub 2014 May 27. link to original article contains verified protocol link to PMC article PubMed
  2. Fowler NH, Davis RE, Rawal S, Nastoupil L, Hagemeister FB, McLaughlin P, Kwak LW, Romaguera JE, Fanale MA, Fayad LE, Westin JR, Shah J, Orlowski RZ, Wang M, Turturro F, Oki Y, Claret LC, Feng L, Baladandayuthapani V, Muzzafar T, Tsai KY, Samaniego F, Neelapu SS. Safety and activity of lenalidomide and rituximab in untreated indolent lymphoma: an open-label, phase 2 trial. Lancet Oncol. 2014 Nov;15(12):1311-8. Epub 2014 Oct 15. link to original article contains protocol link to PMC article PubMed

O-FC

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O-FC: Ofatumumab, Fludarabine, Cyclophosphamide

Regimen

Study Evidence
Wierda et al. 2011 (407 Study) Phase II

Chemotherapy

  • Ofatumumab (Arzerra) as follows:
    • Cycle 1: 300 mg IV once on day 1
    • Cycles 2 to 6: 500 mg or 1000 mg IV once on day 1
  • Fludarabine (Fludara) as follows:
    • Cycle 1: 25 mg/m2 IV once per day on days 2 to 4
    • Cycles 2 to 6: 25 mg/m2 IV once per day on days 1 to 3 (note: there was ambiguity in Wierda et al. 2011 about whether both fludarabine and cyclophosphamide are given three days per cycle, or whether fludarabine is given once per cycle and only cyclophosphamide is given three days per cycle)
  • Cyclophosphamide (Cytoxan) as follows:
    • Cycle 1: 250 mg/m2 IV once per day on days 2 to 4
    • Cycle 2 to 6: 250 mg/m2 IV once per day on days 1 to 3

Supportive medications

28-day cycle for 6 cycles

References

  1. Wierda WG, Kipps TJ, Dürig J, Griskevicius L, Stilgenbauer S, Mayer J, Smolej L, Hess G, Griniute R, Hernandez-Ilizaliturri FJ, Padmanabhan S, Gorczyca M, Chang CN, Chan G, Gupta I, Nielsen TG, Russell CA; 407 Study Investigators. Chemoimmunotherapy with O-FC in previously untreated patients with chronic lymphocytic leukemia. Blood. 2011 Jun 16;117(24):6450-8. Epub 2011 Apr 15. link to original article contains verified protocol link to PMC article PubMed

PCO

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PCO: Pentostatin, Cyclophosphamide, Ofatumumab

Regimen

Study Evidence
Tedeschi et al. 2015 Phase II
Strati et al. 2016 Phase II

Chemotherapy

21-day cycle for 6 cycles

Patients in Strati et al. 2016 proceeded to ofatumumab consolidation.

References

  1. Shanafelt T, Lanasa MC, Call TG, Beaven AW, Leis JF, LaPlant B, Bowen D, Conte M, Jelinek DF, Hanson CA, Kay NE, Zent CS. Ofatumumab-based chemoimmunotherapy is effective and well tolerated in patients with previously untreated chronic lymphocytic leukemia (CLL). Cancer. 2013 Nov 1;119(21):3788-96. Epub 2013 Aug 6. Erratum in: Cancer. 2014 Mar 15;120(6):926. Dosage error in article text. link to PMC article PubMed
  2. Tedeschi A, Rossi D, Motta M, Quaresmini G, Rossi M, Coscia M, Anastasia A, Rossini F, Cortelezzi A, Nador G, Scarfò L, Cairoli R, Frustaci AM, Dalceggio D, Picardi P, De Paoli L, Orlandi E, Rambaldi A, Massaia M, Gaidano G, Montillo M; Rete Ematologica Lombarda–CLL Workgroup. A phase II multi-center trial of pentostatin plus cyclophosphamide with ofatumumab in older previously untreated chronic lymphocytic leukemia patients. Haematologica. 2015 Dec;100(12):e501-4. Epub 2015 Aug 20. link to original article contains verified protocol link to PMC article PubMed
  3. Strati P, Lanasa M, Call TG, Leis JF, Brander DM, LaPlant BR, Pettinger AM, Ding W, Parikh SA, Hanson CA, Chanan-Khan AA, Bowen DA, Conte M, Kay NE, Shanafelt TD. Ofatumumab monotherapy as a consolidation strategy in patients with previously untreated chronic lymphocytic leukaemia: a phase 2 trial. Lancet Haematol. 2016 Sep;3(9):e407-14. Epub 2016 Aug 1. link to original article contains protocol PubMed

PCR

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PCR: Pentostatin, Cyclophosphamide, Rituximab

Regimen #1

Study Evidence
Samaniego et al. 2015 Phase II

This regimen was specifically studied in SLL, not CLL.

Chemotherapy

Supportive medications

21-day cycle for 6 cycles

Regimen #2

Study Evidence
Kay et al. 2007 Phase II
Shanafelt et al. 2007 Phase II

Chemotherapy

Supportive medications

28-day cycle for 6 cycles

References

  1. Kay NE, Geyer SM, Call TG, Shanafelt TD, Zent CS, Jelinek DF, Tschumper R, Bone ND, Dewald GW, Lin TS, Heerema NA, Smith L, Grever MR, Byrd JC. Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia. Blood. 2007 Jan 15;109(2):405-11. Epub 2006 Sep 28. link to original article contains protocol link to PMC article PubMed
  2. Shanafelt TD, Lin T, Geyer SM, Zent CS, Leung N, Kabat B, Bowen D, Grever MR, Byrd JC, Kay NE. Pentostatin, cyclophosphamide, and rituximab regimen in older patients with chronic lymphocytic leukemia. Cancer. 2007 Jun 1;109(11):2291-8. link to original article PubMed
  3. Samaniego F, Hagemeister F, Romaguera JE, Fanale MA, Pro B, McLaughlin P, Rodriguez MA, Neelapu SS, Fayad L, Younes A, Feng L, Berkova Z, Khashab T, Sehgal L, Vega-Vasquez F, Kwak LW. Pentostatin, cyclophosphamide and rituximab for previously untreated advanced stage, low-grade B-cell lymphomas. Br J Haematol. 2015 Jun;169(6):814-23. Epub 2015 Mar 31. link to original article contains verified protocol link to PMC article PubMed

Rituximab monotherapy

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Regimen #1

Study Evidence
Williams et al. 2016 (RESORT) Non-randomized

This regimen was intended for patients with SLL.

Chemotherapy

  • Rituximab (Rituxan) 375 mg/m2 IV once per week; initial infusion rate of 50 mg/H, then increased as tolerated by 50 mg/H every 30 minutes, to a maximum rate of 300 mg/H

Supportive medications

4-week course

Patients with PR/CR were randomized to indefinite rituximab versus salvage rituximab at time of progression.

Regimen #2

Study Evidence
Hainsworth et al. 2003 Phase II

Chemotherapy

  • Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1, 8, 15, 22
    • Optional alternate initial dosing for patients with WBC count greater than 100 x 109/L: 100 mg IV once on day 1, with remainder of the 375 mg/m2 dosage given on day 2
    • Initial infusion rate with first dose of rituximab: 50 mg/hr, then increased as tolerated by 50 mg/hr every 30 minutes to a maximum of 400 mg/hr. Infusion rate with subsequent doses of rituximab (if first dose tolerated): 100 mg/hr, then increased as tolerated by 100 mg/hr every 30 minutes to a maximum of 400 mg/hr.

Supportive medications

28-day cycle for 6 cycles

Patients with response or stable disease then received maintenance rituximab.

References

  1. Hainsworth JD, Litchy S, Barton JH, Houston GA, Hermann RC, Bradof JE, Greco FA; Minnie Pearl Cancer Research Network. Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol. 2003 May 1;21(9):1746-51. link to original article PubMed
  2. Williams ME, Hong F, Gascoyne RD, Wagner LI, Krauss JC, Habermann TM, Swinnen LJ, Schuster SJ, Peterson CG, Sborov MD, Martin SE, Weiss M, Ehmann WC, Horning SJ, Kahl BS. Rituximab extended schedule or retreatment trial for low tumour burden non-follicular indolent B-cell non-Hodgkin lymphomas: Eastern Cooperative Oncology Group Protocol E4402. Br J Haematol. 2016 Jun;173(6):867-75. Epub 2016 Mar 11. link to original article contains protocol link to PMC article PubMed

Ruxolitinib (Jakafi)

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Regimen

Study Evidence
Jain et al. 2017 Phase II

Note: this was a trial focused on symptom control, not efficacy.

Chemotherapy

References

  1. Jain P, Keating M, Renner S, Cleeland C, Xuelin H, Gonzalez GN, Harris D, Li P, Liu Z, Veletic I, Rozovski U, Jain N, Thompson P, Bose P, DiNardo C, Ferrajoli A, O'Brien S, Burger J, Wierda W, Verstovsek S, Kantarjian H, Estrov Z. Ruxolitinib for symptom control in patients with chronic lymphocytic leukaemia: a single-group, phase 2 trial. Lancet Haematol. 2017 Jan 11. [Epub ahead of print] link to original article contains protocol link to PMC article PubMed

Consolidation and/or maintenance after upfront therapy

Alemtuzumab (Campath)

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Regimen

Study Evidence
Varghese et al. 2017 (NCRN CLL 207) Phase II

Chemotherapy

6 week course

References

  1. Varghese AM, Howard DR, Pocock C, Rawstron AC, Follows G, McCarthy H, Dearden C, Fegan C, Milligan D, Smith AF, Gregory W, Hillmen P; NCRI CLL Sub-Group. Eradication of minimal residual disease improves overall and progression-free survival in patients with chronic lymphocytic leukaemia, evidence from NCRN CLL207: a phase II trial assessing alemtuzumab consolidation. Br J Haematol. 2017 Feb;176(4):573-582. Epub 2016 Dec 29. link to original article contains protocol PubMed

Observation

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Regimen

Study Evidence Comparator Efficacy
Hochster et al. 2009 (ECOG1496) Phase III Rituximab Inferior PFS
Foà et al. 2014 Phase III Rituximab Might have inferior PFS
Greil et al. 2016 (AGMT CLL-8a) Phase III Rituximab Inferior PFS

No further treatment; used as a comparator arm. Preceded by CVP in ECOG1496, Clb-R in Foà et al. 2014, and "rituximab-containing chemoimmunotherapy" in AGMT CLL-8a.

References

  1. 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 verified protocol link to PMC article PubMed
  2. Foà R, Del Giudice I, Cuneo A, Del Poeta G, Ciolli S, Di Raimondo F, Lauria F, Cencini E, Rigolin GM, Cortelezzi A, Nobile F, Callea V, Brugiatelli M, Massaia M, Molica S, Trentin L, Rizzi R, Specchia G, Di Serio F, Orsucci L, Ambrosetti A, Montillo M, Zinzani PL, Ferrara F, Morabito F, Mura MA, Soriani S, Peragine N, Tavolaro S, Bonina S, Marinelli M, De Propris MS, Starza ID, Piciocchi A, Alietti A, Runggaldier EJ, Gamba E, Mauro FR, Chiaretti S, Guarini A. Chlorambucil plus rituximab with or without maintenance rituximab as first-line treatment for elderly chronic lymphocytic leukemia patients. Am J Hematol. 2014 May;89(5):480-6. Epub 2014 Feb 18. link to original article contains verified protocol PubMed
  3. Greil R, Obrtlíková P, Smolej L, Kozák T, Steurer M, Andel J, Burgstaller S, Mikušková E, Gercheva L, Nösslinger T, Papajík T, Ladická M, Girschikofsky M, Hrubiško M, Jäger U, Fridrik M, Pecherstorfer M, Králiková E, Burcoveanu C, Spasov E, Petzer A, Mihaylov G, Raynov J, Oexle H, Zabernigg A, Flochová E, Palášthy S, Stehlíková O, Doubek M, Altenhofer P, Pleyer L, Melchardt T, Klingler A, Mayer J, Egle A. Rituximab maintenance versus observation alone in patients with chronic lymphocytic leukaemia who respond to first-line or second-line rituximab-containing chemoimmunotherapy: final results of the AGMT CLL-8a Mabtenance randomised trial. Lancet Haematol. 2016 Jul;3(7):e317-29. Epub 2016 Jun 16. link to original article contains protocol PubMed

Ofatumumab (Arzerra)

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Regimen

Study Evidence
Strati et al. 2016 Phase II

Treatment preceded by PCO x 6.

Chemotherapy

28-day cycle for 6 cycles

References

  1. Strati P, Lanasa M, Call TG, Leis JF, Brander DM, LaPlant BR, Pettinger AM, Ding W, Parikh SA, Hanson CA, Chanan-Khan AA, Bowen DA, Conte M, Kay NE, Shanafelt TD. Ofatumumab monotherapy as a consolidation strategy in patients with previously untreated chronic lymphocytic leukaemia: a phase 2 trial. Lancet Haematol. 2016 Sep;3(9):e407-14. Epub 2016 Aug 1. link to original article contains protocol PubMed

Rituximab monotherapy

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Regimen #1

Study Evidence Comparator Efficacy
Bosch et al. 2009 Phase II
Greil et al. 2016 (AGMT CLL-8a) Phase III Observation Superior PFS

Treatment in Bosch et al. 2009 preceded by R-FCM. Treatment in AGMT CLL-8a preceded by "rituximab-containing chemoimmunotherapy".

Chemotherapy

2 years total (8 doses)

Regimen #2

Study Evidence Comparator Efficacy
Williams et al. 2016 (RESORT) Phase III Salvage rituximab Seems to have superior TTTF

Intended for patients with SLL. Treatment preceded by rituximab.

Chemotherapy

Continued until treatment failure

Regimen #3

Study Evidence Comparator Efficacy
Foà et al. 2014 Phase III Observation Might have superior PFS

Treatment preceded by Clb-R.

Chemotherapy

12 doses total

Regimen #4

Study Evidence Comparator Efficacy
Hochster et al. 2009 (ECOG1496) Phase III Observation Superior PFS

This trial included patients with SLL, but they were grouped into an "other" non-follicular lymphoma category. Treatment preceded by CVP.

Chemotherapy

One course every 6 months (16 total doses)

Regimen #5

Study Evidence
Foon et al. 2009 Phase II

Treatment preceded by FCR-Lite for 6.

Chemotherapy

Continued until relapse

Regimen #6

Study Evidence
Hainsworth et al. 2003 Phase II

Treatment preceded by single-agent rituximab

Chemotherapy

Supportive medications

6-month cycle for 4 cycles

References

  1. Hainsworth JD, Litchy S, Barton JH, Houston GA, Hermann RC, Bradof JE, Greco FA; Minnie Pearl Cancer Research Network. Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol. 2003 May 1;21(9):1746-51. link to original article PubMed
  2. Foon KA, Boyiadzis M, Land SR, Marks S, Raptis A, Pietragallo L, Meisner D, Laman A, Sulecki M, Butchko A, Schaefer P, Lenzer D, Tarhini A. Chemoimmunotherapy with low-dose fludarabine and cyclophosphamide and high dose rituximab in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009 Feb 1;27(4):498-503. Epub 2008 Dec 15. link to original article contains verified protocol PubMed
    1. Update: Foon KA, Mehta D, Lentzsch S, Kropf P, Marks S, Lenzner D, Pietragallo L, Sulecki M, Tarhini A, Boyiadzis M. Long-term results of chemoimmunotherapy with low-dose fludarabine, cyclophosphamide and high-dose rituximab as initial treatment for patients with chronic lymphocytic leukemia. Blood. 2012 Mar 29;119(13):3184-5. link to original article PubMed
  3. 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 verified protocol link to PMC article PubMed
  4. 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 verified protocol PubMed
    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 verified protocol PubMed
  5. Foà R, Del Giudice I, Cuneo A, Del Poeta G, Ciolli S, Di Raimondo F, Lauria F, Cencini E, Rigolin GM, Cortelezzi A, Nobile F, Callea V, Brugiatelli M, Massaia M, Molica S, Trentin L, Rizzi R, Specchia G, Di Serio F, Orsucci L, Ambrosetti A, Montillo M, Zinzani PL, Ferrara F, Morabito F, Mura MA, Soriani S, Peragine N, Tavolaro S, Bonina S, Marinelli M, De Propris MS, Starza ID, Piciocchi A, Alietti A, Runggaldier EJ, Gamba E, Mauro FR, Chiaretti S, Guarini A. Chlorambucil plus rituximab with or without maintenance rituximab as first-line treatment for elderly chronic lymphocytic leukemia patients. Am J Hematol. 2014 May;89(5):480-6. Epub 2014 Feb 18. link to original article contains verified protocol PubMed
  6. Williams ME, Hong F, Gascoyne RD, Wagner LI, Krauss JC, Habermann TM, Swinnen LJ, Schuster SJ, Peterson CG, Sborov MD, Martin SE, Weiss M, Ehmann WC, Horning SJ, Kahl BS. Rituximab extended schedule or retreatment trial for low tumour burden non-follicular indolent B-cell non-Hodgkin lymphomas: Eastern Cooperative Oncology Group Protocol E4402. Br J Haematol. 2016 Jun;173(6):867-75. Epub 2016 Mar 11. link to original article contains protocol link to PMC article PubMed
  7. Greil R, Obrtlíková P, Smolej L, Kozák T, Steurer M, Andel J, Burgstaller S, Mikušková E, Gercheva L, Nösslinger T, Papajík T, Ladická M, Girschikofsky M, Hrubiško M, Jäger U, Fridrik M, Pecherstorfer M, Králiková E, Burcoveanu C, Spasov E, Petzer A, Mihaylov G, Raynov J, Oexle H, Zabernigg A, Flochová E, Palášthy S, Stehlíková O, Doubek M, Altenhofer P, Pleyer L, Melchardt T, Klingler A, Mayer J, Egle A. Rituximab maintenance versus observation alone in patients with chronic lymphocytic leukaemia who respond to first-line or second-line rituximab-containing chemoimmunotherapy: final results of the AGMT CLL-8a Mabtenance randomised trial. Lancet Haematol. 2016 Jul;3(7):e317-29. Epub 2016 Jun 16. link to original article contains protocol PubMed

Relapsed/refractory, randomized data

Bendamustine

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Regimen #1

Study Evidence Comparator Efficacy
Robak et al. 2016 Randomized Phase II Bendamustine & Otlertuzumab Seems to have inferior PFS

Chemotherapy

  • Bendamustine 70 mg/m2 IV over 30 minutes once per day on days 1 & 2

28-day cycle for 6 cycles

Regimen #2

Study Evidence Comparator Efficacy
Niederle et al. 2013 Phase III Fludarabine Seems non-inferior

Chemotherapy

Note: these infusion instructions are for the Treanda formulation, which was discontinued on 3/31/2016.

  • Bendamustine 100 mg/m2 IV over 30 minutes once per day on days 1 & 2

28-day cycle for up to 8 cycles

References

  1. Niederle N, Megdenberg D, Balleisen L, Heit W, Knauf W, Weiß J, Freier W, Hinke A, Ibach S, Eimermacher H. Bendamustine compared to fludarabine as second-line treatment in chronic lymphocytic leukemia. Ann Hematol. 2013 May;92(5):653-60. Epub 2013 Jan 23. link to original article contains verified protocol PubMed
  2. Robak T, Hellmann A, Kloczko J, Loscertales J, Lech-Maranda E, Pagel JM, Mato A, Byrd JC, Awan FT, Hebart H, Garcia-Marco JA, Hill BT, Hallek M, Eisenfeld AJ, Stromatt SC, Jaeger U. Randomized phase 2 study of otlertuzumab and bendamustine versus bendamustine in patients with relapsed chronic lymphocytic leukaemia. Br J Haematol. 2017 Feb;176(4):618-628. Epub 2016 Dec 15. link to original article contains verified protocol link to PMC article PubMed

BR

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BR: Bendamustine, Rituximab

Regimen

Study Evidence Comparator Efficacy
Fischer et al. 2011 Phase II
Chanan-Khan et al. 2015 (HELIOS) Phase III BR & Ibrutinib Inferior PFS
Zelenetz et al. 2017 Phase III BR & Idelalisib Inferior PFS

Chemotherapy

  • Bendamustine 70 mg/m2 IV once per day on days 1 & 2 (HELIOS gave 1st cycle on days 2 & 3)
  • Rituximab (Rituxan) as follows:
    • Cycle 1: 375 mg/m2 IV once on day 0 (HELIOS gave on day 1)
    • Cycles 2 to 6: 500 mg/m2 IV once on day 1

28-day cycle for up to 6 cycles based on response and toxicity

References

  1. Fischer K, Cramer P, Busch R, Stilgenbauer S, Bahlo J, Schweighofer CD, Böttcher S, Staib P, Kiehl M, Eckart MJ, Kranz G, Goede V, Elter T, Bühler A, Winkler D, Kneba M, Döhner H, Eichhorst BF, Hallek M, Wendtner CM. Bendamustine combined with rituximab in patients with relapsed and/or refractory chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. 2011 Sep 10;29(26):3559-66. Epub 2011 Aug 15. link to original article contains protocol PubMed
  2. Retrospective: Kolibaba KS, Sterchele JA, Joshi AD, Forsyth M, Alwon E, Beygi H, Kennealey GT. Demographics, treatment patterns, safety, and real-world effectiveness in patients aged 70 years and over with chronic lymphocytic leukemia receiving bendamustine with or without rituximab: a retrospective study. Ther Adv Hematol. 2013 Jun;4(3):157-71. link to PMC article PubMed
  3. Chanan-Khan A, Cramer P, Demirkan F, Fraser G, Silva RS, Grosicki S, Pristupa A, Janssens A, Mayer J, Bartlett NL, Dilhuydy MS, Pylypenko H, Loscertales J, Avigdor A, Rule S, Villa D, Samoilova O, Panagiotidis P, Goy A, Mato A, Pavlovsky MA, Karlsson C, Mahler M, Salman M, Sun S, Phelps C, Balasubramanian S, Howes A, Hallek M; HELIOS investigators. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol. 2016 Feb;17(2):200-11. Epub 2015 Dec 5. link to original article contains protocol PubMed
  4. Zelenetz AD, Barrientos JC, Brown JR, Coiffier B, Delgado J, Egyed M, Ghia P, Illés Á, Jurczak W, Marlton P, Montillo M, Morschhauser F, Pristupa AS, Robak T, Sharman JP, Simpson D, Smolej L, Tausch E, Adewoye AH, Dreiling LK, Kim Y, Stilgenbauer S, Hillmen P. Idelalisib or placebo in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia: interim results from a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2017 Mar;18(3):297-311. Epub 2017 Jan 28. link to original article contains protocol PubMed

BR & Ibrutinib

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BR: Bendamustine, Rituximab

Regimen

Study Evidence Comparator Efficacy
Brown et al. 2015 (PCYC-1108) Phase II
Chanan-Khan et al. 2015 (HELIOS) Phase III BR Superior PFS

PCYC-1108 also evaluated FCR-ibrutinib (non-randomized) but accrual to that arm was extremely low and it was prematurely discontinued.

Chemotherapy

  • Bendamustine 70 mg/m2 IV once per day on days 1 & 2 (HELIOS gave 1st cycle on days 2 & 3)
  • Rituximab (Rituxan) as follows:
    • Cycle 1: 375 mg/m2 IV once on day 1 or split between days 1 & 2 (option described in PCYC-1108)
    • Cycles 2 to 6: 500 mg/m2 IV once on day 1
  • Ibrutinib (Imbruvica) 420 mg PO once per day

28-day cycle for up to 6 cycles (BR) and indefinitely (ibrutinib)

References

  1. Brown JR, Barrientos JC, Barr PM, Flinn IW, Burger JA, Tran A, Clow F, James DF, Graef T, Friedberg JW, Rai K, O'Brien S. The Bruton tyrosine kinase inhibitor ibrutinib with chemoimmunotherapy in patients with chronic lymphocytic leukemia. Blood. 2015 May 7;125(19):2915-22. Epub 2015 Mar 9. link to original article contains verified protocol link to PMC article PubMed
  2. Chanan-Khan A, Cramer P, Demirkan F, Fraser G, Silva RS, Grosicki S, Pristupa A, Janssens A, Mayer J, Bartlett NL, Dilhuydy MS, Pylypenko H, Loscertales J, Avigdor A, Rule S, Villa D, Samoilova O, Panagiotidis P, Goy A, Mato A, Pavlovsky MA, Karlsson C, Mahler M, Salman M, Sun S, Phelps C, Balasubramanian S, Howes A, Hallek M; HELIOS investigators. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol. 2016 Feb;17(2):200-11. Epub 2015 Dec 5. link to original article contains protocol PubMed

BR & Idelalisib

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BR: Bendamustine, Rituximab

Regimen

Study Evidence Comparator Efficacy
Zelenetz et al. 2017 Phase III BR Superior PFS

Chemotherapy

28-day cycle for up to 6 cycles (BR) and continued until progression or excess toxicity (idelalisib)

References

  1. Zelenetz AD, Barrientos JC, Brown JR, Coiffier B, Delgado J, Egyed M, Ghia P, Illés Á, Jurczak W, Marlton P, Montillo M, Morschhauser F, Pristupa AS, Robak T, Sharman JP, Simpson D, Smolej L, Tausch E, Adewoye AH, Dreiling LK, Kim Y, Stilgenbauer S, Hillmen P. Idelalisib or placebo in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia: interim results from a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2017 Mar;18(3):297-311. Epub 2017 Jan 28. link to original article contains protocol PubMed

CC

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CC: Cladribine, Cyclophosphamide

Regimen

Study Evidence Comparator Efficacy
Robak et al. 2006 (PALG CLL2) Phase III Cladribine Might have superior CR rate
CMC Seems to have inferior CR rate

Chemotherapy

Supportive medications

  • No routine prophylaxis with antibiotics, antiviral agents, or growth factors.

28-day cycle for up to 6 cycles

References

  1. 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 Leukemia Group (PALG CLL2). 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 PubMed

Cladribine (Leustatin)

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Regimen

Study Evidence Comparator Efficacy
Robak et al. 2006 (PALG CLL2) Phase III CC Might have inferior CR rate
CMC Inferior CR rate

Chemotherapy

28-day cycle for up to 6 cycles

References

  1. 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 Leukemia Group (PALG CLL2). 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 PubMed

CMC

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CMC: Cladribine, Mitoxantrone, Cyclophosphamide

Regimen

Study Evidence Comparator Efficacy
Robak et al. 2006 (PALG CLL2) Phase III Cladribine Superior CR rate
CC Seems to have superior CR rate

Chemotherapy

28-day cycle for up to 6 cycles

References

  1. 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 Leukemia Group (PALG CLL2). 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 protocol PubMed

FC

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FC: Fludarabine, Cyclophosphamide

Regimen

Study Evidence Comparator Efficacy
Robak et al. 2010 Phase III R-FC Inferior PFS

Chemotherapy

Supportive medications

28-day cycle for 6 cycles

References

  1. 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 protocol PubMed content property of HemOnc.org

FCR, R-FC

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FCR: Fludarabine, Cyclophosphamide, Rituximab
R-FC: Rituximab, Fludarabine, Cyclophosphamide

Regimen #1

Study Evidence Comparator Efficacy
Awan et al. 2014 (LUCID) Phase III Lumiliximab + FCR Seems not superior

Chemotherapy

  • Fludarabine (Fludara) as follows:
    • Cycle 1: 25 mg/m2 IV over at least 10 to 30 minutes once per day on days 2 to 4
    • Cycles 2 to 6: 25 mg/m2 IV over at least 10 to 30 minutes once per day on days 1 to 3
  • Cyclophosphamide (Cytoxan) as follows:
    • Cycle 1: 250 mg/m2 IV over at least 10 to 30 minutes once per day on days 2 to 4
    • Cycles 2 to 6: 250 mg/m2 IV over at least 10 to 30 minutes once per day on days 1 to 3
  • Rituximab (Rituxan) as follows:
    • Cycle 1: 50 mg/m2 IV over 4 hours once on day 1, then 450 mg/m2 IV once on day 3
    • Cycles 2 to 6: 500 mg/m2 IV once on day 1

Supportive medications

28-day cycle for 6 cycles

Regimen #2

Study Evidence Comparator Efficacy
Robak et al. 2010 Phase III FC Superior PFS

Chemotherapy

Supportive medications

28-day cycle for 6 cycles

References

  1. 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 protocol PubMed content property of HemOnc.org
  2. Awan FT, Hillmen P, Hellmann A, Robak T, Hughes SG, Trone D, Shannon M, Flinn IW, Byrd JC; LUCID trial investigators. A randomized, open-label, multicentre, phase 2/3 study to evaluate the safety and efficacy of lumiliximab in combination with fludarabine, cyclophosphamide and rituximab versus fludarabine, cyclophosphamide and rituximab alone in subjects with relapsed chronic lymphocytic leukaemia. Br J Haematol. 2014 Nov;167(4):466-77. Epub 2014 Aug 8. link to original article contains verified protocol PubMed

Fludarabine (Fludara)

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Regimen

Study Evidence Comparator Efficacy
Niederle et al. 2013 Phase III Bendamustine Seems non-inferior

Chemotherapy

28-day cycle for up to 6 to 12 cycles

References

  1. Niederle N, Megdenberg D, Balleisen L, Heit W, Knauf W, Weiß J, Freier W, Hinke A, Ibach S, Eimermacher H. Bendamustine compared to fludarabine as second-line treatment in chronic lymphocytic leukemia. Ann Hematol. 2013 May;92(5):653-60. Epub 2013 Jan 23. link to original article contains verified protocol PubMed

Ibrutinib (Imbruvica)

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Regimen

Study Evidence Comparator Efficacy
Byrd et al. 2013 (PCYC-1102) Phase II
Byrd et al. 2014 (RESONATE) Phase III Ofatumumab Superior OS
Farooqui et al. 2014 Phase II, <20 pts
O'Brien et al. 2016 (RESONATE-17) Phase II
Sharman et al. 2017 (GENUINE) Phase III Ibrutinib & Ublituximab Inferior ORR

Both 420 mg and 840 mg doses were investigated in PCYC-1102: "the similar response in the two dose groups provide support for the use of the 420-mg dose of ibrutinib for relapsed CLL." The others used the 420 mg dose. RESONATE-17 was intended for patients with 17p deletion.

Chemotherapy

Given until progression of disease or unacceptable toxicity

References

  1. Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, Grant B, Sharman JP, Coleman M, Wierda WG, Jones JA, Zhao W, Heerema NA, Johnson AJ, Sukbuntherng J, Chang BY, Clow F, Hedrick E, Buggy JJ, James DF, O'Brien S. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013 Jul 4;369(1):32-42. link to original article contains verified protocol link to PMC article PubMed
    1. Update: Byrd JC, Furman RR, Coutre SE, Burger JA, Blum KA, Coleman M, Wierda WG, Jones JA, Zhao W, Heerema NA, Johnson AJ, Shaw Y, Bilotti E, Zhou C, James DF, O'Brien S. Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015 Apr 16;125(16):2497-506. Epub 2015 Feb 19. link to original article link to PMC article PubMed
    2. Update: Abstract: John C. Byrd, Peter Hillmen, Susan Mary O'Brien, Jacqueline Claudia Barrientos, Nishitha M. Reddy, Steven Coutre, ... Constantine S. Tam, Stephen P. Mulligan, Ulrich Jäger, Paul M. Barr, Richard R. Furman, Thomas J. Kipps, Patrick Thornton, John M. Pagel, Jan Andreas Burger, Jeffrey Alan Jones, Sandra Dai, Remus N. Vezan, Danelle Frances James, Jennifer R. Brown. Long-term efficacy and safety with ibrutinib (ibr) in previously treated chronic lymphocytic leukemia (CLL): Up to four years follow-up of the RESONATE study. Journal of Clinical Oncology 35, no. 15_suppl (May 2017) 7510-7510. link to abstract
  2. Byrd JC, Brown JR, O'Brien S, Barrientos JC, Kay NE, Reddy NM, Coutre S, Tam CS, Mulligan SP, Jaeger U, Devereux S, Barr PM, Furman RR, Kipps TJ, Cymbalista F, Pocock C, Thornton P, Caligaris-Cappio F, Robak T, Delgado J, Schuster SJ, Montillo M, Schuh A, de Vos S, Gill D, Bloor A, Dearden C, Moreno C, Jones JJ, Chu AD, Fardis M, McGreivy J, Clow F, James DF, Hillmen P; the RESONATE Investigators. Ibrutinib versus Ofatumumab in Previously Treated Chronic Lymphoid Leukemia. N Engl J Med. 2014 Jul 17;371(3):213-23. Epub 2014 May 31. link to original article contains verified protocol link to PMC article PubMed
  3. Farooqui MZ, Valdez J, Martyr S, Aue G, Saba N, Niemann CU, Herman SE, Tian X, Marti G, Soto S, Hughes TE, Jones J, Lipsky A, Pittaluga S, Stetler-Stevenson M, Yuan C, Lee YS, Pedersen LB, Geisler CH, Calvo KR, Arthur DC, Maric I, Childs R, Young NS, Wiestner A. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol. 2015 Feb;16(2):169-76. Epub 2014 Dec 31. link to original article contains protocol link to PMC article PubMed
  4. O'Brien S, Jones JA, Coutre SE, Mato AR, Hillmen P, Tam C, Österborg A, Siddiqi T, Thirman MJ, Furman RR, Ilhan O, Keating MJ, Call TG, Brown JR, Stevens-Brogan M, Li Y, Clow F, James DF, Chu AD, Hallek M, Stilgenbauer S. Ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia with 17p deletion (RESONATE-17): a phase 2, open-label, multicentre study. Lancet Oncol. 2016 Oct;17(10):1409-1418. Epub 2016 Sep 13. link to original article contains protocol PubMed
  5. Ryan CE, Sahaf B, Logan AC, O'Brien S, Byrd JC, Hillmen P, Brown JR, Dyer MJ, Mato AR, Keating MJ, Jaglowski S, Clow F, Rezvani AR, Styles L, Coutre SE, Miklos DB. Ibrutinib efficacy and tolerability in patients with relapsed chronic lymphocytic leukemia following allogeneic HCT. Blood. 2016 Dec 22;128(25):2899-2908. link to original article link to PMC article PubMed
  6. Abstract: Jeff Porter Sharman, Danielle M. Brander, Anthony R. Mato, Suman Kambhampati, John M. Burke, Frederick Lansigan, Marshall T. Schreeder, Scott D. Lunin, Nilanjan Ghosh, Alexander Zweibach, Mikhail Shtivelband, Patrick M. Travis, Jason Claud Chandler, Kathryn S. Kolibaba, Peter Sportelli, Hari P. Miskin, Michael S. Weiss, and Ian Flinn. Ublituximab and ibrutinib for previously treated genetically high-risk chronic lymphocytic leukemia: Results of the GENUINE phase 3 study. Journal of Clinical Oncology 2017 35:15_suppl, 7504-7504 link to abstract

Idelalisib & Ofatumumab

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Regimen

Study Evidence Comparator Efficacy
Jones et al. 2017 Phase III Ofatumumab Superior PFS

Chemotherapy

  • Idelalisib (Zydelig) 150 mg PO BID
  • Ofatumumab (Arzerra) as follows:
    • Cycle 1: 300 mg IV once on day 1, then 1000 mg IV once per day on days 8, 15, 22
    • Cycle 2: 1000 mg IV once per day on days 1, 8, 15, 22
    • Cycles 3 to 6: 1000 mg IV once on day 1

28-day cycle for 6 cycles

References

  1. Jones JA, Robak T, Brown JR, Awan FT, Badoux X, Coutre S, Loscertales J, Taylor K, Vandenberghe E, Wach M, Wagner-Johnston N, Ysebaert L, Dreiling L, Dubowy R, Xing G, Flinn IW, Owen C. Efficacy and safety of idelalisib in combination with ofatumumab for previously treated chronic lymphocytic leukaemia: an open-label, randomised phase 3 trial. Lancet Haematol. 2017 Mar;4(3):e114-e126. link to original article contains protocol PubMed

Idelalisib & Rituximab

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Regimen

Study Evidence Comparator Efficacy
Furman et al. 2014 (Study 116) Phase III Rituximab Seems to have superior OS

Chemotherapy

Rituximab is given for 8 total doses; idelalisib continues until progression, and can be increased to 300 mg PO BID at that point

References

  1. Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, Barrientos JC, Zelenetz AD, Kipps TJ, Flinn I, Ghia P, Eradat H, Ervin T, Lamanna N, Coiffier B, Pettitt AR, Ma S, Stilgenbauer S, Cramer P, Aiello M, Johnson DM, Miller LL, Li D, Jahn TM, Dansey RD, Hallek M, O'Brien SM. Idelalisib and Rituximab in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2014 Mar 13;370(11):997-1007. Epub 2014 Jan 22. link to original article contains verified protocol link to PMC article PubMed

Ofatumumab (Arzerra)

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Regimen #1

Study Evidence Comparator Efficacy
Coiffier et al. 2007 Phase I/II
Wierda et al. 2010 (Hx-CD20-406) Phase II
Byrd et al. 2014 (RESONATE) Phase III Ibrutinib Inferior OS
Jones et al. 2017 Phase III Idelalisib & Ofatumumab Inferior PFS

Note: this regimen is sometimes described as 300 mg IV once on day 1, then 2000 mg IV once per week for 7 weeks, then 2000 mg IV once every 4 weeks for 16 weeks.

Chemotherapy

  • Ofatumumab (Arzerra) as follows:
    • Cycle 1: 300 mg IV once on day 1, then 2000 mg IV once per day on days 8, 15, 22
    • Cycle 2: 2000 mg IV once per day on days 1, 8, 15, 22
    • Cycles 3 to 6: 2000 mg IV once on day 1

Supportive medications

  • Prednisolone (Millipred) 100 mg or equivalent once before infusions 1, 2, and 9 (question whether this was a typo), reduced to lower doses if initial infusions well-tolerated

28-day cycle for 6 cycles

Regimen #2

Study Evidence
Österborg et al. 2015 (GEN416) Phase II

Patients in this trial were fludarabine refractory and had previously received ofatumumab; this is a re-treatment trial.

Chemotherapy

Supportive medications

8-week course

Patients with SD or better could proceed to ofatumumab maintenance.

References

  1. Coiffier B, Lepretre S, Pedersen LM, Gadeberg O, Fredriksen H, van Oers MH, Wooldridge J, Kloczko J, Holowiecki J, Hellmann A, Walewski J, Flensburg M, Petersen J, Robak T. Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1-2 study. Blood. 2008 Feb 1;111(3):1094-100. Epub 2007 Nov 14. link to original article PubMed
  2. Wierda WG, Kipps TJ, Mayer J, Stilgenbauer S, Williams CD, Hellmann A, Robak T, Furman RR, Hillmen P, Trneny M, Dyer MJ, Padmanabhan S, Piotrowska M, Kozak T, Chan G, Davis R, Losic N, Wilms J, Russell CA, Osterborg A; Hx-CD20-406 Study Investigators. Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol. 2010 Apr 1;28(10):1749-55. Epub 2010 Mar 1. link to original article contains protocol link to PMC article PubMed
    1. Subgroup analysis: Wierda WG, Padmanabhan S, Chan GW, Gupta IV, Lisby S, Osterborg A; Hx-CD20-406 Study Investigators. Ofatumumab is active in patients with fludarabine-refractory CLL irrespective of prior rituximab: results from the phase 2 international study. Blood. 2011 Nov 10;118(19):5126-9. Epub 2011 Aug 19. link to original article link to PMC article PubMed
    2. Update: Österborg A, Jewell RC, Padmanabhan-Iyer S, Kipps TJ, Mayer J, Stilgenbauer S, Williams CD, Hellmann A, Furman RR, Robak T, Hillmen P, Trnêný M, Dyer MJ, Piotrowska M, Kozak T, Gupta IV, Phillips JL, Goldstein N, Struemper H, Losic N, Lisby S, Wierda WG; Hx-CD20-406 Study Investigators. Ofatumumab monotherapy in fludarabine-refractory chronic lymphocytic leukemia: final results from a pivotal study. Haematologica. 2015 Aug;100(8):e311-4. Epub 2015 Mar 13. link to original article link to PMC article PubMed
  3. Byrd JC, Brown JR, O'Brien S, Barrientos JC, Kay NE, Reddy NM, Coutre S, Tam CS, Mulligan SP, Jaeger U, Devereux S, Barr PM, Furman RR, Kipps TJ, Cymbalista F, Pocock C, Thornton P, Caligaris-Cappio F, Robak T, Delgado J, Schuster SJ, Montillo M, Schuh A, de Vos S, Gill D, Bloor A, Dearden C, Moreno C, Jones JJ, Chu AD, Fardis M, McGreivy J, Clow F, James DF, Hillmen P; the RESONATE Investigators. Ibrutinib versus Ofatumumab in Previously Treated Chronic Lymphoid Leukemia. N Engl J Med. 2014 Jul 17;371(3):213-23. Epub 2014 May 31. link to original article contains verified protocol link to PMC article PubMed
    1. Update: Byrd JC, Furman RR, Coutre SE, Burger JA, Blum KA, Coleman M, Wierda WG, Jones JA, Zhao W, Heerema NA, Johnson AJ, Shaw Y, Bilotti E, Zhou C, James DF, O'Brien S. Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015 Apr 16;125(16):2497-506. Epub 2015 Feb 19. link to original article link to PMC article PubMed
    2. Update: Abstract: John C. Byrd, Peter Hillmen, Susan Mary O'Brien, Jacqueline Claudia Barrientos, Nishitha M. Reddy, Steven Coutre, ... Constantine S. Tam, Stephen P. Mulligan, Ulrich Jäger, Paul M. Barr, Richard R. Furman, Thomas J. Kipps, Patrick Thornton, John M. Pagel, Jan Andreas Burger, Jeffrey Alan Jones, Sandra Dai, Remus N. Vezan, Danelle Frances James, Jennifer R. Brown. Long-term efficacy and safety with ibrutinib (ibr) in previously treated chronic lymphocytic leukemia (CLL): Up to four years follow-up of the RESONATE study. Journal of Clinical Oncology 35, no. 15_suppl (May 2017) 7510-7510. link to abstract
  4. Retrospective: Moreno C, Montillo M, Panayiotidis P, Dimou M, Bloor A, Dupuis J, Schuh A, Norin S, Geisler C, Hillmen P, Doubek M, Trněný M, Obrtlikova P, Laurenti L, Stilgenbauer S, Smolej L, Ghia P, Cymbalista F, Jaeger U, Stamatopoulos K, Stavroyianni N, Carrington P, Zouabi H, Leblond V, Gomez-Garcia JC, Rubio M, Marasca R, Musuraca G, Rigacci L, Farina L, Paolini R, Pospisilova S, Kimby E, Bradley C, Montserrat E. Ofatumumab in poor-prognosis chronic lymphocytic leukemia: a Phase 4, non--interventional, observational study from the European Research Initiative on Chronic Lymphocytic Leukemia. Haematologica. 2015 Apr;100(4):511-6. Epub 2015 Jan 16. link to original article link to PMC article PubMed
  5. Österborg A, Wierda WG, Mayer J, Hess G, Hillmen P, Schetelig J, Schuh A, Smolej L, Beck C, Dreyfus B, Hellman A, Kozlowski P, Pfreundschuh M, Rizzi R, Spacek M, Phillips JL, Gupta IV, Williams V, Jewell RC, Nebot N, Lisby S, Dyer MJ. Ofatumumab retreatment and maintenance in fludarabine-refractory chronic lymphocytic leukaemia patients. Br J Haematol. 2015 Jul;170(1):40-9. Epub 2015 Mar 30. link to original article contains verified protocol PubMed
  6. Jones JA, Robak T, Brown JR, Awan FT, Badoux X, Coutre S, Loscertales J, Taylor K, Vandenberghe E, Wach M, Wagner-Johnston N, Ysebaert L, Dreiling L, Dubowy R, Xing G, Flinn IW, Owen C. Efficacy and safety of idelalisib in combination with ofatumumab for previously treated chronic lymphocytic leukaemia: an open-label, randomised phase 3 trial. Lancet Haematol. 2017 Mar;4(3):e114-e126. link to original article contains protocol PubMed

Rituximab monotherapy

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Regimen #1

Study Evidence Comparator Efficacy
McLaughlin et al. 1998 Phase II
Williams et al. 2016 (RESORT) Phase III Maintenance rituximab Seems to have inferior TTTF

Treatment in RESORT was preceded by rituximab and is given at time of progression.

Chemotherapy

One course

Regimen #2

Study Evidence Comparator Efficacy
Furman et al. 2014 (Study 116) Phase III Idelalisib & Rituximab Seems to have inferior OS

Chemotherapy

  • Rituximab (Rituxan) 375 mg/m2 IV once on first dose, then 500 mg/m2 IV once on subsequent doses

Given every two weeks for 5 doses then every three weeks for 3 doses for 8 total doses.

References

  1. McLaughlin P, Grillo-López AJ, Link BK, Levy R, Czuczman MS, Williams ME, Heyman MR, Bence-Bruckler I, White CA, Cabanillas F, Jain V, Ho AD, Lister J, Wey K, Shen D, Dallaire BK. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998 Aug;16(8):2825-33. link to original article contains verified protocol PubMed
  2. Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, Barrientos JC, Zelenetz AD, Kipps TJ, Flinn I, Ghia P, Eradat H, Ervin T, Lamanna N, Coiffier B, Pettitt AR, Ma S, Stilgenbauer S, Cramer P, Aiello M, Johnson DM, Miller LL, Li D, Jahn TM, Dansey RD, Hallek M, O'Brien SM. Idelalisib and Rituximab in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2014 Mar 13;370(11):997-1007. Epub 2014 Jan 22. link to original article contains verified protocol link to PMC article PubMed
  3. Williams ME, Hong F, Gascoyne RD, Wagner LI, Krauss JC, Habermann TM, Swinnen LJ, Schuster SJ, Peterson CG, Sborov MD, Martin SE, Weiss M, Ehmann WC, Horning SJ, Kahl BS. Rituximab extended schedule or retreatment trial for low tumour burden non-follicular indolent B-cell non-Hodgkin lymphomas: Eastern Cooperative Oncology Group Protocol E4402. Br J Haematol. 2016 Jun;173(6):867-75. Epub 2016 Mar 11. link to original article contains protocol link to PMC article PubMed

Relapsed/refractory, non-randomized or retrospective data

Alemtuzumab (Campath)

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Regimen #1

Study Evidence
Keating et al. 2002 Phase II
Rai et al. 2002 Phase II

Chemotherapy

  • Alemtuzumab (Campath) as follows:
    • 3 mg IV once per day, then increased as tolerated in terms of infusion reactions to 10 mg IV once per day, and then to 30 mg IV once per day
    • Once 30 mg dose is tolerated: 30 mg IV over 2 hours, 3 times per week

Supportive medications

Up to 12 to 16 weeks of therapy; total course varies depending on reference

Regimen #2

Study Evidence
Lozanski et al. 2004 Phase II

Chemotherapy

  • Alemtuzumab (Campath) 3 mg IV once on day 1, then 10 mg IV once on day 2, then 30 mg IV once on day 3, then 30 mg IV 3 days per week

Supportive medications

12 weeks of therapy

References

  1. Keating MJ, Flinn I, Jain V, Binet JL, Hillmen P, Byrd J, Albitar M, Brettman L, Santabarbara P, Wacker B, Rai KR. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood. 2002 May 15;99(10):3554-61. link to original article contains protocol PubMed
  2. Rai KR, Freter CE, Mercier RJ, Cooper MR, Mitchell BS, Stadtmauer EA, Santábarbara P, Wacker B, Brettman L. Alemtuzumab in previously treated chronic lymphocytic leukemia patients who also had received fludarabine. J Clin Oncol. 2002 Sep 15;20(18):3891-7. link to original article contains protocol PubMed
  3. Lozanski G, Heerema NA, Flinn IW, Smith L, Harbison J, Webb J, Moran M, Lucas M, Lin T, Hackbarth ML, Proffitt JH, Lucas D, Grever MR, Byrd JC. Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions. Blood. 2004 May 1;103(9):3278-81. Epub 2004 Jan 15. link to original article contains protocol PubMed

Alemtuzumab & Rituximab

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Regimen

Study Evidence
Faderl et al. 2003 Phase II

Chemotherapy

  • Alemtuzumab (Campath) 3 mg IV once on day 1, 10 mg IV once on day 2, 30 mg IV once on day 3 of week 1, then 30 mg IV once per day on days 10, 12, 17, 19, 24, 26 (i.e. days 3 and 5 of weeks 2 to 4)
  • Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1, 8, 15, 22
    • For patients with WBC count greater than 50 x 109/L, the first dose of Rituximab (Rituxan) was split into 100 mg/m2 IV once on day 1 and 275 mg/m2 IV once on day 2

Supportive medications

28-day cycle for 1 to 2 cycles depending on response and toxicity

References

  1. Faderl S, Thomas DA, O'Brien S, Garcia-Manero G, Kantarjian HM, Giles FJ, Koller C, Ferrajoli A, Verstovsek S, Pro B, Andreeff M, Beran M, Cortes J, Wierda W, Tran N, Keating MJ. Experience with alemtuzumab plus rituximab in patients with relapsed and refractory lymphoid malignancies. Blood. 2003 May 1;101(9):3413-5. Epub 2003 Jan 9. link to original article contains protocol Pubmed

Allogeneic stem cell transplant

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Regimen #1, FluBuATG

Study Evidence
Schetelig et al. 2003 Phase II

The authors cite the preparative regimen used in Slavin et al. 1998, with some minor local variations (see text for details).

Preparative regimen

Regimen #2, Fludarabine and Low-dose TBI

Study Evidence
Sorror et al. 2005 Phase II

Preparative regimen

  • Fludarabine (Fludara) 30 mg/m2 IV once per day on days -4 to -2
  • Total body irradiation (TBI) 2 Gy at a rate of 0.07 Gy/min on day 0

GVHD prophylaxis

  • Cyclosporine (type not specified) 6.25 mg/kg PO BID starting 4 to 6 hours after transplant, tapered at day 100 over 80 days (if no GVHD)
  • Mycophenolate mofetil (CellCept) 15 mg/kg PO BID starting 4 to 6 hours after transplant, tapered at day 40 over 56 days (if no GVHD)

Regimen #3, FluCy

Study Evidence
Dreger et al. 2010 (CLL3X) Phase II

This reduced-intensity conditioning regimen is intended for related donors.

Preparative regimen

Regimen #4, FluCyATG

Study Evidence
Dreger et al. 2010 (CLL3X) Phase II

This reduced-intensity conditioning regimen is intended for unrelated donors.

Preparative regimen

References

  1. Khouri IF, Keating M, Körbling M, Przepiorka D, Anderlini P, O'Brien S, Giralt S, Ippoliti C, von Wolff B, Gajewski J, Donato M, Claxton D, Ueno N, Andersson B, Gee A, Champlin R. Transplant-lite: induction of graft-versus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies. J Clin Oncol. 1998 Aug;16(8):2817-24. link to original article PubMed
    1. Update: Khouri IF, Bassett R, Poindexter N, O'Brien S, Bueso-Ramos CE, Hsu Y, Ferrajoli A, Keating MJ, Champlin R, Fernandez-Vina M. Nonmyeloablative allogeneic stem cell transplantation in relapsed/refractory chronic lymphocytic leukemia: long-term follow-up, prognostic factors, and effect of human leukocyte histocompatibility antigen subtype on outcome. Cancer. 2011 Oct 15;117(20):4679-88. Epub 2011 Mar 31. link to original article link to PMC article PubMed
  2. Schetelig J, Thiede C, Bornhauser M, Schwerdtfeger R, Kiehl M, Beyer J, Sayer HG, Kroger N, Hensel M, Scheffold C, Held TK, Hoffken K, Ho AD, Kienast J, Neubauer A, Zander AR, Fauser AA, Ehninger G, Siegert W; Cooperative German Transplant Study Group. Evidence of a graft-versus-leukemia effect in chronic lymphocytic leukemia after reduced-intensity conditioning and allogeneic stem-cell transplantation: the Cooperative German Transplant Study Group. J Clin Oncol. 2003 Jul 15;21(14):2747-53. link to original article contains reference to protocol PubMed
  3. Sorror ML, Maris MB, Sandmaier BM, Storer BE, Stuart MJ, Hegenbart U, Agura E, Chauncey TR, Leis J, Pulsipher M, McSweeney P, Radich JP, Bredeson C, Bruno B, Langston A, Loken MR, Al-Ali H, Blume KG, Storb R, Maloney DG. Hematopoietic cell transplantation after nonmyeloablative conditioning for advanced chronic lymphocytic leukemia. J Clin Oncol. 2005 Jun 1;23(16):3819-29. Epub 2005 Apr 4. link to original article PubMed
    1. Update: Sorror ML, Storer BE, Sandmaier BM, Maris M, Shizuru J, Maziarz R, Agura E, Chauncey TR, Pulsipher MA, McSweeney PA, Wade JC, Bruno B, Langston A, Radich J, Niederwieser D, Blume KG, Storb R, Maloney DG. Five-year follow-up of patients with advanced chronic lymphocytic leukemia treated with allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. J Clin Oncol. 2008 Oct 20;26(30):4912-20. Epub 2008 Sep 15. link to original article link to PMC article PubMed
  4. Delgado J, Thomson K, Russell N, Ewing J, Stewart W, Cook G, Devereux S, Lovell R, Chopra R, Marks DI, Mackinnon S, Milligan DW; British Society of Blood and Marrow Transplantation. Results of alemtuzumab-based reduced-intensity allogeneic transplantation for chronic lymphocytic leukemia: a British Society of Blood and Marrow Transplantation Study. Blood. 2006 Feb 15;107(4):1724-30. Epub 2005 Oct 20. link to original article PubMed
  5. Dreger P, Döhner H, Ritgen M, Böttcher S, Busch R, Dietrich S, Bunjes D, Cohen S, Schubert J, Hegenbart U, Beelen D, Zeis M, Stadler M, Hasenkamp J, Uharek L, Scheid C, Humpe A, Zenz T, Winkler D, Hallek M, Kneba M, Schmitz N, Stilgenbauer S; German CLL Study Group. Allogeneic stem cell transplantation provides durable disease control in poor-risk chronic lymphocytic leukemia: long-term clinical and MRD results of the German CLL Study Group CLL3X trial. Blood. 2010 Oct 7;116(14):2438-47. Epub 2010 Jul 1. link to original article contains verified protocol PubMed
    1. Update: Dreger P, Schnaiter A, Zenz T, Böttcher S, Rossi M, Paschka P, Bühler A, Dietrich S, Busch R, Ritgen M, Bunjes D, Zeis M, Stadler M, Uharek L, Scheid C, Hegenbart U, Hallek M, Kneba M, Schmitz N, Döhner H, Stilgenbauer S. TP53, SF3B1, and NOTCH1 mutations and outcome of allotransplantation for chronic lymphocytic leukemia: six-year follow-up of the GCLLSG CLL3X trial. Blood. 2013 Apr 18;121(16):3284-8. Epub 2013 Feb 22. link to original article PubMed

Bendamustine

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Regimen

Study Evidence
Friedberg et al. 2008 Phase II
Kahl et al. 2010 Phase II

Chemotherapy

Note: these infusion instructions are for the Treanda formulation, which was discontinued on 3/31/2016.

  • Bendamustine 120 mg/m2 IV over 60 to 120 minutes once per day on days 1 & 2

21-day cycle for 6 to 8 cycles (up to 12 in Friedberg et al. 2008)

References

  1. Friedberg JW, Cohen P, Chen L, Robinson KS, Forero-Torres A, La Casce AS, Fayad LE, Bessudo A, Camacho ES, Williams ME, van der Jagt RH, Oliver JW, Cheson BD. Bendamustine in patients with rituximab-refractory indolent and transformed non-Hodgkin's lymphoma: results from a phase II multicenter, single-agent study. J Clin Oncol. 2008 Jan 10;26(2):204-10. Erratum in: J Clin Oncol. 2008 Apr 10;26(11) 1911. link to original article contains verified protocol PubMed
  2. Kahl BS, Bartlett NL, Leonard JP, Chen L, Ganjoo K, Williams ME, Czuczman MS, Robinson KS, Joyce R, van der Jagt RH, Cheson BD. Bendamustine is effective therapy in patients with rituximab-refractory, indolent B-cell non-Hodgkin lymphoma: results from a Multicenter Study. Cancer. 2010 Jan 1;116(1):106-14. link to original article contains verified protocol link to PMC article PubMed
  3. Retrospective: Kolibaba KS, Sterchele JA, Joshi AD, Forsyth M, Alwon E, Beygi H, Kennealey GT. Demographics, treatment patterns, safety, and real-world effectiveness in patients aged 70 years and over with chronic lymphocytic leukemia receiving bendamustine with or without rituximab: a retrospective study. Ther Adv Hematol. 2013 Jun;4(3):157-71. link to PMC article PubMed

BendOfa

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BendOfa: Bendamustine, Ofatumumab

Regimen

Study Evidence
Cortelezzi et al. 2013 (GIMEMA CLL0809) Phase II

Chemotherapy

  • Bendamustine 70 mg/m2 IV once per day on days 1 & 2
  • Ofatumumab (Arzerra) as follows:
    • Cycle 1: 300 mg IV once on day 1, then 1000 mg IV once on day 7
    • Cycle 2 onwards: 1000 mg IV once on day 1

Supportive medications

28-day cycle up to 6 cycles

References

  1. Cortelezzi A, Sciumè M, Liberati AM, Vincenti D, Cuneo A, Reda G, Laurenti L, Zaja F, Marasca R, Chiarenza A, Gritti G, Orsucci L, Storti S, Angelucci E, Cascavilla N, Gobbi M, Mauro FR, Morabito F, Fabris S, Piciocchi A, Vignetti M, Neri A, Rossi D, Giannarelli D, Guarini A, Foà R. Bendamustine in combination with Ofatumumab in relapsed or refractory chronic lymphocytic leukemia: a GIMEMA Multicenter Phase II Trial. Leukemia. 2014 Mar;28(3):642-8. Epub 2013 Nov 13. link to original article contains verified protocol PubMed

CFAR

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CFAR: Cyclophosphamide, Fludarabine, Alemtuzumab, Rituximab

Regimen

Study Evidence
Badoux et al. 2011 Phase II

Chemotherapy

Supportive medications

28-day cycle for 6 cycles

References

  1. Badoux XC, Keating MJ, Wang X, O'Brien SM, Ferrajoli A, Faderl S, Burger J, Koller C, Lerner S, Kantarjian H, Wierda WG. Cyclophosphamide, fludarabine, alemtuzumab, and rituximab as salvage therapy for heavily pretreated patients with chronic lymphocytic leukemia. Blood. 2011 Aug 25;118(8):2085-93. Epub 2011 Jun 13. link to original article contains protocol link to PMC article PubMed

FCR; R-FC

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FCR: Fludarabine, Cyclophosphamide, Rituximab
R-FC: Rituximab, Fludarabine, Cyclophosphamide

Regimen #1

Study Evidence
Wierda et al. 2005 Phase II

Chemotherapy

  • Fludarabine (Fludara) as follows:
    • Cycle 1: 25 mg/m2 IV once per day on days 2 to 4
    • Cycles 2 to 6: 25 mg/m2 IV once per day on days 1 to 3
  • Cyclophosphamide (Cytoxan) as follows:
    • Cycle 1: 250 mg/m2 IV once per day on days 2 to 4
    • Cycles 2 to 6: 250 mg/m2 IV once per day on days 1 to 3
  • Rituximab (Rituxan) as follows:
    • Cycle 1: 375 mg/m2 IV once on day 1
    • Cycles 2 to 6: 500 mg/m2 IV once on day 1

Supportive medications

28-day cycle for up to 6 cycles

Regimen #2

Study Evidence
Tam et al. 2006 Phase II

Chemotherapy

28-day cycle for up to 6 cycles or "attainment of maximum response"

References

  1. Wierda W, O'Brien S, Wen S, Faderl S, Garcia-Manero G, Thomas D, Do KA, Cortes J, Koller C, Beran M, Ferrajoli A, Giles F, Lerner S, Albitar M, Kantarjian H, Keating M. Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. J Clin Oncol. 2005 Jun 20;23(18):4070-8. Epub 2005 Mar 14. link to original article contains verified protocol PubMed
    1. Update: Badoux XC, Keating MJ, Wang X, O'Brien SM, Ferrajoli A, Faderl S, Burger J, Koller C, Lerner S, Kantarjian H, Wierda WG. Fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy is highly effective treatment for relapsed patients with CLL. Blood. 2011 Mar 17;117(11):3016-24. Epub 2011 Jan 18. link to original article link to PMC article PubMed
  2. Tam CS, Wolf M, Prince HM, Januszewicz EH, Westerman D, Lin KI, Carney D, Seymour JF. Fludarabine, cyclophosphamide, and rituximab for the treatment of patients with chronic lymphocytic leukemia or indolent non-Hodgkin lymphoma. Cancer. 2006 Jun 1;106(11):2412-20. link to original article contains verified protocol PubMed

FluCam

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FluCam: Fludarabine, Campath

Regimen

Study Evidence
Elter et al. 2005 Phase II

Chemotherapy

  • Fludarabine (Fludara) 30 mg/m2 IV once per day on days 1 to 3
  • Alemtuzumab (Campath) as follows:
    • Cycle 1: 3 mg IV once on day 1, then 10 mg IV once on day 2, then 30 mg IV once on day 3
    • Cycles 2 to 6: 30 mg IV once per day on days 1 to 3

Supportive medications

28-day cycle for 6 cycles

References

  1. Elter T, Borchmann P, Schulz H, Reiser M, Trelle S, Schnell R, Jensen M, Staib P, Schinköthe T, Stützer H, Rech J, Gramatzki M, Aulitzky W, Hasan I, Josting A, Hallek M, Engert A. Fludarabine in combination with alemtuzumab is effective and feasible in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: results of a phase II trial. J Clin Oncol. 2005 Oct 1;23(28):7024-31. Epub 2005 Sep 6. link to original article contains protocol PubMed

Fludarabine & Prednisone

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Regimen

Study Evidence
O'Brien et al. 1993 Phase II

Chemotherapy

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 protocol 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

HDMP-R

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HDMP-R: High Dose, MethylPrednisolone, Rituximab

Regimen #1

Study Evidence
Pileckyte et al. 2011 Phase II

Chemotherapy

  • Methylprednisolone (Solumedrol) 1000 mg/m2 IV once per day over 4 hours on days 1 to 5
  • Rituximab (Rituxan) as follows:
    • Cycle 1: 50 mg IV once on day 1, then 150 mg IV once on day 2, then remainder of a 375 mg/m2 dose on day 3, then 500 mg/m2 IV once on day 5
    • Cycles 2 to 6: 500 mg/m2 IV once per day on days 1 & 5

Supportive medications

21-day cycle for 6 cycles

Regimen #2

Study Evidence
Bowen et al. 2007 Retrospective

Chemotherapy

Supportive medications

28-day cycles

References

  1. Retrospective: Bowen DA, Call TG, Jenkins GD, Zent CS, Schwager SM, Van Dyke DL, Jelinek DF, Kay NE, Shanafelt TD. Methylprednisolone-rituximab is an effective salvage therapy for patients with relapsed chronic lymphocytic leukemia including those with unfavorable cytogenetic features. Leuk Lymphoma. 2007 Dec;48(12):2412-7. link to original article contains protocol PubMed
  2. Castro JE, Sandoval-Sus JD, Bole J, Rassenti L, Kipps TJ. Rituximab in combination with high-dose methylprednisolone for the treatment of fludarabine refractory high-risk chronic lymphocytic leukemia. Leukemia. 2008 Nov;22(11):2048-53. Epub 2008 Aug 28. link to PMC article PubMed
  3. Pileckyte R, Jurgutis M, Valceckiene V, Stoskus M, Gineikiene E, Sejoniene J, Degulys A, Zvirblis T, Griskevicius L. Dose-dense high-dose methylprednisolone and rituximab in the treatment of relapsed or refractory high-risk chronic lymphocytic leukemia. Leuk Lymphoma. 2011 Jun;52(6):1055-65. link to original article contains protocol PubMed

Ibrutinib & Ofatumumab

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Regimen #1, concurrent ibrutinib and ofatumumab

Study Evidence
Jaglowski et al. 2015 Phase II

This study to patients who had failed two or more prior therapies, or had Richter's transformation.

Chemotherapy

  • Ibrutinib (Imbruvica) 420 mg PO once per day
  • Ofatumumab (Arzerra) as follows:
    • Dose 1: 300 mg IV once on day 1
    • Doses 2 to 8: 2000 mg IV once per week on weeks 2 to 8
    • Doses 9 to 12: 2000 mg IV once per month on weeks 13, 17, 21, 25

One course; ibrutinib given until progression of disease or unacceptable toxicity

Regimen #2, ibrutinib lead-in

Study Evidence
Jaglowski et al. 2015 Phase II

This study to patients who had failed two or more prior therapies, or had Richter's transformation.

Chemotherapy

  • Ibrutinib (Imbruvica) 420 mg PO once per day
  • Ofatumumab (Arzerra) as follows:
    • Dose 1: 300 mg IV once on week 5
    • Doses 2 to 8: 2000 mg IV once per week on weeks 6 to 12
    • Doses 9 to 12: 2000 mg IV once per month on weeks 17, 21, 25, 29

One course; ibrutinib given until progression of disease or unacceptable toxicity

Regimen #3, ofatumumab lead-in

Study Evidence
Jaglowski et al. 2015 Phase II

This study to patients who had failed two or more prior therapies, or had Richter's transformation.

Chemotherapy

  • Ibrutinib (Imbruvica) 420 mg PO once per day, starting on week 9
  • Ofatumumab (Arzerra) as follows:
    • Dose 1: 300 mg IV once on day 1
    • Doses 2 to 8: 2000 mg IV once per week on weeks 2 to 8
    • Doses 9 to 12: 2000 mg IV once per month on weeks 13, 17, 21, 25

One course; ibrutinib given until progression of disease or unacceptable toxicity

References

  1. Jaglowski SM, Jones JA, Nagar V, Flynn JM, Andritsos LA, Maddocks KJ, Woyach JA, Blum KA, Grever MR, Smucker K, Ruppert AS, Heerema NA, Lozanski G, Stefanos M, Munneke B, West JS, Neuenburg JK, James DF, Hall N, Johnson AJ, Byrd JC. Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab in chronic lymphocytic leukemia: a phase 1b/2 study. Blood. 2015 Aug 13;126(7):842-50. Epub 2015 Jun 26. link to original article contains verified protocol link to PMC article PubMed

Ibrutinib & Rituximab

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Regimen

Study Evidence
Burger et al. 2014 Phase II

This study was open to patients with high-risk CLL (del17p or TP53 mutation, PFS less than 36 months from initial therapy, or relapsed CLL with del11q). Only 4 patients in the published study were untreated.

Chemotherapy

28-day cycles; ibrutinib given until progression of disease or unacceptable toxicity

References

  1. Burger JA, Keating MJ, Wierda WG, Hartmann E, Hoellenriegel J, Rosin NY, de Weerdt I, Jeyakumar G, Ferrajoli A, Cardenas-Turanzas M, Lerner S, Jorgensen JL, Nogueras-González GM, Zacharian G, Huang X, Kantarjian H, Garg N, Rosenwald A, O'Brien S. Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study. Lancet Oncol. 2014 Sep;15(10):1090-9. Epub 2014 Aug 20. link to original article contains verified protocol link to PMC article PubMed
    1. Update: Jain P, Keating MJ, Wierda WG, Sivina M, Thompson PA, Ferrajoli A, Estrov Z, Kantarjian H, O'Brien S, Burger JA. Long-term Follow-up of Treatment with Ibrutinib and Rituximab in Patients with High-Risk Chronic Lymphocytic Leukemia. Clin Cancer Res. 2016 Oct 19. [Epub ahead of print] link to original articlelink to PMC article PubMed

Idelalisib (Zydelig)

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Regimen

Study Evidence
Gopal et al. 2014 (DELTA) Phase II

Chemotherapy

Continued until progression, death, or unacceptable toxicity

References

  1. Gopal AK, Kahl BS, de Vos S, Wagner-Johnston ND, Schuster SJ, Jurczak WJ, Flinn IW, Flowers CR, Martin P, Viardot A, Blum KA, Goy AH, Davies AJ, Zinzani PL, Dreyling M, Johnson D, Miller LL, Holes L, Li D, Dansey RD, Godfrey WR, Salles GA. PI3Kd Inhibition by Idelalisib in Patients with Relapsed Indolent Lymphoma. N Engl J Med. 2014 Mar 13;370(11):1008-18. Epub 2014 Jan 22. link to original article contains verified protocol link to PMC article PubMed
    1. Update: Abstract: Ajay K. Gopal, MD, Brad S. Kahl, MD, Sven de Vos, MD, PhD, Nina D. Wagner-Johnston, MD, Stephen J. Schuster, MD, Wojciech Jurczak, MD, PhD, Ian W. Flinn, MD, PhD, Christopher R. Flowers, MD, Peter Martin, MD, Andreas Viardot, MD, Kristie A. Blum, MD, Andre Goy, MD, Andrew Davies, BM PhD, Pier Luigi Zinzani, MD, Martin H. Dreyling, MD, PhD, Leanne M. Holes, Bess Sorensen, PhD, Wayne R. Godfrey, MD and Gilles Andre Salles, MD, PhD. Mature Follow up from a Phase 2 Study of PI3K-Delta Inhibitor Idelalisib in Patients with Double (Rituximab and Alkylating agent)-Refractory Indolent B-Cell Non-Hodgkin Lymphoma (iNHL). ASH Annual Meeting 2014, Abstract 1708 link to abstract
  2. Brown JR, Byrd JC, Coutre SE, Benson DM, Flinn IW, Wagner-Johnston ND,Spurgeon SE, Kahl BS, Bello C, Webb HK, Johnson DM, Peterman S, Li D, Jahn TM, Lannutti BJ, Ulrich RG, Yu AS, Miller LL, Furman RR. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110d, for relapsed/refractory chronic lymphocytic leukemia. Blood. 2014 May 29;123(22):3390-7. Epub 2014 Mar 10. link to original article link to PMC article PubMed

Lenalidomide monotherapy

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Regimen #1

Study Evidence
Chanan-Khan et al. 2006 Phase II

Chemotherapy

  • Lenalidomide (Revlimid) 5 mg PO once per day, escalated by 5 mg every 1 to 2 weeks to a target maximum dose of 25 mg PO once per day on days 1 to 21

Supportive medications

  • Allopurinol (Zyloprim) 300 mg PO once per day starting 2 to 3 days prior to therapy, and continued up to a total of 14 days

28-day cycles

Regimen #2

Study Evidence
Ferrajoli et al. 2008 Phase II

Chemotherapy

  • Lenalidomide (Revlimid) 10 mg PO once per day, then increased by 5 mg every 28 days to a target maximum dose of 25 mg PO once per day

28-day cycles

Regimen #3

Study Evidence
Witzig et al. 2009 (NHL-001) Phase II, <20 patients in this subgroup

Patients studied in this trial and in this subgroup had a diagnosis of SLL.

Chemotherapy

28-day cycles until disease progression or unacceptable toxicity

References

  1. Chanan-Khan A, Miller KC, Musial L, Lawrence D, Padmanabhan S, Takeshita K, Porter CW, Goodrich DW, Bernstein ZP, Wallace P, Spaner D, Mohr A, Byrne C, Hernandez-Ilizaliturri F, Chrystal C, Starostik P, Czuczman MS. Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study. J Clin Oncol. 2006 Dec 1;24(34):5343-9. Epub 2006 Nov 6. link to original article contains protocol PubMed
  2. Ferrajoli A, Lee BN, Schlette EJ, O'Brien SM, Gao H, Wen S, Wierda WG, Estrov Z, Faderl S, Cohen EN, Li C, Reuben JM, Keating MJ. Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood. 2008 Jun 1;111(11):5291-7. Epub 2008 Mar 11. link to original article link to PMC article PubMed
  3. Witzig TE, Wiernik PH, Moore T, Reeder C, Cole C, Justice G, Kaplan H, Voralia M, Pietronigro D, Takeshita K, Ervin-Haynes A, Zeldis JB, Vose JM. Lenalidomide oral monotherapy produces durable responses in relapsed or refractory indolent non-Hodgkin's Lymphoma. J Clin Oncol. 2009 Nov 10;27(32):5404-9. Epub 2009 Oct 5. link to original article contains verified protocol PubMed

Lenalidomide & Ofatumumab

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Regimen #1

Study Evidence
Vitale et al. 2016 Phase II

Chemotherapy

  • Lenalidomide (Revlimid) 10 mg PO once per day, starting on day 9 of cycle 1
  • Ofatumumab (Arzerra) as follows:
    • Cycle 1: 300 mg IV once on day 1, then 1000 mg IV once per day on days 8, 15, 22
    • Cycles 3 to 6: 1000 mg IV once on day 1
    • Cycles 7 to 24: 1000 mg IV once on day 1 of every other cycle

Supportive medications

28-day cycle for 24 cycles

Patients with a sustained PR or CR were allowed to continue treatment with lenalidomide monotherapy indefinitely.

References

  1. Vitale C, Falchi L, Ten Hacken E, Gao H, Shaim H, Van Roosbroeck K, Calin G, O'Brien S, Faderl S, Wang X, Wierda WG, Rezvani K, Reuben JM, Burger JA, Keating MJ, Ferrajoli A. Ofatumumab and Lenalidomide for Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia: Correlation between Responses and Immune Characteristics. Clin Cancer Res. 2016 May 15;22(10):2359-67. Epub 2016 Jan 5. link to original article contains verified protocol link to PMC article PubMed

Lenalidomide & Rituximab

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Regimen #1

Study Evidence
Chanan-Khan et al. 2006 Phase II

Chemotherapy

  • Lenalidomide (Revlimid) 5 mg PO once per day, escalated by 5 mg every 1 to 2 weeks to a target maximum dose of 25 mg PO once per day on days 1 to 21
  • Rituximab (Rituxan) as follows:
    • Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15
    • Subsequent Cycles: 375 mg/m2 IV once per day on days 1 & 15

Supportive medications

  • Allopurinol (Zyloprim) 300 mg PO once per day starting 2 to 3 days prior to therapy, and continued up to a total of 14 days

28-day cycles

Regimen #2

Study Evidence
Badoux et al. 2013 Phase II

Chemotherapy

  • Lenalidomide (Revlimid) as follows:
    • Cycle 1: 10 mg PO once per day on days 9 to 28
    • Subsequent Cycles: 10 mg PO once per day on days 1 to 28
  • Rituximab (Rituxan) as follows:
    • Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15, 22
    • Cycle 2: no rituximab given
    • Cycles 3 to 12: 375 mg/m2 IV once on day 1

Supportive medications

28-day cycle for 12 cycles

Lenalidomide could continue indefinitely in responders.

References

  1. Chanan-Khan A, Miller KC, Musial L, Lawrence D, Padmanabhan S, Takeshita K, Porter CW, Goodrich DW, Bernstein ZP, Wallace P, Spaner D, Mohr A, Byrne C, Hernandez-Ilizaliturri F, Chrystal C, Starostik P, Czuczman MS. Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study. J Clin Oncol. 2006 Dec 1;24(34):5343-9. Epub 2006 Nov 6. link to original article contains protocol PubMed
  2. Badoux XC, Keating MJ, Wen S, Wierda WG, O'Brien SM, Faderl S, Sargent R, Burger JA, Ferrajoli A. Phase II Study of Lenalidomide and Rituximab As Salvage Therapy for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia. J Clin Oncol. 2013 Feb 10;31(5):584-91. Epub 2012 Dec 26. link to original article contains verified protocol link to PMC article PubMed

Obinutuzumab monotherapy

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Regimen

Study Evidence
Cartron et al. 2014 (GAUGUIN) Phase II

Note: Dose here is the phase II dose

Chemotherapy

  • Obinutuzumab (Gazyva) as follows:
    • Cycle 1: 1000 mg IV once per day on days 1, 8, 15
    • Cycle 2 onwards: 1000 mg IV once on day 1

Supportive medications

  • Acetaminophen (Tylenol) 650 to 1000 mg PO 30 minutes prior to first infusion, repeat for those at risk of tumor lysis or with history of reaction
  • Antihistamine (no drug or dose specified) PO 30 minutes prior to first infusion, repeat for those at risk of tumor lysis or with history of reaction
  • Corticosteroids (no drug/dose/route specified) before first infusion for patients at "high risk" of severe infusion reaction, including those with a history of severe Rituximab (Rituxan) reactions

21-day cycle up to 10 doses (8 cycles)

References

  1. Cartron G, de Guibert S, Dilhuydy MS, Morschhauser F, Leblond V, Dupuis J, Mahe B, Bouabdallah R, Lei G, Wenger M, Wassner-Fritsch E, Hallek M. Obinutuzumab (GA101) in relapsed/refractory chronic lymphocytic leukemia: final data from the phase 1/2 GAUGUIN study. Blood. 2014 Oct 2;124(14):2196-202. Epub 2014 Aug 20. link to original article contains verified protocol PubMed

OFAR

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OFAR: Oxaliplatin, Fludarabine, Ara-C (Cytarabine), Rituximab

Regimen

Study Evidence
Tsimberidou et al. 2008 Phase II

Chemotherapy

  • Oxaliplatin (Eloxatin) 25 mg/m2 IV over 2 hours once per day on days 1 to 4
  • Fludarabine (Fludara) 30 mg/m2 IV once per day on days 2 & 3, administered within 30 minutes of completion of oxaliplatin
  • Cytarabine (Cytosar) 1000 mg/m2 IV over 2 hours once per day on days 2 & 3, 4 hours after fludarabine started
  • Rituximab (Rituxan) as follows:
    • Cycle 1: 375 mg/m2 IV over 4 to 6 hours once on day 3
    • Cycles 2 to 6: 375 mg/m2 IV over 4 to 6 hours once on day 1

Supportive medications

28-day cycle for up to 6 cycles

References

  1. Tsimberidou AM, Wierda WG, Plunkett W, Kurzrock R, O'Brien S, Wen S, Ferrajoli A, Ravandi-Kashani F, Garcia-Manero G, Estrov Z, Kipps TJ, Brown JR, Fiorentino A, Lerner S, Kantarjian HM, Keating MJ. Phase I-II study of oxaliplatin, fludarabine, cytarabine, and rituximab combination therapy in patients with Richter's syndrome or fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol. 2008 Jan 10;26(2):196-203. link to original article contains protocol PubMed

PCR

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PCR: Pentostatin, Cyclophosphamide, Rituximab

Regimen

Study Evidence
Lamanna et al. 2006 Phase II

Chemotherapy

Supportive medications

21-day cycle for 6 cycles

References

  1. Lamanna N, Kalaycio M, Maslak P, Jurcic JG, Heaney M, Brentjens R, Zelenetz AD, Horgan D, Gencarelli A, Panageas KS, Scheinberg DA, Weiss MA. Pentostatin, cyclophosphamide, and rituximab is an active, well-tolerated regimen for patients with previously treated chronic lymphocytic leukemia. J Clin Oncol. 2006 Apr 1;24(10):1575-81. Epub 2006 Mar 6. link to original article contains protocol PubMed

R-BAC

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R-BAC: Rituximab, Bendamustine, Ara-C (Cytarabine)

Regimen

Study Evidence
Visco et al. 2013 Pilot, <20 patients reported

Chemotherapy

Note: the bendamustine infusion instructions are for the Treanda formulation, which was discontinued on 3/31/2016.

  • Rituximab (Rituxan) as follows:
    • Cycle 1: 375 mg/m2 IV once on day 1
    • Subsequent cycles: 500 mg/m2 IV once on day 1
  • Bendamustine 70 mg/m2 IV over 60 minutes once per day on days 1 & 2
  • Cytarabine (Cytosar) 800 mg/m2 IV over 2 hours once per day on days 1 to 3, beginning 2 hours after bendamustine

Supportive medications

  • Primary prophylaxis with granulocyte colony-stimulating factor was routinely used starting from Day 5 after chemotherapy completion, and lasting for 3 to 6 days or until neutrophil count recovery.

28-day cycle for up to 4 cycles with dose delay and modification based on response and toxicity

References

  1. Visco C, Finotto S, Pomponi F, Sartori R, Laveder F, Trentin L, Paolini R, Di Bona E, Ruggeri M, Rodeghiero F. The combination of rituximab, bendamustine, and cytarabine for heavily pretreated relapsed/refractory cytogenetically high-risk patients with chronic lymphocytic leukemia. Am J Hematol. 2013 Apr;88(4):289-93. Epub 2013 Feb 28. link to original article contains verified protocol PubMed

Ruxolitinib (Jakafi)

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Regimen

Study Evidence
Jain et al. 2017 Phase II, <20 pts in this subgroup

Note: this was a trial focused on symptom control, not efficacy.

Chemotherapy

References

  1. Jain P, Keating M, Renner S, Cleeland C, Xuelin H, Gonzalez GN, Harris D, Li P, Liu Z, Veletic I, Rozovski U, Jain N, Thompson P, Bose P, DiNardo C, Ferrajoli A, O'Brien S, Burger J, Wierda W, Verstovsek S, Kantarjian H, Estrov Z. Ruxolitinib for symptom control in patients with chronic lymphocytic leukaemia: a single-group, phase 2 trial. Lancet Haematol. 2017 Jan 11. [Epub ahead of print] link to original article contains protocol link to PMC article PubMed

Venetoclax (Venclexta)

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Regimen

Study Evidence
Roberts et al. 2015 Phase I/II
Stilgenbauer et al. 2016 Phase II

This is the dosing schedule used in the phase II expansion cohort of Roberts et al. 2015. See paper for supportive care details during initial dosing.

Chemotherapy

  • Venetoclax (Venclexta) as follows:
    • Week 1: 20 mg PO once per day
    • Week 2: 50 mg PO once per day
    • Week 3: 100 mg PO once per day
    • Week 4: 200 mg PO once per day
    • Week 5 onwards: 400 mg PO once per day

Continued until disease progression or unacceptable toxicity

References

  1. Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF, Kipps TJ, Anderson MA, Brown JR, Gressick L, Wong S, Dunbar M, Zhu M, Desai MB, Cerri E, Enschede SH, Humerickhouse RA, Wierda WG, Seymour JF. Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2016 Jan 28;374(4):311-22. Epub 2015 Dec 6. link to original article contains verified protocol PubMed
  2. Stilgenbauer S, Eichhorst B, Schetelig J, Coutre S, Seymour JF, Munir T, Puvvada SD, Wendtner CM, Roberts AW, Jurczak W, Mulligan SP, Böttcher S, Mobasher M, Zhu M, Desai M, Chyla B, Verdugo M, Enschede SH, Cerri E, Humerickhouse R, Gordon G, Hallek M, Wierda WG. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 2016 Jun;17(6):768-78. Epub 2016 May 10. link to original article contains protocol PubMed

Consolidation and/or maintenance after salvage therapy

Observation

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Regimen

Study Evidence Comparator Efficacy
van Oers et al. 2015 (PROLONG) Phase III Ofatumumab Inferior PFS
Greil et al. 2016 (AGMT CLL-8a) Phase III Rituximab Inferior PFS

No further treatment offered to patients in their second or third CR or PR; prior treatment was not specified in PROLONG. Preceded by "rituximab-containing chemoimmunotherapy" in AGMT CLL-8a.

References

  1. van Oers MH, Kuliczkowski K, Smolej L, Petrini M, Offner F, Grosicki S, Levin MD, Gupta I, Phillips J, Williams V, Manson S, Lisby S, Geisler C; PROLONG study investigators. Ofatumumab maintenance versus observation in relapsed chronic lymphocytic leukaemia (PROLONG): an open-label, multicentre, randomised phase 3 study. Lancet Oncol. 2015 Oct;16(13):1370-9. Epub 2015 Sep 13. link to original article contains verified protocol PubMed
  2. Greil R, Obrtlíková P, Smolej L, Kozák T, Steurer M, Andel J, Burgstaller S, Mikušková E, Gercheva L, Nösslinger T, Papajík T, Ladická M, Girschikofsky M, Hrubiško M, Jäger U, Fridrik M, Pecherstorfer M, Králiková E, Burcoveanu C, Spasov E, Petzer A, Mihaylov G, Raynov J, Oexle H, Zabernigg A, Flochová E, Palášthy S, Stehlíková O, Doubek M, Altenhofer P, Pleyer L, Melchardt T, Klingler A, Mayer J, Egle A. Rituximab maintenance versus observation alone in patients with chronic lymphocytic leukaemia who respond to first-line or second-line rituximab-containing chemoimmunotherapy: final results of the AGMT CLL-8a Mabtenance randomised trial. Lancet Haematol. 2016 Jul;3(7):e317-29. Epub 2016 Jun 16. link to original article contains protocol PubMed

Ofatumumab (Arzerra)

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Regimen #1

Study Evidence Comparator Efficacy
van Oers et al. 2015 (PROLONG) Phase III Observation Superior PFS

Treatment offered to patients in their second or third CR or PR; prior treatment was not specified.

Chemotherapy

Supportive medications

Up to 2-year course

Regimen #2

Study Evidence
Österborg et al. 2015 (GEN416) Phase II

Treatment preceded by ofatumumab x 8.

Chemotherapy

Supportive medications

Up to 2 years (24 doses)

References

  1. Österborg A, Wierda WG, Mayer J, Hess G, Hillmen P, Schetelig J, Schuh A, Smolej L, Beck C, Dreyfus B, Hellman A, Kozlowski P, Pfreundschuh M, Rizzi R, Spacek M, Phillips JL, Gupta IV, Williams V, Jewell RC, Nebot N, Lisby S, Dyer MJ. Ofatumumab retreatment and maintenance in fludarabine-refractory chronic lymphocytic leukaemia patients. Br J Haematol. 2015 Jul;170(1):40-9. Epub 2015 Mar 30. link to original article contains verified protocol PubMed
  2. van Oers MH, Kuliczkowski K, Smolej L, Petrini M, Offner F, Grosicki S, Levin MD, Gupta I, Phillips J, Williams V, Manson S, Lisby S, Geisler C; PROLONG study investigators. Ofatumumab maintenance versus observation in relapsed chronic lymphocytic leukaemia (PROLONG): an open-label, multicentre, randomised phase 3 study. Lancet Oncol. 2015 Oct;16(13):1370-9. Epub 2015 Sep 13. link to original article contains verified protocol PubMed

Rituximab monotherapy

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Regimen

Study Evidence Comparator Efficacy
Greil et al. 2016 (AGMT CLL-8a) Phase III Observation Superior PFS

Treatment preceded by "rituximab-containing chemoimmunotherapy".

Chemotherapy

2 years total (8 doses)

References

  1. Greil R, Obrtlíková P, Smolej L, Kozák T, Steurer M, Andel J, Burgstaller S, Mikušková E, Gercheva L, Nösslinger T, Papajík T, Ladická M, Girschikofsky M, Hrubiško M, Jäger U, Fridrik M, Pecherstorfer M, Králiková E, Burcoveanu C, Spasov E, Petzer A, Mihaylov G, Raynov J, Oexle H, Zabernigg A, Flochová E, Palášthy S, Stehlíková O, Doubek M, Altenhofer P, Pleyer L, Melchardt T, Klingler A, Mayer J, Egle A. Rituximab maintenance versus observation alone in patients with chronic lymphocytic leukaemia who respond to first-line or second-line rituximab-containing chemoimmunotherapy: final results of the AGMT CLL-8a Mabtenance randomised trial. Lancet Haematol. 2016 Jul;3(7):e317-29. Epub 2016 Jun 16. link to original article contains protocol PubMed

Response criteria

NCI Sponsored Working Group Criteria (1996)

  1. Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O'Brien S, Rai KR. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood. 1996 Jun 15;87(12):4990-7. link to original article PubMed

International Workshop on Chronic Lymphocytic Leukemia guidelines (2008)

  1. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, Hillmen P, Keating MJ, Montserrat E, Rai KR, Kipps TJ; International Workshop on Chronic Lymphocytic Leukemia. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008 Jun 15;111(12):5446-56. Epub 2008 Jan 23. Erratum in: Blood. 2008 Dec 15;112(13):5259. link to original article link to PMC article PubMed

Prognosis

These are various staging and risk prediction systems that are in approximate chronological order.

Original Rai staging (1975)

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  • Stage 0: bone marrow and blood lymphocytosis only
  • Stage I: lymphocytosis with enlarged nodes
  • Stage II: lymphocytosis with enlarged spleen or liver or both
  • Stage III: lymphocytosis with anemia
  • Stage IV: lymphocytosis with thrombocytopenia
  1. Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. Clinical staging of chronic lymphocytic leukemia. Blood. 1975 Aug;46(2):219-34. link to original article PubMed

Binet staging (1981)

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  • Group A: no anemia, no thrombocytopenia, less than three involved areas
  • Group B: no anemia, no thrombocytopenia, three or more involved areas (counting as one each of the following: axillary, cervical, inguinal, lymph nodes, whether unilateral or bilateral, spleen and liver)
  • Group C: anemia (hemoglobin less than 10 g/dL) and/or thrombocytopenia (platelets less than 100 x 109/L)
  1. Binet JL, Auquier A, Dighiero G, Chastang C, Piguet H, Goasguen J, Vaugier G, Potron G, Colona P, Oberling F, Thomas M, Tchernia G, Jacquillat C, Boivin P, Lesty C, Duault MT, Monconduit M, Belabbes S, Gremy F. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer. 1981 Jul 1;48(1):198-206. link to original article PubMed

Risk by karyotype (1984)

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Classic NEJM paper establishing abnormal karyotype as an adverse prognostic marker

  1. Han T, Ozer H, Sadamori N, Emrich L, Gomez GA, Henderson ES, Bloom ML, Sandberg AA. Prognostic importance of cytogenetic abnormalities in patients with chronic lymphocytic leukemia. N Engl J Med. 1984 Feb 2;310(5):288-92. to original article PubMed

Risk by lymphocyte doubling time

  1. Montserrat E, Sanchez-Bisono J, Viñolas N, Rozman C. Lymphocyte doubling time in chronic lymphocytic leukaemia: analysis of its prognostic significance. Br J Haematol. 1986 Mar;62(3):567-75. link to original article PubMed
  2. Molica S, Alberti A. Prognostic value of the lymphocyte doubling time in chronic lymphocytic leukemia. Cancer. 1987 Dec 1;60(11):2712-6. link to original article PubMed

Risk by FISH

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  • Classic 2000 NEJM paper establishing that 17p deletion has the worst prognosis:
  1. Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L, Döhner K, Bentz M, Lichter P. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000 Dec 28;343(26):1910-6. link to original article PubMed
  • This article and abstract explore the significance of 13q deletions in more detail:
  1. Van Dyke DL, Shanafelt TD, Call TG, Zent CS, Smoley SA, Rabe KG, Schwager SM, Sonbert JC, Slager SL, Kay NE. A comprehensive evaluation of the prognostic significance of 13q deletions in patients with B-chronic lymphocytic leukaemia. Br J Haematol. 2010 Feb;148(4):544-50. Epub 2009 Nov 6. link to original article link to PMC article PubMed
  2. Abstract: Claudia Haferlach, Melanie Zenger, Vera Grossmann, Frank Dicker, Sabine Jeromin, Alexander Kohlmann, Susanne Schnittger, Wolfgang Kern, Torsten Haferlach. The Impact of Homozygosity and Size of the 13q Deletion in Patients with CLL. Blood 2012 120:3892 abstract 3892 link to abstract

Risk by TP53 mutation

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  1. Zenz T, Eichhorst B, Busch R, Denzel T, Häbe S, Winkler D, Bühler A, Edelmann J, Bergmann M, Hopfinger G, Hensel M, Hallek M, Döhner H, Stilgenbauer S. TP53 mutation and survival in chronic lymphocytic leukemia. J Clin Oncol. 2010 Oct 10;28(29):4473-9. Epub 2010 Aug 9. link to original articlePubMed

Risk by CD38 expression

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  1. Damle RN, Wasil T, Fais F, Ghiotto F, Valetto A, Allen SL, Buchbinder A, Budman D, Dittmar K, Kolitz J, Lichtman SM, Schulman P, Vinciguerra VP, Rai KR, Ferrarini M, Chiorazzi N. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood. 1999 Sep 15;94(6):1840-7. link to original article PubMed
  2. Review: Malavasi F, Deaglio S, Damle R, Cutrona G, Ferrarini M, Chiorazzi N. CD38 and chronic lymphocytic leukemia: a decade later. Blood. 2011 Sep 29;118(13):3470-8. link to original article link to PMC article PubMed

Risk by ZAP-70 expression (2003)

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  1. Crespo M, Bosch F, Villamor N, Bellosillo B, Colomer D, Rozman M, Marcé S, López-Guillermo A, Campo E, Montserrat E. ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med. 2003 May 1;348(18):1764-75. link to original article PubMed

Prognostic scoring system using molecular and cytogenetic features (2012)

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  1. Rossi D, Rasi S, Spina V, Bruscaggin A, Monti S, Ciardullo C, Deambrogi C, Khiabanian H, Serra R, Bertoni F, Forconi F, Laurenti L, Marasca R, Dal-Bo M, Rossi FM, Bulian P, Nomdedeu J, Del Poeta G, Gattei V, Pasqualucci L, Rabadan R, Foà R, Dalla-Favera R, Gaidano G. Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia. Blood. 2013 Feb 21;121(8):1403-12. Epub 2012 Dec 13. link to original article link to PMC article PubMed

CLL-IPI (2016)

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  1. International CLL-IPI working group. An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncol. 2016 Jun;17(6):779-90. Epub 2016 May 13. link to original article PubMed
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