Difference between revisions of "Chronic lymphocytic leukemia"

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'''On 3/21/2016 Gilead announced that they were stopping seven clinical trials in patients with CLL, SLL, and iNHL due to excess deaths and increased rates of SAEs. A [http://www.zydeligrems.com/ REMS program] has also been announced.'''
  
 
===Regimen {{#subobject:33cbcc|Variant=1}}===
 
===Regimen {{#subobject:33cbcc|Variant=1}}===

Revision as of 19:19, 6 April 2016

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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
133 variants on this page


Untreated, randomized data

Alemtuzumab (Campath)

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Regimen

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

  • 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 (see references for details, as they differ by paper):

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 (Treanda)

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Regimen

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

28-day cycle x 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 original article PubMed

BR

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BR: Bendamustine, Rituximab

Regimen

Study Evidence Comparator Efficacy
Fischer et al. 2012 Phase II
Eichhorst et al. 2013 (GCLLSG CLL10) Phase III FCR Decreased PFS

28-day cycles x 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 original article PubMed
  3. Abstract: Barbara Eichhorst, MD, Anna-Maria Fink, MD, Raymonde Busch, PhD, Elisabeth Lange, MD, Hubert Köppler, Prof. Dr., Michael Kiehl, MD, Martin Sökler, MD, Rudolf Schlag, MD, Ursula Vehling-Kaiser, MD, Georg Köchling, MD, Christoph Plöger, MD, Michael Gregor, MD, Torben Plesner, MD, Marek Trneny, MD, Ph.D., Prof, Kirsten Fischer, MD, Hartmut Döhner, MD, Michael Kneba, MD, Clemens Wendtner, MD, Wolfram Klapper, Karl-Anton Kreuzer, Dr. med., Stephan Stilgenbauer, MD, Sebastian Böttcher, MD, and Michael Hallek, MD. Chemoimmunotherapy With Fludarabine (F), Cyclophosphamide (C), and Rituximab (R) (FCR) Versus Bendamustine and Rituximab (BR) In Previously Untreated and Physically Fit Patients (pts) With Advanced Chronic Lymphocytic Leukemia (CLL): Results Of a Planned Interim Analysis Of The CLL10 Trial, An International, Randomized Study Of The German CLL Study Group (GCLLSG). 2013 ASH Annual Symposium abstract 526 link to abstract

CAP

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CAP: Cyclophosphamide, Adriamycin (Doxorubicin), Prednisone

Regimen

Study Evidence Comparator
Leporrier et al. 2001 Phase III CHOP
Fludarabine

Monthly cycle x 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 Equivalent RR

Supportive medications:

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

28-day cycles x up to 6 cycles

Regimen #2

Study Evidence Comparator
Robak et al. 2006 (PALG CLL2) Phase III Cladribine
CMC

Supportive medications:

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

28-day cycle x 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
Fludarabine 		Inferior PFS
Hillmen et al. 2015 (COMPLEMENT 1) Phase III Chlorambucil & Ofatumumab Inferior PFS

Supportive medications (Catovsky et al. 2007):

  • Patients with stage C disease (hemoglobin <10 g/dL or platelet count <100 x 10^9/L) received Prednisolone (Millipred) 30 mg/m2 PO once per day x 3 weeks, then 1 week taper before starting Chlorambucil (Leukeran) to reduce its myelotoxicity

28-day cycle x up to 12 cycles

Regimen #2

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

28-day cycle x 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 Decreased 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.

  • 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 x up to 6 cycles

Regimen #4

Study Evidence Comparator Efficacy
Eichhorst et al. 2009 (GCLLSG CLL5) Phase III Fludarabine Decreased TTTF

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 < 3 months) or symptoms from enlarged lymph nodes and organs, or if they had severe B symptoms.

  • 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 x up to 24 cycles

Regimen #5

Study Evidence Comparator Efficacy
Rai et al. 2000 (CALGB 9011) Phase III Fludarabine Decreased PFS
Hillmen et al. 2007 (CAM 307) Phase III Alemtuzumab Decreased 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.

28-day cycle x up to 12 cycles

Regimen #6

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

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

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 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 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 Increased OS
Chlorambucil & Rituximab Increased PFS
  • 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 x 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

Supportive medications:

28-day cycles x 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
Raphael et al. 1991 Phase III CVP

14-day cycles x up to 18 months

Regimen #2

Study Evidence Comparator
Dighiero et al. 1998 Phase III Observation

1-month cycles x 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 Increased PFS
Chlorambucil & Obinutuzumab Decreased PFS

28-day cycle x 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
Leporrier et al. 2001 Phase III CAP
Fludarabine

28-day cycle x 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
Robak et al. 2006 (PALG CLL2) Phase III CC
CMC

Supportive medications:

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

28-day cycle x 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
Raphael et al. 1991 Phase III Chlorambucil & Prednisone

21-day cycles x 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
Geisler et al. 2014 (HOVON-68) Phase III FCA

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 < 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.

Supportive medications:

OR

28-day cycle x 6 cycles

Regimen #2

Study Evidence Comparator Efficacy
Catovsky et al. 2007 (LRF CLL4) Phase III Chlorambucil Increased PFS
Fludarabine Increased PFS
Robak et al. 2010 (PALG-CLL3) Phase III CC Equivalent RR
Hallek et al. 2010 (GCLLSG CLL8) Phase III FCR Decreased OS

Supportive medications (per Robak et al. 2010):

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

28-day cycle x up to 6 cycles

Regimen #3

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

This regimen was intended for untreated patients ≥ 18 years with a diagnosis of progressive CLL using the National Cancer Institute criteria.

28-day cycle x up to 6 cycles

Regimen #4, PO regimen

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

28-day cycle x up to 6 cycles

Regimen #5

Study Evidence Comparator
Eichhorst et al. 2006 (GCLLSG CLL4) Phase III Fludarabine

Supportive medications:

  • No routine antibiotic, antiviral, or growth factor use

28-day cycle x 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
  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 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)

Note: FCCam has been reported as inferior to FCR in abstract form only; the regimen is therefore not included here until if/when published in manuscript format.

Regimen

Study Evidence Comparator
Lepetre et al. 2009 (GOELAMS CLL2007FMP) Phase III FCR
Geisler et al. 2014 (HOVON-68) Phase III FC

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 < 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.

Supportive medications:

OR

28-day cycle x 6 cycles

References

  1. Abstract: Lepretre S, Aurran T, Mahe B, Cazin B, Tournihlac O, Maisonneuve H, et al. Immunochemotherapy with fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) versus fludarabine (F), cyclophosphamide (C) and MabCampath (Cam) (FCCam) in previously untreated patients (pts) with advanced B-chronic lymphocytic leukemia (B-CLL): experience on safety and efficacy within a randomised multicenter phase III trial of the French Cooperative Group on CLL and WM (FCGCLL/MW) and the "Groupe Ouest-Est d'Etudes Des Leucemies Aigues Et Autres Maladies Du Sang" (GOELAMS) : CLL2007FMP (for fit medically patients). Blood 2009;114:538. link to abstract
  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
Hillmen et al. 2011 (NCRI CLL201) Randomized Phase II, >20 per arm FCM-R

28-day cycle x 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
Hillmen et al. 2011 (NCRI CLL201) Randomized Phase II, >20 per arm FCM

28-day cycle x 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
Lepetre et al. 2009 (GOELAMS CLL2007FMP) Phase III FCCam
Hallek et al. 2010 (GCLLSG CLL8) Phase III FC Superior OS
Schweighofer et al. 2013 (GCLLSG CLL7) Phase III Observation
Eichhorst et al. 2013 (GCLLSG CLL10) Phase III BR Increased PFS

Supportive medications:

28-day cycle x 6 cycles

Regimen #2

Study Evidence Comparator Efficacy
Awan et al. 2014 (LUCID) Phase III FCR+L Seems not superior
  • 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 x 6 cycles

References

  1. Abstract: Lepretre S, Aurran T, Mahe B, Cazin B, Tournihlac O, Maisonneuve H, et al. Immunochemotherapy with fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) versus fludarabine (F), cyclophosphamide (C) and MabCampath (Cam) (FCCam) in previously untreated patients (pts) with advanced B-chronic lymphocytic leukemia (B-CLL): experience on safety and efficacy within a randomised multicenter phase III trial of the French Cooperative Group on CLL and WM (FCGCLL/MW) and the "Groupe Ouest-Est d'Etudes Des Leucemies Aigues Et Autres Maladies Du Sang" (GOELAMS) : CLL2007FMP (for fit medically patients). Blood 2009;114:538. link to abstract
  2. 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
  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: Barbara Eichhorst, MD, Anna-Maria Fink, MD, Raymonde Busch, PhD, Elisabeth Lange, MD, Hubert Köppler, Prof. Dr., Michael Kiehl, MD, Martin Sökler, MD, Rudolf Schlag, MD, Ursula Vehling-Kaiser, MD, Georg Köchling, MD, Christoph Plöger, MD, Michael Gregor, MD, Torben Plesner, MD, Marek Trneny, MD, Ph.D., Prof, Kirsten Fischer, MD, Hartmut Döhner, MD, Michael Kneba, MD, Clemens Wendtner, MD, Wolfram Klapper, Karl-Anton Kreuzer, Dr. med., Stephan Stilgenbauer, MD, Sebastian Böttcher, MD, and Michael Hallek, MD. Chemoimmunotherapy With Fludarabine (F), Cyclophosphamide (C), and Rituximab (R) (FCR) Versus Bendamustine and Rituximab (BR) In Previously Untreated and Physically Fit Patients (pts) With Advanced Chronic Lymphocytic Leukemia (CLL): Results Of a Planned Interim Analysis Of The CLL10 Trial, An International, Randomized Study Of The German CLL Study Group (GCLLSG). 2013 ASH Annual Symposium abstract 526 link to abstract
  5. 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 #1

Study Evidence Comparator
Rai et al. 2000 (CALGB 9011) Phase III Chlorambucil
Chlorambucil & Fludarabine
Leporrier et al. 2001 Phase III CAP
CHOP
Eichorst et al. 2006 (GCLLSG CLL4) Phase III FC
Flinn et al. 2007 (ECOG E2997) Phase III FC
Catovsky et al. 2007 (LRF CLL4) Phase III Chlorambucil
FC
Eichhorst et al. 2009 (GCLLSG CLL5) Phase III Chlorambucil
Bergmann et al. 2013 (GCLLSG CLL1) Phase III Observation

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 ≥ 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 < 3 months) or symptoms from enlarged lymph nodes and organs, or if they had severe B symptoms.
  • Fludarabine (Fludara) 25 mg/m2 IV once per day on days 1 to 5

28-day cycle x up to 6 to 12 cycles

Regimen #2, Catovsky et al. 2007

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

28-day cycle x 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
  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 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). 2013 ASH Annual Symposium link to abstract

FR

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FR: Fludarabine, Rituximab

Regimen

Study Evidence Comparator
Byrd et al. 2002 (CALGB 9712) Randomized Phase II F -> R
  • 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 x 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 PubMed

Ibrutinib (Imbruvica)

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Regimen

Study Evidence Comparator
O'Brien et al. 2013 (PCYC-1102) Phase II
Farooqui et al. 2014 Phase II
Burger et al. 2015 (RESONATE-2) Phase III Chlorambucil

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.

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 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 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 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 PubMed

Obinutuzumab (Gazyva)

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Regimen #1, standard-dose (1000 mg)

Study Evidence Comparator
Byrd et al. 2015 Randomized Phase II High-dose obinutuzumab
  • 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
Byrd et al. 2015 Randomized Phase II Standard-dose obinutuzumab
  • 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 PubMed

Observation

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Regimen

Study Evidence Comparator
Dighiero et al. 1998 Phase III Chlorambucil
Bergmann et al. 2013 (GCLLSG CLL1) Phase III Fludarabine
Schweighofer et al. 2013 (GCLLSG CLL7) Phase III FCR

No active treatment, also known as "watchful waiting". Note that in both Dighiero et al. 1998 and Bergmann et al. 2013, the treatment arm was not superior to the placebo arm, reinforcing the "watch and wait" approach for early stage CLL. Whereas, Schweighofer et al. 2013 show that early FCR improves event-free survival.

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). 2013 ASH Annual Symposium abstract 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

Untreated, non-randomized or retrospective data

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

28-day cycles x 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

28-day cycle x 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 PubMed

Cladribine (Leustatin)

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Regimen

Study Evidence
Saven et al. 1995 Phase II

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

21-day cycle x 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 PubMed

FCM

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FCM: Fludarabine, Cyclophosphamide, Mitoxantrone

Regimen

Study Evidence
Bosch et al. 2008 Phase II

Supportive medications:

28-day cycle x 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

Supportive medications:

28-day cycle x 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
  • 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 x 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 PubMed

FCR

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FCR: Fludarabine, Cyclophosphamide, Rituximab

Regimen #1, "FCR-Lite"

Study Evidence
Foon et al. 2009 Phase II
  • 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 x 6 cycles

Treatment followed by indefinite rituximab maintenance.

Regimen #2

Study Evidence
Tam et al. 2006 Phase II

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

Regimen #3

Study Evidence
Keating et al. 2005 Phase II

Supportive medications (varied according to reference):

28-day cycles x 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 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 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

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
  • 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 (Treanda) 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 x 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 PubMed

G-FC

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

Regimen

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

HDMP-R

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HDMP-R: High Dose, MethylPrednisolone, Rituximab

Regimen

Study Evidence
Castro et al. 2009 Phase II
  • 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 x 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. link to PubMed Central article contains protocol PubMed

Idelalisib & Rituximab

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On 3/21/2016 Gilead announced that they were stopping seven clinical trials in patients with CLL, SLL, and iNHL due to excess deaths and increased rates of SAEs. A REMS program has also been announced.

Regimen

Study Evidence
O'Brien et al. 2015 Phase II

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 PubMed

Lenalidomide (Revlimid)

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Regimen #1

Study Evidence
Badoux et al. 2011 Phase II
  • 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
  • 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 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 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 PMC article link to original article PubMed

Lenalidomide & Rituximab

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Regimen #1

Study Evidence
James et al. 2014 Phase II
  • 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.

28-day cycles 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 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 PubMed

O-FC

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O-FC: Ofatumumab, Fludarabine, Cyclophosphamide

Regimen

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

Supportive medications:

21-day cycle x 6 cycles

Regimen #2

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

Supportive medications (see references for details, as they differ by paper):

28-day cycle x 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 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 PubMed

Rituximab (Rituxan)

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Regimen

Study Evidence
Hainsworth et al. 2003 Phase II
  • Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1, 8, 15, 22
    • Optional alternate initial dosing for patients with WBC count >100 x 103/uL: 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 cycles x 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

Consolidation and/or maintenance after upfront therapy

Observation

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Regimen

Study Evidence Comparator Efficacy
Hochster et al. 2009 (ECOG1496) Phase III Rituximab Decreased PFS
Foà et al. 2014 Phase III Rituximab Equivalent PFS

No further treatment; used as a comparator arm. Preceded by CVP (Hochster et al. 2009) or Clb-R (Foà et al. 2014).

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 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

Rituximab (Rituxan)

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Regimen #1

Study Evidence Comparator Efficacy
Foà et al. 2014 Phase III Observation Equivalent PFS

Trend towards improved PFS in the rituximab maintenance group (P=0.07); stay tuned for longer-term follow-up. Treatment preceded by Clb-R.

12 doses total

Regimen #2

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

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

One course every 6 months (16 total doses)

Regimen #3

Study Evidence
Foon et al. 2009 Phase II

Treatment preceded by FCR-Lite x 6.

Continued until relapse

Regimen #4

Study Evidence
Bosch et al. 2009 Phase II

Treatment preceded by R-FCM.

2 years total (8 doses)

Regimen #5

Study Evidence
Hainsworth et al. 2003 Phase II

Treatment preceded by single-agent rituximab

Supportive medications:

6-month cycles x 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 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

Relapsed/refractory

Alemtuzumab (Campath)

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Regimen #1

Study Evidence
Keating et al. 2002 Phase II
Rai et al. 2002 Phase II
  • 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 (see references for details, as they differ by paper):

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

Regimen #2

Study Evidence
Lozanski et al. 2004 Phase II
  • 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
  • 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 >50,000/uL, 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 cycles x 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).

Regimen #2, Fludarabine and Low-dose TBI

Study Evidence
Sorror et al. 2005 Phase II
  • 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

Supportive medications for 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.

Regimen #4, FluCyATG

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

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

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 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 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 (Treanda)

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Regimen #1

Study Evidence Comparator Efficacy
Niederle et al. 2013 Phase III Fludarabine Equivalent PFS

28-day cycle x up to 8 cycles

Regimen #2

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

21-day cycle x 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 PubMed
  3. 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
  4. 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 original article PubMed

BendOfa

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BendOfa: Bendamustine, Ofatumumab

Regimen

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

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

BR

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BR: Bendamustine, Rituximab

Regimen

Study Evidence Comparator
Fischer et al. 2011 Phase II
Zelenetz et al. 2015 Phase III BR & Idelalilisb

28-day cycle x 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 original article PubMed
  3. Abstract: Andrew D Zelenetz, MD, PhD et al. Idelalisib Plus Bendamustine and Rituximab (BR) Is Superior to BR Alone in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia: Results of a Phase 3 Randomized Double-Blind Placebo-Controlled Study. ASH 2015 Abstract LBA5 link to abstract

BR-ibrutinib

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BR: Bendamustine, Rituximab

Regimen

Study Evidence
Brown et al. 2015 (PCYC-1108) Phase II

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

28-day cycle x 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 PubMed

BR & Idelalisib

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BR: Bendamustine, Rituximab

Regimen

Study Evidence Comparator
Zelenetz et al. 2015 Phase III BR

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

References

  1. Abstract: Andrew D Zelenetz, MD, PhD et al. Idelalisib Plus Bendamustine and Rituximab (BR) Is Superior to BR Alone in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia: Results of a Phase 3 Randomized Double-Blind Placebo-Controlled Study. ASH 2015 Abstract LBA5 link to abstract

CFAR

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CFAR: Cyclophosphamide, Fludarabine, Alemtuzumab, Rituximab

Regimen

Study Evidence
Badoux et al. 2011 Phase II

Supportive medications:

28-day cycle x 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 PubMed

Cladribine (Leustatin)

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Regimen

Study Evidence Comparator
Robak et al. 2006 (PALG CLL2) Phase III CC
CMC

28-day cycle x 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

CC

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CC: Cladribine, Cyclophosphamide

Regimen

Study Evidence Comparator
Robak et al. 2006 (PALG CLL2) Phase III Cladribine
CMC

Supportive medications:

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

28-day cycle x 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
Robak et al. 2006 (PALG CLL2) Phase III Cladribine
CC

28-day cycle x 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
Robak et al. 2010 Phase III R-FC

Supportive medications (varied according to reference):

28-day cycle x 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
  • 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 x 6 cycles

Regimen #2

Study Evidence Comparator
Robak et al. 2010 Phase III FC

Supportive medications (varied according to reference):

28-day cycle x 6 cycles

Regimen #3

Study Evidence
Wierda et al. 2005 Phase II
  • 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 x up to 6 cycles

Regimen #4

Study Evidence
Tam et al. 2006 Phase II

28-day cycles x 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 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. 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
  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

FluCam

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FluCam: Fludarabine, Campath

Regimen

Study Evidence
Elter et al. 2005 Phase II
  • 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 x 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 (Fludara)

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Regimen

Study Evidence Comparator Efficacy
Niederle et al. 2013 Phase III Bendamustine Equivalent PFS

28-day cycles x 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

Fludarabine & Prednisone

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Regimen

Study Evidence
O'Brien et al. 1993 Phase II

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
  • 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 x 6 cycles

Regimen #2

Study Evidence
Bowen et al. 2007 Retrospective

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. 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 (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 Increased OS
Farooqui et al. 2014 Phase II, <20 pts

Both 420 mg and 840 mg doses were investigated in Byrd et al. 2013: "the similar response in the two dose groups provide support for the use of the 420-mg dose of ibrutinib for relapsed CLL." The randomized RESONATE trial and Farooqui et al. used the 420 mg dose.

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 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 PubMed
  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 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 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.

  • 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.

  • 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.

  • 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 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.

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 PubMed

Idelalisib (Zydelig)

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Regimen

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

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 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 PubMed

Idelalisib & Rituximab

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Regimen

Study Evidence Comparator
Furman et al. 2014 Phase III Rituximab

Rituximab is given every two weeks x 5 doses then every three weeks x 3 doses 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 PubMed

Lenalidomide (Revlimid)

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Regimen #1

Study Evidence
Chanan-Khan et al. 2006 Phase II
  • 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
  • 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.

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 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 & Rituximab

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Regimen #1

Study Evidence
Chanan-Khan et al. 2006 Phase II
  • 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
  • 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 x 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 PubMed

Obinutuzumab (Gazyva)

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Regimen

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

Note: Dose here is the phase II dose

  • 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
  • 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 x 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

Ofatumumab (Arzerra)

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Regimen #1

Study Evidence Comparator Efficacy
Byrd et al. 2014 (RESONATE) Phase III Ibrutinib Decreased OS
  • Ofatumumab (Arzerra) 300 mg IV once on day 1, then 2000 mg IV once per week x 7 weeks, then 2000 mg IV once every 4 weeks x 16 weeks

24-week course (12 doses total)

Regimen #2

Study Evidence
Coiffier et al. 2008 Phase II
Wierda et al. 2010 (Study 406) Phase II
  • 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 x 6 cycles

Regimen #3

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.

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 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 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 PubMed
  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 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

PCR

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PCR: Pentostatin, Cyclophosphamide, Rituximab

Regimen

Study Evidence
Lamanna et al. 2006 Phase II

Supportive medications; paper says they were "administered prophylactically," without additional details:

21-day cycle x 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

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 x 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

Rituximab (Rituxan)

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Regimen #1

Study Evidence Comparator
Furman et al. 2014 Phase III Idelalisib & Rituximab
  • Rituximab (Rituxan) 375 mg/m2 IV once on first dose, then 500 mg/m2 IV once on subsequent doses

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

Regimen #2

Study Evidence
McLaughlin et al. 1998 Phase II

4-week course

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 PubMed

Consolidation and/or maintenance after salvage therapy

Observation

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Regimen

Study Evidence Comparator
van Oers et al. 2015 (PROLONG) Phase III Ofatumumab

No further treatment offered to patients in their second or third CR or PR; prior treatment was not specified.

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 SD article contains verified protocol PubMed

Ofatumumab (Arzerra)

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Regimen #1

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

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

Supportive medications:

Up to 2-year course

Regimen #2

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

Treatment preceded by ofatumumab x 8.

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 SD article contains verified 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 PubMed

Prognosis

Original Rai staging (1975)

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  • 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 < 10 g/dL) and/or thrombocytopenia (platelets < 100,000/mm3)
  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 FISH (2000)

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Cassic 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

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
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