Difference between revisions of "Chronic lymphocytic leukemia"

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border-style:solid;">Phase III</span>
 
border-style:solid;">Phase III</span>
  
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*[[Chlorambucil (Leukeran)]] orally (10mg/m2 at days 1-7
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*[[Chlorambucil (Leukeran)]] orally 10mg/m2 at days 1-7
  
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*[[Ofatumumab (Arzerra)]] IV Cycle 1: 300mg day 1 and 1000mg day 8, subsequent cycles: 1000mg at day 1
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*[[Ofatumumab (Arzerra)]] IV cycle 1: 300mg day 1 and 1000mg day 8, subsequent cycles: 1000mg at day 1
  
 
Supportive medications: premedicate with acetaminophen, antihistamine and glucocorticoid
 
Supportive medications: premedicate with acetaminophen, antihistamine and glucocorticoid

Revision as of 18:07, 23 May 2014

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Untreated

Alemtuzumab (Campath)

Regimen, Hillmen et al. 2007 (CAM 307)

Phase III

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)

Regimen, Knauf et al. 2009

Phase III

28-day cycles x 6 cycles; Niederle et al. 2013 treated patients for up to 8 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
  2. 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
  3. Retrospective: Kolibaba KS, Sterchele JA, Joshi AD, Forsyth M, Alwon E, Beygi H, Kennealey GT. Demographics, treatment patterns, safety, and real-world effectiveness in patients aged 70 years and over with chronic lymphocytic leukemia receiving bendamustine with or without rituximab: a retrospective study. Ther Adv Hematol. 2013 Jun;4(3):157-71. link to original article PubMed

BR

BR: Bendamustine, Rituximab

Regimen, Eichhorst et al. 2013 (GCLLSG CLL10)

Phase III

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. 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

CAP: Cyclophosphamide, Adriamycin, Prednisone

Regimen #1, Leporrier et al. 2001

Phase III

Monthly cycles 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

CC: Cladribine, Cyclophosphamide

Regimen, Robak et al. 2010 (PALG-CLL3)

Phase III

Supportive medications:

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

28-day cycles x up to 6 cycles

References

  1. 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)

Regimen #1, Catovsky et al. 2007 (LRF CLL4)

Phase III

Supportive medications:

  • 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 cycles x up to 12 cycles

Regimen #2, Dighiero et al. 1998

Phase III

continue until progression

Regimen #3, Rai et al. 2000 (CALGB 9011) & Hillmen et al. 2007 (CAM 307)

Phase III

28-day cycles x up to 12 cycles

Regimen #4, Knauf et al. 2009

Phase III

  • Chlorambucil (Leukeran) 0.8 mg/kg PO once per day on days 1 & 15
    • Alternate schedule, "divided doses on days 1 to 2 and 15 to 16 for patient comfort in some individual cases": Chlorambucil (Leukeran) 0.4 mg/kg PO once per day on days 1 to 2, 15 to 16

28-day cycles x up to 6 cycles

Regimen #5, Eichhorst et al. 2009 (GCLLSG CLL5)

Phase III

14-day cycles x up to 24 cycles

Regimen #6, Goede et al. 2013 (CLL11/BO21004)

Phase III

28-day cycles x 6 cycles

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
  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
  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. 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
  8. Abstract: Valentin Goede, Kirsten Fischer, Kathryn Humphrey, Elina Asikanius, Raymonde Busch, Anja Engelke, Clemens M. Wendtner, Olga Samoylova, Tatiana Chagorova, Marie-Sarah Dilhuydy, Javier De La Serna Torroba, Thomas Illmer, Stephen Opat, Carolyn Owen, Karl A Kreuzer, Anton W Langerak, Matthias Ritgen, Stephan Stilgenbauer, Michael Wenger, Michael Hallek; German CLL Study Group. Obinutuzumab (GA101) plus chlorambucil (Clb) or rituximab (R) plus Clb versus Clb alone in patients with chronic lymphocytic leukemia (CLL) and preexisting medical conditions (comorbidities): Final stage 1 results of the CLL11 (BO21004) phase III trial. J Clin Oncol 31, 2013 (suppl; abstr 7004) link to abstract
  9. 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 Jan 8. [Epub ahead of print] link to original article contains verified protocol PubMed

Chlorambucil & Obinutuzumab (GClb)

GClb: GA101 (obinutuzumab), Chlorambucil

Regimen, Goede et al. 2013 (CLL11/BO21004)

Phase III

28-day cycles x 6 cycles

References

  1. Abstract: Valentin Goede, Kirsten Fischer, Kathryn Humphrey, Elina Asikanius, Raymonde Busch, Anja Engelke, Clemens M. Wendtner, Olga Samoylova, Tatiana Chagorova, Marie-Sarah Dilhuydy, Javier De La Serna Torroba, Thomas Illmer, Stephen Opat, Carolyn Owen, Karl A Kreuzer, Anton W Langerak, Matthias Ritgen, Stephan Stilgenbauer, Michael Wenger, Michael Hallek; German CLL Study Group. Obinutuzumab (GA101) plus chlorambucil (Clb) or rituximab (R) plus Clb versus Clb alone in patients with chronic lymphocytic leukemia (CLL) and preexisting medical conditions (comorbidities): Final stage 1 results of the CLL11 (BO21004) phase III trial. J Clin Oncol 31, 2013 (suppl; abstr 7004) link to abstract
  2. 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 Jan 8. [Epub ahead of print] link to original article contains verified protocol PubMed


Chlorambucil & Ofatumumab

Regimen Hillmen at el 2013

Phase III

Supportive medications: premedicate with acetaminophen, antihistamine and glucocorticoid

28-day cycles minimum of 3 cycles, until best response up to a maximum of 12 cycles

References

  1. Hillmen P, Tadeusz R, Janssens A, Govindbabu K, Grosicki S, Mayer J, et al. Ofatumumab + Chlorambucil Versus Chlorambucil Alone In Patients With Untreated Chronic Lymphocytic Leukemia (CLL): Results Of The Phase III Study Complement 1 (OMB110911). link to abstract

Chlorambucil & Prednisone

Regimen #1, Raphael et al. 1991

Phase III

14-day cycles x up to 18 months

Regimen #2, Dighiero et al. 1998

Phase III

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)

RClb: Rituximab, Chlorambucil

Regimen #1, Goede et al. 2013 (CLL11/BO21004)

Phase III

28-day cycles x 6 cycles

Regimen #2, 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

References

  1. Abstract: Valentin Goede, Kirsten Fischer, Kathryn Humphrey, Elina Asikanius, Raymonde Busch, Anja Engelke, Clemens M. Wendtner, Olga Samoylova, Tatiana Chagorova, Marie-Sarah Dilhuydy, Javier De La Serna Torroba, Thomas Illmer, Stephen Opat, Carolyn Owen, Karl A Kreuzer, Anton W Langerak, Matthias Ritgen, Stephan Stilgenbauer, Michael Wenger, Michael Hallek; German CLL Study Group. Obinutuzumab (GA101) plus chlorambucil (Clb) or rituximab (R) plus Clb versus Clb alone in patients with chronic lymphocytic leukemia (CLL) and preexisting medical conditions (comorbidities): Final stage 1 results of the CLL11 (BO21004) phase III trial. J Clin Oncol 31, 2013 (suppl; abstr 7004) link to abstract
  2. 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 Jan 8. [Epub ahead of print] link to original article contains verified protocol PubMed
  3. 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 Mar 17. [Epub ahead of print] link to original article contains verified protocol PubMed

CHOP

CHOP: Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone

Regimen

Phase III

28-day cycles 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)

Regimen, 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

CVP: Cyclophosphamide, Vincristine, Prednisone

Regimen #1, Raphael et al. 1991

Phase III

21-day cycles x up to 18 months

===Regimen #2, Hochster et al. 2009 (ECOG1496)

Phase III

21-day cycles x 6 to 8 cycles

Patients were then randomized to maintenance Rituximab (Rituxan) or observation.

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
  2. 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

FC

FC: Fludarabine, Cyclophosphamide

Regimen #1, Catovsky et al. 2007 (LRF CLL4); Robak et al. 2010 (PALG-CLL3); Hallek et al. 2010 (GCLLSG CLL8)

Phase III

Supportive medications (per Robak et al. 2010):

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

28-day cycles x up to 6 cycles

Regimen #2, Eichhorst et al. 2006 (GCLLSG CLL4)

Phase III

Supportive medications:

  • No routine antibiotic, antiviral, or growth factor use

28-day cycles x up to 6 cycles

Regimen #3, Flinn et al. 2007 (ECOG E2997)

Phase III

28-day cycles x up to 6 cycles

Regimen #4, Catovsky et al. 2007 (LRF CLL4 PO regimen)

Phase III

28-day cycles 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
  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

FCR

FCR: Fludarabine, Cyclophosphamide, Rituximab

Regimen #1, Tam et al. 2006

Phase II

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

Regimen #2, Keating et al. 2005; Tam et al. 2008

Phase II

Supportive medications (varied according to reference):

28-day cycles x 6 cycles

Regimen #3, Hallek et al. 2010 (GCLLSG CLL8); Eichhorst et al. 2013 (GCLLSG CLL10)

Phase III

Supportive medications:

  • PCP (Pneumocystis jirovecii pneumonia) prophylaxis recommended for severe leukopenia >7 days
  • No routine prophylaxis with antiviral medications or G-CSF

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
  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. 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
  4. 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
  5. 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
  6. 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

Fludarabine (Fludara)

Regimen #1, Rai et al. 2000 (CALGB 9011); Leporrier et al. 2001; Eichorst et al. 2006 (GCLLSG CLL4); Flinn et al. 2007 (ECOG E2997); Catovsky et al. 2007 (LRF CLL4); Eichhorst et al. 2009 (GCLLSG CLL5)

Phase III

28-day cycles x up to 6 to 12 cycles

Regimen #2, Catovsky et al. 2007

Phase III

28-day cycles x up to 6 to 12 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
  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. 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
  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. 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

Fludarabine & Prednisone

Regimen

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
  2. 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

FR

FR: Fludarabine, Rituximab

Regimen, Byrd et al. 2003 (CALGB 9712)

Phase II

Supportive medications:

28-day cycles 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
  2. 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

HDMP-R

HDMP-R: High Dose, MethylPrednisolone, Rituximab

Regimen, Castro et al. 2009

Phase II

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 original article contains protocol PubMed

Ibrutinib (Imbruvica)

Regimen, O'Brien et al. 2013

Phase II

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.

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

Idelalisib & Rituximab

Regimen, O'Brien et al. 2013

Phase II

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

References

  1. Susan Mary O'Brien, Nicole Lamanna, Thomas J. Kipps, Ian Flinn, Andrew David Zelenetz, Jan Andreas Burger, Leanne Holes, David Michael Johnson, Jessie Gu, Roger D. Dansey, Ronald L. Dubowy, Steven E. Coutre. A phase II study of the selective phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor idelalisib (GS-1101) in combination with rituximab (R) in treatment-naive patients (pts) ≥65 years with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). J Clin Oncol 31, 2013 (suppl; abstr 7005) link to abstract

Lenalidomide (Revlimid)

Regimen #1, Badoux et al. 2011; Strati et al. 2013

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, Chen et al. 2010 & 2014

Phase II

  • Lenalidomide (Revlimid) 2.5 mg PO once per day on days 1 to 21 of cycle 1; increased if tolerated to 5 mg PO once per day on days 1 to 21 of cycle 2; increased if tolerated to 10 mg PO once per day on days 1 to 21 of subsequent cycles

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
  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
  3. 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 Jun 25. [Epub ahead of print] link to original article PubMed
  4. Update: Christine I. Chen, Harminder Paul, Trina Wang, Lisa W. Le, Nimisha Dave, Vishal Kukreti, Ellen Nong Wei, Anthea Lau, Peter Leif Bergsage, Suzanne Trudel. Long-term follow-up of a phase 2 trial of single agent lenalidomide in previously untreated patients with chronic lymphocytic leukaemia. [Epub ahead of print] link to original article

Lenalidomide & Rituximab

Regimen

Phase II

This combination was only studied in SLL (as opposed to CLL).

28-day cycles up to 12 cycles

References

  1. N. H. Fowler, P. McLaughlin, F. B. Hagemeister, L. W. Kwak, M. A. Fanale, S. S. Neelapu, L. Fayad, R. Z. Orlowski, M. Wang, F. Samaniego. Complete response rates with lenalidomide plus rituximab for untreated indolent B-cell non-Hodgkin's lymphoma. J Clin Oncol 28:15s, 2010 (suppl; abstr 8036). 2010 ASCO Annual Meeting abstract 8036. link to abstract
  2. Nathan H Fowler, MD, Sattva S. Neelapu, MD, Fredrick B Hagemeister, MD, Peter McLaughlin, MD, Larry W. Kwak, MD, PhD, Jorge E Romaguera, MD, Michelle A. Fanale, MD, Luis E Fayad, MD, Robert Z. Orlowski, M.D., Ph.D., Michael Wang, M.D., Francesco Turturro, MD, Yasuhiro Oki, MD, Linda Catherine Lacerte, RN and Felipe Samaniego, MD, MPH. Lenalidomide and Rituximab for Untreated Indolent Lymphoma: Final Results of a Phase II Study. 2012 ASH Annual Meeting abstract 901. link to abstract

O-FC

O-FC: Ofatumumab, Fludarabine, Cyclophosphamide

Regimen

Phase II

  • Ofatumumab (Arzerra) 300 mg IV once on day 1 of cycle 1; then 500 mg or 1000 mg IV once on day 1 of cycles 2 to 6
  • Fludarabine (Fludara) 25 mg/m2 IV once per day on days 2 to 4 of cycle 1; then 25 mg/m2 IV once per day on days 1 to 3 of subsequent cycles (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) 250 mg/m2 IV once per day on days 2 to 4 of cycle 1; then 250 mg/m2 IV once per day on days 1 to 3 of subsequent cycles

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

PCR: Pentostatin, Cyclophosphamide, Rituximab

Regimen, Kay et al. 2007 & Shanafelt et al. 2007

Phase II

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

28-day cycles 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

Placebo (Observation)

Regimen, Dighiero et al. 1998; Bergmann et al. 2013 (GCLLSG CLL1); Schweighofer et al. 2013 (GCLLSG CLL7)

Phase III

No treatment. Placed here because one or more randomized clinical trials included a placebo arm in this disease context. 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. 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. 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

Rituximab (Rituxan)

Regimen

Phase II

  • Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1, 8, 15, 22
  • Optional alternate dosing for patients with WBC count >100 x 103/uL:
    • Rituximab (Rituxan) 100 mg IV once on day 1, with remainder of the 375 mg/m2 dosage given once on day 2

Initial infusion rate with first dose of rituximab: 50 mg/H, then increased as tolerated by 50 mg/H every 30 minutes to a maximum of 400 mg/H Infusion rate with subsequent doses of rituximab (if first dose tolerated): 100 mg/H, then increased as tolerated by 100 mg/H ever 30 minutes to a maximum of 400 mg/H

Supportive medications:

28-day cycles x 6 cycles

Patients with response or stable disease then received:

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

Maintenance

Observation

Regimen

Phase III

No treatment; used as a comparator arm and here for reference purposes only.

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

Rituximab (Rituxan)

Regimen #1, Hainsworth et al. 2002

Phase II

  • Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1, 8, 15, 22
  • Optional alternate dosing for patients with WBC count >100 x 103/uL:
    • Rituximab (Rituxan) 100 mg IV once on day 1, with remainder of the 375 mg/m2 dosage given once on day 2

Initial infusion rate with first dose of rituximab: 50 mg/H, then increased as tolerated by 50 mg/H every 30 minutes to a maximum of 400 mg/H Infusion rate with subsequent doses of rituximab (if first dose tolerated): 100 mg/H, then increased as tolerated by 100 mg/H ever 30 minutes to a maximum of 400 mg/H

Supportive medications:

28-day cycles x 6 cycles

Patients with response or stable disease then received:

Supportive medications:

6-month cycles x 4 cycles

Regimen #2, Hochster et al. 2009 (ECOG1496)

Phase III

Four courses, every 6 months (16 total doses)

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. 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

Relapsed/refractory

Alemtuzumab (Campath)

Regimen #1, Keating et al. 2002; Rai et al. 2002

Phase II

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, Lozanski et al. 2004

Phase II

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

Regimen

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

Bendamustine (Treanda)

Regimen #1, Niederle et al. 2013

Phase III

28-day cycles x 6 cycles; Niederle et al. 2013 treated patients for up to 8 cycles

Regimen #2, Friedberg et al. 2008; 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

BendOfa: Bendamustine, Ofatumumab

Regimen, 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

BR: Bendamustine, Rituximab

Regimen

Phase II

28-day cycles 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

CFAR

CFAR: Cyclophosphamide, Fludarabine, Alemtuzumab, Rituximab

Regimen

Phase II

Supportive medications:

28-day cycles 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)

Regimen, Robak et al. 2006 (PALG CLL2)

Phase III

28-day cycles 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

CC: Cladribine, Cyclophosphamide

Regimen, Robak et al. 2006 (PALG CLL2)

Phase III

Supportive medications:

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

28-day cycles 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

CMC: Cladribine, Mitoxantrone, Cyclophosphamide

Regimen, Robak et al. 2006 (PALG CLL2)

Phase III

28-day cycles 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

FC: Fludarabine, Cyclophosphamide

Regimen, Robak et al. 2010

Phase III

28-day cycles x 6 cycles

Supportive medications (varied according to reference):

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

FCR: Fludarabine, Cyclophosphamide, Rituximab

Regimen #1, Tam et al. 2006

Phase II

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

Regimen #2, Robak et al. 2010

Phase III

Supportive medications (varied according to reference):

28-day cycles x 6 cycles

References

  1. 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
  2. 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

FluCam

FluCam: Fludarabine, Campath

Regimen

Phase II

  • Fludarabine (Fludara) 30 mg/m2 IV once per day on days 1 to 3
  • Alemtuzumab (Campath) 3 mg IV once on day 1, 10 mg IV once on day 2, 30 mg IV once on day 3 of cycle 1; then 30 mg IV once per day on days 1 to 3 for cycles 2 to 6

Supportive medications:

  • Trimethoprim/Sulfamethoxazole 960 mg (paper did not specify which component was 960 mg) PO once per day, started on day 1 and continued at least 2 months after treatment is complete
  • Valacyclovir (Valtrex) 500 mg PO BID, started on day 1 and continued at least 2 months after treatment is complete
    • If patients experienced CMV (cytomegalovirus) reactivation, valacyclovir was replaced by "oral or intravenous ganciclovir" 500 mg TID
  • [Fluconazole (Diflucan)]] 100 mg PO once per day, started if patients had evidence of fungal infection, continued until resolution
  • Acetaminophen (Tylenol) 1000 mg PO once prior to first dose of Alemtuzumab (Campath), then with subsequent doses if clinically indicated
  • Clemastine (Tavist) 2 mg IV once prior to first dose of Alemtuzumab (Campath), then with subsequent doses if clinically indicated
  • Prednisone (Sterapred) 100 mg IV once prior to first dose of Alemtuzumab (Campath), then with subsequent doses if clinically indicated
  • For patients with WBC >50,000/uL, bulky disease, or history of hyperuricemia: Allopurinol (Zyloprim) 300 mg PO once prior to first dose of Alemtuzumab (Campath), and used later if clinically indicated

28-day cycles 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)

Regimen #1, Niederle et al. 2013

Phase III

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

Regimen

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
  2. Update: Keating MJ, O'Brien S, Lerner S, Koller C, Beran M, Robertson LE, Freireich EJ, Estey E, Kantarjian H. Long-term follow-up of patients with chronic lymphocytic leukemia (CLL) receiving fludarabine regimens as initial therapy. Blood. 1998 Aug 15;92(4):1165-71. link to original article PubMed

HDMP-R

HDMP-R: High Dose, MethylPrednisolone, Rituximab

Regimen #1, 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) 50 mg IV once on cycle 1 day 1; 150 mg IV once on cycle 1 day 2; remainder of a 375 mg/m2 dose on cycle 1 day 3; subsequently 500 mg/m2 IV once on cycle 1 day 5 and days 1 and 5 of other cycles

Supportive medications:

21-day cycles x 6 cycles

Regimen #2, Bowen et al. 2007

Retrospective

Supportive medications:

28-day cycles

References

  1. 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)

Regimen, Byrd et al. 2013

Phase II

Both 420 mg and 840 mg doses were investigated. Per 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."

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

Lenalidomide (Revlimid)

Regimen #1, 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
  • 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, Ferrajoli et al. 2008

Phase II

  • Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 28, then increased by 5 mg every 28 days to a target maximum dose of 25 mg PO once per day on days 1 to 28

28-day cycles

Regimen #3, Witzig et al. 2009 (NHL-001)

Phase II, <20 patients reported

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

Regimen #1, 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) 375 mg/m2 IV once per day on days 1, 8, 15 of cycle 1; then 375 mg/m2 IV once per day on days 1 & 15 of subsequent cycles

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, Badoux et al. 2013

Phase II

  • Lenalidomide (Revlimid) 10 mg PO once per day on days 9 to 28 of cycle 1; then 10 mg PO once per day on days 1 to 28 of subsequent cycles
  • Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1, 8, 15, 22 of cycle 1; then 375 mg/m2 IV once on day 1 of cycles 3 to 12 (no rituximab dose during cycle 2)

Supportive medications:

  • Allopurinol (Zyloprim) (dose/schedule not specified) on days 1 to 14 of cycle 1
  • No mandatory antibacterial, antiviral, DVT, or tumor flare prophylaxis
  • Growth factor use allowed per ASCO guidelines

28-day cycles 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

OFAR

OFAR: Oxaliplatin, Fludarabine, Ara-C, Rituximab

Regimen

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, adminstered within 30 minutes of completion of oxaliplantin
  • Cytarabine (Cytosar) 1000 mg/m2 IV over 2 hours once per day on days 2 & 3, 4 hours after fludarabine started
  • Rituximab (Rituxan) 375 mg/m2 IV over 4 to 6 hours once on day 3 of cycle 1; then 375 mg/m2 IV over 4 to 6 hours once on day 1 of cycles 2 to 6

Supportive medications:

28-day cycles 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)

Regimen

Phase II

  • Ofatumumab (Arzerra) 300 mg IV once on day 1 of cycle 1, then 2000 mg IV once per day on days 8, 15, 22 of cycle 1; then 2000 mg IV once per day on days 1, 8, 15, 22 of cycle 2; then 2000 mg IV once on day 1 of cycles 3 to 6

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 cycles x 6 cycles

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

PCR

PCR: Pentostatin, Cyclophosphamide, Rituximab

Regimen, Lamanna et al. 2006

Phase II

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

21-day cycles 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

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

Regimen

Pilot, <20 patients reported

  • Rituximab (Rituxan) 375 mg/m2 IV once on day 1 of the first cycle, then 500 mg/m2 IV once on day 1 of cycle 2 and subsequent cycles
  • Bendamustine (Treanda) 70 mg/m2 IV once per day over 60 minutes on days 1 & 2
  • Cytarabine (Cytosar) 800 mg/m2 IV once per day over 2 hours beginning 2 hours after bendamustine on days 1 to 3

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

28-day cycles 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)

Regimen, Furman et al. 2014

Phase III

This is the rituximab + placebo arm of the idelalisib phase III trial.

  • 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 doses, total

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 Jan 22. [Epub ahead of print] link to original article contains verified protocol PubMed

Hairy cell leukemia

Regimens have been moved to Hairy cell leukemia page.

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