Chronic lymphocytic leukemia

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Single agent

Alemtuzumab (Campath)

Regimen #1, Keating, et al. 2002; Rai, et al. 2002; Hillmen, et al. 2007

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

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

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

• Diphenhydramine (Benadryl) 50 mg PO 30 minutes prior to alemtuzumab
• Acetaminophen (Tylenol) 650 mg PO 30 minutes prior to alemtuzumab
• Trimethoprim/Sulfamethoxazole (Bactrim DS) 160/800 mg PO 3 times per week, starting on day 8, continuing at a minimum until 2 months after treatment is complete
• Famciclovir (Famvir) 250 mg PO BID, starting on day 8, continuing at a minimum until 2 months after treatment is complete

Regimen #2, Lozanski, et al. 2004

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

12 weeks of therapy

Supportive medications:

• G-CSF or GM-CSF per institutional protocol
• Trimethoprim/Sulfamethoxazole (Bactrim DS) 160/800 mg PO 3 times per week during therapy and continued for 6 months after treatment is complete
• Acyclovir (Zovirax) 800 mg PO TID during therapy and continued for 6 months after treatment is complete; similar medication can be used if intolerant of acyclovir

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
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

Bendamustine (Treanda)

Regimen

• Bendamustine (Treanda) 100 mg/m2 IV over 30 minutes once daily on days 1 & 2

28-day cycles 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 protocol PubMed
2. 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. doi: 10.1111/bjh.12000. Epub 2012 Aug 4. link to original article 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. doi: 10.1007/s00277-012-1660-6. Epub 2013 Jan 23. link to original article PubMed

Chlorambucil (Leukeran)

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

• Chlorambucil (Leukeran) 10 mg/m2 PO daily on days 1-7

28-day cycles x up to 12 cycles

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 daily x 3 weeks, then 1 week taper before starting chlorambucil to reduce its myelotoxicity

Regimen #2, Dighiero, et al. 1998

• Chlorambucil (Leukeran) 0.1 mg/kg PO daily

continue until progression

Regimen #3, Rai, et al. 2000; Hillmen, et al. 2007

• Chlorambucil (Leukeran) 40 mg/m2 PO once on day 1

28-day cycles x up to 12 cycles

Regimen #4, Knauf, et al. 2009 & 2012

• Chlorambucil (Leukeran) 0.8 mg/kg PO on days 1 & 15

28-day cycles x up to 6 cycles

Regimen #5, Eichhorst, et al. 2009

• Chlorambucil (Leukeran) 0.4 mg/kg PO 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 on day 1

14-day cycles x up to 24 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 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. 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. doi: 10.1111/bjh.12000. Epub 2012 Aug 4. link to original article PubMed

Cladribine (Leustatin)

Regimen #1, Saven, et al. 1995

• Cladribine (Leustatin) 0.1 mg/m2/day IV continuous infusion on days 1-7 (total dose per cycle: 0.7 mg/m2)

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

Regimen #2, Robak, et al. 2006

• Cladribine (Leustatin) 0.12 mg/kg IV over 2 hours once daily on days 1-5

28-day cycles x up to 6 cycles

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
2. 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

Fludarabine (Fludara)

Regimen #1, Rai, et al. 2000; Catovsky, et al. 2007; Eichhorst, et al. 2009; Niederle, et al. 2013

• Fludarabine (Fludara) 25 mg/m2 IV once daily on days 1-5

28-day cycles x up to 6-12 cycles

Regimen #2, Catovsky, et al. 2007

• Fludarabine (Fludara) 40 mg/m2 PO once daily on days 1-5

28-day cycles x up to 6-12 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. 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
3. 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
4. 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. doi: 10.1007/s00277-012-1660-6. Epub 2013 Jan 23. link to original article PubMed

Lenalidomide (Revlimid)

Regimen #1, Chanan-Khan, et al. 2006

• Lenalidomide (Revlimid) 5 mg PO once daily, escalated by 5 mg every 1-2 weeks to a target maximum dose of 25 mg PO once daily on days 1-21
• Allopurinol (Aloprim) 300 mg PO once daily starting 2-3 days prior to therapy, and continued up to a total of 14 days

28-day cycles

Regimen #2, Ferrajoli, et al. 2008

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

28-day cycles

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

Ofatumumab (Arzerra)

Regimen

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

28-day cycles x 6 cycles

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

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

Rituximab (Rituxan)

Regimen

• Rituximab (Rituxan) 375 mg/m2 IV once daily 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

28-day cycles x 6 cycles

Patients with response or stable disease then received:

• Rituximab (Rituxan) 375 mg/m2 IV once daily on days 1, 8, 15, 22

6-month cycles x 4 cycles

Supportive medications:

• If WBC >50 or massive lymphadenopathy: Allopurinol (Aloprim) 300 mg PO once daily starting 3 days before the first dose of rituximab
• Acetaminophen (Tylenol) 650 mg PO once 30 minutes prior to rituximab
• Diphenhydramine (Benadryl) 50 mg IV once 30 minutes prior to rituximab
• Cimetidine (Tagamet) 300 mg OR ranitidine (Zantac) 50 mg IV once 30 minutes prior to 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

Combination therapy

Alemtuzumab (Campath) & Rituximab (Rituxan)

Regimen

• 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 daily on days 10, 12, 17, 19, 24, 26 (i.e. days 3 and 5 of weeks 2-4)
• Rituximab (Rituxan) 375 mg/m2 IV once daily 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

28-day cycles x 1-2 cycles depending on response and toxicity

Supportive medications:

• Prophylactic Trimethoprim/Sulfamethoxazole (Bactrim DS), given during therapy and continuing at a minimum until 2 months after treatment is complete
• Prophylactic Valacyclovir (Valtrex) (or equivalent), given during therapy and continuing at a minimum until 2 months after treatment is complete

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) & Rituximab (Rituxan)

Regimen

• Bendamustine (Treanda) 70 mg/m2 IV once daily on days 1 & 2
• Rituximab (Rituxan) 375 mg/m2 IV once on day 0 of the first cycle, then 500 mg/m2 IV once on day 1 on cycle 2 and subsequent cycles

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

CC

CC: Cladribine, Cyclophosphamide

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

• Cladribine (Leustatin) 0.12 mg/kg IV over 30 minutes once per day on days 1 to 3
• Cyclophosphamide (Cytoxan) 250 mg/m2 IV over 30 to 60 minutes once per day on days 1 to 3

28-day cycles x up to 6 cycles

Supportive medications:

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

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. doi:10.1200/JCO.2009.25.9630. Epub 2010 Mar 8. link to original article contains verified protocol PubMed

Chlorambucil (Leukeran) & Prednisone (Sterapred)

Regimen #1, Raphael, et al. 1991

• Chlorambucil (Leukeran) 30 mg/m2 PO once on day 1
• Prednisone (Sterapred) 80 mg PO once daily on days 1-5

14-day cycles x up to 18 months

Regimen #2, Dighiero, et al. 1998

• Chlorambucil (Leukeran) 0.3 mg/kg PO once daily on days 1-5
• Prednisone (Sterapred) 40 mg/m2 PO once daily on days 1-5

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

CHOP

CHOP: Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone

Regimen

• Cyclophosphamide (Cytoxan) 300 mg/m2 PO once daily on days 1-5
• Doxorubicin (Adriamycin) 25 mg/m2 IV once on day 1
• Vincristine (Oncovin) 1 mg/m2 IV once on day 1
• Prednisone (Sterapred) 40 mg/m2 PO once daily on days 1-5

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

CFAR

CFAR: Cyclophosphamide, Fludarabine, Alemtuzumab, Rituximab

Regimen

• Cyclophosphamide (Cytoxan) 250 mg/m2 IV once daily on days 3-5
• Fludarabine (Fludara) 25 mg/m2 IV once daily on days 3-5
• Alemtuzumab (Campath) 30 mg IV once daily on days 1, 3, 5
• Rituximab (Rituxan) 375 mg/m2 IV once on day 2 of cycle 1; then 500 mg/m2 IV once on day 2 of cycles 2-6

28-day cycles x 6 cycles

Supportive medications:

• Allopurinol (Aloprim) 300 mg PO once daily on days 1-7 of cycle 1
• Trimethoprim/Sulfamethoxazole (Bactrim DS) 160/800 mg PO BID
• Antiviral prophylaxis with:
  • EITHER Valacyclovir (Valtrex) 500 mg PO once daily
  • OR Valgancyclovir (Valcyte) 450 mg PO BID
• Pegfilgrastim (Neulasta) 6 mg SC once on day 6

• At physician's discretion:
  • Acetaminophen (Tylenol) 650 mg PO once 30 minutes prior to rituxumab/alemtuzumab
  • Diphenhydramine (Benadryl) 25-50 mg PO/IV once 30 minutes prior to rituxumab/alemtuzumab
  • Hydrocortisone (Cortef) 100 mg IV once 30 minutes prior to alemtuzumab

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

CMC

CMC: Cladribine, Mitoxantrone, Cyclophosphamide

Regimen

• Cladribine (Leustatin) 0.12 mg/kg IV over 2 hours once daily on days 1-3
• Mitoxantrone (Novantrone) 10 mg/m2 IV once on day 1
• Cyclophosphamide (Cytoxan) 650 mg/m2 IV once on day 1

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

CVP

CVP: Cyclophosphamide, Vincristine, Prednisone

Regimen

• Cyclophosphamide (Cytoxan) 300 mg/m2 PO once daily on days 1-5
• Vincristine (Oncovin) 1.4 mg/m2 IV once on day 1
• Prednisone (Sterapred) 100 mg/m2 PO once daily on days 1-5

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

FluCam

FluCam: Fludarabine, Campath

Regimen

• Fludarabine (Fludara) 30 mg/m2 IV once daily on days 1-3
• 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 daily on days 1-3 for cycles 2-6

28-day cycles x 6 cycles

Supportive medications:

• Trimethoprim/Sulfamethoxazole 960 mg (paper did not specify which component was 960 mg) PO daily, 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 100 mg PO once daily, started if patients had evidence of fungal infection, continued until resolution
• Acetaminophen (Tylenol) 1000 mg PO once prior to first dose of alemtuzumab, then with subsequent doses if clinically indicated
• Clemastine 2 mg IV once prior to first dose of alemtuzumab, then with subsequent doses if clinically indicated
• Prednisone (Sterapred) 100 mg IV once prior to first dose of alemtuzumab, then with subsequent doses if clinically indicated
• For patients with WBC >50,000/uL, bulky disease, or history of hyperuricemia: Allopurinol (Aloprim) 300 mg PO once prior to first dose of alemtuzumab, and used later if clinically indicated

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

FC

FC: Fludarabine, Cyclophosphamide

Regimen #1, Catovsky, et al. 2007 (LRF CLL4) & Robak, et al. 2010 (PALG-CLL3)

• Fludarabine (Fludara) 25 mg/m2 IV once per day on days 1 to 3
• Cyclophosphamide (Cytoxan) 250 mg/m2 IV over 30 to 60 minutes once per day on days 1 to 3

28-day cycles x up to 6 cycles

Supportive medications (per Robak, et al. 2010):

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

Regimen #2, Eichhorst, et al. 2006

• Fludarabine (Fludara) 30 mg/m2 IV over 30 minutes once per day on days 1 to 3
• Cyclophosphamide (Cytoxan) 250 mg/m2 IV over 30 minutes once per day on days 1 to 3

28-day cycles x up to 6 cycles

Supportive medications:

• No routine antibiotic, antiviral, or growth factor use

Regimen #3, Flinn, et al. 2007

• Fludarabine (Fludara) 20 mg/m2 IV once per day on days 1 to 5
• Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1

28-day cycles x up to 6 cycles

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

• Fludarabine (Fludara) 24 mg/m2 PO once per day on days 1 to 5
• Cyclophosphamide (Cytoxan) 150 mg/m2 PO once per day on days 1 to 5

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 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. doi:10.1200/JCO.2009.25.9630. Epub 2010 Mar 8. link to original article contains verified protocol PubMed

Fludarabine (Fludara) & Prednisone (Sterapred)

Regimen

• Fludarabine (Fludara) 30 mg/m2 IV over 30 minutes once per day on days 1 to 5
• Prednisone (Sterapred) 30 mg/m2 PO once per day on days 1 to 5

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

FR

FR: Fludarabine, Rituximab

Regimen

• Fludarabine (Fludara) 25 mg/m2 IV over 20 to 30 minutes once per day on days 1 to 5
• Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1 & 4 of cycle 1; then Rituximab (Rituxan) 375 mg/m2 IV once on day 1 of cycles 2 to 6

28-day cycles x 6 cycles

Supportive medications:

• Allopurinol (Aloprim) 300 mg PO once per day on days 1 to 14 of cycle 1
• Diphenhydramine (Benadryl) 50 mg IV once 30 minutes prior to rituximab
• Acetaminophen (Tylenol) 650 mg PO once 30 minutes prior to rituximab

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

• Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1, 8, 15, 22

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. 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

FCR

FCR: Fludarabine, Cyclophosphamide, Rituximab

Regimen #1, Tam, et al. 2006

• Fludarabine (Fludara) 25 mg/m2 IV over 15-30 minutes once daily on days 1-3
• Cyclophosphamide (Cytoxan) 250 mg/m2 IV over 15-30 minutes once daily on days 1-3
• Rituximab (Rituxan) 375 mg/m2 IV once on day 1

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

Regimen #2, Keating, et al. 2005 & Robak, et al. 2010

• Fludarabine (Fludara) 25 mg/m2 IV once daily on days 1-3
• Cyclophosphamide (Cytoxan) 250 mg/m2 IV once daily on days 1-3
• Rituximab (Rituxan) 375 mg/m2 IV once on day 1 of cycle 1; then 500 mg/m2 IV once on day 1 of cycles 2-6

28-day cycles x 6 cycles

Supportive medications (varied according to reference):

• Diphenhydramine (Benadryl) 25 mg IV once 30 minutes prior to rituximab
• Acetaminophen (Tylenol) 650 mg PO once 30 minutes prior to rituximab
• Allopurinol (Aloprim) 300 mg PO once daily on days 1-7 of cycle 1
• Some patients received:
  • Trimethoprim/Sulfamethoxazole (Bactrim DS) 160/800 mg PO two times per week
  • Valacyclovir (Valtrex) 500 mg daily

Regimen #3, Hallek, et al. 2010

• Fludarabine (Fludara) 25 mg/m2 IV once daily on days 1-3
• Cyclophosphamide (Cytoxan) 250 mg/m2 IV once daily on days 1-3
• Rituximab (Rituxan) 375 mg/m2 IV once on day 0 of cycle 1; then 500 mg/m2 IV once on day 1 of cycles 2-6

28-day cycles x 6 cycles

Supportive medications:

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

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 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. 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. 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

GClb

GClb: GA101 (obinutuzumab), Chlorambucil

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

• Obinutuzumab (GA101) 100 mg IV once on day 1, 900 mg IV once on day 2, 1000 mg IV once per week on days 8, 15 of cycle 1; 1000 mg IV once on day 1 of subsequent cycles
• Chlorambucil (Leukeran) 0.5 mg/kg PO once on days 1 and 15

28-day cycles x 6 cycles

References

1. 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

HDMP-R

HDMP-R: High Dose, MethylPrednisolone, Rituximab

Regimen #1, Bowen, et al. 2007

• Methylprednisolone (Solu-Medrol) 1000 mg/m2 IV once daily on days 1-5
• Rituximab (Rituxan) 375 mg/m2 IV once daily on days 1, 8, 15, 22

28-day cycles

Supportive medications:

• No standard prophylaxis, but some sites used trimethoprim/sulfamethoxazole and/or Acyclovir (Zovirax)

Regimen #2, Castro, et al. 2009

• Methylprednisolone (Solu-Medrol) 1000 mg/m2 IV over 90 minutes once daily on days 1-3
• Rituximab (Rituxan) 375 mg/m2 total divided over 2 days IV on days 1 & 2 of cycle 1; then 375 mg/m2 IV once daily on days 8, 15, 22 of cycle 1; 375 mg/m2 IV once daily on days 1, 8, 15, 22 of cycles 2-3

28-day cycles x 3 cycles

Supportive medications:

• Cimetidine as premedication for methylprednisolone
• Acetaminophen (Tylenol) as premedication for rituximab
• Diphenhydramine (Benadryl) as premedication for rituximab
• Trimethoprim/Sulfamethoxazole (Bactrim DS) (or equivalent) prophylaxis during therapy and continuing for 2 months after treatment is complete
• Acyclovir (Zovirax) (or equivalent) prophylaxis during therapy and continuing for 2 months after treatment is complete
• Fluconazole (Diflucan) (or equivalent) prophylaxis during therapy and continuing for 2 months after treatment is complete
• Allopurinol (Aloprim) 300 mg PO once daily started 3 days before the start of therapy and continued during treatment
• Patients with glucose >200 on days of treatment received regular insulin SC sliding scale on days of treatment

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. 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

Lenalidomide (Revlimid) & Rituximab (Rituxan)

Regimen #1, Chanan-Khan, et al. 2006

• Lenalidomide (Revlimid) 5 mg PO once daily, escalated by 5 mg every 1-2 weeks to a target maximum dose of 25 mg PO once daily on days 1-21
• Rituximab (Rituxan) 375 mg/m2 IV once daily on days 1, 8, 15 of cycle 1; then 375 mg/m2 IV once daily on days 1 & 15 of subsequent cycles

Supportive medications:

• Allopurinol (Aloprim) 300 mg PO once daily starting 2-3 days prior to therapy, and continued up to a total of 14 days

28-day cycles

Regimen #2, Badoux, et al. 2013

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

Supportive medications:

• Allopurinol (Aloprim) (dose/schedule not specified) on days 1-14 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. doi: 10.1200/JCO.2012.42.8623. Epub 2012 Dec 26. link to original article contains verified protocol PubMed

OFAR

OFAR: Oxaliplatin, Fludarabine, Ara-C, Rituximab

Regimen

• Oxaliplatin (Eloxatin) 25 mg/m2 IV over 2 hours once daily on days 1-4
• Fludarabine (Fludara) 30 mg/m2 IV once daily on days 2 & 3, adminstered within 30 minutes of completion of oxaliplantin
• Cytarabine (Cytosar) 1000 mg/m2 IV over 2 hours once daily on days 2 & 3, 4 hours after fludarabine started
• Rituximab (Rituxan) 375 mg/m2 IV over 4-6 hours once on day 3 of cycle 1; then 375 mg/m2 IV over 4-6 hours once on day 1 of cycles 2-6

28-day cycles x up to 6 cycles

Supportive medications:

• Pegfilgrastim (Neulasta) 6 mg SC once on day 6
• Herpes zoster and PCP (Pneumocystis jiroveci pneumonia) prophylaxis used

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

O-FC

O-FC: Ofatumumab, Fludarabine, Cyclophosphamide

Regimen

• 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 2-6
• Fludarabine (Fludara) 25 mg/m2 IV once daily on days 2-4 of cycle 1; then 25 mg/m2 IV once daily on days 1-3 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 daily on days 2-4 of cycle 1; then 250 mg/m2 IV once daily on days 1-3 of subsequent cycles

28-day cycles x 6 cycles

Supportive medications:

• Acetaminophen (Tylenol) 1000 mg PO as premedication prior to ofatumumab
• Cetirizine (Zyrtec) 10 mg (or equivalent) PO as premedication prior to ofatumumab
• Prednisolone (Millipred) 100 mg (or equivalent) PO once before doses 1 & 2 of ofatumumab, then reduced by physician discretion for later doses
• May be used at physician discretion:
  • Allopurinol (Aloprim) for tumor lysis syndrome prophylaxis
  • Antiviral and PCP (Pneumocystis jiroveci pneumonia) prophylaxis
  • Growth factor support

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 #1, Kay, et al. 2007 & Shanafelt, et al. 2007

• Pentostatin (Nipent) 2 mg/m2 IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
• Rituximab (Rituxan) 100 mg/m2 IV once on cycle 1 day 1, then 375 mg/m2 IV once on days 3 & 5 of cycle 1; then 375 mg/m2 IV once on day 1 of cycles 2-6

28-day cycles x 6 cycles

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

• Filgrastim (Neupogen) once daily starting on day 3 x up to 10 days or until ANC >1 x 10^9/L for 2 straight days
• Allopurinol (Aloprim) 300 mg PO once daily on days 1-15 of cycle 1
• Prophylactic Trimethoprim/Sulfamethoxazole (Bactrim DS) x 1 year
• Prophylactic Acyclovir (Zovirax) x 1 year

Regimen #2, Lamanna, et al. 2006

• Pentostatin (Nipent) 4 mg/m2 IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
• Rituximab (Rituxan) 375 mg/m2 IV once on day 1 of cycle 2 and on (omitted from cycle 1)

21-day cycles x 6 cycles

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

• Filgrastim (Neupogen)
• Trimethoprim/Sulfamethoxazole (Bactrim DS)
• Acyclovir (Zovirax)

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
2. 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
3. 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

Hairy cell leukemia

Cladribine (Leustatin)

Regimen #1 (Chadha, et al. 2005)

• Cladribine (Leustatin) 0.1 mg/kg/day IV continuous infusion on days 1-7 (total dose per cycle: 0.7 mg/kg)

7-day course

Regimen #2 (Zenhäusern, et al. 2009)

• Cladribine (Leustatin) 0.14 mg/kg/day IV continuous infusion on days 1-5 (total dose per cycle: 0.7 mg/kg)

5-day course

Regimen #3 (Zenhäusern, et al. 2009)

• Cladribine (Leustatin) 0.14 mg/kg/day IV once daily on days 1, 8, 15, 22, and 29

5-week course

References

1. Chadha P, Rademaker AW, Mendiratta P, Kim B, Evanchuk DM, Hakimian D, Peterson LC, Tallman MS. Treatment of hairy cell leukemia with 2-chlorodeoxyadenosine (2-CdA): long-term follow-up of the Northwestern University experience. Blood. 2005 Jul 1;106(1):241-6. Epub 2005 Mar 10. link to original article contains protocol PubMed
2. Zenhäusern R, Schmitz SF, Solenthaler M, Heim D, Meyer-Monard S, Hess U, Leoncini L, Bargetzi M, Rufener B, Tobler A. Randomized trial of daily versus weekly administration of 2-chlorodeoxyadenosine in patients with hairy cell leukemia: a multicenter phase III trial (SAKK 32/98). Leuk Lymphoma. 2009 Sep;50(9):1501-11. doi: 10.1080/10428190903131755. link to original article contains protocol PubMed

Pentostatin (Nipent)

Regimen

• Pentostatin (Nipent) 5 mg/m2 IV over 2 minutes once daily on days 1 & 2

14-day cycles, continued to the point of maximal response or treatment failure

Supportive medications:

• Allopurinol (Aloprim) 300 mg PO once daily in "the initial courses of treatment" for prophylaxis

References

1. Cassileth PA, Cheuvart B, Spiers AS, Harrington DP, Cummings FJ, Neiman RS, Bennett JM, O'Connell MJ. Pentostatin induces durable remissions in hairy cell leukemia. J Clin Oncol. 1991 Feb;9(2):243-6. link to original article contains protocol PubMed