Chronic lymphocytic leukemia

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Single agent

Alemtuzumab (Campath)

Regimen

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

28-day cycles x 6 cycles

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

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. 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

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

Chlorambucil (Leukeran)

Regimen

28-day cycles x up to 12 cycles

Alternate schedule/dosing #1 (Rai, et al. 2000; Hillmen, et al. 2007)

28-day cycles x up to 12 cycles

Alternate schedule/dosing #2 (Knauf, et al. 2009)

28-day cycles x up to 6 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. 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
  4. 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

Cladribine (Leustatin)

Regimen

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

Alternate schedule (Robak, et al. 2006)

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

28-day cycles x 6 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

Lenalidomide (Revlimid)

Regimen

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

28-day cycles

Alternative schedule (Ferrajoli, et al. 2008)

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

Rituximab (Rituxan)

Regimen

  • Rituximab (Rituxan) 375 mg/m2 IV on days 1, 8, 15, 22
  • Optional alternative dosing for patients with WBC count >100 x 10^3/μL:

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:

6-month cycles x 4 cycles

Supportive medications:

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

Chlorambucil (Leukeran) & Prednisone (Sterapred)

Regimen

14-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

CFAR

CFAR: Cyclophosphamide, Fludarabine, Alemtuzumab, Rituximab

Regimen

28-day cycles x 6 cycles

Supportive medications:

  • Allopurinol (Aloprim) 300 mg PO 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 daily
    • OR Valgancyclovir (Valcyte) 450 mg PO BID
  • Pegfilgrastim (Neulasta) 6 mg SC on day 6
  • At physician's discretion:
    • Acetaminophen (Tylenol) 650 mg PO 30 minutes prior to rituxumab/alemtuzumab
    • Diphenhydramine (Benadryl) 25-50 mg PO/IV 30 minutes prior to rituxumab/alemtuzumab
    • Hydrocortisone (Cortef) 100 mg IV 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

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

CVP

CVP: Cyclophosphamide, Vincristine, Prednisone

Regimen

21-day cycles x up to 18 months

References

  1. Raphael B, Andersen JW, Silber R, Oken M, Moore D, Bennett J, Bonner H, Hahn R, Knospe WH, Mazza J, et al. Comparison of chlorambucil and prednisone versus cyclophosphamide, vincristine, and prednisone as initial treatment for chronic lymphocytic leukemia: long-term follow-up of an Eastern Cooperative Oncology Group randomized clinical trial. J Clin Oncol. 1991 May;9(5):770-6. link to original article contains protocol PubMed

FC

FC: Fludarabine, Cyclophosphamide

Regimen

28-day cycles x up to 6 cycles

Alternative IV schedule (Eichhorst, et al. 2006)

28-day cycles x up to 6 cycles

Alternative IV schedule #2 (Flinn, et al. 2007)

28-day cycles x up to 6 cycles

PO regimen

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.
  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

Fludarabine (Fludara) & Prednisone (Sterapred)

Regimen

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 paper

FR

FR: Fludarabine, Rituximab

Regimen

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
  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

28-day cycles x 6 cycles

Alternative rituximab dosing (Keating, et al. 2005)

28-day cycles x 6 cycles

Supportive medications:

  • Diphenhydramine (Benadryl) 25 mg IV 30 minutes prior to rituximab
  • Acetaminophen (Tylenol) 650 mg PO 30 minutes prior to rituximab
  • Allopurinol (Aloprim) 300 mg PO 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

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]
  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 protocol PubMed

Lenalidomide (Revlimid) & Rituximab (Rituxan)

Regimen

  • Lenalidomide (Revlimid) 5 mg PO daily, escalated by 5 mg every 1-2 weeks to a target maximum dose of 25 mg PO daily on days 1-21
  • Rituximab (Rituxan) 375 mg/m2 IV on days 1, 8, 15 of cycle 1; then 375 mg/m2 IV on days 1 & 15 of subsequent cycles
  • Allopurinol (Aloprim) 300 mg PO daily starting 2-3 days prior to therapy, and continued up to a total of 14 days

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

PCR

PCR: Pentostatin, Cyclophosphamide, Rituximab

Regimen

28-day cycles x 6 cycles

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

Alternate dosing (Lamanna, et al. 2006)

21-day cycles x 6 cycles

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

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
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