Difference between revisions of "Chronic lymphocytic leukemia - historical"
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Revision as of 16:18, 22 March 2018
The purpose of this page is to provide references to regimens that are obsolete, outdated, or of historical interest only. As a general rule, this includes the inferior arm(s) of a randomized study, unless said regimens continue to be recommended by trustworthy sources such as the NCCN Guidelines. Is there a regimen missing from this list? Please go to the main CLL/SLL regimen page to find other regimens.
22 regimens on this page
42 variants on this page
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First-line therapy
CAP
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CAP: Cyclophosphamide, Adriamycin (Doxorubicin), Prednisone
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Leporrier et al. 2001 | Phase III | CHOP | Inferior ORR rate |
Fludarabine | Inferior ORR rate |
Chemotherapy
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Prednisone (Sterapred) 40 mg/m2 PO once per day on days 1 to 5
Monthly cycle for 6 cycles
References
- 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
Chlorambucil monotherapy
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Regimen #1
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Catovsky et al. 2007 (LRF CLL4) | Phase III | FC | Inferior PFS |
Fludarabine | Seems not superior | ||
Hillmen et al. 2015 (COMPLEMENT 1) | Phase III | Chlorambucil & Ofatumumab | Inferior PFS |
Chemotherapy
- Chlorambucil (Leukeran) 10 mg/m2 PO once per day on days 1 to 7
Supportive medications
- Per Catovsky et al. 2007: Patients with stage C disease (hemoglobin less than 10 g/dL or platelet count less than 100 x 109/L) received Prednisolone (Millipred) 30 mg/m2 PO once per day for 3 weeks, then 1 week taper before starting Chlorambucil (Leukeran) to reduce its myelotoxicity
28-day cycle for up to 12 cycles
Regimen #2
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Goede et al. 2014 (GCLLSG CLL11) | Phase III | Chlorambucil & Obinutuzumab | Inferior OS |
Chlorambucil & Rituximab | Inferior PFS | ||
Burger et al. 2015 (RESONATE-2) | Phase III | Ibrutinib | Inferior OS |
Chemotherapy
- Chlorambucil (Leukeran) 0.5 mg/kg PO once per day on days 1 & 15
28-day cycle for 6 to 12 cycles
Patients enrolled on RESONATE-2 were allowed to increase the dose up to 0.8 mg/kg if "there was not an unacceptable level of toxic effects."
Regimen #3
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Knauf et al. 2009 | Phase III | Bendamustine | Inferior PFS |
This regimen was intended for previously untreated CLL patients up to 75 years of age with Binet stage B or C disease in need for treatment per the NCI-WG guidelines or IWCLL guidelines.
Chemotherapy
- Chlorambucil (Leukeran) 0.8 mg/kg PO once per day on days 1 & 15
- Alternate schedule: 0.4 mg/kg PO once per day on days 1 to 2, 15 to 16
28-day cycle for up to 6 cycles
Regimen #4
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Eichhorst et al. 2009 (GCLLSG CLL5) | Phase III | Fludarabine | Seems not superior |
This regimen was intended for untreated patients between 65 and 80 years with Binet stage C, or Binet stage B or A if they had rapid disease progression (lymphocyte doubling time less than 3 months) or symptoms from enlarged lymph nodes and organs, or if they had severe B symptoms.
Chemotherapy
- Chlorambucil (Leukeran) as follows:
- Cycle 1: 0.4 mg/kg PO once on day 1
- To be increased as tolerated by 0.1 mg/kg each cycle, up to a maximum of 0.8 mg/kg PO once on day 1
14-day cycle for up to 24 cycles
Regimen #5
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Rai et al. 2000 (CALGB 9011) | Phase III | Chlorambucil & Fludarabine | Not reported |
Fludarabine | Inferior PFS | ||
Hillmen et al. 2007 (CAM 307) | Phase III | Alemtuzumab | Inferior PFS |
In CALGB 9011, this regimen was intended for previously untreated patients with CLL who were high-risk (Rai stage III or IV) or intermediate-risk (Rai stage I or II) if they had at least one of the following: disease-related symptoms such as weight loss, extreme fatigue, night sweats, or fever without evidence of infection; massive or progressive splenomegaly or lymphadenopathy, or more than a 50 percent increase in the number of peripheral-blood lymphocytes over a 2-month period or an anticipated doubling of these cells within less than 12 months. In CAM 307, this regimen was intended for patients who were at least 18 years old with flow cytometry–confirmed diagnosis of B-cell CLL, Rai stage I through IV with evidence of progression according to the National Cancer Institute Working Group (NCI-WG) 1996 criteria, no previous chemotherapy for CLL, a life expectancy of at least 12 weeks, WHO performance status of 0 to 2, and adequate renal and liver function.
Chemotherapy
- Chlorambucil (Leukeran) 40 mg/m2 PO once on day 1
28-day cycle for up to 12 cycles
Regimen #6
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Dighiero et al. 1998 | Phase III | Observation | Seems to have superior PFS |
This is one of two trials reported in the same paper; the other was comparing chlorambucil & prednisone vs. observation.
Chemotherapy
- Chlorambucil (Leukeran) 0.1 mg/kg PO once per day
Continued until progression
References
- 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
- 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
- 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
- Update: Else M, Wade R, Oscier D, Catovsky D. The long-term outcome of patients in the LRF CLL4 trial: the effect of salvage treatment and biological markers in those surviving 10 years. Br J Haematol. 2016 Jan;172(2):228-37. Epub 2015 Oct 12. link to original article link to PMC article PubMed
- 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
- 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
- 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
- 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
- Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, Chagorova T, de la Serna J, Dilhuydy MS, Illmer T, Opat S, Owen CJ, Samoylova O, Kreuzer KA, Stilgenbauer S, Döhner H, Langerak AW, Ritgen M, Kneba M, Asikanius E, Humphrey K, Wenger M, Hallek M. Obinutuzumab plus Chlorambucil in Patients with CLL and Coexisting Conditions. N Engl J Med. 2014 Mar 20;370(12):1101-10. Epub 2014 Jan 8. link to original article contains verified protocol PubMed
- Update: Goede V, Fischer K, Engelke A, Schlag R, Lepretre S, Montero LF, Montillo M, Fegan C, Asikanius E, Humphrey K, Fingerle-Rowson G, Hallek M. Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study. Leukemia. 2015 Jul;29(7):1602-4. Epub 2015 Jan 30. link to original article PubMed
- Hillmen P, Robak T, Janssens A, Babu KG, Kloczko J, Grosicki S, Doubek M, Panagiotidis P, Kimby E, Schuh A, Pettitt AR, Boyd T, Montillo M, Gupta IV, Wright O, Dixon I, Carey JL, Chang CN, Lisby S, McKeown A, Offner F; COMPLEMENT 1 Study Investigators. Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial. Lancet. 2015 May 9;385(9980):1873-83. Epub 2015 Apr 13. link to original article contains protocol PubMed
- Burger JA, Tedeschi A, Barr PM, Robak T, Owen C, Ghia P, Bairey O, Hillmen P, Bartlett NL, Li J, Simpson D, Grosicki S, Devereux S, McCarthy H, Coutre S, Quach H, Gaidano G, Maslyak Z, Stevens DA, Janssens A, Offner F, Mayer J, O'Dwyer M, Hellmann A, Schuh A, Siddiqi T, Polliack A, Tam CS, Suri D, Cheng M, Clow F, Styles L, James DF, Kipps TJ; RESONATE-2 Investigators. Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. N Engl J Med. 2015 Dec 17;373(25):2425-37. Epub 2015 Dec 6. link to original article contains verified protocol link to PMC article PubMed
CHOP
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CHOP: Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Leporrier et al. 2001 | Phase III | CAP | Superior ORR rate |
Fludarabine | Seems not superior |
Chemotherapy
- Cyclophosphamide (Cytoxan) 300 mg/m2 PO once per day on days 1 to 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 per day on days 1 to 5
28-day cycle for 6 cycles
References
- 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
FC
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FC: Fludarabine, Cyclophosphamide
Regimen #1
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Geisler et al. 2014 (HOVON-68) | Phase III | FCA | Inferior PFS |
This regimen was intended for patients with previously untreated CLL diagnosed and in need of treatment according to the National Cancer Institute guidelines, 18 to 75 years of age, with WHO performance status less than 3 and no severe comorbidities, with high-risk CLL as defined by the presence of either unmutated IGHV, 17p deletion, 11q deletion, or trisomy 12 by FISH.
Chemotherapy
- Fludarabine (Fludara) 40 mg/m2 PO once per day on days 1 to 3
- Cyclophosphamide (Cytoxan) 250 mg/m2 PO once per day on days 1 to 3
Supportive medications
- Cotrimoxazole 400/80 mg PO once per day until 6 months after end of treatment
- Acyclovir (Zovirax) 400 mg PO TID until 3 months after end of treatment
OR
- Valacyclovir (Valtrex) 500 mg PO BID until 3 months after end of treatment
28-day cycle for 6 cycles
Regimen #2
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Catovsky et al. 2007 (LRF CLL4) | Phase III | Chlorambucil | Superior PFS |
Fludarabine | Superior PFS | ||
Robak et al. 2010 (PALG-CLL3) | Phase III | CC | Seems not superior |
Hallek et al. 2010 (GCLLSG CLL8) | Phase III | FCR | Inferior OS (*) |
Note: efficacy for GCLLSG CLL8 is based on the updated 2016 results.
Chemotherapy
- 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
Supportive medications
- Per Robak et al. 2010: "No routine prophylaxis with antibiotics, antiviral agents, or growth factors."
28-day cycle for up to 6 cycles
Regimen #3
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Flinn et al. 2007 (ECOG E2997) | Phase III | Fludarabine | Superior PFS |
This regimen was intended for untreated patients greater than or equal to 18 years with a diagnosis of progressive CLL using the National Cancer Institute criteria.
Chemotherapy
- 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 cycle for up to 6 cycles
Regimen #4, PO regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Catovsky et al. 2007 (LRF CLL4) | Phase III | Chlorambucil | Superior PFS |
Fludarabine | Superior PFS |
Chemotherapy
- 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 cycle for up to 6 cycles
Regimen #5
Study | Evidence | Comparator | Efficacy | Toxicity |
---|---|---|---|---|
Eichhorst et al. 2005 (GCLLSG CLL4) | Phase III | Fludarabine | Superior PFS | No statistical difference in HRQoL |
Chemotherapy
- 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
Supportive medications
- No routine antibiotic, antiviral, or growth factor use
28-day cycle for up to 6 cycles
References
- 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
- HRQoL analysis: Eichhorst BF, Busch R, Obwandner T, Kuhn-Hallek I, Herschbach P, Hallek M; German CLL Study Group. Health-related quality of life in younger patients with chronic lymphocytic leukemia treated with fludarabine plus cyclophosphamide or fludarabine alone for first-line therapy: a study by the German CLL Study Group. J Clin Oncol. 2007 May 1;25(13):1722-31. Epub 2007 Mar 26. link to original article PubMed
- 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
- Update: Lucas DM, Ruppert AS, Lozanski G, Dewald GW, Lozanski A, Claus R, Plass C, Flinn IW, Neuberg DS, Paietta EM, Bennett JM, Jelinek DF, Gribben JG, Hussein MA, Appelbaum FR, Larson RA, Moore DF Jr, Tallman MS, Byrd JC, Grever MR. Cytogenetic prioritization with inclusion of molecular markers predicts outcome in previously untreated patients with chronic lymphocytic leukemia treated with fludarabine or fludarabine plus cyclophosphamide: a long-term follow-up study of the US intergroup phase III trial E2997. Leuk Lymphoma. 2015;56(11):3031-7. Epub 2015 Mar 30. link to original article link to PMC article PubMed
- 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
- Update: Else M, Wade R, Oscier D, Catovsky D. The long-term outcome of patients in the LRF CLL4 trial: the effect of salvage treatment and biological markers in those surviving 10 years. Br J Haematol. 2016 Jan;172(2):228-37. Epub 2015 Oct 12. link to original article link to PMC article PubMed
- 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
- 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
- Update: Fischer K, Bahlo J, Fink AM, Goede V, Herling CD, Cramer P, Langerbeins P, von Tresckow J, Engelke A, Maurer C, Kovacs G, Herling M, Tausch E, Kreuzer KA, Eichhorst B, Böttcher S, Seymour JF, Ghia P, Marlton P, Kneba M, Wendtner CM, Döhner H, Stilgenbauer S, Hallek M. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016 Jan 14;127(2):208-15. Epub 2015 Oct 20. link to original article PubMed
- HRQoL analysis: Kutsch N, Busch R, Bahlo J, Mayer J, Hensel M, Hopfinger G, Hess G, von Grünhagen U, Wendtner CM, Maria Fink A, Fischer K, Hallek M, Eichhorst B. FCR front-line therapy and quality of life in patients with chronic lymphocytic leukemia. Leuk Lymphoma. 2017 Feb;58(2):399-407. Epub 2016 Jun 29. link to original article PubMed
- Geisler CH, van T' Veer MB, Jurlander J, Walewski J, Tjønnfjord G, Itälä Remes M, Kimby E, Kozak T, Polliack A, Wu KL, Wittebol S, Abrahamse-Testroote MC, Doorduijn J, Ghidey Alemayehu W, van Oers MH. Frontline low-dose alemtuzumab with fludarabine and cyclophosphamide prolongs progression-free survival in high-risk CLL. Blood. 2014 May 22;123(21):3255-62. Epub 2014 Apr 15. link to original article contains verified protocol PubMed
Fludarabine monotherapy
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Regimen #1
Study | Evidence | Comparator | Efficacy | Toxicity |
---|---|---|---|---|
Rai et al. 2000 (CALGB 9011) | Phase III | Chlorambucil | Superior PFS | |
Chlorambucil & Fludarabine | Seems not superior | |||
Leporrier et al. 2001 | Phase III | CAP | Superior ORR rate | |
CHOP | Seems not superior | |||
Eichorst et al. 2005 (GCLLSG CLL4) | Phase III | FC | Inferior PFS | No statistical difference in HRQoL |
Flinn et al. 2007 (ECOG E2997) | Phase III | FC | Inferior PFS | |
Catovsky et al. 2007 (LRF CLL4) | Phase III | Chlorambucil | Seems not superior | |
FC | Inferior PFS | |||
Eichhorst et al. 2009 (GCLLSG CLL5) | Phase III | Chlorambucil | Seems not superior | |
Bergmann et al. 2013 (GCLLSG CLL1) | Phase III | Observation | Superior PFS |
Eligibility criteria:'
- CALGB 9011: intended for previously untreated patients with CLL who were high-risk (Rai stage III or IV) or intermediate-risk (Rai stage I or II) if they had at least one of the following: disease-related symptoms such as weight loss, extreme fatigue, night sweats, or fever without evidence of infection; massive or progressive splenomegaly or lymphadenopathy, or more than a 50 percent increase in the number of peripheral-blood lymphocytes over a 2-month period or an anticipated doubling of these cells within less than 12 months.
- ECOG E2997: intended for untreated patients greater than or equal to 18 years with a diagnosis of progressive CLL using the National Cancer Institute criteria.
- GCLLSG CLL5: intended for untreated patients between 65 and 80 years with Binet stage C, or Binet stage B or A if they had rapid disease progression (lymphocyte doubling time less than 3 months) or symptoms from enlarged lymph nodes and organs, or if they had severe B symptoms.
Chemotherapy
- Fludarabine (Fludara) 25 mg/m2 IV once per day on days 1 to 5
28-day cycle for up to 6 to 12 cycles
Regimen #2
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Catovsky et al. 2007 (LRF CLL4) | Phase III | Chlorambucil | Seems not superior |
FC | Inferior PFS |
Chemotherapy
- Fludarabine (Fludara) 40 mg/m2 PO once per day on days 1 to 5
28-day cycle for up to 6 to 12 cycles
References
- 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
- 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
- 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
- HRQoL analysis: Eichhorst BF, Busch R, Obwandner T, Kuhn-Hallek I, Herschbach P, Hallek M; German CLL Study Group. Health-related quality of life in younger patients with chronic lymphocytic leukemia treated with fludarabine plus cyclophosphamide or fludarabine alone for first-line therapy: a study by the German CLL Study Group. J Clin Oncol. 2007 May 1;25(13):1722-31. Epub 2007 Mar 26. link to original article PubMed
- 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
- Update: Lucas DM, Ruppert AS, Lozanski G, Dewald GW, Lozanski A, Claus R, Plass C, Flinn IW, Neuberg DS, Paietta EM, Bennett JM, Jelinek DF, Gribben JG, Hussein MA, Appelbaum FR, Larson RA, Moore DF Jr, Tallman MS, Byrd JC, Grever MR. Cytogenetic prioritization with inclusion of molecular markers predicts outcome in previously untreated patients with chronic lymphocytic leukemia treated with fludarabine or fludarabine plus cyclophosphamide: a long-term follow-up study of the US intergroup phase III trial E2997. Leuk Lymphoma. 2015;56(11):3031-7. Epub 2015 Mar 30. link to original article link to PMC article PubMed
- 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
- Update: Else M, Wade R, Oscier D, Catovsky D. The long-term outcome of patients in the LRF CLL4 trial: the effect of salvage treatment and biological markers in those surviving 10 years. Br J Haematol. 2016 Jan;172(2):228-37. Epub 2015 Oct 12. link to original article link to PMC article PubMed
- 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
- Abstract: Manuela A. Bergmann, MD, Raymonde Busch, PhD, Barbara Eichhorst, MD, Andreas Buehler, MD, Norbert Fischer, MD, Michael J Eckart, MD, Ursula Vehling-Kaiser, MD, Ulrich Jäger, MD, Georg Hopfinger, MD, Clemens Wendtner, MD, Kirsten Fischer, MD, Bertold Emmerich, MD, Hartmut Döhner, MD, Michael Hallek, M.D. Ph.D. and Stephan Stilgenbauer, MD. Overall Survival In Early Stage Chronic Lymphocytic Leukemia Patients With Treatment Indication Due To Disease Progression: Follow-Up Data Of The CLL1 Trial Of The German CLL Study Group (GCLLSG). Blood 2013 122:4127. link to abstract
Fludarabine & Prednisone
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Regimen
Study | Evidence |
---|---|
O'Brien et al. 1993 | Phase II |
Chemotherapy
- 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
- 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
- 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
FR
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FR: Fludarabine, Rituximab
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Byrd et al. 2002 (CALGB 9712) | Randomized Phase II | F, then R | Seems not superior |
Chemotherapy
- Fludarabine (Fludara) 25 mg/m2 IV over 20 to 30 minutes once per day on days 1 to 5
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once per day on days 1 & 4
- Cycles 2 to 6: 375 mg/m2 IV once on day 1
Supportive medications
- Allopurinol (Zyloprim) 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 (Rituxan)
- Acetaminophen (Tylenol) 650 mg PO once 30 minutes prior to Rituximab (Rituxan)
28-day cycle for 6 cycles
If restaging done 2 months after 6 cycles of therapy shows stable disease or better, patient were then treated with:
- Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1, 8, 15, 22
28-day course
References
- 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
- 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
- Update: Woyach JA, Ruppert AS, Heerema NA, Peterson BL, Gribben JG, Morrison VA, Rai KR, Larson RA, Byrd JC. Chemoimmunotherapy with fludarabine and rituximab produces extended overall survival and progression-free survival in chronic lymphocytic leukemia: long-term follow-up of CALGB study 9712. J Clin Oncol. 2011 Apr 1;29(10):1349-55. Epub 2011 Feb 14. link to original article link to PMC article PubMed
Subsequent lines of therapy
FC
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FC: Fludarabine, Cyclophosphamide
Regimen
Study | Evidence | Comparator | Efficacy |
---|---|---|---|
Robak et al. 2010 | Phase III | R-FC | Inferior PFS |
Robak et al. 2016 (COMPLEMENT 2) | Phase III | O-FC | Inferior PFS |
Chemotherapy
- Fludarabine (Fludara) 25 mg/m2 IV once per day on days 1 to 3
- Cyclophosphamide (Cytoxan) 250 mg/m2 IV once per day on days 1 to 3
Supportive medications
- Note: varied according to reference.
- Allopurinol (Zyloprim) 300 mg PO once per day on days 1 to 7 of cycle 1
- Some patients received:
- Trimethoprim/Sulfamethoxazole (Bactrim DS) 160/800 mg PO two times per week
- Valacyclovir (Valtrex) 500 mg once per day
28-day cycle for 6 cycles
References
- 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
- Robak T, Warzocha K, Govind Babu K, Kulyaba Y, Kuliczkowski K, Abdulkadyrov K, Loscertales J, Kryachok I, Kłoczko J, Rekhtman G, Homenda W, Błoński JZ, McKeown A, Gorczyca MM, Carey JL, Chang CN, Lisby S, Gupta IV, Grosicki S. Ofatumumab plus fludarabine and cyclophosphamide in relapsed chronic lymphocytic leukemia: results from the COMPLEMENT 2 trial. Leuk Lymphoma. 2017 May;58(5):1084-1093. Epub 2016 Oct 12. link to original article PubMed