Chronic lymphocytic leukemia - historical

The purpose of this page is to provide references to regimens that are obsolete, outdated, or of historical interest only. 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

First-line therapy

CAP

CAP: Cyclophosphamide, Adriamycin (Doxorubicin), Prednisone

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Keating et al. 1990 (SWOG-7410)	1974-1979	Phase 2
Johnson et al. 1996	1990-1992	Phase 3 (C)	Fludarabine	Inferior TTP1
Leporrier et al. 2001 (FCGCLL 1996)	1990-1998	Phase 3 (C)	1. CHOP	Did not meet primary endpoint of OS
			2. Fludarabine	Did not meet primary endpoint of OS

¹The inferior endpoint in Johnson et al. 1996 was only observed in this subgroup, not pretreated patients.
Note: To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 40 mg/m² PO once per day on days 1 to 5

1-month cycle for 6 cycles

References

1. SWOG-7410: Keating MJ, Hester JP, McCredie KB, Burgess MA, Murphy WK, Freireich EJ. Long-term results of CAP therapy in chronic lymphocytic leukemia. Leuk Lymphoma. 1990;2(6):391-7. link to original article PubMed
2. Johnson S, Smith AG, Löffler H, Osby E, Juliusson G, Emmerich B, Wyld PJ, Hiddemann W; French Cooperative Group on CLL. Multicentre prospective randomised trial of fludarabine versus cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of advanced-stage chronic lymphocytic leukaemia. Lancet. 1996 May 25;347(9013):1432-8. link to original article contains dosing details in abstract PubMed
3. FCGCLL 1996: 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 dosing details in abstract PubMed

Chlorambucil monotherapy

Regimen variant #1, 0.1 mg/kg

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Binet et al. 1986 (FRE-CLL-80)	1980-1985	Phase 3 (E-esc)	Watchful waiting1	Did not meet primary endpoint of OS
Binet et al. 1986 (FRE-CLL-80)	1980-1985	Phase 3 (C)	CVP1	Did not meet primary endpoint of OS
Dighiero et al. 1998 (FRE-CLL-85)	1980-1985	Phase 3 (E-esc)	Watchful waiting	Seems to have superior PFS

¹In FRE-CLL-80, this was the experimental arm for Binet Stage A and the control arm for Binet Stage B.
Note: FRE-CLL-85 is one of two trials reported in Dighiero et al. 1998; the other was comparing chlorambucil & prednisone vs. observation.

Chemotherapy

• Chlorambucil (Leukeran) 0.1 mg/kg PO once per day

Continued indefinitely

Regimen variant #2, 0.4 mg/kg

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Knauf et al. 2009	2002-2006	Phase 3 (C)	Bendamustine	Inferior PFS
Zhou et al. 2022 (SIM-79-001)	2009-2016	Phase 3 (C)	Bendamustine	Inferior PFS

Note: In Knauf et al. 2009, 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. To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

• Chlorambucil (Leukeran) 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 variant #3, 0.4 mg/kg, with dose escalation

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Eichhorst et al. 2009 (GCLLSG CLL5)	1999-2004	Phase 3 (C)	Fludarabine	Did not meet co-primary endpoints of PFS/OS

Note: 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. Dose was increased only if the prior dose was tolerated. To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

• Chlorambucil (Leukeran) as follows:
  • Cycle 1: 0.4 mg/kg PO once on day 1
  • Cycle 2: 0.5 mg/kg PO once on day 1
  • Cycle 3: 0.6 mg/kg PO once on day 1
  • Cycle 4: 0.7 mg/kg PO once on day 1
  • Cycles 5 up to 24: 0.8 mg/kg PO once on day 1

14-day cycle for up to 24 cycles

Regimen variant #4, 0.5 mg/kg

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Goede et al. 2014 (GCLLSG CLL11)	2010-2012	Phase 3 (C)	1. Chlorambucil & Obinutuzumab	Inferior OS
			2. Chlorambucil & Rituximab	Inferior PFS
Burger et al. 2015 (RESONATE-2)	2013-NR	Phase 3 (C)	Ibrutinib	Inferior OS1

¹Reported efficacy for RESONATE-2 is based on the 2019 update.
Note: 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." To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

• Chlorambucil (Leukeran) 0.5 mg/kg PO once per day on days 1 & 15

28-day cycle for 6 to 12 cycles

Regimen variant #5, 0.8 mg/kg

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Knauf et al. 2009	2002-2006	Phase 3 (C)	Bendamustine	Inferior PFS
Chanan-Khan et al. 2017 (ORIGIN)	2009-2013	Phase 3 (C)	Lenalidomide	Did not meet primary endpoint of PFS

Note: 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. To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

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

28-day cycle for up to 6 cycles (Knauf et al. 2009) or indefinitely (ORIGIN)

Regimen variant #6, 10 mg/m² x 7 days

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Catovsky et al. 2007 (LRF CLL4)	1999-2004	Phase 3 (C)	1. FC	Did not meet primary endpoint of OS
			2. Fludarabine	Did not meet primary endpoint of OS
Hillmen et al. 2015 (COMPLEMENT 1)	2008-2011	Phase 3 (C)	Chlorambucil & Ofatumumab	Inferior PFS

Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

• Chlorambucil (Leukeran) 10 mg/m² PO once per day on days 1 to 7

Supportive therapy

• 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 variant #7, 10 mg/m² x 10 days

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Mulligan et al. 2014	1997-2004	Phase 3 (C)	1. Cladribine 2. Fludarabine	Did not meet primary endpoint of ORR

Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

• Chlorambucil (Leukeran) 10 mg/m² PO once per day on days 1 to 10

28-day cycle for up to 6 cycles

Regimen variant #8, 40 mg/m²

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rai et al. 2000 (CALGB 9011)	1990-1994	Phase 3 (C)	1. Chlorambucil & Fludarabine	Not reported
			2. Fludarabine	Inferior PFS
Hillmen et al. 2007 (CAM 307)	2001-2004	Phase 3 (C)	Alemtuzumab	Inferior PFS

Note: 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. To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

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

28-day cycle for up to 12 cycles

References

1. Ezdinli EZ, Stutzman L. Chlorambucil therapy for lymphomas and chronic lymphocytic leukemia. JAMA. 1965 Feb 8;191:444-50. link to original article PubMed
2. FRE-CLL-80: Binet JL, Chastang C, Dighiero G, Travad P; French Cooperative Group on Chronic Lymphocytic Leukaemia. Effectiveness of "CHOP" regimen in advanced untreated chronic lymphocytic leukaemia. Lancet. 1986 Jun 14;1(8494):1346-9. link to original article contains dosing details in manuscript PubMed
3. Catovsky D, Richards S, Fooks J, Hamblin TJ. CLL Trials in the United Kingdom the Medical Research Council CLL Trials 1, 2 and 3. Leuk Lymphoma. 1991;5 Suppl 1:105-11. link to original article PubMed
4. FRE-CLL-85: Dighiero G, Maloum K, Desablens B, Cazin B, Navarro M, Leblay R, Leporrier M, Jaubert J, Lepeu G, Dreyfus B, Binet JL, Travade P; French Cooperative Group on Chronic Lymphocytic Leukemia. Chlorambucil in indolent chronic lymphocytic leukemia. N Engl J Med. 1998 May 21;338(21):1506-14. link to original article contains dosing details in manuscript PubMed
5. CALGB 9011: 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 dosing details in abstract PubMed
6. LRF CLL4: 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 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 dosing details in manuscript PubMed NCT00004218
   1. Update: Else M, Wade R, Oscier D, Catovsky D. The long-term outcome of patients in the LRF CLL4 trial: the effect of salvage treatment and biological markers in those surviving 10 years. Br J Haematol. 2016 Jan;172(2):228-37. Epub 2015 Oct 12. link to original article link to PMC article PubMed
7. CAM 307: 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 dosing details in abstract PubMed NCT00046683
8. 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 dosing details in manuscript PubMed
   1. Update: Knauf WU, Lissitchkov T, Aldaoud A, Liberati AM, Loscertales J, Herbrecht R, Juliusson G, Postner G, Gercheva L, Goranov S, Becker M, Fricke HJ, Huguet F, Del Giudice I, Klein P, Merkle K, Montillo M. Bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukaemia: updated results of a randomized phase III trial. Br J Haematol. 2012 Oct;159(1):67-77. Epub 2012 Aug 4. link to original article contains dosing details in manuscript PubMed
9. GCLLSG CLL5: 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. 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 dosing details in abstract PubMed NCT00262795
10. GCLLSG CLL11: 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 dosing details in manuscript PubMed NCT01010061
    1. Update: Goede V, Fischer K, Engelke A, Schlag R, Lepretre S, Casado 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
11. Mulligan SP, Karlsson K, Strömberg M, Jønsson V, Gill D, Hammerström J, Hertzberg M, McLennan R, Uggla B, Norman J, Wallvik J, Sundström G, Johansson H, Brandberg Y, Liliemark J, Juliusson G; Scandinavian Lymphoma Group; ALLG. Cladribine prolongs progression-free survival and time to second treatment compared to fludarabine and high-dose chlorambucil in chronic lymphocytic leukemia. Leuk Lymphoma. 2014 Dec;55(12):2769-77. Epub 2014 Apr 16. link to original article contains dosing details in manuscript PubMed
12. COMPLEMENT 1: Hillmen P, Robak T, Janssens A, Babu KG, Kloczko J, Grosicki S, Doubek M, Panagiotidis P, Kimby E, Schuh A, Pettitt AR, Boyd T, Montillo M, Gupta IV, Wright O, Dixon I, Carey JL, Chang CN, Lisby S, McKeown A, Offner F; COMPLEMENT 1 Study Investigators. Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial. Lancet. 2015 May 9;385(9980):1873-83. Epub 2015 Apr 13. link to original article contains dosing details in abstract PubMed NCT00748189
    1. Update: Offner F, Robak T, Janssens A, Govind Babu K, Kloczko J, Grosicki S, Mayer J, Panagiotidis P, Schuh A, Pettitt A, Montillo M, Werner O, Vincent G, Khanna S, Hillmen P. A five-year follow-up of untreated patients with chronic lymphocytic leukaemia treated with ofatumumab and chlorambucil: final analysis of the Complement 1 phase 3 trial. Br J Haematol. 2020 Sep;190(5):736-740. Epub 2020 Mar 31. link to original article PubMed
13. RESONATE-2: 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 dosing details in manuscript link to PMC article PubMed NCT01722487
    1. Update: Barr PM, Robak T, Owen C, Tedeschi A, Bairey O, Bartlett NL, Burger JA, Hillmen P, Coutre S, Devereux S, Grosicki S, McCarthy H, Li J, Simpson D, Offner F, Moreno C, Zhou C, Styles L, James D, Kipps TJ, Ghia P. Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: extended phase 3 results from RESONATE-2. Haematologica. 2018 Sep;103(9):1502-1510. Epub 2018 Jun 7. link to original article link to PMC article PubMed
    2. Update: Burger JA, Barr PM, Robak T, Owen C, Ghia P, Tedeschi A, Bairey O, Hillmen P, Coutre SE, Devereux S, Grosicki S, McCarthy H, Simpson D, Offner F, Moreno C, Dai S, Lal I, Dean JP, Kipps TJ. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia. 2020 Mar;34(3):787-798. Epub 2019 Oct 18. link to original article PubMed
14. ORIGIN: Chanan-Khan A, Egyed M, Robak T, Martinelli de Oliveira FA, Echeveste MA, Dolan S, Desjardins P, Blonski JZ, Mei J, Golany N, Zhang J, Gribben JG. Randomized phase 3 study of lenalidomide versus chlorambucil as first-line therapy for older patients with chronic lymphocytic leukemia (the ORIGIN trial). Leukemia. 2017 May;31(5):1240-1243. Epub 2017 Jan 31. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00910910
15. SIM-79-001: Zhou D, Xu W, Ma H, Zhao C, Hu Y, Zhao Y, Wu D, Zhao X, He Y, Yan J, Wang C, Meng F, Jin J, Zhang X, Yu K, Hu J, Lv Y. Bendamustine versus chlorambucil in treatment of chronic lymphocytic leukaemia in China: a randomized, open-label, parallel-controlled, phase III clinical trial. Invest New Drugs. 2022 Apr;40(2):349-360. Epub 2022 Jan 15. link to original article contains dosing details in manuscript PubMed NCT01109264

Chlorambucil & Prednisone

Regimen variant #1, 0.3/40

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Dighiero et al. 1998 (FRE-CLL-90)	1985-1990	Phase 3 (E-esc)	Watchful waiting	Superior PFS

Chemotherapy

• Chlorambucil (Leukeran) 0.3 mg/kg PO once per day on days 1 to 5

Glucocorticoid therapy

• Prednisone (Sterapred) 40 mg/m² PO once per day on days 1 to 5

1-month cycle for up to 36 cycles (3 years)

Regimen variant #2, 12/30

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Robak et al. 2000 (PALG CLL1)	1995-1998	Phase 3 (C)	Cladribine & Prednisone	Inferior ORR

Chemotherapy

• Chlorambucil (Leukeran) 12 mg/m² PO once per day on days 1 to 7

Glucocorticoid therapy

• Prednisone (Sterapred) 30 mg/m² PO once per day on days 1 to 7

28-day cycles, continued until CR

Regimen variant #3, 30/80

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Raphael et al. 1991 (ECOG E2480)	NR	Phase 3 (C)	CVP	Did not meet efficacy endpoints

Chemotherapy

• Chlorambucil (Leukeran) 30 mg/m² PO once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 80 mg PO once per day on days 1 to 5

14-day cycle for up to 39 cycles (18 months)

References

1. ECOG E2480: Raphael B, Andersen JW, Silber R, Oken M, Moore D, Bennett J, Bonner H, Hahn R, Knospe WH, Mazza J, Glick J. 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 dosing details in manuscript PubMed
2. FRE-CLL-90: Dighiero G, Maloum K, Desablens B, Cazin B, Navarro M, Leblay R, Leporrier M, Jaubert J, Lepeu G, Dreyfus B, Binet JL, Travade P; French Cooperative Group on Chronic Lymphocytic Leukemia. Chlorambucil in indolent chronic lymphocytic leukemia. N Engl J Med. 1998 May 21;338(21):1506-14. link to original article contains dosing details in manuscript PubMed
3. PALG CLL1: Robak T, Bloński JZ, Kasznicki M, Blasińska-Morawiec M, Krykowski E, Dmoszyńska A, Mrugala-Spiewak H, Skotnicki AB, Nowak W, Konopka L, Ceglarek B, Maj S, Dwilewicz-Trojaczek J, Hellmann A, Urasiński I, Zdziarska B, Kotlarek-Haus S, Potoczek S, Grieb P. Cladribine with prednisone versus chlorambucil with prednisone as first-line therapy in chronic lymphocytic leukemia: report of a prospective, randomized, multicenter trial. Blood. 2000 Oct 15;96(8):2723-9. link to original article contains dosing details in abstract PubMed

CHOP

CHOP: Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Binet et al. 1986 (FRE-CLL-80)	1980-1985	Phase 3 (E-esc)	CVP	Superior OS
Leporrier et al. 2001 (FCGCLL 1996)	1990-1998	Phase 3 (C)	1. CAP	Did not meet primary endpoint of OS
			2. Fludarabine	Did not meet primary endpoint of OS

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

Glucocorticoid therapy

• Prednisone (Sterapred) 40 mg/m² PO once per day on days 1 to 5

28-day cycle for 6 cycles

References

1. FRE-CLL-80: Binet JL, Chastang C, Dighiero G, Travad P; French Cooperative Group on Chronic Lymphocytic Leukaemia. Effectiveness of "CHOP" regimen in advanced untreated chronic lymphocytic leukaemia. Lancet. 1986 Jun 14;1(8494):1346-9. link to original article contains dosing details in manuscript PubMed
   1. Update: Benichou J, Binet JL, Chastang C, Chevret S, Dighiero G, Travade P; French Cooperative Group on Chronic Lymphocytic Leukaemia. Long-term results of the CHOP regimen in stage C chronic lymphocytic leukaemia. Br J Haematol. 1989 Nov;73(3):334-40. link to original article PubMed
2. FCGCLL 1996: 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 dosing details in abstract PubMed

Cladribine & Prednisone

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Robak et al. 2000 (PALG CLL1)	1995-1998	Phase 3 (E-switch-ic)	Chlorambucil & Prednisone	Superior ORR

Chemotherapy

• Cladribine (Leustatin) 0.2 mg/kg IV once per day on days 1 to 5

Glucocorticoid therapy

• Prednisone (Sterapred) 30 mg/m² PO once per day on days 1 to 5

28-day cycle for at least 3 cycles

References

1. PALG CLL1: Robak T, Bloński JZ, Kasznicki M, Blasińska-Morawiec M, Krykowski E, Dmoszyńska A, Mrugala-Spiewak H, Skotnicki AB, Nowak W, Konopka L, Ceglarek B, Maj S, Dwilewicz-Trojaczek J, Hellmann A, Urasiński I, Zdziarska B, Kotlarek-Haus S, Potoczek S, Grieb P. Cladribine with prednisone versus chlorambucil with prednisone as first-line therapy in chronic lymphocytic leukemia: report of a prospective, randomized, multicenter trial. Blood. 2000 Oct 15;96(8):2723-9. link to original article contains dosing details in abstract PubMed

CMC

CMC: Cladribine, Mitoxantrone, Cyclophosphamide

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Robak et al. 2006 (PALG CLL2)	1998-2003	Phase 3 (E-esc)	1. Cladribine	Superior CR rate (primary endpoint)
			2. CC	Seems to have superior CR rate (primary endpoint)

Chemotherapy

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

28-day cycle for up to 6 cycles

References

1. PALG CLL2: 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 Adult Leukemia Group. 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 dosing details in abstract PubMed

CVP

CVP: Cyclophosphamide, Vincristine, Prednisone

Regimen variant #1, PO cyclophosphamide; uncapped vincristine

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Raphael et al. 1991 (ECOG E2480)	NR	Phase 3 (E-switch-ic)	Chlorambucil & Prednisone	Did not meet efficacy endpoints

Chemotherapy

• Cyclophosphamide (Cytoxan) 300 mg/m² PO once per day on days 1 to 5
• Vincristine (Oncovin) 1.4 mg/m² IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 100 mg/m² PO once per day on days 1 to 5

21-day cycle for up to 26 cycles (18 months)

Regimen variant #2, capped vincristine

Study	Dates of enrollment	Evidence
Hochster et al. 2009 (ECOG E1496)	NR	Non-randomized part of phase 3 RCT

Chemotherapy

• Cyclophosphamide (Cytoxan) 1000 mg/m² IV once on day 1
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 100 mg/m² PO once per day on days 1 to 5

21-day cycle for 6 to 8 cycles

Subsequent treatment

• Rituximab maintenance versus observation

References

1. ECOG E2480: Raphael B, Andersen JW, Silber R, Oken M, Moore D, Bennett J, Bonner H, Hahn R, Knospe WH, Mazza J, Glick J. 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 dosing details in abstract PubMed
2. ECOG E1496: Hochster H, Weller E, Gascoyne RD, Habermann TM, Gordon LI, Ryan T, Zhang L, Colocci N, Frankel S, Horning SJ. Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG1496 Study. J Clin Oncol. 2009 Apr 1;27(10):1607-14. Epub 2009 Mar 2. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00003204

Cyclophosphamide & Fludarabine (FC)

FC: Fludarabine, Cyclophosphamide

Regimen variant #1, 75/750 (IV fludarabine)

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Catovsky et al. 2007 (LRF CLL4)	1999-2004	Phase 3 (E-esc)	1. Chlorambucil	Did not meet primary endpoint of OS
			2. Fludarabine	Did not meet primary endpoint of OS
Hallek et al. 2010 (GCLLSG CLL8)	2003-2006	Phase 3 (C)	FCR	Inferior OS1
Robak et al. 2010 (PALG-CLL3)	2004-2007	Phase 3 (E-switch-ic)	CC	Did not meet primary endpoint of CR rate

¹Reported 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 therapy

• Per Robak et al. 2010: "No routine prophylaxis with antibiotics, antiviral agents, or growth factors."

28-day cycle for up to 6 cycles

Regimen variant #2, 90/750

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Eichhorst et al. 2005 (GCLLSG CLL4)	1999-2003	Phase 3 (E-esc)	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 therapy

• No routine antibiotic, antiviral, or growth factor use

28-day cycle for up to 6 cycles

Regimen variant #3, 100/600

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Flinn et al. 2007 (ECOG E2997)	1999-NR	Phase 3 (E-esc)	Fludarabine	Superior PFS (secondary endpoint) Superior CR rate

Note: 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 variant #4, 120/750 (PO fludarabine)

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Geisler et al. 2014 (HOVON-68)	2006-2010	Phase 3 (C)	FCA	Inferior PFS

Note: 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 therapy

• Cotrimoxazole 400/80 mg PO once per day until 6 months after end of treatment
• One of the following:
  • Acyclovir (Zovirax) 400 mg PO three times per day until 3 months after end of treatment
  • Valacyclovir (Valtrex) 500 mg PO twice per day until 3 months after end of treatment

28-day cycle for 6 cycles

Regimen variant #5, 120/750 (all PO)

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Catovsky et al. 2007 (LRF CLL4)	1999-2004	Phase 3 (E-esc)	1. Chlorambucil	Did not meet primary endpoint of OS
			2. Fludarabine	Did not meet primary endpoint of OS

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

References

1. GCLLSG CLL4: 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 dosing details in abstract PubMed NCT00276848
   1. 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
2. ECOG E2997: 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 dosing details in manuscript PubMed NCT00003764
   1. 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
3. LRF CLL4: 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 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 dosing details in manuscript PubMed NCT00004218
   1. Update: Else M, Wade R, Oscier D, Catovsky D. The long-term outcome of patients in the LRF CLL4 trial: the effect of salvage treatment and biological markers in those surviving 10 years. Br J Haematol. 2016 Jan;172(2):228-37. Epub 2015 Oct 12. link to original article link to PMC article PubMed
4. PALG-CLL3: 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; Polish Adult Leukemia Group. 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 dosing details in manuscript PubMed
5. GCLLSG CLL8: 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 dosing details in abstract PubMed NCT00281918
   1. Update: Fischer K, Bahlo J, Fink AM, Goede V, Herling CD, Cramer P, Langerbeins P, von Tresckow J, Engelke A, Maurer C, Kovacs G, Herling M, Tausch E, Kreuzer KA, Eichhorst B, Böttcher S, Seymour JF, Ghia P, Marlton P, Kneba M, Wendtner CM, Döhner H, Stilgenbauer S, Hallek M. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016 Jan 14;127(2):208-15. Epub 2015 Oct 20. link to original article PubMed
   2. 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
6. HOVON-68: 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 dosing details in manuscript PubMed NTR529

FCM

FCM: Fludarabine, Cyclophosphamide, Mitoxantrone

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hillmen et al. 2011 (NCRI CLL201)	2005-2007	Randomized Phase 2 (C)	FCM-R	Did not meet primary endpoint of ORR at 2 mo

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

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
• Mitoxantrone (Novantrone) 6 mg/m² IV once on day 1

28-day cycle for 6 cycles

Regimen variant #2

Study	Dates of enrollment	Evidence
Bosch et al. 2008	2001-2004	Phase 2

Chemotherapy

• Fludarabine (Fludara) 25 mg/m² IV over 30 minutes once per day on days 1 to 3
• Cyclophosphamide (Cytoxan) 200 mg/m² IV over 60 minutes once per day on days 1 to 3
• Mitoxantrone (Novantrone) 6 mg/m² IV over 30 minutes once on day 1

Supportive therapy

• Granulocyte colony-stimulating factor (type not specified) 300 mcg SC once per day on days 1 to 7
• Allopurinol (Zyloprim) 300 mg PO once per day on days 1 to 5

28-day cycle for 6 cycles

References

1. Bosch F, Ferrer A, Villamor N, González M, Briones J, González-Barca E, Abella E, Gardella S, Escoda L, Pérez-Ceballos E, Asensi A, Sayas MJ, Font L, Altés A, Muntañola A, Bertazzoni P, Rozman M, Aymerich M, Giné E, Montserrat E. Fludarabine, cyclophosphamide, and mitoxantrone as initial therapy of chronic lymphocytic leukemia: high response rate and disease eradication. Clin Cancer Res. 2008 Jan 1;14(1):155-61. link to original article contains dosing details in manuscript PubMed
2. Hillmen P, Cohen DR, Cocks K, Pettitt A, Sayala HA, Rawstron AC, Kennedy DB, Fegan C, Milligan DW, Radford J, Mercieca J, Dearden C, Ezekwisili R, Smith AF, Brown J, Booth GA, Varghese AM, Pocock C; NCRI CLL Sub-Group. A randomized phase II trial of fludarabine, cyclophosphamide and mitoxantrone (FCM) with or without rituximab in previously treated chronic lymphocytic leukaemia. Br J Haematol. 2011 Mar;152(5):570-8. Epub 2011 Jan 14. link to original article contains dosing details in manuscript PubMed

Fludarabine monotherapy

F: Fludarabine

Regimen variant #1, IV

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Johnson et al. 1996	1990-1992	Phase 3 (E-de-esc)	CAP	Superior TTP1
Rai et al. 2000 (CALGB 9011)	1990-1994	Phase 3 (E-switch-ic)	1. Chlorambucil	Superior PFS
			2. Chlorambucil & Fludarabine	Did not meet primary endpoint of CR rate
Leporrier et al. 2001 (FCGCLL 1996)	1990-1998	Phase 3 (E-de-esc)	1. CAP	Did not meet primary endpoint of OS
			2. CHOP	Did not meet primary endpoint of OS
Hoechstetter et al. 2017 (GCLLSG CLL1)	1997-2004	Phase 3 (E-esc)	Watchful waiting	Superior PFS Median PFS: 30.1 vs 12.9 mo
Eichorst et al. 2005 (GCLLSG CLL4)	1999-2003	Phase 3 (C)	FC	Inferior PFS	No statistical difference in HRQoL
Flinn et al. 2007 (ECOG E2997)	1999-NR	Phase 3 (C)	FC	Inferior PFS
Catovsky et al. 2007 (LRF CLL4)	1999-2004	Phase 3 (C)	1. Chlorambucil	Did not meet primary endpoint of OS
			2. FC	Did not meet primary endpoint of OS
Eichhorst et al. 2009 (GCLLSG CLL5)	1999-2004	Phase 3 (E-switch-ic)	Chlorambucil	Did not meet co-primary endpoints of PFS/OS
Elter et al. 2011 (CAM 314)	2004-2008	Phase 3 (C)	Fludarabine & Alemtuzumab	Seems to have inferior OS

¹The superior endpoint in Johnson et al. 1996 was only observed in this subgroup, not pretreated patients.

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 variant #2, PO

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Catovsky et al. 2007 (LRF CLL4)	1999-2004	Phase 3 (C)	1. Chlorambucil	Did not meet primary endpoint of OS
			2. FC	Did not meet primary endpoint of OS

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

1. Johnson S, Smith AG, Löffler H, Osby E, Juliusson G, Emmerich B, Wyld PJ, Hiddemann W; French Cooperative Group on CLL. Multicentre prospective randomised trial of fludarabine versus cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of advanced-stage chronic lymphocytic leukaemia. Lancet. 1996 May 25;347(9013):1432-8. link to original article contains dosing details in abstract PubMed
2. CALGB 9011: 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 dosing details in abstract PubMed
3. FCGCLL 1996: 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 dosing details in abstract PubMed
4. GCLLSG CLL4: 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 dosing details in abstract PubMed NCT00276848
   1. 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
5. ECOG E2997: 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 dosing details in manuscript PubMed NCT00003764
   1. 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
6. LRF CLL4: 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 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 dosing details in abstract PubMed NCT00004218
   1. Update: Else M, Wade R, Oscier D, Catovsky D. The long-term outcome of patients in the LRF CLL4 trial: the effect of salvage treatment and biological markers in those surviving 10 years. Br J Haematol. 2016 Jan;172(2):228-37. Epub 2015 Oct 12. link to original article link to PMC article PubMed
7. GCLLSG CLL5: 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. 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 dosing details in abstract PubMed NCT00262795
8. CAM 314: Elter T, Gercheva-Kyuchukova L, Pylylpenko H, Robak T, Jaksic B, Rekhtman G, Kyrcz-Krzemień S, Vatutin M, Wu J, Sirard C, Hallek M, Engert A. Fludarabine plus alemtuzumab versus fludarabine alone in patients with previously treated chronic lymphocytic leukaemia: a randomised phase 3 trial. Lancet Oncol. 2011 Dec;12(13):1204-13. Epub 2011 Oct 10. link to original article PubMed NCT00086580
9. GCLLSG CLL1: Hoechstetter MA, Busch R, Eichhorst B, Bühler A, Winkler D, Eckart MJ, Vehling-Kaiser U, Schimke H, Jäger U, Hurtz HJ, Hopfinger G, Hartmann F, Fuss H, Abenhardt W, Blau I, Freier W, Müller L, Goebeler M, Wendtner CM, Bahlo J, Fischer K, Bentz M, Emmerich B, Döhner H, Hallek M, Stilgenbauer S. Early, risk-adapted treatment with fludarabine in Binet stage A chronic lymphocytic leukemia patients: results of the CLL1 trial of the German CLL study group. Leukemia. 2017 Dec;31(12):2833-2837. Epub 2017 Aug 14. link to original article PubMed NCT00262782

Fludarabine & Prednisone

Regimen

Study	Dates of enrollment	Evidence
O'Brien et al. 1993	1988-1991	Phase 2

Chemotherapy

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

Glucocorticoid therapy

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

Fludarabine & Rituximab (FR)

FR: Fludarabine, Rituximab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Byrd et al. 2002 (CALGB 9712)	1998-2000	Randomized Phase 2 (E-switch-ic)	F, then R	Did not meet primary endpoint of CR rate

Chemotherapy

• Fludarabine (Fludara) 25 mg/m² IV over 20 to 30 minutes once per day on days 1 to 5

Targeted therapy

• 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 therapy

• Cycle 1: Allopurinol (Zyloprim) 300 mg PO once per day on days 1 to 14
• Diphenhydramine (Benadryl) 50 mg IV once per infusion, 30 minutes prior to rituximab
• Acetaminophen (Tylenol) 650 mg PO once per infusion, 30 minutes prior to rituximab

28-day cycle for 6 cycles

Subsequent treatment

• CALGB 9712, if restaging done 2 months after 6 cycles of therapy showed SD or better: Rituximab consolidation

References

1. CALGB 9712: 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 dosing details in abstract PubMed
   1. Update: Byrd JC, Rai K, Peterson BL, Appelbaum FR, Morrison VA, Kolitz JE, Shepherd L, Hines JD, Schiffer CA, Larson RA. Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and CALGB 9011. Blood. 2005 Jan 1;105(1):49-53. Epub 2004 May 11. link to original article PubMed
   2. Update: Woyach JA, Ruppert AS, Heerema NA, Peterson BL, Gribben JG, Morrison VA, Rai KR, Larson RA, Byrd JC. Chemoimmunotherapy with fludarabine and rituximab produces extended overall survival and progression-free survival in chronic lymphocytic leukemia: long-term follow-up of CALGB study 9712. J Clin Oncol. 2011 Apr 1;29(10):1349-55. Epub 2011 Feb 14. link to original article link to PMC article PubMed

Idelalisib & Rituximab

Regimen

Study	Dates of enrollment	Evidence
O'Brien et al. 2015 (Study 101-08)	2010-NR	Phase 2

Note: In a letter dated 2016-03-21, Gilead stated that idelalisib should not be used for first line treatment of CLL.

Targeted therapy

• Idelalisib (Zydelig) 150 mg PO twice per day
• Rituximab (Rituxan) as follows:
  • Cycles 1 & 2: 375 mg/m² IV once per day on days 1, 8, 15, 22

28-day cycle for 12 or more cycles

References

1. Study 101-08: O'Brien SM, Lamanna N, Kipps TJ, Flinn I, Zelenetz AD, Burger JA, Keating M, Mitra S, Holes L, Yu AS, Johnson DM, Miller LL, Kim Y, Dansey RD, Dubowy RL, Coutre SE. A phase 2 study of idelalisib plus rituximab in treatment-naïve older patients with chronic lymphocytic leukemia. Blood. 2015 Dec 17;126(25):2686-94. Epub 2015 Oct 15. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01203930

Lenalidomide monotherapy

Regimen variant #1, target 10 mg/day

Study	Evidence	Efficacy
Chen et al. 2010 (Rev-CLL)	Phase 2	ORR: 56%

Note: dose is escalated only if the prior dose was tolerated.

Targeted therapy

• Lenalidomide (Revlimid) as follows:
  • Cycle 1: 2.5 mg PO once per day on days 1 to 21
  • Cycle 2: 5 mg PO once per day on days 1 to 21
  • Cycle 3 onwards: 10 mg PO once per day on days 1 to 21

Supportive therapy

• Aspirin 81 mg PO once per day on days 1 to 28

28-day cycles

Regimen variant #2, target 15 mg/day

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Chanan-Khan et al. 2017 (ORIGIN)	2009-2013	Phase 3 (E-switch-ooc)	Chlorambucil	Did not meet primary endpoint of PFS

Note: This was an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have been previously published with encouraging non-randomized results.

Targeted therapy

• Lenalidomide (Revlimid) 5 mg PO once per day, increased to a target dose of 15 mg PO once per day

Continued indefinitely

Regimen variant #3, target 25 mg/day

Study	Evidence	Efficacy
Badoux et al. 2011 (MDACC 2006-0715)	Phase 2	ORR: 65%

Targeted therapy

• Lenalidomide (Revlimid) 5 mg PO once per day on days 1 to 56, then increased to a target dose of 25 mg PO once per day

Continued indefinitely

References

1. Rev-CLL: Chen CI, Bergsagel PL, Paul H, Xu W, Lau A, Dave N, Kukreti V, Wei E, Leung-Hagesteijn C, Li ZH, Brandwein J, Pantoja M, Johnston J, Gibson S, Hernandez T, Spaner D, Trudel S. Single-agent lenalidomide in the treatment of previously untreated chronic lymphocytic leukemia. J Clin Oncol. 2011 Mar 20;29(9):1175-81. Epub 2010 Dec 28. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00751296
   1. Update: Chen CI, Paul H, Wang T, Le LW, Dave N, Kukreti V, Nong Wei E, Lau A, Bergsagel PL, Trudel S. Long-term follow-up of a phase 2 trial of single agent lenalidomide in previously untreated patients with chronic lymphocytic leukaemia. Br J Haematol. 2014 Jun;165(5):731-3. Epub 2014 Feb 24. link to original article PubMed
2. MDACC 2006-0715: Badoux XC, Keating MJ, Wen S, Lee BN, Sivina M, Reuben J, Wierda WG, O'Brien SM, Faderl S, Kornblau SM, Burger JA, Ferrajoli A. Lenalidomide as initial therapy of elderly patients with chronic lymphocytic leukemia. Blood. 2011 Sep 29;118(13):3489-98. Epub 2011 Jul 1. link to original article contains dosing details in abstract link to PMC article PubMed
   1. Update: Strati P, Keating MJ, Wierda WG, Badoux XC, Calin S, Reuben JM, O'Brien S, Kornblau SM, Kantarjian HM, Gao H, Ferrajoli A. Lenalidomide induces long-lasting responses in elderly patients with chronic lymphocytic leukemia. Blood. 2013 Aug 1;122(5):734-7. Epub 2013 Jun 25. link to original article link to PMC article PubMed
3. ORIGIN: Chanan-Khan A, Egyed M, Robak T, Martinelli de Oliveira FA, Echeveste MA, Dolan S, Desjardins P, Blonski JZ, Mei J, Golany N, Zhang J, Gribben JG. Randomized phase 3 study of lenalidomide versus chlorambucil as first-line therapy for older patients with chronic lymphocytic leukemia (the ORIGIN trial). Leukemia. 2017 May;31(5):1240-1243. Epub 2017 Jan 31. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00910910

miniCHOP-F

miniCHOP-F: mini-dose Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone, followed by Fludarabine

Regimen variant #1, IV fludarabine

Study	Dates of enrollment	Evidence
Sutton et al. 2011 (Auto-LLC 2001)	2001-2007	Non-randomized part of phase 3 RCT

Chemotherapy, miniCHOP portion (cycles 1 to 3)

• 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

Glucocorticoid therapy, miniCHOP portion (cycles 1 to 3)

• Prednisone (Sterapred) 40 mg/m² PO once per day on days 1 to 5

Chemotherapy, F portion (cycles 4 to 6)

• Fludarabine (Fludara) 25 mg/m² IV once per day on days 1 to 5

1-month cycle for 6 cycles (miniCHOP x 3; F x 3)

Subsequent treatment

• Auto-LLC 2001, CR: Observation versus Cy/TBI, then auto HSCT consolidation

Regimen variant #2, oral fludarabine

Study	Dates of enrollment	Evidence
Sutton et al. 2011 (Auto-LLC 2001)	2001-2007	Non-randomized part of phase 3 RCT

Chemotherapy, miniCHOP portion (cycles 1 to 3)

• 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

Glucocorticoid therapy, miniCHOP portion (cycles 1 to 3)

• Prednisone (Sterapred) 40 mg/m² PO once per day on days 1 to 5

Chemotherapy, F portion (cycles 4 to 6)

• Fludarabine (Fludara) 40 mg/m² PO once per day on days 1 to 5

1-month cycle for 6 cycles (miniCHOP x 3; F x 3)

Subsequent treatment

• Auto-LLC 2001, CR: Observation versus Cy/TBI, then auto HSCT consolidation

References

1. Auto-LLC 2001: Sutton L, Chevret S, Tournilhac O, Diviné M, Leblond V, Corront B, Leprêtre S, Eghbali H, Van Den Neste E, Michallet M, Maloisel F, Bouabdallah K, Decaudin D, Berthou C, Brice P, Gonzalez H, Chapiro E, Radford-Weiss I, Leporrier N, Maloum K, Nguyen-Khac F, Davi F, Lejeune J, Merle-Béral H, Leporrier M; Société Française de Greffe de Moelle et de Thérapie Cellulaire; Groupe Français d'étude de la Leucémie Lymphoïde Chronique. Autologous stem cell transplantation as a first-line treatment strategy for chronic lymphocytic leukemia: a multicenter, randomized, controlled trial from the SFGM-TC and GFLLC. Blood. 2011 Jun 9;117(23):6109-19. Epub 2011 Mar 15. link to original article contains dosing details in manuscript PubMed NCT00931645

R-FCM

R-FCM: Rituximab, Fludarabine, Cyclophosphamide, Mitoxantrone
FCM-R: Fludarabine, Cyclophosphamide, Mitoxantrone, Rituximab

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hillmen et al. 2011 (NCRI CLL201)	2005-2007	Randomized Phase 2 (E-esc)	FCM	Did not meet primary endpoint of ORR at 2 mo

Targeted therapy

• Rituximab (Rituxan) as follows:
  • Cycle 1: 375 mg/m² IV once on day 1
  • Cycles 2 to 6: 500 mg/m² IV once on day 1

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
• Mitoxantrone (Novantrone) 6 mg/m² IV once on day 1

28-day cycle for 6 cycles

Regimen variant #2

Study	Evidence
Bosch et al. 2009	Phase 2

Targeted therapy

• Rituximab (Rituxan) as follows:
  • Cycle 1: 375 mg/m² IV once on day 1
  • Cycles 2 to 6: 500 mg/m² IV once on day 1

Chemotherapy

• Fludarabine (Fludara) 25 mg/m² IV over 30 minutes once per day on days 1 to 3
• Cyclophosphamide (Cytoxan) 200 mg/m² IV over 60 minutes once per day on days 1 to 3
• Mitoxantrone (Novantrone) 6 mg/m² IV over 30 minutes once on day 1

Supportive therapy

• Pegylated granulocyte colony-stimulating factor once on day 4
• Allopurinol (Zyloprim) 300 mg PO once per day on days 1 to 5
• Trimethoprim-Sulfamethoxazole (Bactrim DS) (dose not specified) PO twice per week for up to 9 months after completion of therapy

28-day cycle for 6 cycles

Subsequent treatment

• Bosch et al. 2009, patients with a PR or CR at 3 months: Rituximab maintenance

Regimen variant #3

Study	Evidence
Faderl et al. 2009	Phase 2

Targeted therapy

• Rituximab (Rituxan) as follows:
  • Cycle 1: 375 mg/m² IV once on day 1
  • Cycles 2 to 6: 500 mg/m² IV once on day 1

Chemotherapy

• Fludarabine (Fludara) as follows:
  • Cycle 1: 25 mg/m²/day (route not specified) on days 2 to 4
  • Cycles 2 to 6: 25 mg/m²/day (route not specified) on days 1 to 3
• Cyclophosphamide (Cytoxan) as follows:
  • Cycle 1: 250 mg/m²/day (route not specified) on days 2 to 4
  • Cycles 2 to 6: 250 mg/m²/day (route not specified) on days 1 to 3
• Mitoxantrone (Novantrone) as follows:
  • Cycle 1: 6 mg/m² IV once on day 2
  • Cycles 2 to 6: 6 mg/m² IV once on day 2

Supportive therapy

• Acetaminophen (Tylenol) 650 mg PO once on day 1, prior to rituximab
• Diphenhydramine (Benadryl) 25 to 50 mg PO once on day 1, prior to rituximab
• Ondansetron (Zofran) 24 mg IV once, prior to chemotherapy
• Pegfilgrastim (Neulasta) (dose not specified) following the last day of each treatment cycle
• Antiviral prophylaxis was at the physician's discretion
• PCP prophylaxis was at the physician's discretion

4- to 6-week cycle for up to 6 cycles

References

1. Bosch F, Abrisqueta P, Villamor N, Terol MJ, González-Barca E, Ferra C, González Diaz M, Abella E, Delgado J, Carbonell F, García Marco JA, Escoda L, Ferrer S, Monzó E, González Y, Estany C, Jarque I, Salamero O, Muntañola A, Montserrat E. Rituximab, fludarabine, cyclophosphamide, and mitoxantrone: a new, highly active chemoimmunotherapy regimen for chronic lymphocytic leukemia. J Clin Oncol. 2009 Sep 20;27(27):4578-84. Epub 2009 Aug 24. link to original article contains dosing details in manuscript PubMed EudraCT 2005-001569-33
   1. Update: Abrisqueta P, Villamor N, Terol MJ, González-Barca E, González M, Ferrà C, Abella E, Delgado J, García-Marco JA, González Y, Carbonell F, Ferrer S, Monzó E, Jarque I, Muntañola A, Constants M, Escoda L, Calvo X, Bobillo S, Montoro JB, Montserrat E, Bosch F. Rituximab maintenance after first-line therapy with rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) for chronic lymphocytic leukemia. Blood. 2013 Dec 5;122(24):3951-9. Epub 2013 Oct 11. link to original article contains dosing details in manuscript PubMed
2. Faderl S, Wierda W, O'Brien S, Ferrajoli A, Lerner S, Keating MJ. Fludarabine, cyclophosphamide, mitoxantrone plus rituximab (FCM-R) in frontline CLL less than 70 Years. Leuk Res. 2010 Mar;34(3):284-8. Epub 2009 Jul 30. link to original article contains dosing details in abstract link to PMC article PubMed
3. NCRI CLL201: Hillmen P, Cohen DR, Cocks K, Pettitt A, Sayala HA, Rawstron AC, Kennedy DB, Fegan C, Milligan DW, Radford J, Mercieca J, Dearden C, Ezekwisili R, Smith AF, Brown J, Booth GA, Varghese AM, Pocock C; NCRI CLL Sub-Group. A randomized phase II trial of fludarabine, cyclophosphamide and mitoxantrone (FCM) with or without rituximab in previously treated chronic lymphocytic leukaemia. Br J Haematol. 2011 Mar;152(5):570-8. Epub 2011 Jan 14. link to original article contains dosing details in manuscript PubMed
4. ADMIRE: Munir T, Howard DR, McParland L, Pocock C, Rawstron AC, Hockaday A, Varghese A, Hamblin M, Bloor A, Pettitt A, Fegan C, Blundell J, Gribben JG, Phillips D, Hillmen P. Results of the randomized phase IIB ADMIRE trial of FCR with or without mitoxantrone in previously untreated CLL. Leukemia. 2017 Oct;31(10):2085-2093. Epub 2017 Apr 20. link to original article PubMed ISRCTN42165735

Uracil mustard monotherapy

Regimen

Study	Evidence
Kennedy & Theologides 1961	Non-randomized

Chemotherapy

• Uracil mustard

References

1. Kennedy BJ, Theologides A. Uracil mustard, a new alkylating agent for oral administration in the management of patients with leukemia and lymphoma. N Engl J Med. 1961 Apr 20;264:790-3. link to original article PubMed

Subsequent lines of therapy

CAP

CAP: Cyclophosphamide, Adriamycin (Doxorubicin), Prednisone

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Johnson et al. 1996	1990-1992	Phase 3 (C)	Fludarabine	Seems to have inferior ORR1

¹The inferior endpoint in Johnson et al. 1996 was only observed in this subgroup, not untreated patients.

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 40 mg/m² PO once per day on days 1 to 5

1-month cycle for 6 cycles

References

1. Johnson S, Smith AG, Löffler H, Osby E, Juliusson G, Emmerich B, Wyld PJ, Hiddemann W; French Cooperative Group on CLL. Multicentre prospective randomised trial of fludarabine versus cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of advanced-stage chronic lymphocytic leukaemia. Lancet. 1996 May 25;347(9013):1432-8. link to original article contains dosing details in abstract PubMed

Fludarabine monotherapy

F: Fludarabine

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Keating et al. 1989	1985-1987	Non-randomized (RT)
Grever et al. 1990	NR in abstract	Phase 1/2 (RT)
Johnson et al. 1996	1990-1992	Phase 3 (E-de-esc)	CAP	Seems to have superior ORR1

¹The superior endpoint in Johnson et al. 1996 was only observed in this subgroup, not untreated patients.

Chemotherapy

• Fludarabine (Fludara) 25 mg/m² IV once per day on days 1 to 5

28-day cycle for 6 cycles

References

1. Keating MJ, Kantarjian H, Talpaz M, Redman J, Koller C, Barlogie B, Velasquez W, Plunkett W, Freireich EJ, McCredie KB. Fludarabine: a new agent with major activity against chronic lymphocytic leukemia. Blood. 1989 Jul;74(1):19-25. link to original article PubMed
2. Grever M, Leiby J, Kraut E, Metz E, Neidhart J, Balcerzak S, Malspeis L. A comprehensive phase I and II clinical investigation of fludarabine phosphate. Semin Oncol. 1990 Oct;17(5 Suppl 8):39-48. PubMed
3. Johnson S, Smith AG, Löffler H, Osby E, Juliusson G, Emmerich B, Wyld PJ, Hiddemann W; French Cooperative Group on CLL. Multicentre prospective randomised trial of fludarabine versus cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of advanced-stage chronic lymphocytic leukaemia. Lancet. 1996 May 25;347(9013):1432-8. link to original article contains dosing details in abstract PubMed

Cyclophosphamide & Fludarabine (FC)

FC: Fludarabine, Cyclophosphamide

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
O'Brien et al. 2007 (GENTA GL303)	2001-2003	Phase 3 (C)	OBL-FC	Seems to have inferior ORR
Robak et al. 2010 (REACH)	2003-2007	Phase 3 (C)	R-FC	Inferior PFS
Robak et al. 2016 (COMPLEMENT 2)	2008-NR	Phase 3 (C)	O-FC	Inferior PFS

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm in this context.

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 therapy

• Note: varied according to reference.
• Cycle 1: Allopurinol (Zyloprim) 300 mg PO once per day on days 1 to 7
• Some patients received:
  • Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg PO twice per week
  • Valacyclovir (Valtrex) 500 mg PO once per day

28-day cycle for 6 cycles

References

1. GENTA GL303: O'Brien S, Moore JO, Boyd TE, Larratt LM, Skotnicki A, Koziner B, Chanan-Khan AA, Seymour JF, Bociek RG, Pavletic S, Rai KR. Randomized phase III trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2007 Mar 20;25(9):1114-20. Epub 2007 Feb 12. Erratum in: J Clin Oncol. 2008 Feb 10;26(5):820. link to original article contains dosing details in abstract PubMed NCT00024440
   1. Update: O'Brien S, Moore JO, Boyd TE, Larratt LM, Skotnicki AB, Koziner B, Chanan-Khan AA, Seymour JF, Gribben J, Itri LM, Rai KR. 5-year survival in patients with relapsed or refractory chronic lymphocytic leukemia in a randomized, phase III trial of fludarabine plus cyclophosphamide with or without oblimersen. J Clin Oncol. 2009 Nov 1;27(31):5208-12. Epub 2009 Sep 8. link to original article link to PMC article PubMed
2. REACH: 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 dosing details in abstract PubMed content property of HemOnc.org NCT00090051
3. COMPLEMENT 2: Robak T, Warzocha K, Govind Babu K, Kulyaba Y, Kuliczkowski K, Abdulkadyrov K, Loscertales J, Kriachok 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 NCT00824265

HDMP

HDMP: High Dose, MethylPrednisolone

Regimen

Study	Evidence
Burningham et al. 1964	Non-randomized, fewer than 20 pts

Glucocorticoid therapy

• Methylprednisolone (Solumedrol)

References

1. Burningham RA, Restrepo A, Pugh RP, Brown EB, Schlossman SF, Khuri PD, Lessner HE, Harrington WJ. Weekly high-dosage glucocorticosteroid treatment of lymphocytic leukemias and lymphomas. N Engl J Med. 1964 May 28;270:1160-6. link to original article PubMed

Tisagenlecleucel monotherapy

Regimen

Study	Evidence
Porter et al. 2011	Pilot

Note: this regimen is of historic interest in this context, this being the first clinical use of CAR-T-cell therapy. It is not FDA approved for this indication.

Immunotherapy

• Tisagenlecleucel (Kymriah)

References

1. Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011 Aug 25;365(8):725-33. Epub 2011 Aug 10. Erratum in: N Engl J Med. 2016 Mar 10;374(10):998. link to original article link to PMC article PubMed
   1. Update: Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A, June CH. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med. 2011 Aug 10;3(95):95ra73. link to original article link to PMC article PubMed
   2. Update: Porter DL, Hwang WT, Frey NV, Lacey SF, Shaw PA, Loren AW, Bagg A, Marcucci KT, Shen A, Gonzalez V, Ambrose D, Grupp SA, Chew A, Zheng Z, Milone MC, Levine BL, Melenhorst JJ, June CH. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 2015 Sep 2;7(303):303ra139. link to original article link to PMC article PubMed