Chronic lymphocytic leukemia
Page editor | Section editor | ||
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Jon Arnason, MD Beth Israel Deaconess Medical Center Boston, MA |
Sanjai Sharma, MD Sequoia Regional Cancer Center Visalia, CA |
Are you looking for a regimen but can't find it here? It is possible that we've moved it to the historical regimens page. If you still can't find it, please let us know so we can add it!
Note: there are several regimens on this page that are specific to small lymphocytic lymphoma (SLL). The vast majority of the regimens here were evaluated in CLL or in mixed populations of CLL and SLL patients.
83 regimens on this page
122 variants on this page
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Guidelines
ASBMT
- 2016: Kharfan-Dabaja et al. Clinical practice recommendations for use of allogeneic hematopoietic cell transplantation in chronic lymphocytic leukemia on behalf of the guidelines committee of the American Society for Blood and Marrow Transplantation
ESMO
- 2016: Ladetto et al. ESMO consensus conference on malignant lymphoma: general perspectives and recommendations for prognostic tools in mature B-cell lymphomas and chronic lymphocytic leukaemia PubMed
- 2015: Eichhorst et al. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2013: Ghielmini et al. ESMO Guidelines consensus conference on malignant lymphoma 2011 part 1: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL) PubMed
"How I Treat"
- 2021: Lew et al. How I treat chronic lymphocytic leukemia after venetoclax
- 2019: Stephens DM, Byrd JC. How I manage ibrutinib intolerance and complications in patients with chronic lymphocytic leukemia. Blood. 2019 Mar 21;133(12):1298-1307. link to PMC article
- 2018: Brown JR. How I treat CLL patients with ibrutinib. Blood. 2018 Jan 25;131(4):379-386. link to original article PubMed
International Workshop on Chronic Lymphocytic Leukemia (iwCLL)
- 2018: Hallek et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL PubMed
Older
- 2008: Hallek et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines
- 1996: Cheson et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment PubMed
NCCN
Older
- 2015: Zelenetz et al. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 1.2015 PubMed
First-line therapy, randomized data
Acalabrutinib monotherapy
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Byrd et al. 2021 (ACE-CL-001 untreated) | 2014-2015 | Phase 1/2 | ||
Sharman et al. 2020 (ELEVATE TN) | 2015-2017 | Phase 3 (E-RT-switch-ooc) | 1. Acalabrutinib & Obinutuzumab | Not reported |
2. Chlorambucil & Obinutuzumab | Superior PFS Median PFS: NYR vs 22.6 mo (HR 0.20, 95% CI 0.13-0.30) |
Note: Byrd et al. 2021 reports on a treatment-naive cohort from a trial that mostly enrolled patients in relapse.
Targeted therapy
- Acalabrutinib (Calquence) 100 mg PO twice per day or 200 mg PO once per day
Continued indefinitely
References
- ELEVATE TN: Sharman JP, Egyed M, Jurczak W, Skarbnik A, Pagel JM, Flinn IW, Kamdar M, Munir T, Walewska R, Corbett G, Fogliatto LM, Herishanu Y, Banerji V, Coutre S, Follows G, Walker P, Karlsson K, Ghia P, Janssens A, Cymbalista F, Woyach JA, Salles G, Wierda WG, Izumi R, Munugalavadla V, Patel P, Wang MH, Wong S, Byrd JC. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020 Apr 18;395(10232):1278-1291. link to original article link to PMC article contains dosing details in abstract PubMed Clinical Trial Registry
- ACE-CL-001 untreated: Byrd JC, Woyach JA, Furman RR, Martin P, O'Brien S, Brown JR, Stephens DM, Barrientos JC, Devereux S, Hillmen P, Pagel JM, Hamdy A, Izumi R, Patel P, Wang MH, Jain N, Wierda WG. Acalabrutinib in treatment-naive chronic lymphocytic leukemia. Blood. 2021 Jun 17;137(24):3327-3338. link to original article link to PMC article contains dosing details in abstract PubMed Clinical Trial Registry
Acalabrutinib & Obinutuzumab
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Sharman et al. 2020 (ELEVATE TN) | 2015-2017 | Phase 3 (E-RT-switch-ooc) | 1. Acalabrutinib | Not reported |
2. Chlorambucil & Obinutuzumab | Superior PFS Median PFS: NYR vs 22.6 mo (HR 0.10, 95% CI 0.06-0.17) |
Targeted therapy
- Acalabrutinib (Calquence) 100 mg PO twice per day
- Obinutuzumab (Gazyva) as follows:
- Cycle 2: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15
- Cycles 3 to 7: 1000 mg IV once on day 1
28-day cycles
References
- ELEVATE TN: Sharman JP, Egyed M, Jurczak W, Skarbnik A, Pagel JM, Flinn IW, Kamdar M, Munir T, Walewska R, Corbett G, Fogliatto LM, Herishanu Y, Banerji V, Coutre S, Follows G, Walker P, Karlsson K, Ghia P, Janssens A, Cymbalista F, Woyach JA, Salles G, Wierda WG, Izumi R, Munugalavadla V, Patel P, Wang MH, Wong S, Byrd JC. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020 Apr 18;395(10232):1278-1291. link to original article link to PMC article contains dosing details in abstract PubMed Clinical Trial Registry
Alemtuzumab monotherapy
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Hillmen et al. 2007 (CAM 307) | 2001-2004 | Phase 3 (E-RT-switch-ooc) | Chlorambucil | Superior PFS1 Median PFS: 15 vs 12 mo (aHR 0.58, 95% CI 0.43-0.77) |
1Median PFS is not reported in the manuscript and is estimated from the K-M curve (Figure 1A)
Eligibility criteria
- 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.
Targeted therapy
- Alemtuzumab (Campath) by the following criteria:
- Starting dose: 3 mg IV once per day
- If tolerated in terms of infusion reactions: 10 mg IV once per day
- If tolerated in terms of infusion reactions: 30 mg IV once per day
- Once 30 mg dose is tolerated: 30 mg IV over 2 hours, 3 times per week
Supportive therapy
- See references for details, as they differ by paper.
- Diphenhydramine (Benadryl) 50 mg PO once per infusion, 30 minutes prior to alemtuzumab
- Acetaminophen (Tylenol) 650 mg PO once per infusion, 30 minutes prior to alemtuzumab
- Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg PO 3 times per week, starting on day 8, continuing at a minimum until 2 months after treatment is complete
- Famciclovir (Famvir) 250 mg PO twice per day, starting on day 8, continuing at a minimum until 2 months after treatment is complete
12- to 16-week course; total course varies depending on reference
References
- 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 Clinical Trial Registry
Bendamustine monotherapy
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Knauf et al. 2009 | 2002-2006 | Phase 3 (E-RT-switch-ic) | Chlorambucil | Superior PFS Median PFS: 21.6 vs 8.3 mo |
Zhou et al. 2022 (SIM-79-001) | 2009-2016 | Phase 3 (E-switch-ic) | Chlorambucil | Superior PFS Median PFS: 16.5 vs 9.6 mo |
Eligibility criteria
- This regimen was intended for previously untreated CLL patients up to 75 years old with Binet stage B or C disease in need for treatment per the NCI-WG guidelines or IWCLL guidelines.
References
- 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
- Update: Knauf WU, Lissitchkov T, Aldaoud A, Liberati AM, Loscertales J, Herbrecht R, Juliusson G, Postner G, Gercheva L, Goranov S, Becker M, Fricke HJ, Huguet F, Del Giudice I, Klein P, Merkle K, Montillo M. Bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukaemia: updated results of a randomized phase III trial. Br J Haematol. 2012 Oct;159(1):67-77. Epub 2012 Aug 4. link to original article PubMed
- Retrospective: Kolibaba KS, Sterchele JA, Joshi AD, Forsyth M, Alwon E, Beygi H, Kennealey GT. Demographics, treatment patterns, safety, and real-world effectiveness in patients aged 70 years and over with chronic lymphocytic leukemia receiving bendamustine with or without rituximab: a retrospective study. Ther Adv Hematol. 2013 Jun;4(3):157-71. link to PMC article PubMed
- 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 Clinical Trial Registry
Bendamustine & Rituximab (BR)
BR: Bendamustine & Rituximab
R-B: Rituximab & Bendamustine
Regimen variant #1, 6 cycles
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Fischer et al. 2012 (GCLLSG CLL2M untreated) | 2007-2008 | Phase 2 | ||
Eichhorst et al. 2016 (GCLLSG CLL10) | 2008-2011 | Phase 3 (E-switch-ic) | FCR | Seems to have inferior PFS |
Michallet et al. 2018 (MABLE) | 2010-2014 | Phase 3b (E-switch-ic) | R-Clb | Superior PFS Median PFS: 39.6 vs 29.9 mo (HR 0.52, 95% CI 0.34-0.81) |
Tam et al. 2022 (SEQUOIACLL) | 2017-2019 | Phase 3 (C) | Zanubrutinib | Inferior PFS |
Biomarker eligibility criteria
- SEQUOIACLL: No 17p deletion
Chemotherapy
- Bendamustine 90 mg/m2 IV once per day on days 1 & 2
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 0 or 1
- Cycle 2 onwards: 500 mg/m2 IV once on day 1
28-day cycle for up to 6 cycles
Regimen variant #2, 6 cycles with maintenance rituximab
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Wang et al. 2022 (SHINE) | 2013-2014 | Phase 3 (C) | BR & Ibrutinib | Seems to have inferior PFS |
Note: the cycle timing changes during rituximab maintenance; the dosing does not change.
Chemotherapy
- Bendamustine as follows:
- Cycles 1 to 6: 90 mg/m2 IV once per day on days 1 & 2
Targeted therapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
28-day cycle for 6 cycles, then 8-week cycle for 12 cycles
References
- GCLLSG CLL2M untreated: Fischer K, Cramer P, Busch R, Böttcher S, Bahlo J, Schubert J, Pflüger KH, Schott S, Goede V, Isfort S, von Tresckow J, Fink AM, Bühler A, Winkler D, Kreuzer KA, Staib P, Ritgen M, Kneba M, Döhner H, Eichhorst BF, Hallek M, Stilgenbauer S, Wendtner CM. Bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. 2012 Sep 10;30(26):3209-16. Epub 2012 Aug 6. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
- Retrospective: Kolibaba KS, Sterchele JA, Joshi AD, Forsyth M, Alwon E, Beygi H, Kennealey GT. Demographics, treatment patterns, safety, and real-world effectiveness in patients aged 70 years and over with chronic lymphocytic leukemia receiving bendamustine with or without rituximab: a retrospective study. Ther Adv Hematol. 2013 Jun;4(3):157-71. link to PMC article PubMed
- GCLLSG CLL10: Eichhorst B, Fink AM, Bahlo J, Busch R, Kovacs G, Maurer C, Lange E, Köppler H, Kiehl M, Sökler M, Schlag R, Vehling-Kaiser U, Köchling G, Plöger C, Gregor M, Plesner T, Trneny M, Fischer K, Döhner H, Kneba M, Wendtner CM, Klapper W, Kreuzer KA, Stilgenbauer S, Böttcher S, Hallek M; International Group of Investigators; GCLLSG. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016 Jul;17(7):928-42. Epub 2016 May 20. link to original article PubMed Clinical Trial Registry2
- MABLE: Michallet AS, Aktan M, Hiddemann W, Ilhan O, Johansson P, Laribi K, Meddeb B, Moreno C, Raposo J, Schuh A, Ünal A, Widenius T, Bernhardt A, Kellershohn K, Messeri D, Osborne S, Leblond V. Rituximab plus bendamustine or chlorambucil for chronic lymphocytic leukemia: primary analysis of the randomized, open-label MABLE study. Haematologica. 2018 Apr;103(4):698-706. Epub 2018 Feb 1. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
- Alliance A041202: Woyach JA, Ruppert AS, Heerema NA, Zhao W, Booth AM, Ding W, Bartlett NL, Brander DM, Barr PM, Rogers KA, Parikh SA, Coutre S, Hurria A, Brown JR, Lozanski G, Blachly JS, Ozer HG, Major-Elechi B, Fruth B, Nattam S, Larson RA, Erba H, Litzow M, Owen C, Kuzma C, Abramson JS, Little RF, Smith SE, Stone RM, Mandrekar SJ, Byrd JC. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018 Dec 27;379(26):2517-2528. Epub 2018 Dec 1. link to original article contains dosing details in abstract link to PMC article PubMed Clinical Trial Registry
- SHINE: Wang ML, Jurczak W, Jerkeman M, Trotman J, Zinzani PL, Belada D, Boccomini C, Flinn IW, Giri P, Goy A, Hamlin PA, Hermine O, Hernández-Rivas JÁ, Hong X, Kim SJ, Lewis D, Mishima Y, Özcan M, Perini GF, Pocock C, Song Y, Spurgeon SE, Storring JM, Walewski J, Zhu J, Qin R, Henninger T, Deshpande S, Howes A, Le Gouill S, Dreyling M; SHINE Investigators. Ibrutinib plus Bendamustine and Rituximab in Untreated Mantle-Cell Lymphoma. N Engl J Med. 2022 Jun 30;386(26):2482-2494. Epub 2022 Jun 3. link to original article PubMed Clinical Trial Registry
- SEQUOIACLL: Tam CS, Brown JR, Kahl BS, Ghia P, Giannopoulos K, Jurczak W, Šimkovič M, Shadman M, Österborg A, Laurenti L, Walker P, Opat S, Chan H, Ciepluch H, Greil R, Tani M, Trněný M, Brander DM, Flinn IW, Grosicki S, Verner E, Tedeschi A, Li J, Tian T, Zhou L, Marimpietri C, Paik JC, Cohen A, Huang J, Robak T, Hillmen P. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022 Aug;23(8):1031-1043. Epub 2022 Jul 7. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
- ACE-CL-311: Clinical Trial Registry
- BRUIN CLL-313: Clinical Trial Registry
- CRISTALLO: Clinical Trial Registry
- GAIA: Clinical Trial Registry
Bendamustine & Rituximab (BR) & Ibrutinib
BR & Ibrutinib: Bendamustine, Rituximab, Ibrutinib
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Wang et al. 2022 (SHINE) | 2013-2014 | Phase 3 (E-esc) | BR | Seems to have superior PFS Median PFS: 80.6 vs 52.9 mo (HR 0.75, 95% CI 0.59-0.96) |
Note: the cycle timing changes during rituximab maintenance; the dosing does not change.
Chemotherapy
- Bendamustine as follows:
- Cycles 1 to 6: 90 mg/m2 IV once per day on days 1 & 2
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycles 1 to 18: 375 mg/m2 IV once on day 1
- Ibrutinib (Imbruvica) 560 mg PO once per day
28-day cycle for 6 cycles, then 8-week cycles
References
- SHINE: Wang ML, Jurczak W, Jerkeman M, Trotman J, Zinzani PL, Belada D, Boccomini C, Flinn IW, Giri P, Goy A, Hamlin PA, Hermine O, Hernández-Rivas JÁ, Hong X, Kim SJ, Lewis D, Mishima Y, Özcan M, Perini GF, Pocock C, Song Y, Spurgeon SE, Storring JM, Walewski J, Zhu J, Qin R, Henninger T, Deshpande S, Howes A, Le Gouill S, Dreyling M; SHINE Investigators. Ibrutinib plus Bendamustine and Rituximab in Untreated Mantle-Cell Lymphoma. N Engl J Med. 2022 Jun 30;386(26):2482-2494. Epub 2022 Jun 3. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
Cladribine & Cyclophosphamide (CC)
CC: Cladribine, Cyclophosphamide
Regimen variant #1, 0.36/650
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Robak et al. 2006 (PALG CLL2) | 1998-2003 | Phase 3 (E-esc) | 1. Cladribine | Might have superior CR rate |
2. CMC | Seems to have inferior CR rate |
Chemotherapy
- Cladribine (Leustatin) 0.12 mg/kg IV over 2 hours once per day on days 1 to 3
- Cyclophosphamide (Cytoxan) 650 mg/m2 IV once on day 1
Supportive therapy
- No routine prophylactic antibiotics, antiviral agents, or growth factor administration was planned.
28-day cycle for up to 6 cycles
Regimen variant #2, 0.36/750
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Robak et al. 2010 (PALG-CLL3) | 2004-2007 | Phase 3 (E-switch-ic) | FC | Did not meet primary endpoint of CR rate |
Chemotherapy
- Cladribine (Leustatin) 0.12 mg/kg IV over 30 minutes once per day on days 1 to 3
- Cyclophosphamide (Cytoxan) 250 mg/m2 IV over 30 to 60 minutes once per day on days 1 to 3
Supportive therapy
- "No routine prophylaxis with antibiotics, antiviral agents, or growth factors."
28-day cycle for up to 6 cycles
References
- 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; PALG. 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 manuscript PubMed
- Update: Robak T, Blonski JZ, Gora-Tybor J, Calbecka M, Dwilewicz-Trojaczek J, Boguradzki P, Dmoszynska A, Kowal M, Kloczko J, Piszcz J, Stella-Holowiecka B, Sulek K, Kuliczkowski K, Potoczek S, Warzocha K, Lech-Maranda E, Skotnicki AB, Piotrowska M, Moskwa A, Zawilska K, Jamroziak K. Long-term results of the Polish Adult Leukemia Group PALG-CLL2 phase III randomized study comparing cladribine-based combinations in chronic lymphocytic leukemia. Leuk Lymphoma. 2014 Mar;55(3):606-10. Epub 2013 Nov 14. link to original article PubMed
- 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. 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
Chlorambucil & Obinutuzumab (GClb)
GClb: GA101 (Obinutuzumab) & Chlorambucil
Regimen variant #1, 6 cycles
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Goede et al. 2014 (GCLLSG CLL11) | 2010-2012 | Phase 3 (E-RT-esc) | 1. Chlorambucil | Superior OS Median OS: NYR vs NYR (HR 0.41, 95% CI 0.23-0.74) |
2. Chlorambucil & Rituximab | Superior PFS | |||
Moreno et al. 2018 (iLLUMINATE) | 2014-2015 | Phase 3 (C) | Ibrutinib & Obinutuzumab | Inferior PFS |
Kater et al. 2022 (GLOW) | 2018-2019 | Phase 3 (E-RT-switch-ooc) | Ibrutinib & Venetoclax | Inferior PFS |
Note: Full reference details for GLOW will be added once NEJM Evidence is MEDLINE-indexed.
Eligibility criteria
- GLOW: At least 65 years old or 18 to 64 years old with a Cumulative Illness Rating Scale (CIRS) score greater than 6
Chemotherapy
- Chlorambucil (Leukeran) 0.5 mg/kg PO once per day on days 1 & 15
Targeted therapy
- Obinutuzumab (Gazyva) as follows:
- Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15
- Cycles 2 to 6: 1000 mg IV once on day 1
28-day cycle for 6 cycles
Regimen variant #2, 12 cycles
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Fischer et al. 2019 (GCLLSG CLL14) | 2015-2016 | Phase 3 (C) | Venetoclax & Obinutuzumab | Inferior PFS |
Note: Obinutuzumab is only given for the first six cycles.
Chemotherapy
- Chlorambucil (Leukeran) 0.5 mg/kg PO once per day on days 1 & 15
Targeted therapy
- Obinutuzumab (Gazyva) as follows:
- Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15
- Cycles 2 to 6: 1000 mg IV once on day 1
28-day cycle for 12 cycles
References
- 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 Clinical Trial Registry
- 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
- iLLUMINATE: Moreno C, Greil R, Demirkan F, Tedeschi A, Anz B, Larratt L, Simkovic M, Samoilova O, Novak J, Ben-Yehuda D, Strugov V, Gill D, Gribben JG, Hsu E, Lih CJ, Zhou C, Clow F, James DF, Styles L, Flinn IW. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019 Jan;20(1):43-56. Epub 2018 Nov 30. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
- GCLLSG CLL14: Fischer K, Al-Sawaf O, Bahlo J, Fink AM, Tandon M, Dixon M, Robrecht S, Warburton S, Humphrey K, Samoylova O, Liberati AM, Pinilla-Ibarz J, Opat S, Sivcheva L, Le Dû K, Fogliatto LM, Niemann CU, Weinkove R, Robinson S, Kipps TJ, Boettcher S, Tausch E, Humerickhouse R, Eichhorst B, Wendtner CM, Langerak AW, Kreuzer KA, Ritgen M, Goede V, Stilgenbauer S, Mobasher M, Hallek M. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019 Jun 6;380(23):2225-2236. Epub 2019 Jun 4. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
- Update: Al-Sawaf O, Zhang C, Tandon M, Sinha A, Fink AM, Robrecht S, Samoylova O, Liberati AM, Pinilla-Ibarz J, Opat S, Sivcheva L, Le Dû K, Fogliatto LM, Niemann CU, Weinkove R, Robinson S, Kipps TJ, Tausch E, Schary W, Ritgen M, Wendtner CM, Kreuzer KA, Eichhorst B, Stilgenbauer S, Hallek M, Fischer K. Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2020 Sep;21(9):1188-1200. link to original article PubMed
- Update: Al-Sawaf O, Zhang C, Lu T, Liao MZ, Panchal A, Robrecht S, Ching T, Tandon M, Fink AM, Tausch E, Schneider C, Ritgen M, Böttcher S, Kreuzer KA, Chyla B, Miles D, Wendtner CM, Eichhorst B, Stilgenbauer S, Jiang Y, Hallek M, Fischer K. Minimal Residual Disease Dynamics after Venetoclax-Obinutuzumab Treatment: Extended Off-Treatment Follow-up From the Randomized CLL14 Study. J Clin Oncol. 2021 Dec 20;39(36):4049-4060. Epub 2021 Oct 28. link to original article link to PMC article PubMed
- GLOW: link to original article contains dosing details in manuscript Clinical Trial Registry
- UNITY-CLL: Clinical Trial Registry
Chlorambucil & Ofatumumab
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Hillmen et al. 2015 (COMPLEMENT 1) | 2008-2011 | Phase 3 (E-RT-esc) | Chlorambucil | Superior PFS Median PFS: 22.4 vs 13.1 mo (HR 0.57, 95% CI 0.45-0.72) |
Chemotherapy
- Chlorambucil (Leukeran) 10 mg/m2 PO once per day on days 1 to 7
Targeted therapy
- Ofatumumab (Arzerra) as follows:
- Cycle 1: 300 mg IV once on day 1, then 1000 mg IV once on day 8
- Cycle 2 onwards: 1000 mg IV once on day 1
Supportive therapy
- Premedication for ofatumumab included Acetaminophen (Tylenol), antihistamines, and glucocorticoids (no doses or further information provided)
28-day cycle for a minimum of 3 cycles, and then given until best response up to a maximum of 12 cycles
References
- 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 Clinical Trial Registry
- 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
Chlorambucil & Rituximab (RClb)
RClb: Rituximab & Chlorambucil
CLB-R: ChLoramBucil & Rituximab
Regimen variant #1, Clb 0.5 mg/kg q2wk
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Goede et al. 2014 (GCLLSG CLL11) | 2010-2012 | Phase 3 (E-esc) | 1. Chlorambucil | Superior PFS Median PFS: 16.3 vs 11.1 mo (HR 0.44, 95% CI 0.34-0.57) |
2. Chlorambucil & Obinutuzumab | Inferior PFS | |||
Awaiting publication (D822BC00001) | 2020-2024 | Phase 3 (C) | Acalabrutinib | TBD |
Chemotherapy
- Chlorambucil (Leukeran) 0.5 mg/kg PO once per day on days 1 & 15
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
28-day cycle for 6 cycles
Regimen variant #2, Clb 8 mg/m2/d, 1 week out of 4
Study | Dates of enrollment | Evidence |
---|---|---|
Foà et al. 2014 (ML21445) | 2008-2013 | Non-randomized part of phase 2 RCT |
Chemotherapy
- Chlorambucil (Leukeran) 8 mg/m2/day PO once per day on days 1 to 7
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 3: 375 mg/m2 IV once on day 1
- Cycle 4 onwards: 500 mg/m2 IV once on day 1
28-day cycle for up to 8 cycles
Subsequent treatment
- ML21445, PR or better: Observation versus Rituximab maintenance
Regimen variant #3, Clb 10 mg/m2/d, 1 week out of 4
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Hillmen et al. 2014 (NCRI CLL208) | 2007-2009 | Phase 2 | ||
Michallet et al. 2018 (MABLE) | 2010-2014 | Phase 3b (E-switch-ic) | BR | Inferior PFS |
Chemotherapy
- Chlorambucil (Leukeran) 10 mg/m2 PO once per day on days 1 to 7
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
28-day cycle for 6 cycles
Subsequent treatment
- NCRI CLL208, patients not achieving CR: Optional chlorambucil x up to 6 cycles
- MABLE, patients not achieving CR: Optional chlorambucil x up to 6 cycles or until CR
References
- 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 Clinical Trial Registry
- 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
- ML21445: Foà R, Del Giudice I, Cuneo A, Del Poeta G, Ciolli S, Di Raimondo F, Lauria F, Cencini E, Rigolin GM, Cortelezzi A, Nobile F, Callea V, Brugiatelli M, Massaia M, Molica S, Trentin L, Rizzi R, Specchia G, Di Serio F, Orsucci L, Ambrosetti A, Montillo M, Zinzani PL, Ferrara F, Morabito F, Mura MA, Soriani S, Peragine N, Tavolaro S, Bonina S, Marinelli M, De Propris MS, Starza ID, Piciocchi A, Alietti A, Runggaldier EJ, Gamba E, Mauro FR, Chiaretti S, Guarini A. Chlorambucil plus rituximab with or without maintenance rituximab as first-line treatment for elderly chronic lymphocytic leukemia patients. Am J Hematol. 2014 May;89(5):480-6. Epub 2014 Feb 18. link to original article contains dosing details in manuscript PubMed EudraCT 2008-001612-20
- NCRI CLL08: Hillmen P, Gribben JG, Follows GA, Milligan D, Sayala HA, Moreton P, Oscier DG, Dearden CE, Kennedy DB, Pettitt AR, Nathwani A, Varghese A, Cohen D, Rawstron A, Oertel S, Pocock CF. Rituximab plus chlorambucil as first-line treatment for chronic lymphocytic leukemia: Final analysis of an open-label phase II study. J Clin Oncol. 2014 Apr 20;32(12):1236-41. Epub 2014 Mar 17. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
- MABLE: Michallet AS, Aktan M, Hiddemann W, Ilhan O, Johansson P, Laribi K, Meddeb B, Moreno C, Raposo J, Schuh A, Ünal A, Widenius T, Bernhardt A, Kellershohn K, Messeri D, Osborne S, Leblond V. Rituximab plus bendamustine or chlorambucil for chronic lymphocytic leukemia: primary analysis of the randomized, open-label MABLE study. Haematologica. 2018 Apr;103(4):698-706. Epub 2018 Feb 1. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
- D822BC00001: contains dosing details on CT.gov Clinical Trial Registry
Cladribine monotherapy
Regimen variant #1, 0.6 mg/kg
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Mulligan et al. 2014 | 1997-2004 | Phase 3 (E-switch-ic) | 1. Chlorambucil 2. Fludarabine |
Superior PFS |
Robak et al. 2006 (PALG CLL2) | 1998-2003 | Phase 3 (C) | 1. CC | Might have inferior CR rate |
2. CMC | Inferior CR rate |
Note: Dosing details for Mulligan et al. 2014 were not available in the abstract.
Chemotherapy
- Cladribine (Leustatin) 0.12 mg/kg IV over 2 hours once per day on days 1 to 5
Supportive therapy
- No routine prophylactic antibiotics, antiviral agents, or growth factor administration was planned.
28-day cycle for up to 6 cycles
Regimen variant #2, 0.7 mg/m2
Study | Dates of enrollment | Evidence |
---|---|---|
Saven et al. 1995 | 1988-1993 | Phase 2 |
Chemotherapy
- Cladribine (Leustatin) 0.1 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose per cycle: 0.7 mg/m2)
28 to 35-day cycles, repeated until maximum response or limiting toxicity
References
- Saven A, Lemon RH, Kosty M, Beutler E, Piro LD. 2-Chlorodeoxyadenosine activity in patients with untreated chronic lymphocytic leukemia. J Clin Oncol. 1995 Mar;13(3):570-4. link to original article contains dosing details in abstract PubMed
- 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 manuscript PubMed
- Update: Robak T, Blonski JZ, Gora-Tybor J, Calbecka M, Dwilewicz-Trojaczek J, Boguradzki P, Dmoszynska A, Kowal M, Kloczko J, Piszcz J, Stella-Holowiecka B, Sulek K, Kuliczkowski K, Potoczek S, Warzocha K, Lech-Maranda E, Skotnicki AB, Piotrowska M, Moskwa A, Zawilska K, Jamroziak K. Long-term results of the Polish Adult Leukemia Group PALG-CLL2 phase III randomized study comparing cladribine-based combinations in chronic lymphocytic leukemia. Leuk Lymphoma. 2014 Mar;55(3):606-10. Epub 2013 Nov 14. link to original article PubMed
- 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 PubMed
FCA
FCA: Fludarabine, Cyclophosphamide, Alemtuzumab
FCCam: Fludarabine, Cyclophosphamide, Campath (Alemtuzumab)
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Geisler et al. 2014 (HOVON-68) | 2006-2010 | Phase 3 (E-esc) | FC | Superior PFS PFS36: 53% vs 37% |
Lepretre et al. 2012 (GOELAMS CLL2007FMP) | 2007-2009 | Phase 3 (E-switch-ic) | FCR | Did not meet primary endpoint of PFS36 |
Note: GOELAMS CLL2007FMP was halted prematurely due to excess mortality.
Eligibility criteria
- HOVON-68: 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 old, 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
Targeted therapy
- Alemtuzumab (Campath) as follows:
- Cycle 1: 30 mg SC once per day on days -1, 0, and 1
- Cycle 2 onwards: 30 mg SC once on day 1
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
References
- GOELAMS CLL2007FMP: Lepretre S, Aurran T, Mahé B, Cazin B, Tournilhac O, Maisonneuve H, Casasnovas O, Delmer A, Leblond V, Royer B, Corront B, Chevret S, Delépine R, Vaudaux S, Van Den Neste E, Béné MC, Letestu R, Cymbalista F, Feugier P. Excess mortality after treatment with fludarabine and cyclophosphamide in combination with alemtuzumab in previously untreated patients with chronic lymphocytic leukemia in a randomized phase 3 trial. Blood. 2012 May 31;119(22):5104-10. Epub 2012 Feb 14. link to original article PubMed Clinical Trial Registry
- 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
FCR
FCR: Fludarabine, Cyclophosphamide, Rituximab
R-FC: Rituximab, Fludarabine, Cyclophosphamide
Regimen variant #1, 25/250/375-500
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Keating et al. 2005 | 1999-2001 | Phase 2 | |||
Hallek et al. 2010 (GCLLSG CLL8) | 2003-2006 | Phase 3 (E-RT-esc) | FC | Superior OS1 Median OS: NYR vs 86 mo (HR 0.68, 95% CI 0.54-0.89) |
Equivalent HRQoL |
Herling et al. 2020 (GCLLSG CLL7) | 2005-2010 | Phase 3 (E-esc) | Observation | Superior EFS Median EFS: NYR vs 18.5 mo (HR 0.22, 95% CI 0.15-0.33) |
|
Lepretre et al. 2012 (GOELAMS CLL2007FMP) | 2007-2009 | Phase 3 (C) | FCCam | Did not meet primary endpoint of PFS36 | |
Eichhorst et al. 2016 (GCLLSG CLL10) | 2008-2011 | Phase 3 (C) | BR | Inconclusive whether non-inferior PFS | |
Shanafelt et al. 2019 (ECOG E1912) | 2014-2016 | Phase 3 (C) | Ibrutinib & Rituximab | Inferior OS |
1Reported efficacy for GCLLSG CLL8 is based on the 2016 update.
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
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 0
- Alternate dosing in ECOG E1912: 50 mg/m2 IV once on day 1, then 325 mg/m2 IV once on day 2
- Cycles 2 to 6: 500 mg/m2 IV once on day 1
- Cycle 1: 375 mg/m2 IV once on day 0
Supportive therapy
- Note: these vary according to reference.
- Diphenhydramine (Benadryl) 25 mg IV once per infusion, 30 minutes prior to rituximab
- Acetaminophen (Tylenol) 650 mg PO once per infusion, 30 minutes prior to rituximab
- 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
- PCP (Pneumocystis jirovecii pneumonia) prophylaxis recommended for severe leukopenia greater than 7 days
- No routine prophylaxis with antiviral medications or G-CSF
28-day cycle for 6 cycles
Regimen variant #2, 25/250/500
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Awan et al. 2014 (LUCID) | 2006-NR | Phase 3 (C) | FCR+L | Did not meet primary endpoint of CR rate |
Chemotherapy
- Fludarabine (Fludara) as follows:
- Cycle 1: 25 mg/m2 IV over at least 10 to 30 minutes once per day on days 2 to 4
- Cycle 2 to 6: 25 mg/m2 IV over at least 10 to 30 minutes once per day on days 1 to 3
- Cyclophosphamide (Cytoxan) as follows:
- Cycle 1: 250 mg/m2 IV over at least 10 to 30 minutes once per day on days 2 to 4
- Cycle 2 to 6: 250 mg/m2 IV over at least 10 to 30 minutes once per day on days 1 to 3
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 50 mg/m2 IV over 4 hours once on day 1, then 450 mg/m2 IV once on day 3
- Cycles 2 to 6: 500 mg/m2 IV once on day 1
Supportive therapy
- Cotrimoxazole or equivalent
- Acyclovir (Zovirax) 400 mg PO twice per day or equivalent
- Growth factors at physician discretion
28-day cycle for 6 cycles
Regimen variant #3, 20/150/375-500 ("FCR-Lite")
Study | Dates of enrollment | Evidence |
---|---|---|
Foon et al. 2009 | 2003-2007 | Phase 2 |
Chemotherapy
- Fludarabine (Fludara) as follows:
- Cycle 1: 20 mg/m2 IV over 30 minutes once per day on days 2 to 4
- Cycles 2 to 6: 20 mg/m2 IV over 30 minutes once per day on days 1 to 3
- Cyclophosphamide (Cytoxan) as follows:
- Cycle 1: 150 mg/m2 IV over 60 minutes once per day on days 2 to 4
- Cycles 2 to 6: 150 mg/m2 IV over 60 minutes once per day on days 1 to 3
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 1, then 500 mg/m2 IV once on day 14
- Cycles 2 to 6: 500 mg/m2 IV once per day on days 1 & 14
Supportive therapy
- Diphenhydramine (Benadryl) 25 mg PO once per day on days 1 & 14, prior to rituximab
- Acetaminophen (Tylenol) 650 mg PO once per day on days 1 & 14, prior to rituximab
- Dexamethasone (Decadron) 10 mg IV or PO once per day on days 1 & 14, prior to rituximab
- Cycle 1: Allopurinol (Zyloprim) 300 mg PO once per day on days 1 to 10
- Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg PO twice per day three times per week, for 6 months past last dose of chemotherapy
- Acyclovir (Zovirax) 400 mg PO three times per day, for 6 months past last dose of chemotherapy
- One of the following:
- Filgrastim (Neupogen) (dose not specified), starting 24 hours after chemotherapy
- Pegfilgrastim (Neulasta) (dose not specified), given 24 hours after chemotherapy
28-day cycle for 6 cycles
Subsequent treatment
- Indefinite rituximab maintenance
Regimen variant #4, 40/250/375-500, oral FC
Study | Dates of enrollment | Evidence |
---|---|---|
Dartigeas et al. 2017 (CLL 2007 SA) | 2007-2014 | Non-randomized part of phase 3 RCT |
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
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 1, then 500 mg/m2 IV once on day 14
- Cycle 2: 500 mg/m2 IV once per day on days 1 & 14
- Cycles 3 & 4: 500 mg/m2 IV once on day 1
1-month cycle for 4 cycles
Subsequent treatment
- Rituximab maintenance versus observation
Regimen variant #5, 25/250/375
Study | Dates of enrollment | Evidence |
---|---|---|
Tam et al. 2006 | 2000-2005 | Phase 2 |
Chemotherapy
- Fludarabine (Fludara) 25 mg/m2 IV over 15 to 30 minutes once per day on days 1 to 3
- Cyclophosphamide (Cytoxan) 250 mg/m2 IV over 15 to 30 minutes once per day on days 1 to 3
Targeted therapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
28-day cycle for up to 6 cycles or "attainment of maximum response"
Regimen variant #6, 24/150/375-500, oral FC
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Munir et al. 2017 (ADMIRE) | 2009-2012 | Randomized phase 2b (C) | FCM-R | Did not meet primary endpoint of CR rate |
Howard et al. 2017 (ARCTICCLL) | 2009-2012 | Randomized phase 2b (C) | FCM-miniR | Superior CR rate |
Note: in contrast to other variants, FC is given over 5 days not 3. ARCTIC should not be confused with the trial by the same name in NSCLC.
Chemotherapy
- Fludarabine (Fludara) 24 mg/m2 PO once per day on days 1 to 5
- Cyclophosphamide (Cytoxan) 150 mg/m2/day PO on days 1 to 5
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
28-day cycle for 6 cycles
References
- Keating MJ, O'Brien S, Albitar M, Lerner S, Plunkett W, Giles F, Andreeff M, Cortes J, Faderl S, Thomas D, Koller C, Wierda W, Detry MA, Lynn A, Kantarjian H. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol. 2005 Jun 20;23(18):4079-88. Epub 2005 Mar 14. link to original article contains dosing details in manuscript PubMed
- Update: Tam CS, O'Brien S, Wierda W, Kantarjian H, Wen S, Do KA, Thomas DA, Cortes J, Lerner S, Keating MJ. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood. 2008 Aug 15;112(4):975-80. Epub 2008 Apr 14. link to original article link to PMC article PubMed
- Update: Thompson PA, Tam CS, O'Brien SM, Wierda WG, Stingo F, Plunkett W, Smith SC, Kantarjian HM, Freireich EJ, Keating MJ. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood. 2016 Jan 21;127(3):303-9. Epub 2015 Oct 22. link to original article link to PMC article PubMed
- Tam CS, Wolf M, Prince HM, Januszewicz EH, Westerman D, Lin KI, Carney D, Seymour JF. Fludarabine, cyclophosphamide, and rituximab for the treatment of patients with chronic lymphocytic leukemia or indolent non-Hodgkin lymphoma. Cancer. 2006 Jun 1;106(11):2412-20. link to original article contains dosing details in manuscript PubMed
- Foon KA, Boyiadzis M, Land SR, Marks S, Raptis A, Pietragallo L, Meisner D, Laman A, Sulecki M, Butchko A, Schaefer P, Lenzer D, Tarhini A. Chemoimmunotherapy with low-dose fludarabine and cyclophosphamide and high dose rituximab in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009 Feb 1;27(4):498-503. Epub 2008 Dec 15. link to original article contains dosing details in manuscript PubMed
- Update: Foon KA, Mehta D, Lentzsch S, Kropf P, Marks S, Lenzner D, Pietragallo L, Sulecki M, Tarhini A, Boyiadzis M. Long-term results of chemoimmunotherapy with low-dose fludarabine, cyclophosphamide and high-dose rituximab as initial treatment for patients with chronic lymphocytic leukemia. Blood. 2012 Mar 29;119(13):3184-5. link to original article PubMed
- 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 manuscript PubMed Clinical Trial Registry
- 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
- GOELAMS CLL2007FMP: Lepretre S, Aurran T, Mahé B, Cazin B, Tournilhac O, Maisonneuve H, Casasnovas O, Delmer A, Leblond V, Royer B, Corront B, Chevret S, Delépine R, Vaudaux S, Van Den Neste E, Béné MC, Letestu R, Cymbalista F, Feugier P. Excess mortality after treatment with fludarabine and cyclophosphamide in combination with alemtuzumab in previously untreated patients with chronic lymphocytic leukemia in a randomized phase 3 trial. Blood. 2012 May 31;119(22):5104-10. Epub 2012 Feb 14. link to original article PubMed Clinical Trial Registry
- GCLLSG CLL7: Herling CD, Cymbalista F, Groß-Ophoff-Müller C, Bahlo J, Robrecht S, Langerbeins P, Fink AM, Al-Sawaf O, Busch R, Porcher R, Cazin B, Dreyfus B, Ibach S, Leprêtre S, Fischer K, Kaiser F, Eichhorst B, Wentner CM, Hoechstetter MA, Döhner H, Leblond V, Kneba M, Letestu R, Böttcher S, Stilgenbauer S, Hallek M, Levy V. Early treatment with FCR versus watch and wait in patients with stage Binet A high-risk chronic lymphocytic leukemia (CLL): a randomized phase 3 trial. Leukemia. 2020 Aug;34(8):2038-2050. Epub 2020 Feb 18. link to original article link to PMC article PubMed Clinical Trial Registry
- LUCID: Awan FT, Hillmen P, Hellmann A, Robak T, Hughes SG, Trone D, Shannon M, Flinn IW, Byrd JC; LUCID trial investigators. A randomized, open-label, multicentre, phase 2/3 study to evaluate the safety and efficacy of lumiliximab in combination with fludarabine, cyclophosphamide and rituximab versus fludarabine, cyclophosphamide and rituximab alone in subjects with relapsed chronic lymphocytic leukaemia. Br J Haematol. 2014 Nov;167(4):466-77. Epub 2014 Aug 8. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
- GCLLSG CLL10: Eichhorst B, Fink AM, Bahlo J, Busch R, Kovacs G, Maurer C, Lange E, Köppler H, Kiehl M, Sökler M, Schlag R, Vehling-Kaiser U, Köchling G, Plöger C, Gregor M, Plesner T, Trneny M, Fischer K, Döhner H, Kneba M, Wendtner CM, Klapper W, Kreuzer KA, Stilgenbauer S, Böttcher S, Hallek M; International Group of Investigators; German CLL Study Group. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016 Jul;17(7):928-42. Epub 2016 May 20. link to original article PubMed Clinical Trial Registry2
- 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 contains dosing details in manuscript PubMed ISRCTN42165735
- ARCTIC: Howard DR, Munir T, McParland L, Rawstron AC, Milligan D, Schuh A, Hockaday A, Allsup DJ, Marshall S, Duncombe AS, O'Dwyer JL, Smith AF, Longo R, Varghese A, Hillmen P. Results of the randomized phase IIB ARCTIC trial of low-dose rituximab in previously untreated CLL. Leukemia. 2017 Nov;31(11):2416-2425. Epub 2017 Mar 24. link to original article contains dosing details in supplement PubMed ISRCTN16544962
- CLL 2007 SA: Dartigeas C, Van Den Neste E, Léger J, Maisonneuve H, Berthou C, Dilhuydy MS, De Guibert S, Leprêtre S, Béné MC, Nguyen-Khac F, Letestu R, Cymbalista F, Rodon P, Aurran-Schleinitz T, Vilque JP, Tournilhac O, Mahé B, Laribi K, Michallet AS, Delmer A, Feugier P, Lévy V, Delépine R, Colombat P, Leblond V; CLL 2007 SA investigators; FILO. Rituximab maintenance versus observation following abbreviated induction with chemoimmunotherapy in elderly patients with previously untreated chronic lymphocytic leukaemia (CLL 2007 SA): an open-label, randomised phase 3 study. Lancet Haematol. 2018 Feb;5(2):e82-e94. Epub 2017 Dec 20. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
- ECOG E1912: Shanafelt TD, Wang XV, Kay NE, Hanson CA, O'Brien S, Barrientos J, Jelinek DF, Braggio E, Leis JF, Zhang CC, Coutre SE, Barr PM, Cashen AF, Mato AR, Singh AK, Mullane MP, Little RF, Erba H, Stone RM, Litzow M, Tallman M. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019 Aug 1;381(5):432-443. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
- Update: Shanafelt TD, Wang XV, Hanson CA, Paietta EM, O'Brien S, Barrientos J, Jelinek DF, Braggio E, Leis JF, Zhang CC, Coutre SE, Barr PM, Cashen AF, Mato AR, Singh AK, Mullane MP, Little RF, Erba H, Stone RM, Litzow M, Tallman M, Kay NE. Long-term outcomes for ibrutinib-rituximab and chemoimmunotherapy in CLL: updated results of the E1912 trial. Blood. 2022 Jul 14;140(2):112-120. link to original article link to PMC article PubMed
- ACE-CL-311: Clinical Trial Registry
- CRISTALLO: Clinical Trial Registry
- GAIA: Clinical Trial Registry
FCR (Rituximab and hyaluronidase)
FCR: Fludarabine, Cyclophosphamide, Rituximab hyaluronidase
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Assouline et al. 2016 (SAWYER) | 2012-2013 | Randomized Phase 1b (E-RT-switch-ic) | FCR | Not reported |
Note: other variants include oral fludarabine and/or cyclophosphamide; to be completed.
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
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 0
- Rituximab and hyaluronidase human (Rituxan Hycela) as follows:
- Cycles 2 to 6: 1600 mg SC once on day 1
28-day cycle for up to 6 cycles
References
- SAWYER: Assouline S, Buccheri V, Delmer A, Gaidano G, Trneny M, Berthillon N, Brewster M, Catalani O, Li S, McIntyre C, Sayyed P, Badoux X. Pharmacokinetics, safety, and efficacy of subcutaneous versus intravenous rituximab plus chemotherapy as treatment for chronic lymphocytic leukaemia (SAWYER): a phase 1b, open-label, randomised controlled non-inferiority trial. Lancet Haematol. 2016 Mar;3(3):e128-38. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
Fludarabine & Alemtuzumab
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Elter et al. 2011 (CAM 314) | 2004-2008 | Phase 3 (E-esc) | Fludarabine | Superior OS Median OS: NYR vs 52.9 mo (HR 0.65, 95% CI 0.45-0.94) |
Chemotherapy
- Fludarabine (Fludara) 30 mg/m2 IV once per day on days 1 to 3
Targeted therapy
- Alemtuzumab (Campath) 30 mg IV once per day on days 1 to 3
28-day cycle for up to 6 cycles
References
- 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 contains dosing details in abstract PubMed Clinical Trial Registry
Ibrutinib monotherapy
Regimen
FDA-recommended dose |
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
O'Brien et al. 2013 (PCYC-1102 untreated) | 2010-2012 | Phase 1b/2 | ||
Farooqui et al. 2014 (NHLBI 12-H-0035) | 2011-2014 | Phase 2 | ||
Burger et al. 2015 (RESONATE-2) | 2013-NR | Phase 3 (E-RT-switch-ooc) | Chlorambucil | Superior OS1 OS60: 83% vs 68% (HR 0.45, 95% CI 0.27-0.76) |
Woyach et al. 2018 (Alliance A041202) | 2013-2016 | Phase 3 (E-switch-ooc) | BR | Superior PFS PFS24: 87% vs 74% (HR 0.39, 95% CI 0.26-0.58) |
Ibrutinib & Rituximab | Did not meet primary endpoint of PFS (HR 1.00, 95% CI 0.62-1.62) | |||
Burger et al. 2018 (MDACC 2013-0703) | 2013-2017 | Phase 3 (C) | Ibrutinib & Rituximab | Did not meet primary endpoint of PFS |
Langerbeins et al. 2022 (CLL12) | 2014-2019 | Phase 3 (E-esc) | Placebo | Superior EFS Median EFS: NYR vs 47.8 mo (HR 0.25, 95% CI 0.14-0.43) |
Awaiting publication (SYMPATICO) | 2017-2023 | Phase 3 (C) | VI | TBD |
Awaiting publication (GCLLSG CLL17) | 2021-2027 | Phase 3 (C) | 1. VG 2. VI |
TBD |
Awaiting publication (BRUIN CLL-314) | 2022-2028 | Phase 3 (C) | Pirtobrutinib | TBD |
1Reported efficacy for RESONATE-2 is based on the 2019 update.
PCYC-1102 was intended for elderly patients. Although both 420 mg and 840 mg doses were planned, the 840 mg cohort was closed due to findings of comparable efficacy in other studies. RESONATE-2 was intended for patients older than 65 years. CLL12 was intended for patients with asymptomatic Binet stage A CLL.
Biomarker eligibility criteria
- NHLBI 12-H-0035: TP53 aberrations
References
- PCYC-1102 untreated: O'Brien S, Furman RR, Coutre SE, Sharman JP, Burger JA, Blum KA, Grant B, Richards DA, Coleman M, Wierda WG, Jones JA, Zhao W, Heerema NA, Johnson AJ, Izumi R, Hamdy A, Chang BY, Graef T, Clow F, Buggy JJ, James DF, Byrd JC. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol. 2014 Jan;15(1):48-58. Epub 2013 Dec 10. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
- Update: Byrd JC, Furman RR, Coutre SE, Burger JA, Blum KA, Coleman M, Wierda WG, Jones JA, Zhao W, Heerema NA, Johnson AJ, Shaw Y, Bilotti E, Zhou C, James DF, O'Brien S. Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015 Apr 16;125(16):2497-506. Epub 2015 Feb 19. link to original article link to PMC article PubMed
- Update: O'Brien S, Furman RR, Coutre S, Flinn IW, Burger JA, Blum K, Sharman J, Wierda W, Jones J, Zhao W, Heerema NA, Johnson AJ, Luan Y, James DF, Chu AD, Byrd JC. Single-agent ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. Blood. 2018 Apr 26;131(17):1910-1919. Epub 2018 Feb 2. link to original article link to PMC article PubMed
- Update: Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum K, Sharman JP, Wierda W, Zhao W, Heerema NA, Luan Y, Liu EA, Dean JP, O'Brien S. Ibrutinib Treatment for First-Line and Relapsed/Refractory Chronic Lymphocytic Leukemia: Final Analysis of the Pivotal Phase Ib/II PCYC-1102 Study. Clin Cancer Res. 2020 Aug 1;26(15):3918-3927. Epub 2020 Mar 24. link to original article link to PMC article PubMed
- NHLBI 12-H-0035: Farooqui MZ, Valdez J, Martyr S, Aue G, Saba N, Niemann CU, Herman SE, Tian X, Marti G, Soto S, Hughes TE, Jones J, Lipsky A, Pittaluga S, Stetler-Stevenson M, Yuan C, Lee YS, Pedersen LB, Geisler CH, Calvo KR, Arthur DC, Maric I, Childs R, Young NS, Wiestner A. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol. 2015 Feb;16(2):169-76. Epub 2014 Dec 31. link to original article contains dosing details in abstract link to PMC article PubMed Clinical Trial Registry
- 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 Clinical Trial Registry
- 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
- 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 link to PMC article PubMed
- Alliance A041202: Woyach JA, Ruppert AS, Heerema NA, Zhao W, Booth AM, Ding W, Bartlett NL, Brander DM, Barr PM, Rogers KA, Parikh SA, Coutre S, Hurria A, Brown JR, Lozanski G, Blachly JS, Ozer HG, Major-Elechi B, Fruth B, Nattam S, Larson RA, Erba H, Litzow M, Owen C, Kuzma C, Abramson JS, Little RF, Smith SE, Stone RM, Mandrekar SJ, Byrd JC. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018 Dec 27;379(26):2517-2528. Epub 2018 Dec 1. link to original article contains dosing details in abstract link to PMC article PubMed Clinical Trial Registry
- MDACC 2013-0703: Burger JA, Sivina M, Jain N, Kim E, Kadia T, Estrov Z, Nogueras-Gonzalez GM, Huang X, Jorgensen J, Li J, Cheng M, Clow F, Ohanian M, Andreeff M, Mathew T, Thompson P, Kantarjian H, O'Brien S, Wierda WG, Ferrajoli A, Keating MJ. Randomized trial of ibrutinib vs ibrutinib plus rituximab in patients with chronic lymphocytic leukemia. Blood. 2019 Mar 7;133(10):1011-1019. Epub 2018 Dec 7. link to original article contains dosing details in abstract link to PMC article PubMed Clinical Trial Registry
- CLL12: Langerbeins P, Zhang C, Robrecht S, Cramer P, Fürstenau M, Al-Sawaf O, von Tresckow J, Fink AM, Kreuzer KA, Vehling-Kaiser U, Tausch E, Müller L, Eckart MJ, Schlag R, Freier W, Gaska T, Balser C, Reiser M, Stauch M, Wendtner CM, Fischer K, Stilgenbauer S, Eichhorst B, Hallek M. The CLL12 trial: ibrutinib vs placebo in treatment-naïve, early-stage chronic lymphocytic leukemia. Blood. 2022 Jan 13;139(2):177-187. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
- BRUIN CLL-314: Clinical Trial Registry
- GCLLSG CLL17: Clinical Trial Registry
- SYMPATICO: Clinical Trial Registry
Ibrutinib & Obinutuzumab
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Moreno et al. 2018 (iLLUMINATE) | 2014-2015 | Phase 3 (E-RT-switch-ooc) | G-Clb | Superior PFS Median PFS: NYR vs 19 mo (HR 0.23, 95% CI 0.15-0.37) |
Targeted therapy
- Ibrutinib (Imbruvica) 420 mg PO once per day
- Obinutuzumab (Gazyva) as follows:
- Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15
- Cycles 2 to 6: 1000 mg IV once on day 1
28-day cycles
References
- iLLUMINATE: Moreno C, Greil R, Demirkan F, Tedeschi A, Anz B, Larratt L, Simkovic M, Samoilova O, Novak J, Ben-Yehuda D, Strugov V, Gill D, Gribben JG, Hsu E, Lih CJ, Zhou C, Clow F, James DF, Styles L, Flinn IW. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019 Jan;20(1):43-56. Epub 2018 Nov 30. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
- ECOG-ACRIN EA9161: Clinical Trial Registry
- Alliance A041702: Clinical Trial Registry
Ibrutinib & Rituximab
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Shanafelt et al. 2019 (ECOG E1912) | 2014-2016 | Phase 3 (E-RT-switch-ooc) | FCR | Superior OS1 OS60: 95% vs 89% (HR 0.47, 95% CI 0.25-0.89) |
1Reported efficacy is based on the 2022 update.
Targeted therapy
- Ibrutinib (Imbruvica) 420 mg PO once per day
- Rituximab (Rituxan) as follows:
- Cycle 2: 50 mg/m2 IV once on day 1, then 325 mg/m2 IV once on day 2
- Cycles 3 to 7: 500 mg/m2 IV once on day 1
28-day cycles
References
- ECOG E1912: Shanafelt TD, Wang XV, Kay NE, Hanson CA, O'Brien S, Barrientos J, Jelinek DF, Braggio E, Leis JF, Zhang CC, Coutre SE, Barr PM, Cashen AF, Mato AR, Singh AK, Mullane MP, Little RF, Erba H, Stone RM, Litzow M, Tallman M. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019 Aug 1;381(5):432-443. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
- Update: Shanafelt TD, Wang XV, Hanson CA, Paietta EM, O'Brien S, Barrientos J, Jelinek DF, Braggio E, Leis JF, Zhang CC, Coutre SE, Barr PM, Cashen AF, Mato AR, Singh AK, Mullane MP, Little RF, Erba H, Stone RM, Litzow M, Tallman M, Kay NE. Long-term outcomes for ibrutinib-rituximab and chemoimmunotherapy in CLL: updated results of the E1912 trial. Blood. 2022 Jul 14;140(2):112-120. link to original article link to PMC article PubMed
Ibrutinib & Venetoclax
VI: Ventoclax & Ibrutinib
Regimen variant #1, 15 cycles
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Kater et al. 2022 (GLOW) | 2018-2019 | Phase 3 (E-switch-ooc) | GClb | Superior PFS PFS24: 84.4% vs 44.1% (HR 0.22, 95% CI 0.13-0.36) |
Note: Full reference details for GLOW will be added once NEJM Evidence is MEDLINE-indexed.
Eligibility criteria
- GLOW: At least 65 years old or 18 to 64 years old with a Cumulative Illness Rating Scale (CIRS) score greater than 6
Targeted therapy
- Ibrutinib (Imbruvica) 420 mg PO once per day
- Venetoclax (Venclexta) as follows:
- Cycle 4: 20 mg PO once per day on days 1 to 7, then 50 mg PO once per day on days 8 to 14, then 100 mg PO once per day on days 15 to 21, then 200 mg PO once per day on days 22 to 28
- Cycles 5 to 15: 400 mg PO once per day
28-day cycle for 15 cycles
Regimen variant #2, 24 cycles
Study | Dates of enrollment | Evidence |
---|---|---|
Jain et al. 2019 (MDACC 2015-0860) | 2016-2018 | Phase 2 |
Note: the starting dose and escalation schedule of venetoclax are not clearly specified in the manuscript; the authors were contacted for clarification and informed us that they used the FDA-recommended dosing, which is replicated here.
Targeted therapy
- Ibrutinib (Imbruvica) 420 mg PO once per day
- Venetoclax (Venclexta) as follows:
- Cycle 4: 20 mg PO once per day on days 1 to 7, then 50 mg PO once per day on days 8 to 14, then 100 mg PO once per day on days 15 to 21, then 200 mg PO once per day on days 22 to 28
- Cycle 5 onwards: 400 mg PO once per day
28-day cycle for up to 24 cycles
References
- MDACC 2015-0860: Jain N, Keating M, Thompson P, Ferrajoli A, Burger J, Borthakur G, Takahashi K, Estrov Z, Fowler N, Kadia T, Konopleva M, Alvarado Y, Yilmaz M, DiNardo C, Bose P, Ohanian M, Pemmaraju N, Jabbour E, Sasaki K, Kanagal-Shamanna R, Patel K, Jorgensen J, Garg N, Wang X, Sondermann K, Cruz N, Wei C, Ayala A, Plunkett W, Kantarjian H, Gandhi V, Wierda W. Ibrutinib and venetoclax for first-line treatment of CLL. N Engl J Med. 2019 May 30;380(22):2095-2103. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
- GLOW: link to original article contains dosing details in manuscript Clinical Trial Registry
Obinutuzumab monotherapy
Regimen variant #1, standard-dose (1000 mg)
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Byrd et al. 2015 (GAGE) | 2011-NR | Randomized Phase 2 (C) | Obinutuzumab; high-dose | Might have inferior ORR rate |
Targeted therapy
- Obinutuzumab (Gazyva) as follows:
- Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15
- Cycle 2 onwards: 1000 mg IV once on day 1
Supportive therapy
- Acetaminophen (Tylenol) 650 to 1000 mg PO once per infusion, 30 to 60 minutes prior to obinutuzumab*Antihistamine "such as" Diphenhydramine (Benadryl) 50 to 100 mg PO once per infusion, 30 to 60 minutes prior to obinutuzumab*Prednisolone (Millipred) (or equivalent) 100 mg IV once per infusion, prior to each of the first three doses of obinutuzumab, afterwards at the discretion of treating physician
21-day cycle up to 8 cycles
Regimen variant #2, high-dose (2000 mg)
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Byrd et al. 2015 (GAGE) | 2011-NR | Randomized Phase 2 (E-esc) | Obinutuzumab; standard-dose | Might have superior ORR rate |
Targeted therapy
- Obinutuzumab (Gazyva) as follows:
- Cycle 1, option A: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once on day 3, then 2000 mg IV once per day on days 8 & 15
- Cycle 1, option B: 100 mg IV once on day 1, then 1900 mg IV once on day 2, then 2000 mg IV once per day on days 8 & 15
- Cycle 2 onwards: 2000 mg IV once on day 1
Supportive therapy
- Acetaminophen (Tylenol) 650 to 1000 mg PO once per infusion, 30 to 60 minutes prior to obinutuzumab*Antihistamine "such as" Diphenhydramine (Benadryl) 50 to 100 mg PO once per infusion, 30 to 60 minutes prior to obinutuzumab*Prednisolone (Millipred) (or equivalent) 100 mg IV once per infusion, prior to each of the first three doses of obinutuzumab, afterwards at the discretion of treating physician
21-day cycle up to 8 cycles
References
- GAGE: Byrd JC, Flynn JM, Kipps TJ, Boxer M, Kolibaba KS, Carlile DJ, Fingerle-Rowson G, Tyson N, Hirata J, Sharman JP. Randomized phase 2 study of obinutuzumab monotherapy in symptomatic, previously untreated chronic lymphocytic leukemia. Blood. 2016 Jan 7;127(1):79-86. Epub 2015 Oct 15. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
Observation
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Dighiero et al. 1998 (FRE-CLL-85) | 1985-1990 | Phase 3 (C) | 1. Chlorambucil | Seems to have inferior PFS |
2. Chlorambucil & Prednisone | Inferior PFS | |||
Hoechstetter et al. 2017 (GCLLSG CLL1) | 1997-2004 | Phase 3 (C) | Fludarabine | Inferior PFS |
Herling et al. 2020 (GCLLSG CLL7) | 2005-2010 | Phase 3 (C) | FCR | Inferior EFS |
Langerbeins et al. 2022 (CLL12) | 2014-2019 | Phase 3 (C) | Ibrutinib | Inferior EFS |
Awaiting publication (GLLC-EARLY) | 2019-2024 | Phase 3 (C) | Acalabrutinib | TBD |
No active treatment, also known as "watchful waiting".
References
- 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
- GCLLSG CLL7: Herling CD, Cymbalista F, Groß-Ophoff-Müller C, Bahlo J, Robrecht S, Langerbeins P, Fink AM, Al-Sawaf O, Busch R, Porcher R, Cazin B, Dreyfus B, Ibach S, Leprêtre S, Fischer K, Kaiser F, Eichhorst B, Wentner CM, Hoechstetter MA, Döhner H, Leblond V, Kneba M, Letestu R, Böttcher S, Stilgenbauer S, Hallek M, Levy V. Early treatment with FCR versus watch and wait in patients with stage Binet A high-risk chronic lymphocytic leukemia (CLL): a randomized phase 3 trial. Leukemia. 2020 Aug;34(8):2038-2050. Epub 2020 Feb 18. link to original article link to PMC article PubMed Clinical Trial Registry
- 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 Clinical Trial Registry
- CLL12: Langerbeins P, Zhang C, Robrecht S, Cramer P, Fürstenau M, Al-Sawaf O, von Tresckow J, Fink AM, Kreuzer KA, Vehling-Kaiser U, Tausch E, Müller L, Eckart MJ, Schlag R, Freier W, Gaska T, Balser C, Reiser M, Stauch M, Wendtner CM, Fischer K, Stilgenbauer S, Eichhorst B, Hallek M. The CLL12 trial: ibrutinib vs placebo in treatment-naïve, early-stage chronic lymphocytic leukemia. Blood. 2022 Jan 13;139(2):177-187. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
- GLLC-EARLY: Clinical Trial Registry
Venetoclax & Obinutuzumab
VG: Venetoclax & Gazyva (Obinutuzumab)
VO: Venetoclax & Obinutuzumab
GVE: Gazyva (Obinutuzumab) & VEnetoclax
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Fischer et al. 2019 (GCLLSG CLL14) | 2015-2016 | Phase 3 (E-RT-switch-ooc) | Chlorambucil & Obinutuzumab | Superior PFS1 Median PFS: NYR vs 36.4 mo (HR 0.33, 95% CI 0.25-0.45) |
Awaiting publication (GCLLSG CLL16) | 2022-2026 | Phase 3 (C) | GAVE | TBD |
Awaiting publication (MAJIC) | 2022-2029 | Phase 3 (C) | Acalabrutinib & Venetoclax | TBD |
1Reported efficacy is based on the 2021 update.
Note: Obinutuzumab is only given for the first six cycles.
Targeted therapy
- Venetoclax (Venclexta) as follows:
- Cycle 1: 20 mg PO once per day on days 22 to 28
- Cycle 2: 50 mg PO once per day on days 1 to 7, then 100 mg PO once per day on days 8 to 14, then 200 mg PO once per day on days 15 to 21, then 400 mg PO once per day on days 22 to 28
- Cycles 3 to 12: 400 mg PO once per day
- Obinutuzumab (Gazyva) as follows:
- Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15
- Cycles 2 to 6: 1000 mg IV once on day 1
28-day cycle for 12 cycles
References
- GCLLSG CLL14: Fischer K, Al-Sawaf O, Bahlo J, Fink AM, Tandon M, Dixon M, Robrecht S, Warburton S, Humphrey K, Samoylova O, Liberati AM, Pinilla-Ibarz J, Opat S, Sivcheva L, Le Dû K, Fogliatto LM, Niemann CU, Weinkove R, Robinson S, Kipps TJ, Boettcher S, Tausch E, Humerickhouse R, Eichhorst B, Wendtner CM, Langerak AW, Kreuzer KA, Ritgen M, Goede V, Stilgenbauer S, Mobasher M, Hallek M. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019 Jun 6;380(23):2225-2236. Epub 2019 Jun 4. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
- Update: Al-Sawaf O, Zhang C, Tandon M, Sinha A, Fink AM, Robrecht S, Samoylova O, Liberati AM, Pinilla-Ibarz J, Opat S, Sivcheva L, Le Dû K, Fogliatto LM, Niemann CU, Weinkove R, Robinson S, Kipps TJ, Tausch E, Schary W, Ritgen M, Wendtner CM, Kreuzer KA, Eichhorst B, Stilgenbauer S, Hallek M, Fischer K. Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2020 Sep;21(9):1188-1200. link to original article PubMed
- Update: Al-Sawaf O, Zhang C, Lu T, Liao MZ, Panchal A, Robrecht S, Ching T, Tandon M, Fink AM, Tausch E, Schneider C, Ritgen M, Böttcher S, Kreuzer KA, Chyla B, Miles D, Wendtner CM, Eichhorst B, Stilgenbauer S, Jiang Y, Hallek M, Fischer K. Minimal Residual Disease Dynamics after Venetoclax-Obinutuzumab Treatment: Extended Off-Treatment Follow-up From the Randomized CLL14 Study. J Clin Oncol. 2021 Dec 20;39(36):4049-4060. Epub 2021 Oct 28. link to original article link to PMC article PubMed
- EVOLVE CLL/SLL: Clinical Trial Registry
- GCLLSG CLL16: Clinical Trial Registry
- MAJIC: Clinical Trial Registry
Zanubrutinib monotherapy
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Tam et al. 2022 (SEQUOIACLL) | 2017-2019 | Phase 3 (E-RT-switch-ooc) | BR | Superior PFS Median PFS: NYR vs NYR (HR 0.42, 95% CI 0.28-0.63) |
Biomarker eligibility criteria
- SEQUOIACLL: No 17p deletion
References
- SEQUOIACLL: Tam CS, Brown JR, Kahl BS, Ghia P, Giannopoulos K, Jurczak W, Šimkovič M, Shadman M, Österborg A, Laurenti L, Walker P, Opat S, Chan H, Ciepluch H, Greil R, Tani M, Trněný M, Brander DM, Flinn IW, Grosicki S, Verner E, Tedeschi A, Li J, Tian T, Zhou L, Marimpietri C, Paik JC, Cohen A, Huang J, Robak T, Hillmen P. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022 Aug;23(8):1031-1043. Epub 2022 Jul 7. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
First-line therapy, non-randomized or retrospective data
Alemtuzumab & Methylprednisolone
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Pettitt et al. 2012 (NCRI CLL206) | 2006-2008 | Phase 2 |
Biomarker eligibility criteria
- TP53 deletion
Targeted therapy
- Alemtuzumab (Campath) as follows:
- Cycle 1: 3 mg IV once on day 1, then 10 mg IV once on day 3, then 30 mg IV once per day on days 5, 8, 10, 12, 15, 17, 19, 22, 24, 26 (three times per week; increased as tolerated)
- Cycles 2 to 4: 30 mg SC once per day on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26 (three times per week)
Glucocorticoid therapy
- Methylprednisolone (Solumedrol) 1000 mg/m2/day (route not specified) on days 1 to 5
28-day cycle for 4 cycles
References
- NCRI CLL206: Pettitt AR, Jackson R, Carruthers S, Dodd J, Dodd S, Oates M, Johnson GG, Schuh A, Matutes E, Dearden CE, Catovsky D, Radford JA, Bloor A, Follows GA, Devereux S, Kruger A, Blundell J, Agrawal S, Allsup D, Proctor S, Heartin E, Oscier D, Hamblin TJ, Rawstron A, Hillmen P. Alemtuzumab in combination with methylprednisolone is a highly effective induction regimen for patients with chronic lymphocytic leukemia and deletion of TP53: final results of the National Cancer Research Institute CLL206 trial. J Clin Oncol. 2012 May 10;30(14):1647-55. Epub 2012 Apr 9. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
AVO
AVO: Acalabrutinib, Venetoclax, Obinutuzumab
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Davids et al. 2021 (DFCI 18-226) | 2018-2019 | Phase 2 |
Note: detailed venetoclax dosing was not available in the abstract.
Targeted therapy
- Acalabrutinib (Calquence) 100 mg PO twice per day
- Venetoclax (Venclexta)
- Obinutuzumab (Gazyva) as follows:
- Cycle 2: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15
- Cycles 3 to 7: 1000 mg IV once on day 1
28-day cycles
References
- DFCI 18-226: Davids MS, Lampson BL, Tyekucheva S, Wang Z, Lowney JC, Pazienza S, Montegaard J, Patterson V, Weinstock M, Crombie JL, Ng SY, Kim AI, Jacobson CA, LaCasce AS, Armand P, Arnason JE, Fisher DC, Brown JR. Acalabrutinib, venetoclax, and obinutuzumab as frontline treatment for chronic lymphocytic leukaemia: a single-arm, open-label, phase 2 study. Lancet Oncol. 2021 Oct;22(10):1391-1402. Epub 2021 Sep 14. link to original article PubMed Clinical Trial Registry
Bendamustine & Obinutuzumab
G-B: Gazyva (Obinutuzumab), Bendamustine
Regimen
Study | Dates of enrollment | Evidence | Efficacy |
---|---|---|---|
Brown et al. 2015 (GALTON) | 2011-NR | Phase 1b | ORR: 90% |
Sharman et al. 2020 (GIBB) | 2015-2016 | Phase 2 | CR rate: 50% |
Chemotherapy
- Bendamustine as follows:
- Cycle 1: 90 mg/m2 IV once per day on days 2 & 3
- Cycles 2 to 6: 90 mg/m2 IV once per day on days 1 & 2
Targeted therapy
- Obinutuzumab (Gazyva) as follows:
- Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15
- Cycles 2 to 6: 1000 mg IV once on day 1
Supportive therapy
- Acetaminophen (Tylenol) (dose not specified) once per infusion, prior to obinutuzumab*Antihistamine e.g. Diphenhydramine (Benadryl) once per infusion, prior to obinutuzumab*Highly potent corticosteroid (e.g. Prednisolone (Millipred) 100 mg IV) once, prior to first dose of obinutuzumab
- Allopurinol (Zyloprim) or Rasburicase (Elitek) recommended for tumor lysis syndrome prophylaxis
- PCP prophylaxis recommended
- Antiviral prophylaxis recommended
28-day cycle for 6 cycles
References
- GALTON: Brown JR, O'Brien S, Kingsley CD, Eradat H, Pagel JM, Lymp J, Hirata J, Kipps TJ. Obinutuzumab plus fludarabine/cyclophosphamide or bendamustine in the initial therapy of CLL patients: the phase 1b GALTON trial. Blood. 2015 Apr 30;125(18):2779-85. Epub 2015 Mar 13. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
- GIBB: Sharman JP, Burke JM, Yimer HA, Boxer MA, Babu S, Li J, Mun Y, Danilov AV; GIBB study investigators. Phase 2, multicenter GIBB study of obinutuzumab plus bendamustine in previously untreated patients with chronic lymphocytic leukemia. Leuk Lymphoma. 2021 Apr;62(4):791-800. Epub 2020 Nov 26. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
CFAR
CFAR: Cyclophosphamide, Fludarabine, Alemtuzumab, Rituximab
Regimen
Study | Dates of enrollment | Evidence | Efficacy |
---|---|---|---|
Parikh et al. 2011 | 2005-2008 | Phase 2 | ORR: 92% |
Note: the doses of cyclophosphamide and fludarabine are lower than in the r/r CFAR regimen.
Chemotherapy
- Cyclophosphamide (Cytoxan) 200 mg/m2 IV once per day on days 3 to 5
- Fludarabine (Fludara) 20 mg/m2 IV once per day on days 3 to 5
Targeted therapy
- Alemtuzumab (Campath) 30 mg IV once per day on days 1, 3, 5
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 2
- Cycles 2 to 6: 500 mg/m2 IV once on day 2
Supportive therapy
- Pegfilgrastim (Neulasta) 6 mg SC once on day 6
- Acetaminophen (Tylenol) 500 mg PO once per day on days 1, 2, 3, 5, prior to rituximab/Alemtuzumab (Campath)
- Diphenhydramine (Benadryl) 25 to 50 mg IV or PO once per day on days 1, 2, 3, 5, prior to rituximab/Alemtuzumab (Campath)
- Hydrocortisone (Cortef) 100 mg IV once per day on days 1, 2, 3, 5, prior to rituximab/Alemtuzumab (Campath)
- Cycle 1: Allopurinol (Zyloprim) 300 mg PO once per day for at least days 1 to 7
- Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg PO once per day during treatment and for at least 3 to 6 months after last course
- Antiviral prophylaxis with ONE of the following:
- Valacyclovir (Valtrex) 500 mg PO once per day during treatment and for at least 3 to 6 months after last course
- OR Valganciclovir (Valcyte) 450 mg PO twice per day during treatment and for at least 3 to 6 months after last course
28-day cycle for 6 cycles
References
- Parikh SA, Keating MJ, O'Brien S, Wang X, Ferrajoli A, Faderl S, Burger J, Koller C, Estrov Z, Badoux X, Lerner S, Wierda WG. Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, alemtuzumab, and rituximab for high-risk chronic lymphocytic leukemia. Blood. 2011 Aug 25;118(8):2062-8. Epub 2011 Jul 12. link to original article link to PMC article contains dosing details in manuscript PubMed
G-FC
G-FC: Gazyva (Obinutuzumab), Fludarabine, Cyclophosphamide
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Brown et al. 2015 (GALTON) | 2011-NR | Phase 1b |
Targeted therapy
- Obinutuzumab (Gazyva) as follows:
- Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15
- Cycles 2 to 6: 1000 mg IV once on day 1
Chemotherapy
- Fludarabine (Fludara) as follows:
- Cycle 1: 25 mg/m2 IV once per day on days 2 to 4
- Cycles 2 to 6: 25 mg/m2 IV once per day on days 1 to 3
- Cyclophosphamide (Cytoxan) as follows:
- Cycle 1: 250 mg/m2 IV once per day on days 2 to 4
- Cycles 2 to 6: 250 mg/m2 IV once per day on days 1 to 3
Supportive therapy
- Acetaminophen (Tylenol) (dose not specified) once per infusion, prior to obinutuzumab*Antihistamine e.g. Diphenhydramine (Benadryl) once per infusion, prior to obinutuzumab*Highly potent corticosteroid (e.g. Prednisolone (Millipred) 100 mg IV) once, prior to first dose of obinutuzumab
- Allopurinol (Zyloprim) or Rasburicase (Elitek) recommended for tumor lysis syndrome prophylaxis
- PCP prophylaxis recommended
- Antiviral prophylaxis recommended
28-day cycle for 6 cycles
References
- GALTON: Brown JR, O'Brien S, Kingsley CD, Eradat H, Pagel JM, Lymp J, Hirata J, Kipps TJ. Obinutuzumab plus fludarabine/cyclophosphamide or bendamustine in the initial therapy of CLL patients: the phase 1b GALTON trial. Blood. 2015 Apr 30;125(18):2779-85. Epub 2015 Mar 13. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
HDMP-R
HDMP-R: High Dose, MethylPrednisolone & Rituximab
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Castro et al. 2009 | NR | Phase 2 |
Glucocorticoid therapy
- Methylprednisolone (Solumedrol) 1000 mg/m2 IV over 90 minutes once per day on days 1 to 3
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 total divided over 2 days IV once on days 1 & 2, then 375 mg/m2 IV once per day on days 8, 15, 22
- Cycles 2 & 3: 375 mg/m2 IV once per day on days 1, 8, 15, 22
Supportive therapy
- Cimetidine (Tagamet) as premedication for methylprednisolone
- Acetaminophen (Tylenol) as premedication for rituximab
- Diphenhydramine (Benadryl) as premedication for rituximab
- Trimethoprim-Sulfamethoxazole (Bactrim DS) (or equivalent) prophylaxis during therapy and continuing for 2 months after treatment is complete
- Acyclovir (Zovirax) (or equivalent) prophylaxis during therapy and continuing for 2 months after treatment is complete
- Fluconazole (Diflucan) (or equivalent) prophylaxis during therapy and continuing for 2 months after treatment is complete
- Allopurinol (Zyloprim) 300 mg PO once per day, started 3 days before the start of therapy and continued during treatment
- Patients with glucose greater than 200 on days of treatment received regular insulin SC sliding scale on days of treatment
28-day cycle for 3 cycles
References
- Castro JE, James DF, Sandoval-Sus JD, Jain S, Bole J, Rassenti L, Kipps TJ. Rituximab in combination with high-dose methylprednisolone for the treatment of chronic lymphocytic leukemia. Leukemia. 2009 Oct;23(10):1779-89. Epub 2009 Aug 20. link to original article contains dosing details in abstract link to PMC article PubMed
Ibrutinib, Venetoclax, Obinutuzumab
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Rogers et al. 2020 (OSU-14266) | 2015-2017 | Phase 2 |
Targeted therapy
- Ibrutinib (Imbruvica) as follows:
- Cycle 2 onwards: 420 mg PO once per day
- Venetoclax (Venclexta) as follows:
- Cycle 3: 20 mg PO once per day on days 1 to 7, then 50 mg PO once per day on days 8 to 14, then 100 mg PO once per day on days 15 to 21, then 200 mg PO once per day on days 22 to 28
- Cycles 4 to 14: 400 mg PO once per day
- Obinutuzumab (Gazyva) as follows:
- Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15
- Cycles 2 to 8: 1000 mg IV once on day 1
28-day cycles
References
- OSU-14266: Rogers KA, Huang Y, Ruppert AS, Abruzzo LV, Andersen BL, Awan FT, Bhat SA, Dean A, Lucas M, Banks C, Grantier C, Heerema NA, Lozanski G, Maddocks KJ, Valentine TR, Weiss DM, Jones JA, Woyach JA, Byrd JC. Phase II Study of Combination Obinutuzumab, Ibrutinib, and Venetoclax in Treatment-Naïve and Relapsed or Refractory Chronic Lymphocytic Leukemia. J Clin Oncol. 2020 Nov 1;38(31):3626-3637. Epub 2020 Aug 14. link to original article link to PMC article contains dosing details in manuscript PubMed Clinical Trial Registry
iFCR
iFCR: ibrutinib, Fludarabine, Cyclophosphamide, Rituximab
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Davids et al. 2019 (DFCI 14-296) | 2014-10 to 2018-04 | Phase 2 |
Note: Patients with undetectable minimal residual disease in bone marrow after 2 years were required to discontinue treatment, after a protocol amendment.
Targeted therapy
- Ibrutinib (Imbruvica) as follows:
- Cycle 0 (pre-phase): 420 mg PO once per day on days 1 to 7
- Cycle 1 onwards: 420 mg PO once per day
- 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:
- Cycles 1 to 6: 25 mg/m2 IV once per day on days 1 to 3
- Cyclophosphamide (Cytoxan) as follows:
- Cycles 1 to 6: 250 mg/m2 IV once per day on days 1 to 3
28-day cycles (see note)
References
- DFCI 14-296: Davids MS, Brander DM, Kim HT, Tyekucheva S, Bsat J, Savell A, Hellman JM, Bazemore J, Francoeur K, Alencar A, Shune L, Omaira M, Jacobson CA, Armand P, Ng S, Crombie J, LaCasce AS, Arnason J, Hochberg EP, Takvorian RW, Abramson JS, Fisher DC, Brown JR; Blood Cancer Research Partnership of the Leukemia & Lymphoma Society. Ibrutinib plus fludarabine, cyclophosphamide, and rituximab as initial treatment for younger patients with chronic lymphocytic leukaemia: a single-arm, multicentre, phase 2 trial. Lancet Haematol. 2019 Aug;6(8):e419-e428. Epub 2019 Jun 14. link to original article link to PMC article contains dosing details in manuscript PubMed Clinical Trial Registry
Lenalidomide & Rituximab (R2)
Regimen variant #1
Study | Dates of enrollment | Evidence |
---|---|---|
James et al. 2014 (CRC014) | 2008-NR | Phase 2 |
Targeted therapy
- Lenalidomide (Revlimid) with escalation in the absence of grade 2 or higher toxicities as follows:
- Cycle 1: 2.5 mg PO once per day on days 1 to 7, then 5 mg PO once per day on days 8 to 21
- Cycle 2: 5 mg PO once per day on days 1 to 21
- Subsequent cycles: 10 mg PO once per day on days 1 to 21
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once per day on days 31 & 33
- Cycle 2: 375 mg/m2 IV once per day on days 1, 8, 15, 22
- Subsequent cycles: 375 mg/m2 IV once on day 1
Supportive therapy
- Allopurinol (Zyloprim) prior to starting lenalidomide and with any dose escalation
- Aspirin 81 mg PO once per day
35-day cycle for 1 cycle, then 28-day cycle for up to 6 cycles
Regimen variant #2
Study | Dates of enrollment | Evidence |
---|---|---|
Fowler et al. 2014 (MDACC 2008-0042) | 2008-2011 | Phase 2 |
Note: This combination was only studied in SLL (as opposed to CLL). Lenalidomide is dose-escalated to avoid tumor flare.
Targeted therapy
- Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21, then escalated by 5 mg/month to goal of 20 mg PO once per day
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
28-day cycle for up to 12 cycles
References
- CRC014: James DF, Werner L, Brown JR, Wierda WG, Barrientos JC, Castro JE, Greaves A, Johnson AJ, Rassenti LZ, Rai KR, Neuberg D, Kipps TJ. Lenalidomide and rituximab for the initial treatment of patients with chronic lymphocytic leukemia: a multicenter clinical-translational study from the Chronic Lymphocytic Leukemia Research Consortium. J Clin Oncol. 2014 Jul 1;32(19):2067-73. Epub 2014 May 27. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
- MDACC 2008-0042: Fowler NH, Davis RE, Rawal S, Nastoupil L, Hagemeister FB, McLaughlin P, Kwak LW, Romaguera JE, Fanale MA, Fayad LE, Westin JR, Shah J, Orlowski RZ, Wang M, Turturro F, Oki Y, Claret LC, Feng L, Baladandayuthapani V, Muzzafar T, Tsai KY, Samaniego F, Neelapu SS. Safety and activity of lenalidomide and rituximab in untreated indolent lymphoma: an open-label, phase 2 trial. Lancet Oncol. 2014 Nov;15(12):1311-8. Epub 2014 Oct 15. link to original article contains dosing details in abstract link to PMC article PubMed Clinical Trial Registry
O-FC
O-FC: Ofatumumab, Fludarabine, Cyclophosphamide
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Wierda et al. 2011 (407 Study) | 2007-NR | Phase 2 |
Targeted therapy
- Ofatumumab (Arzerra) as follows:
- Cycle 1: 300 mg IV once on day 1
- Cycles 2 to 6: 500 mg or 1000 mg IV once on day 1
Chemotherapy
- Fludarabine (Fludara) as follows:
- Cycle 1: 25 mg/m2 IV once per day on days 2 to 4
- Cycles 2 to 6: 25 mg/m2 IV once per day on days 1 to 3 (note: there was ambiguity in Wierda et al. 2011 about whether both fludarabine and cyclophosphamide are given three days per cycle, or whether fludarabine is given once per cycle and only cyclophosphamide is given three days per cycle)
- Cyclophosphamide (Cytoxan) as follows:
- Cycle 1: 250 mg/m2 IV once per day on days 2 to 4
- Cycle 2 to 6: 250 mg/m2 IV once per day on days 1 to 3
Supportive therapy
- Acetaminophen (Tylenol) 1000 mg PO once on day 1, prior to ofatumumab
- Cetirizine (Zyrtec) 10 mg (or equivalent) PO once on day 1, prior to ofatumumab
- Prednisolone (Millipred) 100 mg (or equivalent) PO once on day 1, prior to doses 1 & 2 of ofatumumab, then reduced by physician discretion for later doses
- May be used at physician discretion:
- Allopurinol (Zyloprim) for tumor lysis syndrome prophylaxis
- Antiviral prophylaxis
- PCP (Pneumocystis jiroveci pneumonia) prophylaxis
- Growth factor support
28-day cycle for 6 cycles
References
- 407 Study: Wierda WG, Kipps TJ, Dürig J, Griskevicius L, Stilgenbauer S, Mayer J, Smolej L, Hess G, Griniute R, Hernandez-Ilizaliturri FJ, Padmanabhan S, Gorczyca M, Chang CN, Chan G, Gupta I, Nielsen TG, Russell CA; 407 Study Investigators. Chemoimmunotherapy with O-FC in previously untreated patients with chronic lymphocytic leukemia. Blood. 2011 Jun 16;117(24):6450-8. Epub 2011 Apr 15. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
PCO
PCO: Pentostatin, Cyclophosphamide, Ofatumumab
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Shanafelt et al. 2013 (MC0983 arm 1) | 2010-2011 | Phase 2 |
Strati et al. 2016 (MC0983 arm 2) | 2011-2012 | Phase 2 |
Tedeschi et al. 2015 | 2011-2013 | Phase 2 |
Chemotherapy
- Pentostatin (Nipent) 2 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Targeted therapy
- Ofatumumab (Arzerra) as follows:
- Cycle 1: 300 mg IV once on day 1, then 1000 mg IV once on day 8
- Cycles 2 to 6: 1000 mg IV once on day 1
Supportive therapy
- Best described in Shanafelt et al. 2013:
- Methylprednisolone (Solumedrol) 80 mg IV once, prior to ofatumumab
- Cycle 1: Allopurinol (Zyloprim) 300 mg PO once per day on days 1 to 14
- Pegfilgrastim (Neulasta) 6 mg SC once on day 2
- Trimethoprim-Sulfamethoxazole (Bactrim DS) or similar for PJP prophylaxis for one year from start of treatment
- Valacyclovir (Valtrex) or similar for HSV prophylaxis for one year from start of treatment
21-day cycle for 6 cycles
Subsequent treatment
- MC0983 arm 2: Ofatumumab consolidation
References
- MC0983 arm 1: Shanafelt T, Lanasa MC, Call TG, Beaven AW, Leis JF, LaPlant B, Bowen D, Conte M, Jelinek DF, Hanson CA, Kay NE, Zent CS. Ofatumumab-based chemoimmunotherapy is effective and well tolerated in patients with previously untreated chronic lymphocytic leukemia (CLL). Cancer. 2013 Nov 1;119(21):3788-96. Epub 2013 Aug 6. Erratum in: Cancer. 2014 Mar 15;120(6):926. Dosage error in article text. link to original article link to PMC article contains dosing details in manuscript PubMed Clinical Trial Registry
- Tedeschi A, Rossi D, Motta M, Quaresmini G, Rossi M, Coscia M, Anastasia A, Rossini F, Cortelezzi A, Nador G, Scarfò L, Cairoli R, Frustaci AM, Dalceggio D, Picardi P, De Paoli L, Orlandi E, Rambaldi A, Massaia M, Gaidano G, Montillo M; Rete Ematologica Lombarda–CLL Workgroup. A phase II multi-center trial of pentostatin plus cyclophosphamide with ofatumumab in older previously untreated chronic lymphocytic leukemia patients. Haematologica. 2015 Dec;100(12):e501-4. Epub 2015 Aug 20. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
- MC0983 arm 2: Strati P, Lanasa M, Call TG, Leis JF, Brander DM, LaPlant BR, Pettinger AM, Ding W, Parikh SA, Hanson CA, Chanan-Khan AA, Bowen DA, Conte M, Kay NE, Shanafelt TD. Ofatumumab monotherapy as a consolidation strategy in patients with previously untreated chronic lymphocytic leukaemia: a phase 2 trial. Lancet Haematol. 2016 Sep;3(9):e407-14. Epub 2016 Aug 1. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
PCR
PCR: Pentostatin, Cyclophosphamide, Rituximab
Regimen variant #1, 2/600/100->375
Study | Dates of enrollment | Evidence |
---|---|---|
Kay et al. 2007 | 2002-2005 | Phase 2 |
Shanafelt et al. 2007 | NR | Phase 2 |
Chemotherapy
- Pentostatin (Nipent) 2 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 100 mg/m2 IV once on day 1, then 375 mg/m2 IV once per day on days 3 & 5
- Cycles 2 to 6: 375 mg/m2 IV once on day 1
Supportive therapy
- Note: see references for details, as they differ by paper.
- Filgrastim (Neupogen) once per day, starting on day 3 for up to 10 days or until ANC greater than 1000/μL for 2 straight days
- Cycle 1: Allopurinol (Zyloprim) 300 mg PO once per day on days 1 to 15
- Prophylactic Trimethoprim-Sulfamethoxazole (Bactrim DS) for 1 year
- Prophylactic Acyclovir (Zovirax) for 1 year
28-day cycle for 6 cycles
Regimen variant #2, 4/600/375
Study | Dates of enrollment | Evidence |
---|---|---|
Samaniego et al. 2015 (MDACC 2004-0818) | 2005-NR | Phase 2 |
Note: this regimen was specifically studied in SLL, not CLL.
Chemotherapy
- Pentostatin (Nipent) 4 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Targeted therapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
Supportive therapy
- Ondansetron (Zofran) 8 mg (route not specified) once on day 1, prior to chemotherapy
- Diphenhydramine (Benadryl) 25 mg (route not specified) once on day 1, prior to chemotherapy
- 500 ml of 5% dextrose/one-half normal saline before and after each pentostatin dose
- Filgrastim (Neupogen) at the discretion of the treating physician
- Cycle 1: Allopurinol (Zyloprim) 300 mg PO once per day on days 1 to 15
- Trimethoprim-Sulfamethoxazole (Bactrim DS) once per day three days per week during and for 1 month following therapy
- Acyclovir (Zovirax) 400 mg PO twice per day during and for 1 month following therapy
21-day cycle for 6 cycles
References
- Kay NE, Geyer SM, Call TG, Shanafelt TD, Zent CS, Jelinek DF, Tschumper R, Bone ND, Dewald GW, Lin TS, Heerema NA, Smith L, Grever MR, Byrd JC. Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia. Blood. 2007 Jan 15;109(2):405-11. Epub 2006 Sep 28. link to original article contains dosing details in abstract link to PMC article PubMed
- Shanafelt TD, Lin T, Geyer SM, Zent CS, Leung N, Kabat B, Bowen D, Grever MR, Byrd JC, Kay NE. Pentostatin, cyclophosphamide, and rituximab regimen in older patients with chronic lymphocytic leukemia. Cancer. 2007 Jun 1;109(11):2291-8. link to original article PubMed
- MDACC 2004-0818: Samaniego F, Hagemeister F, Romaguera JE, Fanale MA, Pro B, McLaughlin P, Rodriguez MA, Neelapu SS, Fayad L, Younes A, Feng L, Berkova Z, Khashab T, Sehgal L, Vega-Vasquez F, Kwak LW. Pentostatin, cyclophosphamide and rituximab for previously untreated advanced stage, low-grade B-cell lymphomas. Br J Haematol. 2015 Jun;169(6):814-23. Epub 2015 Mar 31. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
RCC
RCC: Rituximab, Cladribine, Cyclophosphamide
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Robak et al. 2018 (PALG CLL4) | 2009-2011 | Non-randomized part of phase 3b RCT |
Targeted therapy
Chemotherapy
28-day cycle for 6 cycles
Subsequent treatment
- Observation versus Rituximab maintenance
References
- PALG CLL4: Robak T, Błoński J, Skotnicki AB, Piotrowska M, Wróbel T, Rybka J, Kłoczko J, Bołkun Ł, Budziszewska BK, Walczak U, Uss A, Fidecka M, Smolewski P. Rituximab, cladribine, and cyclophosphamide (RCC) induction with rituximab maintenance in chronic lymphocytic leukemia: PALG - CLL4 (ML21283) trial. Eur J Haematol. 2018 May;100(5):465-474. Epub 2018 Mar 22. link to original article PubMed Clinical Trial Registry
Rituximab monotherapy
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Hainsworth et al. 2003 | 2000-2001 | Phase 2 |
Williams et al. 2016 (RESORT substudy) | 2003-2008 | Non-randomized part of phase 3 RCT |
Targeted therapy
- Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1, 8, 15, 22
- In Hainsworth et al. 2003, optional alternate initial dosing for patients with WBC count greater than 100 x 109/L: 100 mg IV once on day 1, with remainder of the 375 mg/m2 dosage given on day 2
Supportive therapy
- Acetaminophen (Tylenol) 650 mg PO once per day on days 1, 8, 15, 22; 30 minutes prior to rituximab
- Diphenhydramine (Benadryl) 50 mg PO or IV once per day on days 1, 8, 15, 22; 30 minutes prior to rituximab
- In Hainsworth et al. 2003, if WBC count greater than 50 x 109/L or massive lymphadenopathy: Allopurinol (Zyloprim) 300 mg PO once per day, starting 3 days before the first dose of rituximab
- In Hainsworth et al. 2003, one of the following:
- Cimetidine (Tagamet) 300 mg IV once per day on days 1, 8, 15, 22; 30 minutes prior to rituximab
- Ranitidine (Zantac) 50 mg IV once per day on days 1, 8, 15, 22; 30 minutes prior to rituximab
4-week course
Subsequent treatment
- Hainsworth et al. 2003, SD or better: Rituximab maintenance
- RESORT substudy, PR/CR: Indefinite rituximab versus salvage rituximab at time of progression
References
- Hainsworth JD, Litchy S, Barton JH, Houston GA, Hermann RC, Bradof JE, Greco FA; Minnie Pearl Cancer Research Network. Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol. 2003 May 1;21(9):1746-51. link to original article PubMed
- RESORT substudy: Williams ME, Hong F, Gascoyne RD, Wagner LI, Krauss JC, Habermann TM, Swinnen LJ, Schuster SJ, Peterson CG, Sborov MD, Martin SE, Weiss M, Ehmann WC, Horning SJ, Kahl BS; Eastern Cooperative Oncology Group. Rituximab extended schedule or retreatment trial for low tumour burden non-follicular indolent B-cell non-Hodgkin lymphomas: Eastern Cooperative Oncology Group Protocol E4402. Br J Haematol. 2016 Jun;173(6):867-75. Epub 2016 Mar 11. link to original article contains dosing details in abstract link to PMC article PubMed Clinical Trial Registry
Ruxolitinib monotherapy
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Jain et al. 2017 (MDACC 2013-0044) | 2014-2015 | Phase 2 |
Note: this was a trial focused on symptom control, not efficacy.
Targeted therapy
- Ruxolitinib (Jakafi) 10 mg PO twice per day
References
- MDACC 2013-0044: Jain P, Keating M, Renner S, Cleeland C, Xuelin H, Gonzalez GN, Harris D, Li P, Liu Z, Veletic I, Rozovski U, Jain N, Thompson P, Bose P, DiNardo C, Ferrajoli A, O'Brien S, Burger J, Wierda W, Verstovsek S, Kantarjian H, Estrov Z. Ruxolitinib for symptom control in patients with chronic lymphocytic leukaemia: a single-group, phase 2 trial. Lancet Haematol. 2017 Feb;4(2):e67-e74. Epub 2017 Jan 11. link to original article contains dosing details in abstract link to PMC article PubMed Clinical Trial Registry
Zanubrutinib & Obinutuzumab
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Tam et al. 2020 | 2016-NR | Phase 1b, >20 pts in this subgroup |
Targeted therapy
- Zanubrutinib (Brukinsa) 160 mg PO twice per day or 320 mg PO once per day
- Obinutuzumab (Gazyva) as follows:
- Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15
- Cycles 2 to 6: 1000 mg IV once on day 1
28-day cycles
References
- Tam CS, Quach H, Nicol A, Badoux X, Rose H, Prince HM, Leahy MF, Eek R, Wickham N, Patil SS, Huang J, Prathikanti R, Cohen A, Elstrom R, Reed W, Schneider J, Flinn IW. Zanubrutinib (BGB-3111) plus obinutuzumab in patients with chronic lymphocytic leukemia and follicular lymphoma. Blood Adv. 2020 Oct 13;4(19):4802-4811. link to original article link to PMC article contains dosing details in manuscript PubMed Clinical Trial Registry
Consolidation and/or maintenance after first-line therapy
Alemtuzumab monotherapy
Regimen variant #1, 6-week course
Study | Dates of enrollment | Evidence |
---|---|---|
Varghese et al. 2017 (NCRN CLL 207) | 2006-2010 | Phase 2 |
Preceding treatment
- Chemotherapy (details not specified)
Targeted therapy
- Alemtuzumab (Campath) 30 mg SC once per day on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26, 29, 31, 33, 36, 38, 40 (three times per week)
6-week course
Regimen variant #2, 12-week course
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Wendtner et al. 2004 (GCLLSG CLL4B) | NR | Phase 3 (E-esc) | Observation | Superior PFS1 |
1Reported efficacy is based on the 2009 update.
Note: this study closed early due to high rates of infections in the experimental arm.
Targeted therapy
- Alemtuzumab (Campath) as follows:
- Day 1: 3 mg SC once
- Day 2, if 3 mg dose is well tolerated: 10 mg SC once
- Day 3 onwards, if 10 mg dose is well tolerated: 30 mg SC once on day 3, then SC 3 times per week
12-week course
References
- GCLLSG CLL4B: Wendtner CM, Ritgen M, Schweighofer CD, Fingerle-Rowson G, Campe H, Jäger G, Eichhorst B, Busch R, Diem H, Engert A, Stilgenbauer S, Döhner H, Kneba M, Emmerich B, Hallek M; German CLL Study Group. Consolidation with alemtuzumab in patients with chronic lymphocytic leukemia (CLL) in first remission--experience on safety and efficacy within a randomized multicenter phase III trial of the German CLL Study Group (GCLLSG). Leukemia. 2004 Jun;18(6):1093-101. link to original article contains dosing details in manuscript PubMed
- Update: Schweighofer CD, Ritgen M, Eichhorst BF, Busch R, Abenhardt W, Kneba M, Hallek M, Wendtner CM. Consolidation with alemtuzumab improves progression-free survival in patients with chronic lymphocytic leukaemia (CLL) in first remission: long-term follow-up of a randomized phase III trial of the German CLL Study Group (GCLLSG). Br J Haematol. 2009 Jan;144(1):95-8. Epub 2008 Oct 30. link to original article PubMed
- NCRN CLL207: Varghese AM, Howard DR, Pocock C, Rawstron AC, Follows G, McCarthy H, Dearden C, Fegan C, Milligan D, Smith AF, Gregory W, Hillmen P; NCRI CLL Sub-Group. Eradication of minimal residual disease improves overall and progression-free survival in patients with chronic lymphocytic leukaemia, evidence from NCRN CLL207: a phase II trial assessing alemtuzumab consolidation. Br J Haematol. 2017 Feb;176(4):573-582. Epub 2016 Dec 29. link to original article contains dosing details in abstract PubMed
Lenalidomide monotherapy
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Fink et al. 2017 (GCLLSG CLLM1) | 2012-2016 | Phase 3 (E-esc) | Observation | Superior PFS Median PFS: NYR vs 13.3 mo (HR 0.17, 95% CI 0.07-0.38) |
Note that while the Clinical Trial Registry NCT record] reports dose increases beyond 15 mg PO once per day, the abstract states that 15 mg PO once per day was the "target dose".
Preceding treatment
- GCLLSG CLLM1: First-line chemoimmunotherapy
Targeted therapy
- Lenalidomide (Revlimid) as follows:
- Cycle 1: 5 mg PO once per day
- If tolerated, Cycles 2 to 6: 10 mg PO once per day
- If tolerated, Cycle 7 onwards: 15 mg PO once per day
28-day cycles
References
- GCLLSG CLLM1: Fink AM, Bahlo J, Robrecht S, Al-Sawaf O, Aldaoud A, Hebart H, Jentsch-Ullrich K, Dörfel S, Fischer K, Wendtner CM, Nösslinger T, Ghia P, Bosch F, Kater AP, Döhner H, Kneba M, Kreuzer KA, Tausch E, Stilgenbauer S, Ritgen M, Böttcher S, Eichhorst B, Hallek M. Lenalidomide maintenance after first-line therapy for high-risk chronic lymphocytic leukaemia (CLLM1): final results from a randomised, double-blind, phase 3 study. Lancet Haematol. 2017 Oct;4(10):e475-e486. Epub 2017 Sep 12. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
Observation
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Wendtner et al. 2004 (GCLLSG CLL4B) | NR | Phase 3 (C) | Alemtuzumab | Inferior PFS1 |
Hochster et al. 2009 (ECOG E1496) | NR | Phase 3 (C) | Rituximab | Inferior PFS |
Michallet et al. 2010 | 2001-2007 | Phase 3 (C) | 1. Cy/TBI, then auto HSCT 2. BEAM, then auto HSCT |
Inferior EFS |
Sutton et al. 2011 (Auto-LLC 2001) | 2001-2007 | Phase 3 (C) | Cy/TBI, then auto HSCT | Inferior EFS |
Foà et al. 2014 (ML21445) | 2008-2013 | Randomized Phase 2 (C) | Rituximab | Might have inferior PFS |
Greil et al. 2016 (AGMT CLL-8a) | 2010-2013 | Phase 3 (C) | Rituximab | Inferior PFS |
Fink et al. 2017 (GCLLSG CLLM1) | 2012-2016 | Phase 3 (C) | Lenalidomide | Inferior PFS |
Dartigeas et al. 2017 (CLL 2007 SA) | 2007-2014 | Phase 3 (C) | Rituximab | Inferior PFS |
1Reported efficacy for GCLLSG CLL4B is based on the 2009 update.
No further treatment; used as a comparator arm. GCLLSG CLL4B closed early due to high rates of infections in the experimental arm
Preceding treatment
- GCLLSG CLL4B: F x 6 versus FC x 6
- ECOG E1496: CVP
- Auto-LLC 2001: mini-CHOP x 3, then F x 3
- ML21445: Clb-R
- AGMT CLL-8a: Rituximab-containing chemoimmunotherapy
- GCLLSG CLLM1: First-line chemoimmunotherapy
- CLL 2007 SA: FCR x 4
References
- GCLLSG CLL4B: Wendtner CM, Ritgen M, Schweighofer CD, Fingerle-Rowson G, Campe H, Jäger G, Eichhorst B, Busch R, Diem H, Engert A, Stilgenbauer S, Döhner H, Kneba M, Emmerich B, Hallek M; German CLL Study Group. Consolidation with alemtuzumab in patients with chronic lymphocytic leukemia (CLL) in first remission--experience on safety and efficacy within a randomized multicenter phase III trial of the German CLL Study Group (GCLLSG). Leukemia. 2004 Jun;18(6):1093-101. link to original article PubMed
- Update: Schweighofer CD, Ritgen M, Eichhorst BF, Busch R, Abenhardt W, Kneba M, Hallek M, Wendtner CM. Consolidation with alemtuzumab improves progression-free survival in patients with chronic lymphocytic leukaemia (CLL) in first remission: long-term follow-up of a randomized phase III trial of the German CLL Study Group (GCLLSG). Br J Haematol. 2009 Jan;144(1):95-8. Epub 2008 Oct 30. link to original article PubMed
- 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 Clinical Trial Registry
- Michallet M, Dreger P, Sutton L, Brand R, Richards S, van Os M, Sobh M, Choquet S, Corront B, Dearden C, Gratwohl A, Herr W, Catovsky D, Hallek M, de Witte T, Niederwieser D, Leporrier M, Milligan D; EBMT Chronic Leukemia Working Party. Autologous hematopoietic stem cell transplantation in chronic lymphocytic leukemia: results of European intergroup randomized trial comparing autografting versus observation. Blood. 2011 Feb 3;117(5):1516-21. Epub 2010 Nov 24. link to original article PubMed
- 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 PubMed Clinical Trial Registry
- ML21445: Foà R, Del Giudice I, Cuneo A, Del Poeta G, Ciolli S, Di Raimondo F, Lauria F, Cencini E, Rigolin GM, Cortelezzi A, Nobile F, Callea V, Brugiatelli M, Massaia M, Molica S, Trentin L, Rizzi R, Specchia G, Di Serio F, Orsucci L, Ambrosetti A, Montillo M, Zinzani PL, Ferrara F, Morabito F, Mura MA, Soriani S, Peragine N, Tavolaro S, Bonina S, Marinelli M, De Propris MS, Starza ID, Piciocchi A, Alietti A, Runggaldier EJ, Gamba E, Mauro FR, Chiaretti S, Guarini A. Chlorambucil plus rituximab with or without maintenance rituximab as first-line treatment for elderly chronic lymphocytic leukemia patients. Am J Hematol. 2014 May;89(5):480-6. Epub 2014 Feb 18. link to original article contains dosing details in manuscript PubMed EudraCT 2008-001612-20
- AGMT CLL-8a: Greil R, Obrtlíková P, Smolej L, Kozák T, Steurer M, Andel J, Burgstaller S, Mikušková E, Gercheva L, Nösslinger T, Papajík T, Ladická M, Girschikofsky M, Hrubiško M, Jäger U, Fridrik M, Pecherstorfer M, Králiková E, Burcoveanu C, Spasov E, Petzer A, Mihaylov G, Raynov J, Oexle H, Zabernigg A, Flochová E, Palášthy S, Stehlíková O, Doubek M, Altenhofer P, Pleyer L, Melchardt T, Klingler A, Mayer J, Egle A. Rituximab maintenance versus observation alone in patients with chronic lymphocytic leukaemia who respond to first-line or second-line rituximab-containing chemoimmunotherapy: final results of the AGMT CLL-8a Mabtenance randomised trial. Lancet Haematol. 2016 Jul;3(7):e317-29. Epub 2016 Jun 16. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
- GCLLSG CLLM1: Fink AM, Bahlo J, Robrecht S, Al-Sawaf O, Aldaoud A, Hebart H, Jentsch-Ullrich K, Dörfel S, Fischer K, Wendtner CM, Nösslinger T, Ghia P, Bosch F, Kater AP, Döhner H, Kneba M, Kreuzer KA, Tausch E, Stilgenbauer S, Ritgen M, Böttcher S, Eichhorst B, Hallek M. Lenalidomide maintenance after first-line therapy for high-risk chronic lymphocytic leukaemia (CLLM1): final results from a randomised, double-blind, phase 3 study. Lancet Haematol. 2017 Oct;4(10):e475-e486. Epub 2017 Sep 12. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
- CLL 2007 SA: Dartigeas C, Van Den Neste E, Léger J, Maisonneuve H, Berthou C, Dilhuydy MS, De Guibert S, Leprêtre S, Béné MC, Nguyen-Khac F, Letestu R, Cymbalista F, Rodon P, Aurran-Schleinitz T, Vilque JP, Tournilhac O, Mahé B, Laribi K, Michallet AS, Delmer A, Feugier P, Lévy V, Delépine R, Colombat P, Leblond V; CLL 2007 SA investigators; FILO. Rituximab maintenance versus observation following abbreviated induction with chemoimmunotherapy in elderly patients with previously untreated chronic lymphocytic leukaemia (CLL 2007 SA): an open-label, randomised phase 3 study. Lancet Haematol. 2018 Feb;5(2):e82-e94. Epub 2017 Dec 20. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
Ofatumumab monotherapy
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Strati et al. 2016 (MC0983 arm 2) | 2011-2012 | Phase 2 |
Preceding treatment
- PCO x 6
References
- MC0983 arm 2: Strati P, Lanasa M, Call TG, Leis JF, Brander DM, LaPlant BR, Pettinger AM, Ding W, Parikh SA, Hanson CA, Chanan-Khan AA, Bowen DA, Conte M, Kay NE, Shanafelt TD. Ofatumumab monotherapy as a consolidation strategy in patients with previously untreated chronic lymphocytic leukaemia: a phase 2 trial. Lancet Haematol. 2016 Sep;3(9):e407-14. Epub 2016 Aug 1. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
Rituximab monotherapy
Regimen variant #1, 1 year
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Foà et al. 2014 (ML21445) | 2008-2013 | Randomized Phase 2 (E-esc) | Observation | Might have superior PFS |
Robak et al. 2018 (PALG CLL4) | 2009-2011 | Phase 3b (E-esc) | Observation | Seems to have superior PFS |
Note: dosing details for PALG CLL4 were not available in the abstract.
Regimen variant #2, 2 years, given q3mo
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Bosch et al. 2009 | 2005-2007 | Phase 2 | ||
Greil et al. 2016 (AGMT CLL-8a) | 2010-2013 | Phase 3 (E-esc) | Observation | Superior PFS Median PFS: 47 vs 35.5 mo (HR 0.50, 95% CI 0.33-0.75) |
Preceding treatment
- Bosch et al. 2009: R-FCM
- AGMT CLL-8a: Rituximab-containing chemoimmunotherapy
Targeted therapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
3-month cycle for 8 cycles (2 years)
Regimen variant #3, 2 years, given q8wk
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Dartigeas et al. 2017 (CLL 2007 SA) | 2007-2014 | Phase 3 (E-esc) | Observation | Superior PFS Median PFS: 59.3 vs 49 mo (HR 0.55, 95% CI 0.40-0.75) |
Note the higher dose used here.
Preceding treatment
- FCR x 4
Targeted therapy
- Rituximab (Rituxan) 500 mg/m2 IV once on day 1
8-week cycle for up to 13 cycles (2 years)
Regimen variant #4, 2 years, given q6mo
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Hainsworth et al. 2003 | 2000-2001 | Phase 2 | ||
Hochster et al. 2009 (ECOG E1496) | NR | Phase 3 (E-esc) | Observation | Superior PFS |
ECOG E1496 included patients with SLL, but they were grouped into an "other" non-follicular lymphoma category.
Targeted therapy
- Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1, 8, 15, 22
Supportive therapy
- Acetaminophen (Tylenol) 650 mg PO once per day on days 1, 8, 15, 22; 30 minutes prior to rituximab
- Diphenhydramine (Benadryl) 50 mg IV once per day on days 1, 8, 15, 22; 30 minutes prior to rituximab
- One of the following:
- Cimetidine (Tagamet) 300 mg IV once per day on days 1, 8, 15, 22; 30 minutes prior to rituximab
- Ranitidine (Zantac) 50 mg IV once per day on days 1, 8, 15, 22; 30 minutes prior to rituximab
6-month cycle for 4 cycles (2 years)
Regimen variant #5, indefinite 375 mg/m2 q3mo
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Williams et al. 2016 (RESORT substudy) | 2003-2008 | Phase 3 (C) | Rituximab salvage | Seems to have superior TTTF |
Intended for patients with SLL.
Preceding treatment
Regimen variant #6, indefinite 500 mg/m2 q3mo
Study | Dates of enrollment | Evidence |
---|---|---|
Foon et al. 2009 | 2003-2007 | Phase 2 |
Preceding treatment
- FCR-Lite x 6
References
- Hainsworth JD, Litchy S, Barton JH, Houston GA, Hermann RC, Bradof JE, Greco FA; Minnie Pearl Cancer Research Network. Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol. 2003 May 1;21(9):1746-51. link to original article PubMed
- Foon KA, Boyiadzis M, Land SR, Marks S, Raptis A, Pietragallo L, Meisner D, Laman A, Sulecki M, Butchko A, Schaefer P, Lenzer D, Tarhini A. Chemoimmunotherapy with low-dose fludarabine and cyclophosphamide and high dose rituximab in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009 Feb 1;27(4):498-503. Epub 2008 Dec 15. link to original article contains dosing details in manuscript PubMed
- Update: Foon KA, Mehta D, Lentzsch S, Kropf P, Marks S, Lenzner D, Pietragallo L, Sulecki M, Tarhini A, Boyiadzis M. Long-term results of chemoimmunotherapy with low-dose fludarabine, cyclophosphamide and high-dose rituximab as initial treatment for patients with chronic lymphocytic leukemia. Blood. 2012 Mar 29;119(13):3184-5. link to original article PubMed
- 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 Clinical Trial Registry
- 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
- 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
- ML21445: Foà R, Del Giudice I, Cuneo A, Del Poeta G, Ciolli S, Di Raimondo F, Lauria F, Cencini E, Rigolin GM, Cortelezzi A, Nobile F, Callea V, Brugiatelli M, Massaia M, Molica S, Trentin L, Rizzi R, Specchia G, Di Serio F, Orsucci L, Ambrosetti A, Montillo M, Zinzani PL, Ferrara F, Morabito F, Mura MA, Soriani S, Peragine N, Tavolaro S, Bonina S, Marinelli M, De Propris MS, Starza ID, Piciocchi A, Alietti A, Runggaldier EJ, Gamba E, Mauro FR, Chiaretti S, Guarini A. Chlorambucil plus rituximab with or without maintenance rituximab as first-line treatment for elderly chronic lymphocytic leukemia patients. Am J Hematol. 2014 May;89(5):480-6. Epub 2014 Feb 18. link to original article contains dosing details in manuscript PubMed EudraCT 2008-001612-20
- RESORT substudy: Williams ME, Hong F, Gascoyne RD, Wagner LI, Krauss JC, Habermann TM, Swinnen LJ, Schuster SJ, Peterson CG, Sborov MD, Martin SE, Weiss M, Ehmann WC, Horning SJ, Kahl BS; Eastern Cooperative Oncology Group. Rituximab extended schedule or retreatment trial for low tumour burden non-follicular indolent B-cell non-Hodgkin lymphomas: Eastern Cooperative Oncology Group Protocol E4402. Br J Haematol. 2016 Jun;173(6):867-75. Epub 2016 Mar 11. link to original article contains dosing details in abstract link to PMC article PubMed Clinical Trial Registry
- AGMT CLL-8a: Greil R, Obrtlíková P, Smolej L, Kozák T, Steurer M, Andel J, Burgstaller S, Mikušková E, Gercheva L, Nösslinger T, Papajík T, Ladická M, Girschikofsky M, Hrubiško M, Jäger U, Fridrik M, Pecherstorfer M, Králiková E, Burcoveanu C, Spasov E, Petzer A, Mihaylov G, Raynov J, Oexle H, Zabernigg A, Flochová E, Palášthy S, Stehlíková O, Doubek M, Altenhofer P, Pleyer L, Melchardt T, Klingler A, Mayer J, Egle A. Rituximab maintenance versus observation alone in patients with chronic lymphocytic leukaemia who respond to first-line or second-line rituximab-containing chemoimmunotherapy: final results of the AGMT CLL-8a Mabtenance randomised trial. Lancet Haematol. 2016 Jul;3(7):e317-29. Epub 2016 Jun 16. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
- CLL 2007 SA: Dartigeas C, Van Den Neste E, Léger J, Maisonneuve H, Berthou C, Dilhuydy MS, De Guibert S, Leprêtre S, Béné MC, Nguyen-Khac F, Letestu R, Cymbalista F, Rodon P, Aurran-Schleinitz T, Vilque JP, Tournilhac O, Mahé B, Laribi K, Michallet AS, Delmer A, Feugier P, Lévy V, Delépine R, Colombat P, Leblond V; CLL 2007 SA investigators; FILO. Rituximab maintenance versus observation following abbreviated induction with chemoimmunotherapy in elderly patients with previously untreated chronic lymphocytic leukaemia (CLL 2007 SA): an open-label, randomised phase 3 study. Lancet Haematol. 2018 Feb;5(2):e82-e94. Epub 2017 Dec 20. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
- PALG CLL4: Robak T, Błoński J, Skotnicki AB, Piotrowska M, Wróbel T, Rybka J, Kłoczko J, Bołkun Ł, Budziszewska BK, Walczak U, Uss A, Fidecka M, Smolewski P. Rituximab, cladribine, and cyclophosphamide (RCC) induction with rituximab maintenance in chronic lymphocytic leukemia: PALG - CLL4 (ML21283) trial. Eur J Haematol. 2018 May;100(5):465-474. Epub 2018 Mar 22. link to original article PubMed Clinical Trial Registry
Relapsed or refractory, randomized data
Acalabrutinib monotherapy
Regimen
FDA-recommended dose |
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Byrd et al. 2015 (ACE-CL-001 r/r) | 2014-NR | Phase 1/2 | ORR: 95% | |
Byrd et al. 2021 (ACE-CL-006) | 2015-2017 | Phase 3 (E-switch-ic) | Ibrutinib | Non-inferior PFS Median PFS: 38.4 vs 38.4 mo (HR 1.00, 95% CI 0.79-1.27) |
Ghia et al. 2020 (ASCEND) | 2017-2018 | Phase 3 (E-RT-switch-ooc) | Investigator's choice of: 1a. BR 1b. Idelalisib & Rituximab |
Superior PFS Median PFS: NYR vs 16.5 mo (HR 0.31, 95% CI 0.20-0.49) |
Biomarker eligibility criteria
- ACE-CL-006: del(17)(p13.1) or del(11)(q22.3)
Prior treatment criteria
- ACE-CL-006 & ASCEND: At least 1 prior systemic therapy
References
- ACE-CL-001 r/r: Byrd JC, Harrington B, O'Brien S, Jones JA, Schuh A, Devereux S, Chaves J, Wierda WG, Awan FT, Brown JR, Hillmen P, Stephens DM, Ghia P, Barrientos JC, Pagel JM, Woyach J, Johnson D, Huang J, Wang X, Kaptein A, Lannutti BJ, Covey T, Fardis M, McGreivy J, Hamdy A, Rothbaum W, Izumi R, Diacovo TG, Johnson AJ, Furman RR. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016 Jan 28;374(4):323-32. Epub 2015 Dec 7. link to original article link to PMC article contains dosing details in manuscript PubMed Clinical Trial Registry
- ASCEND: Ghia P, Pluta A, Wach M, Lysak D, Kozak T, Simkovic M, Kaplan P, Kraychok I, Illes A, de la Serna J, Dolan S, Campbell P, Musuraca G, Jacob A, Avery E, Lee JH, Liang W, Patel P, Quah C, Jurczak W. ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. J Clin Oncol. 2020 Sep 1;38(25):2849-2861. Epub 2020 May 27. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
- ACE-CL-006: Byrd JC, Hillmen P, Ghia P, Kater AP, Chanan-Khan A, Furman RR, O'Brien S, Yenerel MN, Illés A, Kay N, Garcia-Marco JA, Mato A, Pinilla-Ibarz J, Seymour JF, Lepretre S, Stilgenbauer S, Robak T, Rothbaum W, Izumi R, Hamdy A, Patel P, Higgins K, Sohoni S, Jurczak W. Acalabrutinib Versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia: Results of the First Randomized Phase III Trial. J Clin Oncol. 2021 Nov 1;39(31):3441-3452. Epub 2021 Jul 26. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
Bendamustine monotherapy
Regimen variant #1, 70 mg/m2
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Robak et al. 2016 (Aptevo 16201) | 2011-2013 | Randomized Phase 2 (C) | Bendamustine & Otlertuzumab | Seems to have inferior PFS |
Chemotherapy
- Bendamustine 70 mg/m2 IV over 30 minutes once per day on days 1 & 2
28-day cycle for 6 cycles
Regimen variant #2, 100 mg/m2
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Niederle et al. 2013 (WiSP RI05) | 2001-2006 | Phase 3 (E-switch-ic) | Fludarabine | Seems to have non-inferior PFS |
Regimen variant #3, 120 mg/m2
Study | Dates of enrollment | Evidence |
---|---|---|
Friedberg et al. 2008 | 2003-2005 | Phase 2 |
Kahl et al. 2010 (SDX-105-01 part 2) | 2005-2007 | Phase 3b |
Chemotherapy
- Bendamustine 120 mg/m2 IV once per day on days 1 & 2
21-day cycle for 6 to 8 (SDX-105-01 part 2) or up to 12 (Friedberg et al. 2008) cycles
References
- Friedberg JW, Cohen P, Chen L, Robinson KS, Forero-Torres A, La Casce AS, Fayad LE, Bessudo A, Camacho ES, Williams ME, van der Jagt RH, Oliver JW, Cheson BD. Bendamustine in patients with rituximab-refractory indolent and transformed non-Hodgkin's lymphoma: results from a phase II multicenter, single-agent study. J Clin Oncol. 2008 Jan 10;26(2):204-10. Erratum in: J Clin Oncol. 2008 Apr 10;26(11) 1911. link to original article contains dosing details in manuscript PubMed
- SDX-105-01 part 2: Kahl BS, Bartlett NL, Leonard JP, Chen L, Ganjoo K, Williams ME, Czuczman MS, Robinson KS, Joyce R, van der Jagt RH, Cheson BD. Bendamustine is effective therapy in patients with rituximab-refractory, indolent B-cell non-Hodgkin lymphoma: results from a multicenter study. Cancer. 2010 Jan 1;116(1):106-14. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
- Retrospective: Kolibaba KS, Sterchele JA, Joshi AD, Forsyth M, Alwon E, Beygi H, Kennealey GT. Demographics, treatment patterns, safety, and real-world effectiveness in patients aged 70 years and over with chronic lymphocytic leukemia receiving bendamustine with or without rituximab: a retrospective study. Ther Adv Hematol. 2013 Jun;4(3):157-71. link to PMC article PubMed
- WiSP RI05: Niederle N, Megdenberg D, Balleisen L, Heit W, Knauf W, Weiß J, Freier W, Hinke A, Ibach S, Eimermacher H. Bendamustine compared to fludarabine as second-line treatment in chronic lymphocytic leukemia. Ann Hematol. 2013 May;92(5):653-60. Epub 2013 Jan 23. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
- Aptevo 16201: Robak T, Hellmann A, Kloczko J, Loscertales J, Lech-Maranda E, Pagel JM, Mato A, Byrd JC, Awan FT, Hebart H, Garcia-Marco JA, Hill BT, Hallek M, Eisenfeld AJ, Stromatt SC, Jaeger U. Randomized phase 2 study of otlertuzumab and bendamustine versus bendamustine in patients with relapsed chronic lymphocytic leukaemia. Br J Haematol. 2017 Feb;176(4):618-628. Epub 2016 Dec 15. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
Bendamustine & Rituximab (BR)
BR: Bendamustine & Rituximab
R-B: Rituximab & Bendamustine
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Fischer et al. 2011 (GCLLSG CLL2M r/r) | 2006-2007 | Phase 2 | ||
Michallet et al. 2018 (MABLE) | 2010-2014 | Phase 3b (E-switch-ic) | R-Clb | Superior CR rate1 |
Chanan-Khan et al. 2015 (HELIOS) | 2012-2014 | Phase 3 (C) | BR & Ibrutinib | Inferior OS2 |
Zelenetz et al. 2017 (Tugela) | 2012-2014 | Phase 3 (C) | BR & Idelalisib | Inferior PFS |
Seymour et al. 2018 (MURANO) | 2014-03-31 to 2015-09-23 | Phase 3 (C) | Venetoclax & Rituximab | Inferior OS |
Ghia et al. 2020 (ASCEND) | 2017-2018 | Phase 3 (C) | Acalabrutinib | Inferior PFS |
Awaiting publication (BRUIN CLL-321) | 2021-2024 | Phase 3 (C) | Pirtobrutinib | TBD |
1Reported efficacy for MABLE is for 2L patients only.
2Reported efficacy for HELIOS is based on the 2020 update.
Prior treatment criteria
- ASCEND: At least 1 prior systemic therapy
Chemotherapy
- Bendamustine 70 mg/m2 IV once per day on days 1 & 2
- HELIOS gave 1st cycle on days 2 & 3
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 0
- HELIOS gave on day 1
- Cycles 2 to 6: 500 mg/m2 IV once on day 1
- Cycle 1: 375 mg/m2 IV once on day 0
28-day cycle for up to 6 cycles
References
- GCLLSG CLL2M r/r: Fischer K, Cramer P, Busch R, Stilgenbauer S, Bahlo J, Schweighofer CD, Böttcher S, Staib P, Kiehl M, Eckart MJ, Kranz G, Goede V, Elter T, Bühler A, Winkler D, Kneba M, Döhner H, Eichhorst BF, Hallek M, Wendtner CM; GCLLSG. Bendamustine combined with rituximab in patients with relapsed and/or refractory chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. 2011 Sep 10;29(26):3559-66. Epub 2011 Aug 15. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
- Retrospective: Kolibaba KS, Sterchele JA, Joshi AD, Forsyth M, Alwon E, Beygi H, Kennealey GT. Demographics, treatment patterns, safety, and real-world effectiveness in patients aged 70 years and over with chronic lymphocytic leukemia receiving bendamustine with or without rituximab: a retrospective study. Ther Adv Hematol. 2013 Jun;4(3):157-71. link to PMC article PubMed
- HELIOS: Chanan-Khan A, Cramer P, Demirkan F, Fraser G, Silva RS, Grosicki S, Pristupa A, Janssens A, Mayer J, Bartlett NL, Dilhuydy MS, Pylypenko H, Loscertales J, Avigdor A, Rule S, Villa D, Samoilova O, Panagiotidis P, Goy A, Mato A, Pavlovsky MA, Karlsson C, Mahler M, Salman M, Sun S, Phelps C, Balasubramanian S, Howes A, Hallek M; HELIOS investigators. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol. 2016 Feb;17(2):200-11. Epub 2015 Dec 5. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
- Update: Fraser G, Cramer P, Demirkan F, Silva RS, Grosicki S, Pristupa A, Janssens A, Mayer J, Bartlett NL, Dilhuydy MS, Pylypenko H, Loscertales J, Avigdor A, Rule S, Villa D, Samoilova O, Panagiotidis P, Goy A, Pavlovsky MA, Karlsson C, Hallek M, Mahler M, Salman M, Sun S, Phelps C, Balasubramanian S, Howes A, Chanan-Khan A. Updated results from the phase 3 HELIOS study of ibrutinib, bendamustine, and rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma. Leukemia. 2019 Apr;33(4):969-980. Epub 2018 Oct 12. link to original article link to PMC article PubMed
- Update: Fraser GAM, Chanan-Khan A, Demirkan F, Santucci Silva R, Grosicki S, Janssens A, Mayer J, Bartlett NL, Dilhuydy MS, Loscertales J, Avigdor A, Rule S, Samoilova O, Pavlovsky MA, Goy A, Mato A, Hallek M, Salman M, Tamegnon M, Sun S, Connor A, Nottage K, Schuier N, Balasubramanian S, Howes A, Cramer P. Final 5-year findings from the phase 3 HELIOS study of ibrutinib plus bendamustine and rituximab in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Leuk Lymphoma. 2020 Dec;61(13):3188-3197. Epub 2020 Aug 6. link to original article link to PMC article PubMed
- Tugela: Zelenetz AD, Barrientos JC, Brown JR, Coiffier B, Delgado J, Egyed M, Ghia P, Illés Á, Jurczak W, Marlton P, Montillo M, Morschhauser F, Pristupa AS, Robak T, Sharman JP, Simpson D, Smolej L, Tausch E, Adewoye AH, Dreiling LK, Kim Y, Stilgenbauer S, Hillmen P. Idelalisib or placebo in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia: interim results from a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2017 Mar;18(3):297-311. Epub 2017 Jan 28. link to original article link to PMC article contains dosing details in abstract PubMed Clinical Trial Registry
- MABLE: Michallet AS, Aktan M, Hiddemann W, Ilhan O, Johansson P, Laribi K, Meddeb B, Moreno C, Raposo J, Schuh A, Ünal A, Widenius T, Bernhardt A, Kellershohn K, Messeri D, Osborne S, Leblond V. Rituximab plus bendamustine or chlorambucil for chronic lymphocytic leukemia: primary analysis of the randomized, open-label MABLE study. Haematologica. 2018 Apr;103(4):698-706. Epub 2018 Feb 1. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
- MURANO: Seymour JF, Kipps TJ, Eichhorst B, Hillmen P, D'Rozario J, Assouline S, Owen C, Gerecitano J, Robak T, De la Serna J, Jaeger U, Cartron G, Montillo M, Humerickhouse R, Punnoose EA, Li Y, Boyer M, Humphrey K, Mobasher M, Kater AP. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018 Mar 22;378(12):1107-1120. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
- Update: Kater AP, Seymour JF, Hillmen P, Eichhorst B, Langerak AW, Owen C, Verdugo M, Wu J, Punnoose EA, Jiang Y, Wang J, Boyer M, Humphrey K, Mobasher M, Kipps TJ. Fixed duration of venetoclax-rituximab in relapsed/refractory chronic lymphocytic leukemia eradicates minimal residual disease and prolongs survival: post-treatment follow-up of the MURANO phase III study. J Clin Oncol. 2019 Feb 1;37(4):269-277. Epub 2018 Dec 3. link to original article PubMed
- Update: Kater AP, Wu JQ, Kipps T, Eichhorst B, Hillmen P, D'Rozario J, Assouline S, Owen C, Robak T, de la Serna J, Jaeger U, Cartron G, Montillo M, Dubois J, Eldering E, Mellink C, Van Der Kevie-Kersemaekers AM, Kim SY, Chyla B, Punnoose E, Bolen CR, Assaf ZJ, Jiang Y, Wang J, Lefebure M, Boyer M, Humphrey K, Seymour JF. Venetoclax Plus Rituximab in Relapsed Chronic Lymphocytic Leukemia: 4-Year Results and Evaluation of Impact of Genomic Complexity and Gene Mutations From the MURANO Phase III Study. J Clin Oncol. 2020 Dec 1;38(34):4042-4054. Epub 2020 Sep 28. link to original article link to PMC article PubMed
- Update: Seymour JF, Kipps TJ, Eichhorst BF, D'Rozario J, Owen CJ, Assouline S, Lamanna N, Robak T, de la Serna J, Jaeger U, Cartron G, Montillo M, Mellink C, Chyla B, Panchal A, Lu T, Wu JQ, Jiang Y, Lefebure M, Boyer M, Kater AP. Enduring undetectable MRD and updated outcomes in relapsed/refractory CLL after fixed-duration venetoclax-rituximab. Blood. 2022 Aug 25;140(8):839-850. link to original article link to PMC article PubMed
- ASCEND: Ghia P, Pluta A, Wach M, Lysak D, Kozak T, Simkovic M, Kaplan P, Kraychok I, Illes A, de la Serna J, Dolan S, Campbell P, Musuraca G, Jacob A, Avery E, Lee JH, Liang W, Patel P, Quah C, Jurczak W. ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. J Clin Oncol. 2020 Sep 1;38(25):2849-2861. Epub 2020 May 27. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
- BRUIN CLL-321: Clinical Trial Registry
Bendamustine & Rituximab (BR) & Ibrutinib
BR & Ibrutinib: Bendamustine, Rituximab, Ibrutinib
IBR: Ibrutinib, Bendamustine, Rituximab
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Brown et al. 2015 (PCYC-1108) | 2011-NR | Phase 2 | ||
Chanan-Khan et al. 2015 (HELIOS) | 2012-2014 | Phase 3 (E-RT-esc) | BR | Superior OS1 Median OS: NYR vs NYR (HR 0.61, 95% CI 0.455-0.82) |
1Reported efficacy for HELIOS is based on the 2020 update.
Note: PCYC-1108 also evaluated FCR-ibrutinib (non-randomized) but accrual to that arm was extremely low and it was prematurely discontinued.
Chemotherapy
- Bendamustine as follows:
- Cycles 1 to 6: 70 mg/m2 IV once per day on days 1 & 2
- HELIOS gave 1st cycle on days 2 & 3
- Cycles 1 to 6: 70 mg/m2 IV once per day on days 1 & 2
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 1
- PCYC-1108 gave the option of splitting the dose between days 1 & 2
- Cycles 2 to 6: 500 mg/m2 IV once on day 1
- Cycle 1: 375 mg/m2 IV once on day 1
- Ibrutinib (Imbruvica) 420 mg PO once per day
28-day cycles
References
- PCYC-1108: Brown JR, Barrientos JC, Barr PM, Flinn IW, Burger JA, Tran A, Clow F, James DF, Graef T, Friedberg JW, Rai K, O'Brien S. The Bruton tyrosine kinase inhibitor ibrutinib with chemoimmunotherapy in patients with chronic lymphocytic leukemia. Blood. 2015 May 7;125(19):2915-22. Epub 2015 Mar 9. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
- HELIOS: Chanan-Khan A, Cramer P, Demirkan F, Fraser G, Silva RS, Grosicki S, Pristupa A, Janssens A, Mayer J, Bartlett NL, Dilhuydy MS, Pylypenko H, Loscertales J, Avigdor A, Rule S, Villa D, Samoilova O, Panagiotidis P, Goy A, Mato A, Pavlovsky MA, Karlsson C, Mahler M, Salman M, Sun S, Phelps C, Balasubramanian S, Howes A, Hallek M; HELIOS investigators. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol. 2016 Feb;17(2):200-11. Epub 2015 Dec 5. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
- Update: Fraser G, Cramer P, Demirkan F, Silva RS, Grosicki S, Pristupa A, Janssens A, Mayer J, Bartlett NL, Dilhuydy MS, Pylypenko H, Loscertales J, Avigdor A, Rule S, Villa D, Samoilova O, Panagiotidis P, Goy A, Pavlovsky MA, Karlsson C, Hallek M, Mahler M, Salman M, Sun S, Phelps C, Balasubramanian S, Howes A, Chanan-Khan A. Updated results from the phase 3 HELIOS study of ibrutinib, bendamustine, and rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma. Leukemia. 2019 Apr;33(4):969-980. Epub 2018 Oct 12. link to original article link to PMC article PubMed
- Update: Fraser GAM, Chanan-Khan A, Demirkan F, Santucci Silva R, Grosicki S, Janssens A, Mayer J, Bartlett NL, Dilhuydy MS, Loscertales J, Avigdor A, Rule S, Samoilova O, Pavlovsky MA, Goy A, Mato A, Hallek M, Salman M, Tamegnon M, Sun S, Connor A, Nottage K, Schuier N, Balasubramanian S, Howes A, Cramer P. Final 5-year findings from the phase 3 HELIOS study of ibrutinib plus bendamustine and rituximab in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Leuk Lymphoma. 2020 Dec;61(13):3188-3197. Epub 2020 Aug 6. link to original article link to PMC article PubMed
Bendamustine & Rituximab (BR) & Idelalisib
BR & Idelalisib: Bendamustine, Rituximab, Idelalisib
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Zelenetz et al. 2017 (Tugela) | 2012-2014 | Phase 3 (E-esc) | BR | Superior PFS Median PFS: 20.8 vs 11.1 mo (HR 0.33, 95% CI 0.25-0.44) |
Chemotherapy
- Bendamustine as follows:
- Cycles 1 to 6: 70 mg/m2 IV once per day on days 1 & 2
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 0
- Cycles 2 to 6: 500 mg/m2 IV once on day 1
- Idelalisib (Zydelig) 150 mg PO twice per day
28-day cycles
References
- Tugela: Zelenetz AD, Barrientos JC, Brown JR, Coiffier B, Delgado J, Egyed M, Ghia P, Illés Á, Jurczak W, Marlton P, Montillo M, Morschhauser F, Pristupa AS, Robak T, Sharman JP, Simpson D, Smolej L, Tausch E, Adewoye AH, Dreiling LK, Kim Y, Stilgenbauer S, Hillmen P. Idelalisib or placebo in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia: interim results from a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2017 Mar;18(3):297-311. Epub 2017 Jan 28. link to original article contains dosing details in abstract link to PMC article PubMed Clinical Trial Registry
Duvelisib monotherapy
Regimen
FDA-recommended dose |
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Flinn et al. 2018 (DUO) | 2014-2015 | Phase 3 (E-RT-switch-ooc) | Ofatumumab | Superior PFS Median PFS: 13.3 vs 9.9 mo (HR 0.52) |
References
- DUO: Flinn IW, Hillmen P, Montillo M, Nagy Z, Illés Á, Etienne G, Delgado J, Kuss BJ, Tam CS, Gasztonyi Z, Offner F, Lunin S, Bosch F, Davids MS, Lamanna N, Jaeger U, Ghia P, Cymbalista F, Portell CA, Skarbnik AP, Cashen AF, Weaver DT, Kelly VM, Turnbull B, Stilgenbauer S. The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL. Blood. 2018 Dec 6;132(23):2446-2455. link to original article link to PMC article contains dosing details in manuscript PubMed Clinical Trial Registry
FCR
FCR: Fludarabine, Cyclophosphamide, Rituximab
R-FC: Rituximab, Fludarabine, Cyclophosphamide
Regimen variant #1
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Awan et al. 2014 (LUCID) | 2006-NR | Phase 3 (C) | FCR+L | Did not meet primary endpoint of CR rate |
Chemotherapy
- Fludarabine (Fludara) as follows:
- Cycle 1: 25 mg/m2 IV over at least 10 to 30 minutes once per day on days 2 to 4
- Cycles 2 to 6: 25 mg/m2 IV over at least 10 to 30 minutes once per day on days 1 to 3
- Cyclophosphamide (Cytoxan) as follows:
- Cycle 1: 250 mg/m2 IV over at least 10 to 30 minutes once per day on days 2 to 4
- Cycles 2 to 6: 250 mg/m2 IV over at least 10 to 30 minutes once per day on days 1 to 3
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 50 mg/m2 IV over 4 hours once on day 1, then 450 mg/m2 IV once on day 3
- Cycles 2 to 6: 500 mg/m2 IV once on day 1
Supportive therapy
- Cotrimoxazole or an equivalent
- Acyclovir (Zovirax) 400 mg PO twice per day or an equivalent
28-day cycle for 6 cycles
Regimen variant #2
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Robak et al. 2010 (REACH) | 2003-2007 | Phase 3 (E-RT-esc) | FC | Superior PFS Median PFS: 30.6 vs 20.6 mo (HR 0.65) |
Chemotherapy
- Fludarabine (Fludara) as follows:
- Cycle 1: 25 mg/m2 IV once per day on days 2 to 4
- Cycles 2 to 6: 25 mg/m2 IV once per day on days 1 to 3
- Cyclophosphamide (Cytoxan) as follows:
- Cycle 1: 250 mg/m2 IV once per day on days 2 to 4
- Cycles 2 to 6: 250 mg/m2 IV once per day on days 1 to 3
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
Supportive therapy
- Note: varied according to reference.
- Diphenhydramine (Benadryl) 25 mg IV once on day 1; 30 minutes prior to rituximab
- Acetaminophen (Tylenol) 650 mg PO once on day 1; 30 minutes prior to rituximab
- Allopurinol (Zyloprim) as follows:
- Cycle 1: 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
Regimen variant #3
Study | Dates of enrollment | Evidence |
---|---|---|
Wierda et al. 2005 | 1999-2001 | Phase 2 |
Chemotherapy
- Fludarabine (Fludara) as follows:
- Cycle 1: 25 mg/m2 IV once per day on days 2 to 4
- Cycles 2 to 6: 25 mg/m2 IV once per day on days 1 to 3
- Cyclophosphamide (Cytoxan) as follows:
- Cycle 1: 250 mg/m2 IV once per day on days 2 to 4
- Cycles 2 to 6: 250 mg/m2 IV once per day on days 1 to 3
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
Supportive therapy
- Diphenhydramine (Benadryl) 25 to 50 mg PO once on day 1, prior to rituximab
- Acetaminophen (Tylenol) 650 mg PO once on day 1, prior to rituximab
- Ondansetron (Zofran) 24 mg IV once, prior to chemotherapy
28-day cycle for up to 6 cycles
Regimen variant #4
Study | Dates of enrollment | Evidence |
---|---|---|
Tam et al. 2006 | 2000-2005 | Phase 2 |
Chemotherapy
- Fludarabine (Fludara) 25 mg/m2 IV over 15 to 30 minutes once per day on days 1 to 3
- Cyclophosphamide (Cytoxan) 250 mg/m2 IV over 15 to 30 minutes once per day on days 1 to 3
Targeted therapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
28-day cycle for up to 6 cycles or "attainment of maximum response"
References
- Wierda W, O'Brien S, Wen S, Faderl S, Garcia-Manero G, Thomas D, Do KA, Cortes J, Koller C, Beran M, Ferrajoli A, Giles F, Lerner S, Albitar M, Kantarjian H, Keating M. Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. J Clin Oncol. 2005 Jun 20;23(18):4070-8. Epub 2005 Mar 14. link to original article contains dosing details in manuscript PubMed
- Update: Badoux XC, Keating MJ, Wang X, O'Brien SM, Ferrajoli A, Faderl S, Burger J, Koller C, Lerner S, Kantarjian H, Wierda WG. Fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy is highly effective treatment for relapsed patients with CLL. Blood. 2011 Mar 17;117(11):3016-24. Epub 2011 Jan 18. link to original article link to PMC article PubMed
- Tam CS, Wolf M, Prince HM, Januszewicz EH, Westerman D, Lin KI, Carney D, Seymour JF. Fludarabine, cyclophosphamide, and rituximab for the treatment of patients with chronic lymphocytic leukemia or indolent non-Hodgkin lymphoma. Cancer. 2006 Jun 1;106(11):2412-20. link to original article contains dosing details in manuscript PubMed
- 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 manuscript PubMed content property of HemOnc.org Clinical Trial Registry
- LUCID: Awan FT, Hillmen P, Hellmann A, Robak T, Hughes SG, Trone D, Shannon M, Flinn IW, Byrd JC; LUCID trial investigators. A randomized, open-label, multicentre, phase 2/3 study to evaluate the safety and efficacy of lumiliximab in combination with fludarabine, cyclophosphamide and rituximab versus fludarabine, cyclophosphamide and rituximab alone in subjects with relapsed chronic lymphocytic leukaemia. Br J Haematol. 2014 Nov;167(4):466-77. Epub 2014 Aug 8. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
Fludarabine monotherapy
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Johnson et al. 1996 | 1990-1992 | Phase 3 (E-de-esc) | CAP | Seems to have superior ORR |
Niederle et al. 2013 (WiSP RI05) | 2001-2006 | Phase 3 (C) | Bendamustine | Seems to have non-inferior PFS |
Note: this is an experimental arm that did not meet its primary endpoint; included here because it was eventually used to establish this regimen as a standard comparator.
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
References
- Johnson S, Smith AG, Löffler H, Osby E, Juliusson G, Emmerich B, Wyld PJ, Hiddemann W; FRE-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
- WiSP RI05: Niederle N, Megdenberg D, Balleisen L, Heit W, Knauf W, Weiß J, Freier W, Hinke A, Ibach S, Eimermacher H. Bendamustine compared to fludarabine as second-line treatment in chronic lymphocytic leukemia. Ann Hematol. 2013 May;92(5):653-60. Epub 2013 Jan 23. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
Ibrutinib monotherapy
Regimen
FDA-recommended dose |
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Byrd et al. 2013 (PCYC-1102 relapsed) | 2010-2011 | Phase 2 (RT) | ||
Farooqui et al. 2014 (NHLBI 12-H-0035) | 2011-2014 | Phase 2, <20 pts | ||
Byrd et al. 2014 (RESONATE) | 2012-2013 | Phase 3 (E-RT-switch-ooc) | Ofatumumab | Superior PFS1 Median PFS: 44.1 vs 8.1 mo (HR 0.15, 95% CI 0.11-0.20) |
O'Brien et al. 2016 (RESONATE-17) | 2013 | Phase 2 | ||
Huang et al. 2018 (CR102604) | 2013-2015 | Phase 3 (E-switch-ooc) | Rituximab | Superior OS OS24: 79.8% vs 57.6% (HR 0.45, 95% CI 0.22-0.90) |
Sharman et al. 2021 (GENUINE) | 2015-2016 | Phase 3 (C) | Ibrutinib & Ublituximab | Seems to have inferior ORR |
Byrd et al. 2021 (ACE-CL-006) | 2015-2017 | Phase 3 (C) | Acalabrutinib | Non-inferior PFS |
Hillmen et al. 2022 (ALPINE) | 2018-2020 | Phase 3 (C) | Zanubrutinib | Inferior PFS2 |
1Reported efficacy for RESONATE is based on the second 2019 update.
2Reported efficacy for ALPINE is based on the 2022 update.
Note: Both 420 mg and 840 mg doses were investigated in PCYC-1102: "the similar response in the two dose groups provide support for the use of the 420-mg dose of ibrutinib for relapsed CLL." The others used the 420 mg dose.
Biomarker eligibility criteria
- RESONATE-17: 17p deletion
- GENUINE: 17p deletion, 11q deletion, or TP53 mutation
- ACE-CL-006: del(17)(p13.1) or del(11)(q22.3)
Prior treatment criteria
- ACE-CL-006 & ALPINE: At least 1 prior systemic therapy
References
- PCYC-1102 relapsed: Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, Grant B, Sharman JP, Coleman M, Wierda WG, Jones JA, Zhao W, Heerema NA, Johnson AJ, Sukbuntherng J, Chang BY, Clow F, Hedrick E, Buggy JJ, James DF, O'Brien S. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013 Jul 4;369(1):32-42. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
- Update: Byrd JC, Furman RR, Coutre SE, Burger JA, Blum KA, Coleman M, Wierda WG, Jones JA, Zhao W, Heerema NA, Johnson AJ, Shaw Y, Bilotti E, Zhou C, James DF, O'Brien S. Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015 Apr 16;125(16):2497-506. Epub 2015 Feb 19. link to original article link to PMC article PubMed
- Update: O'Brien S, Furman RR, Coutre S, Flinn IW, Burger JA, Blum K, Sharman J, Wierda W, Jones J, Zhao W, Heerema NA, Johnson AJ, Luan Y, James DF, Chu AD, Byrd JC. Single-agent ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. Blood. 2018 Apr 26;131(17):1910-1919. Epub 2018 Feb 2. link to original article link to PMC article PubMed
- Update: Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum K, Sharman JP, Wierda W, Zhao W, Heerema NA, Luan Y, Liu EA, Dean JP, O'Brien S. Ibrutinib Treatment for First-Line and Relapsed/Refractory Chronic Lymphocytic Leukemia: Final Analysis of the Pivotal Phase Ib/II PCYC-1102 Study. Clin Cancer Res. 2020 Aug 1;26(15):3918-3927. Epub 2020 Mar 24. link to original article link to PMC article PubMed
- RESONATE: Byrd JC, Brown JR, O'Brien S, Barrientos JC, Kay NE, Reddy NM, Coutre S, Tam CS, Mulligan SP, Jaeger U, Devereux S, Barr PM, Furman RR, Kipps TJ, Cymbalista F, Pocock C, Thornton P, Caligaris-Cappio F, Robak T, Delgado J, Schuster SJ, Montillo M, Schuh A, de Vos S, Gill D, Bloor A, Dearden C, Moreno C, Jones JJ, Chu AD, Fardis M, McGreivy J, Clow F, James DF, Hillmen P; the RESONATE Investigators. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014 Jul 17;371(3):213-23. Epub 2014 May 31. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
- Update: Brown JR, Hillmen P, O'Brien S, Barrientos JC, Reddy NM, Coutre SE, Tam CS, Mulligan SP, Jaeger U, Barr PM, Furman RR, Kipps TJ, Cymbalista F, Thornton P, Caligaris-Cappio F, Delgado J, Montillo M, De Vos S, Moreno C, Pagel JM, Munir T, Burger JA, Chung D, Lin J, Gau L, Chang B, Cole G, Hsu E, James DF, Byrd JC. Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL. Leukemia. 2018 Jan;32(1):83-91. Epub 2017 Jun 8. link to original article link to PMC article PubMed
- Update: Byrd JC, Hillmen P, O'Brien S, Barrientos JC, Reddy NM, Coutre S, Tam CS, Mulligan SP, Jaeger U, Barr PM, Furman RR, Kipps TJ, Thornton P, Moreno C, Montillo M, Pagel JM, Burger JA, Woyach JA, Dai S, Vezan R, James DF, Brown JR. Long-term follow-up of the RESONATE phase 3 trial of ibrutinib vs ofatumumab. Blood. 2019 May 9;133(19):2031-2042. Epub 2019 Mar 6. link to original article link to PMC article PubMed
- Update: Munir T, Brown JR, O'Brien S, Barrientos JC, Barr PM, Reddy NM, Coutre S, Tam CS, Mulligan SP, Jaeger U, Kipps TJ, Moreno C, Montillo M, Burger JA, Byrd JC, Hillmen P, Dai S, Szoke A, Dean JP, Woyach JA. Final analysis from RESONATE: Up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma. Am J Hematol. 2019 Dec;94(12):1353-1363. Epub 2019 Oct 13. link to original article link to PMC article PubMed
- NHLBI 12-H-0035: Farooqui MZ, Valdez J, Martyr S, Aue G, Saba N, Niemann CU, Herman SE, Tian X, Marti G, Soto S, Hughes TE, Jones J, Lipsky A, Pittaluga S, Stetler-Stevenson M, Yuan C, Lee YS, Pedersen LB, Geisler CH, Calvo KR, Arthur DC, Maric I, Childs R, Young NS, Wiestner A. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol. 2015 Feb;16(2):169-76. Epub 2014 Dec 31. link to original article contains dosing details in abstract link to PMC article PubMed Clinical Trial Registry
- RESONATE-17: O'Brien S, Jones JA, Coutre SE, Mato AR, Hillmen P, Tam C, Österborg A, Siddiqi T, Thirman MJ, Furman RR, Ilhan O, Keating MJ, Call TG, Brown JR, Stevens-Brogan M, Li Y, Clow F, James DF, Chu AD, Hallek M, Stilgenbauer S. Ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia with 17p deletion (RESONATE-17): a phase 2, open-label, multicentre study. Lancet Oncol. 2016 Oct;17(10):1409-1418. Epub 2016 Sep 13. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
- Retrospective: Ryan CE, Sahaf B, Logan AC, O'Brien S, Byrd JC, Hillmen P, Brown JR, Dyer MJ, Mato AR, Keating MJ, Jaglowski S, Clow F, Rezvani AR, Styles L, Coutre SE, Miklos DB. Ibrutinib efficacy and tolerability in patients with relapsed chronic lymphocytic leukemia following allogeneic HCT. Blood. 2016 Dec 22;128(25):2899-2908. link to original article link to PMC article PubMed
- CR102604: Huang X, Qiu L, Jin J, Zhou D, Chen X, Hou M, Hu J, Hu Y, Ke X, Li J, Liang Y, Liu T, Lv Y, Ren H, Sun A, Wang J, Zhao C, Salman M, Sun S, Howes A, Wang J, Wu P, Li J. Ibrutinib versus rituximab in relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma: a randomized, open-label phase 3 study. Cancer Med. 2018 Apr;7(4):1043-1055. Epub 2018 Mar 13. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
- GENUINE: Sharman JP, Brander DM, Mato AR, Ghosh N, Schuster SJ, Kambhampati S, Burke JM, Lansigan F, Schreeder MT, Lunin SD, Zweibach A, Shtivelband M, Travis PM, Chandler JC, Kolibaba KS, Sportelli P, Miskin HP, Weiss MS, Flinn IW. Ublituximab plus ibrutinib versus ibrutinib alone for patients with relapsed or refractory high-risk chronic lymphocytic leukaemia (GENUINE): a phase 3, multicentre, open-label, randomised trial. Lancet Haematol. 2021 Apr;8(4):e254-e266. Epub 2021 Feb 22. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
- ACE-CL-006: Byrd JC, Hillmen P, Ghia P, Kater AP, Chanan-Khan A, Furman RR, O'Brien S, Yenerel MN, Illés A, Kay N, Garcia-Marco JA, Mato A, Pinilla-Ibarz J, Seymour JF, Lepretre S, Stilgenbauer S, Robak T, Rothbaum W, Izumi R, Hamdy A, Patel P, Higgins K, Sohoni S, Jurczak W. Acalabrutinib Versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia: Results of the First Randomized Phase III Trial. J Clin Oncol. 2021 Nov 1;39(31):3441-3452. Epub 2021 Jul 26. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
- ALPINE: Hillmen P, Eichhorst B, Brown JR, Lamanna N, O'Brien SM, Tam CS, Qiu L, Kazmierczak M, Zhou K, Šimkovič M, Mayer J, Gillespie-Twardy A, Shadman M, Ferrajoli A, Ganly PS, Weinkove R, Grosicki S, Mital A, Robak T, Österborg A, Yimer HA, Salmi T, Ji M, Yecies J, Idoine A, Wu K, Huang J, Jurczak W. Zanubrutinib Versus Ibrutinib in Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma: Interim Analysis of a Randomized Phase III Trial. J Clin Oncol. 2023 Feb 10;41(5):1035-1045. Epub 2022 Nov 17. link to original article link to PMC article PubMed Clinical Trial Registry
- Update: Brown JR, Eichhorst B, Hillmen P, Jurczak W, Kaźmierczak M, Lamanna N, O'Brien SM, Tam CS, Qiu L, Zhou K, Simkovic M, Mayer J, Gillespie-Twardy A, Ferrajoli A, Ganly PS, Weinkove R, Grosicki S, Mital A, Robak T, Osterborg A, Yimer HA, Salmi T, Wang MD, Fu L, Li J, Wu K, Cohen A, Shadman M. Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. N Engl J Med. 2023 Jan 26;388(4):319-332. Epub 2022 Dec 13. link to original article PubMed
Idelalisib & Ofatumumab
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Jones et al. 2017 (GS-US-312-0119) | 2012-2014 | Phase 3 (E-esc) | Ofatumumab | Superior PFS Median PFS: 16.3 vs 8 mo (HR 0.27, 95% CI 0.19-0.39) |
Targeted therapy
- Idelalisib (Zydelig) 150 mg PO twice per day
- Ofatumumab (Arzerra) as follows:
- Cycle 1: 300 mg IV once on day 1, then 1000 mg IV once per day on days 8, 15, 22
- Cycle 2: 1000 mg IV once per day on days 1, 8, 15, 22
- Cycles 3 to 6: 1000 mg IV once on day 1
28-day cycle for 6 cycles
References
- GS-US-312-0119: Jones JA, Robak T, Brown JR, Awan FT, Badoux X, Coutre S, Loscertales J, Taylor K, Vandenberghe E, Wach M, Wagner-Johnston N, Ysebaert L, Dreiling L, Dubowy R, Xing G, Flinn IW, Owen C. Efficacy and safety of idelalisib in combination with ofatumumab for previously treated chronic lymphocytic leukaemia: an open-label, randomised phase 3 trial. Lancet Haematol. 2017 Mar;4(3):e114-e126. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
Idelalisib & Rituximab
IdelaR: Idelalisib & Rituximab
Regimen variant #1, finite duration
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Furman et al. 2014 (GS-US-312-0116) | 2012-2013 | Phase 3 (E-RT-esc) | Rituximab | Superior PFS PFS6: 93% vs 46% (aHR 0.15, 95% CI 0.08-0.28) |
Note: Upon progression, idelalisib can be increased to 300 mg PO twice per day.
Targeted therapy
- Idelalisib (Zydelig) 150 mg PO twice per day
- Rituximab (Rituxan) as follows:
- Week 1: 375 mg/m2 IV once
- Weeks 3, 5, 7, 9, 13, 17, 21: 500 mg/m2 IV once
21-day cycle for 1 cycle, then 28-day cycle for up to 17 cycles (18 cycles total)
Regimen variant #2, indefinite
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Ghia et al. 2020 (ASCEND) | 2017-2018 | Phase 3 (C) | Acalabrutinib | Inferior PFS |
Prior treatment criteria
- ASCEND: At least 1 prior systemic therapy
Targeted therapy
- Idelalisib (Zydelig) 150 mg PO twice per day
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 1
- Cycles 2 to 3: 500 mg/m2 IV once per day on days 1 & 15
- Cycles 4 to 6: 500 mg/m2 IV once on day 1
14-day cycle for 1 cycle, then 28-day cycles
References
- GS-US-312-0116: Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, Barrientos JC, Zelenetz AD, Kipps TJ, Flinn I, Ghia P, Eradat H, Ervin T, Lamanna N, Coiffier B, Pettitt AR, Ma S, Stilgenbauer S, Cramer P, Aiello M, Johnson DM, Miller LL, Li D, Jahn TM, Dansey RD, Hallek M, O'Brien SM. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014 Mar 13;370(11):997-1007. Epub 2014 Jan 22. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
- Update: Sharman JP, Coutre SE, Furman RR, Cheson BD, Pagel JM, Hillmen P, Barrientos JC, Zelenetz AD, Kipps TJ, Flinn IW, Ghia P, Eradat H, Ervin T, Lamanna N, Coiffier B, Pettitt AR, Ma S, Tausch E, Cramer P, Huang J, Mitra S, Hallek M, O'Brien SM, Stilgenbauer S. Final results of a randomized, phase III study of rituximab with or without idelalisib followed by open-label idelalisib in patients with relapsed chronic lymphocytic leukemia. J Clin Oncol. 2019 Jun 1;37(16):1391-1402. Epub 2019 Apr 17. link to original article PubMed
- ASCEND: Ghia P, Pluta A, Wach M, Lysak D, Kozak T, Simkovic M, Kaplan P, Kraychok I, Illes A, de la Serna J, Dolan S, Campbell P, Musuraca G, Jacob A, Avery E, Lee JH, Liang W, Patel P, Quah C, Jurczak W. ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. J Clin Oncol. 2020 Sep 1;38(25):2849-2861. Epub 2020 May 27. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
- BRUIN CLL-321: Clinical Trial Registry
Ofatumumab monotherapy
Regimen variant #1, 2 cycles
Study | Dates of enrollment | Evidence |
---|---|---|
Österborg et al. 2015 (GEN416) | 2009-2011 | Phase 2 |
Note: Patients in this trial were fludarabine refractory and had previously received ofatumumab; this is a re-treatment trial.
Targeted therapy
- Ofatumumab (Arzerra) as follows:
- Cycle 1: 300 mg IV once on day 1, then 2000 mg IV once per day on days 8, 15, 22
- Cycle 2: 2000 mg IV once per day on days 1, 8, 15, 22
Supportive therapy
- Acetaminophen (Tylenol) 1000 mg PO once per day on days 1, 8, 15, 22, prior to ofatumumab
- Cetirizine (Zyrtec) (or equivalent) 10 mg PO once per day on days 1, 8, 15, 22, prior to ofatumumab
- Prednisolone (Millipred) 100 mg (or equivalent) PO once, prior to infusions 1, 2, and 9 (question whether this was a typo), reduced or omitted if initial infusions well-tolerated
28-day cycle for 2 cycles
Subsequent treatment
- GEN416, patients with SD or better: ofatumumab maintenance
Regimen variant #2, 6 cycles
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Coiffier et al. 2007 | 2004-2006 | Phase 1/2 | ||
Wierda et al. 2010 (Hx-CD20-406) | 2006-NR | Phase 2 (RT) | ||
Österborg et al. 2016 (Novartis 114242) | 2011-NR | Phase 3 (E-switch) | Physician's choice | Did not meet primary endpoint of PFS |
Byrd et al. 2014 (RESONATE) | 2012-2013 | Phase 3 (C) | Ibrutinib | Inferior PFS1 |
Jones et al. 2017 (GS-US-312-0119) | 2012-2014 | Phase 3 (C) | Idelalisib & Ofatumumab | Inferior PFS |
Flinn et al. 2018 (DUO) | 2014-2015 | Phase 3 (C) | Duvelisib | Inferior PFS |
1Reported efficacy for RESONATE is based on the second 2019 update.
Note: this regimen is sometimes described as 300 mg IV once on day 1, then 2000 mg IV once per week for 7 weeks, then 2000 mg IV once every 4 weeks for 16 weeks. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.
Targeted therapy
- Ofatumumab (Arzerra) as follows:
- Cycle 1: 300 mg IV once on day 1, then 2000 mg IV once per day on days 8, 15, 22
- Cycle 2: 2000 mg IV once per day on days 1, 8, 15, 22
- Cycles 3 to 6: 2000 mg IV once on day 1
Supportive therapy
- Prednisolone (Millipred) 100 mg (or equivalent) PO once, prior to infusions 1, 2, and 9 (question whether this was a typo), reduced to lower doses if initial infusions well-tolerated
28-day cycle for 6 cycles
Regimen variant #3, 12 cycles
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Ghia et al. 2017 (P07714) | 2012-NR | Phase 3 (C) | Dinaciclib | Not reported |
Note: this trial was terminated early and no statistical tests were performed; note also that cycle 3 is "skipped".
Targeted therapy
- Ofatumumab (Arzerra) as follows:
- Cycle 1: 300 mg IV once on day 1, then 2000 mg IV once per day on days 8, 15, 22
- Cycle 2: 2000 mg IV once per day on days 1, 8, 15, 22
- Cycle 3: no treatment
- Cycles 4 to 12: 2000 mg IV once on day 1
28-day cycle for 12 cycles
References
- Coiffier B, Lepretre S, Pedersen LM, Gadeberg O, Fredriksen H, van Oers MH, Wooldridge J, Kloczko J, Holowiecki J, Hellmann A, Walewski J, Flensburg M, Petersen J, Robak T. Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1-2 study. Blood. 2008 Feb 1;111(3):1094-100. Epub 2007 Nov 14. link to original article PubMed
- Hx-CD20-406: Wierda WG, Kipps TJ, Mayer J, Stilgenbauer S, Williams CD, Hellmann A, Robak T, Furman RR, Hillmen P, Trneny M, Dyer MJ, Padmanabhan S, Piotrowska M, Kozak T, Chan G, Davis R, Losic N, Wilms J, Russell CA, Osterborg A; Hx-CD20-406 Study Investigators. Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol. 2010 Apr 1;28(10):1749-55. Epub 2010 Mar 1. link to original article contains dosing details in abstract link to PMC article PubMed Clinical Trial Registry
- Subgroup analysis: Wierda WG, Padmanabhan S, Chan GW, Gupta IV, Lisby S, Osterborg A; Hx-CD20-406 Study Investigators. Ofatumumab is active in patients with fludarabine-refractory CLL irrespective of prior rituximab: results from the phase 2 international study. Blood. 2011 Nov 10;118(19):5126-9. Epub 2011 Aug 19. link to original article link to PMC article PubMed
- Update: Österborg A, Jewell RC, Padmanabhan-Iyer S, Kipps TJ, Mayer J, Stilgenbauer S, Williams CD, Hellmann A, Furman RR, Robak T, Hillmen P, Trnêný M, Dyer MJ, Piotrowska M, Kozak T, Gupta IV, Phillips JL, Goldstein N, Struemper H, Losic N, Lisby S, Wierda WG; Hx-CD20-406 Study Investigators. Ofatumumab monotherapy in fludarabine-refractory chronic lymphocytic leukemia: final results from a pivotal study. Haematologica. 2015 Aug;100(8):e311-4. Epub 2015 Mar 13. link to original article link to PMC article PubMed
- RESONATE: Byrd JC, Brown JR, O'Brien S, Barrientos JC, Kay NE, Reddy NM, Coutre S, Tam CS, Mulligan SP, Jaeger U, Devereux S, Barr PM, Furman RR, Kipps TJ, Cymbalista F, Pocock C, Thornton P, Caligaris-Cappio F, Robak T, Delgado J, Schuster SJ, Montillo M, Schuh A, de Vos S, Gill D, Bloor A, Dearden C, Moreno C, Jones JJ, Chu AD, Fardis M, McGreivy J, Clow F, James DF, Hillmen P; the RESONATE Investigators. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014 Jul 17;371(3):213-23. Epub 2014 May 31. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
- Update: Brown JR, Hillmen P, O'Brien S, Barrientos JC, Reddy NM, Coutre SE, Tam CS, Mulligan SP, Jaeger U, Barr PM, Furman RR, Kipps TJ, Cymbalista F, Thornton P, Caligaris-Cappio F, Delgado J, Montillo M, De Vos S, Moreno C, Pagel JM, Munir T, Burger JA, Chung D, Lin J, Gau L, Chang B, Cole G, Hsu E, James DF, Byrd JC. Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL. Leukemia. 2018 Jan;32(1):83-91. Epub 2017 Jun 8. link to original article link to PMC article PubMed
- Update: Byrd JC, Hillmen P, O'Brien S, Barrientos JC, Reddy NM, Coutre S, Tam CS, Mulligan SP, Jaeger U, Barr PM, Furman RR, Kipps TJ, Thornton P, Moreno C, Montillo M, Pagel JM, Burger JA, Woyach JA, Dai S, Vezan R, James DF, Brown JR. Long-term follow-up of the RESONATE phase 3 trial of ibrutinib vs ofatumumab. Blood. 2019 May 9;133(19):2031-2042. Epub 2019 Mar 6. link to original article link to PMC article PubMed
- Update: Munir T, Brown JR, O'Brien S, Barrientos JC, Barr PM, Reddy NM, Coutre S, Tam CS, Mulligan SP, Jaeger U, Kipps TJ, Moreno C, Montillo M, Burger JA, Byrd JC, Hillmen P, Dai S, Szoke A, Dean JP, Woyach JA. Final analysis from RESONATE: Up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma. Am J Hematol. 2019 Dec;94(12):1353-1363. Epub 2019 Oct 13. link to original article link to PMC article PubMed
- Retrospective: Moreno C, Montillo M, Panayiotidis P, Dimou M, Bloor A, Dupuis J, Schuh A, Norin S, Geisler C, Hillmen P, Doubek M, Trněný M, Obrtlikova P, Laurenti L, Stilgenbauer S, Smolej L, Ghia P, Cymbalista F, Jaeger U, Stamatopoulos K, Stavroyianni N, Carrington P, Zouabi H, Leblond V, Gomez-Garcia JC, Rubio M, Marasca R, Musuraca G, Rigacci L, Farina L, Paolini R, Pospisilova S, Kimby E, Bradley C, Montserrat E. Ofatumumab in poor-prognosis chronic lymphocytic leukemia: a Phase 4, non--interventional, observational study from the European Research Initiative on Chronic Lymphocytic Leukemia. Haematologica. 2015 Apr;100(4):511-6. Epub 2015 Jan 16. link to original article link to PMC article PubMed
- GEN416: Österborg A, Wierda WG, Mayer J, Hess G, Hillmen P, Schetelig J, Schuh A, Smolej L, Beck C, Dreyfus B, Hellman A, Kozlowski P, Pfreundschuh M, Rizzi R, Spacek M, Phillips JL, Gupta IV, Williams V, Jewell RC, Nebot N, Lisby S, Dyer MJ. Ofatumumab retreatment and maintenance in fludarabine-refractory chronic lymphocytic leukaemia patients. Br J Haematol. 2015 Jul;170(1):40-9. Epub 2015 Mar 30. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
- Novartis 114242: Österborg A, Udvardy M, Zaritskey A, Andersson PO, Grosicki S, Mazur G, Kaplan P, Steurer M, Schuh A, Montillo M, Kryachok I, Middeke JM, Kulyaba Y, Rekhtman G, Gorczyca M, Daly S, Chang CN, Lisby S, Gupta I. Phase III, randomized study of ofatumumab versus physicians' choice of therapy and standard versus extended-length ofatumumab in patients with bulky fludarabine-refractory chronic lymphocytic leukemia. Leuk Lymphoma. 2016 Sep;57(9):2037-46. Epub 2016 Jan 19. link to original articlePubMed Clinical Trial Registry
- Update: Miklos U, Strugov V, Lewerin C, Grosicki S, Mazur G, Steurer M, Montillo M, Kryachok I, Middeke JM, Rekhtman G, Stefanelli T, Vincent G, Govindaraju S, Österborg A. Five-year survival follow-up of a phase III randomised trial comparing ofatumumab versus physicians' choice for bulky fludarabine-refractory chronic lymphocytic leukaemia: a short report. Br J Haematol. 2020 May;189(4):689-693. Epub 2020 Jan 28. link to original article PubMed
- GS-US-312-0119: Jones JA, Robak T, Brown JR, Awan FT, Badoux X, Coutre S, Loscertales J, Taylor K, Vandenberghe E, Wach M, Wagner-Johnston N, Ysebaert L, Dreiling L, Dubowy R, Xing G, Flinn IW, Owen C. Efficacy and safety of idelalisib in combination with ofatumumab for previously treated chronic lymphocytic leukaemia: an open-label, randomised phase 3 trial. Lancet Haematol. 2017 Mar;4(3):e114-e126. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
- P07714: Ghia P, Scarfò L, Perez S, Pathiraja K, Derosier M, Small K, McCrary Sisk C, Patton N. Efficacy and safety of dinaciclib vs ofatumumab in patients with relapsed/refractory chronic lymphocytic leukemia. Blood. 2017 Mar 30;129(13):1876-1878. Epub 2017 Jan 26. link to original article PubMed Clinical Trial Registry
- DUO: Flinn IW, Hillmen P, Montillo M, Nagy Z, Illés Á, Etienne G, Delgado J, Kuss BJ, Tam CS, Gasztonyi Z, Offner F, Lunin S, Bosch F, Davids MS, Lamanna N, Jaeger U, Ghia P, Cymbalista F, Portell CA, Skarbnik AP, Cashen AF, Weaver DT, Kelly VM, Turnbull B, Stilgenbauer S. The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL. Blood. 2018 Dec 6;132(23):2446-2455. link to original article link to PMC article contains dosing details in manuscript PubMed Clinical Trial Registry
O-FC
O-FC: Ofatumumab, Fludarabine, Cyclophosphamide
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Robak et al. 2016 (COMPLEMENT 2) | 2008-NR | Phase 3 (E-RT-esc) | FC | Superior PFS Median PFS: 28.9 vs 18.8 mo (HR 0.67, 95% CI 0.51-0.88) |
Targeted therapy
- Ofatumumab (Arzerra) as follows:
- Cycle 1: 300 mg IV once on day 1, then 1000 mg IV once on day 8
- Cycles 2 to 6: 1000 mg IV once on day 1
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
- Acetaminophen (Tylenol) 1000 mg PO once on day 1, prior to ofatumumab
- Cetirizine (Zyrtec) 10 mg (or equivalent) PO once on day 1, prior to ofatumumab
- Prednisolone (Millipred) 100 mg (or equivalent) PO once on day 1, prior to doses 1 & 2 of ofatumumab, then reduced by physician discretion for later doses
- May be used at physician discretion:
- Allopurinol (Zyloprim) for tumor lysis syndrome prophylaxis
- Antiviral prophylaxis
- PCP (Pneumocystis jiroveci pneumonia) prophylaxis
- Growth factor support
28-day cycle for 6 cycles
References
- COMPLEMENT 2: 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 contains dosing details in manuscript PubMed Clinical Trial Registry
Rituximab monotherapy
Regimen variant #1, 4-week course
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
McLaughlin et al. 1998 | 1995-1996 | Phase 2 | ||
Williams et al. 2016 (RESORT substudy) | 2003-2008 | Phase 3 (E-de-esc) | Rituximab maintenance | Seems to have inferior TTTF |
Preceding treatment
- RESORT substudy: Rituximab, with progression
Regimen variant #2, 8 doses
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Furman et al. 2014 (GS-US-312-0116) | 2012-2013 | Phase 3 (C) | Idelalisib & Rituximab | Inferior PFS |
Note: Reported efficacy is based on the 2019 update.
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 1
- Cycles 2 to 8: 500 mg/m2 IV once on day 1
14-day cycle for 4 cycles, then 21-day cycle for 4 cycles
Regimen variant #3, 8 doses alternate schedule
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Huang et al. 2018 (CR102604) | 2013-2015 | Phase 3 (C) | Ibrutinib | Seems to have inferior OS |
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 1, then 500 mg/m2 IV once on day 15
- Cycle 2: 500 mg/m2 IV once per day on days 1 & 15
- Cycles 3 to 6: 500 mg/m2 IV once on day 1
28-day cycle for 6 cycles
References
- McLaughlin P, Grillo-López AJ, Link BK, Levy R, Czuczman MS, Williams ME, Heyman MR, Bence-Bruckler I, White CA, Cabanillas F, Jain V, Ho AD, Lister J, Wey K, Shen D, Dallaire BK. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998 Aug;16(8):2825-33. link to original article contains dosing details in manuscript PubMed
- GS-US-312-0116: Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, Barrientos JC, Zelenetz AD, Kipps TJ, Flinn I, Ghia P, Eradat H, Ervin T, Lamanna N, Coiffier B, Pettitt AR, Ma S, Stilgenbauer S, Cramer P, Aiello M, Johnson DM, Miller LL, Li D, Jahn TM, Dansey RD, Hallek M, O'Brien SM. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014 Mar 13;370(11):997-1007. Epub 2014 Jan 22. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
- Update: Sharman JP, Coutre SE, Furman RR, Cheson BD, Pagel JM, Hillmen P, Barrientos JC, Zelenetz AD, Kipps TJ, Flinn IW, Ghia P, Eradat H, Ervin T, Lamanna N, Coiffier B, Pettitt AR, Ma S, Tausch E, Cramer P, Huang J, Mitra S, Hallek M, O'Brien SM, Stilgenbauer S. Final results of a randomized, phase III study of rituximab with or without idelalisib followed by open-label idelalisib in patients with relapsed chronic lymphocytic leukemia. J Clin Oncol. 2019 Jun 1;37(16):1391-1402. Epub 2019 Apr 17. link to original article PubMed
- RESORT substudy: Williams ME, Hong F, Gascoyne RD, Wagner LI, Krauss JC, Habermann TM, Swinnen LJ, Schuster SJ, Peterson CG, Sborov MD, Martin SE, Weiss M, Ehmann WC, Horning SJ, Kahl BS; Eastern Cooperative Oncology Group. Rituximab extended schedule or retreatment trial for low tumour burden non-follicular indolent B-cell non-Hodgkin lymphomas: Eastern Cooperative Oncology Group Protocol E4402. Br J Haematol. 2016 Jun;173(6):867-75. Epub 2016 Mar 11. link to original article contains dosing details in abstract link to PMC article PubMed Clinical Trial Registry
- CR102604: Huang X, Qiu L, Jin J, Zhou D, Chen X, Hou M, Hu J, Hu Y, Ke X, Li J, Liang Y, Liu T, Lv Y, Ren H, Sun A, Wang J, Zhao C, Salman M, Sun S, Howes A, Wang J, Wu P, Li J. Ibrutinib versus rituximab in relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma: a randomized, open-label phase 3 study. Cancer Med. 2018 Apr;7(4):1043-1055. Epub 2018 Mar 13. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
Venetoclax & Rituximab
VenR: Venetoclax & Rituximab
Regimen
FDA-recommended dose |
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Seymour et al. 2018 (MURANO) | 2014-03-31 to 2015-09-23 | Phase 3 (E-RT-switch-ooc) | BR | Superior PFS (primary endpoint) PFS24: 84.9% vs 36.3% (HR 0.17, 95% CI 0.11-0.25) Superior OS1 (secondary endpoint) OS48: 85.3% vs 66.8% (HR 0.41, 95% CI 0.26-0.65) |
Awaiting publication (BRUIN CLL-322) | 2021-2025 | Phase 3 (C) | Pirtobrutinib, Venetoclax, Rituximab | TBD |
1Reported efficacy for OS in MURANO is based on the 2020 update.
Targeted therapy
- Venetoclax (Venclexta) as follows:
- Week 1: 20 mg PO once per day
- Week 2: 50 mg PO once per day
- Week 3: 100 mg PO once per day
- Week 4: 200 mg PO once per day
- Week 5 onwards: 400 mg PO once per day
- Rituximab (Rituxan) as follows:
- Week 6: 375 mg/m2 IV once on day 1
- Weeks 10, 14, 18, 22, 26: 500 mg/m2 IV once on day 1
Up to 2-year course
References
- MURANO: Seymour JF, Kipps TJ, Eichhorst B, Hillmen P, D'Rozario J, Assouline S, Owen C, Gerecitano J, Robak T, De la Serna J, Jaeger U, Cartron G, Montillo M, Humerickhouse R, Punnoose EA, Li Y, Boyer M, Humphrey K, Mobasher M, Kater AP. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018 Mar 22;378(12):1107-1120. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
- Update: Kater AP, Seymour JF, Hillmen P, Eichhorst B, Langerak AW, Owen C, Verdugo M, Wu J, Punnoose EA, Jiang Y, Wang J, Boyer M, Humphrey K, Mobasher M, Kipps TJ. Fixed duration of venetoclax-rituximab in relapsed/refractory chronic lymphocytic leukemia eradicates minimal residual disease and prolongs survival: post-treatment follow-up of the MURANO phase III study. J Clin Oncol. 2019 Feb 1;37(4):269-277. Epub 2018 Dec 3. link to original article PubMed
- Update: Kater AP, Wu JQ, Kipps T, Eichhorst B, Hillmen P, D'Rozario J, Assouline S, Owen C, Robak T, de la Serna J, Jaeger U, Cartron G, Montillo M, Dubois J, Eldering E, Mellink C, Van Der Kevie-Kersemaekers AM, Kim SY, Chyla B, Punnoose E, Bolen CR, Assaf ZJ, Jiang Y, Wang J, Lefebure M, Boyer M, Humphrey K, Seymour JF. Venetoclax Plus Rituximab in Relapsed Chronic Lymphocytic Leukemia: 4-Year Results and Evaluation of Impact of Genomic Complexity and Gene Mutations From the MURANO Phase III Study. J Clin Oncol. 2020 Dec 1;38(34):4042-4054. Epub 2020 Sep 28. link to original article link to PMC article PubMed
- Update: Seymour JF, Kipps TJ, Eichhorst BF, D'Rozario J, Owen CJ, Assouline S, Lamanna N, Robak T, de la Serna J, Jaeger U, Cartron G, Montillo M, Mellink C, Chyla B, Panchal A, Lu T, Wu JQ, Jiang Y, Lefebure M, Boyer M, Kater AP. Enduring undetectable MRD and updated outcomes in relapsed/refractory CLL after fixed-duration venetoclax-rituximab. Blood. 2022 Aug 25;140(8):839-850. link to original article link to PMC article PubMed
- BRUIN CLL-322: Clinical Trial Registry
Zanubrutinib monotherapy
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Hillmen et al. 2022 (ALPINE) | 2018-2020 | Phase 3 (E-switch-ic) | Ibrutinib | Superior PFS1 (secondary endpoint) PFS24: 78.4% vs 65.9% (HR 0.65, 95% CI 0.49-0.86) |
1Reported efficacy is based on the 2022 update.
Prior treatment criteria
- ALPINE: At least 1 prior systemic therapy
References
- ALPINE: Hillmen P, Eichhorst B, Brown JR, Lamanna N, O'Brien SM, Tam CS, Qiu L, Kazmierczak M, Zhou K, Šimkovič M, Mayer J, Gillespie-Twardy A, Shadman M, Ferrajoli A, Ganly PS, Weinkove R, Grosicki S, Mital A, Robak T, Österborg A, Yimer HA, Salmi T, Ji M, Yecies J, Idoine A, Wu K, Huang J, Jurczak W. Zanubrutinib Versus Ibrutinib in Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma: Interim Analysis of a Randomized Phase III Trial. J Clin Oncol. 2023 Feb 10;41(5):1035-1045. Epub 2022 Nov 17. link to original article link to PMC article PubMed Clinical Trial Registry
- Update: Brown JR, Eichhorst B, Hillmen P, Jurczak W, Kaźmierczak M, Lamanna N, O'Brien SM, Tam CS, Qiu L, Zhou K, Simkovic M, Mayer J, Gillespie-Twardy A, Ferrajoli A, Ganly PS, Weinkove R, Grosicki S, Mital A, Robak T, Osterborg A, Yimer HA, Salmi T, Wang MD, Fu L, Li J, Wu K, Cohen A, Shadman M. Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. N Engl J Med. 2023 Jan 26;388(4):319-332. Epub 2022 Dec 13. link to original article PubMed
Relapsed or refractory, non-randomized or retrospective data
Alemtuzumab monotherapy
Regimen variant #1
Study | Dates of enrollment | Evidence |
---|---|---|
Keating et al. 2002 | 1998 | Phase 2 (RT) |
Rai et al. 2002 | NR-1994 | Phase 2 (RT) |
Note: total course varies depending on reference.
Targeted therapy
- Alemtuzumab (Campath) by the following criteria:
- Starting dose: 3 mg IV once per day
- If tolerated in terms of infusion reactions: 10 mg IV once per day
- If tolerated in terms of infusion reactions: 30 mg IV once per day
- Once 30 mg dose is tolerated: 30 mg IV over 2 hours, 3 times per week
Supportive therapy
- Note: see references for details, as they differ by paper.
- Diphenhydramine (Benadryl) 50 mg PO once per infusion; 30 minutes prior to alemtuzumab
- Acetaminophen (Tylenol) 650 mg PO once per infusion; 30 minutes prior to alemtuzumab
- Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg PO 3 times per week, starting on day 8, continuing at a minimum until 2 months after treatment is complete
- Famciclovir (Famvir) 250 mg PO twice per day, starting on day 8, continuing at a minimum until 2 months after treatment is complete
12- to 16-week course
Regimen variant #2
Study | Dates of enrollment | Evidence |
---|---|---|
Lozanski et al. 2004 | NR | Phase 2 (RT) |
Targeted therapy
- Alemtuzumab (Campath) 3 mg IV once on day 1, then 10 mg IV once on day 2, then 30 mg IV once on day 3, then 30 mg IV 3 days per week
Supportive therapy
- G-CSF or GM-CSF per institutional protocol
- Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg PO 3 times per week during therapy and continued for 6 months after treatment is complete
- Acyclovir (Zovirax) 800 mg PO three times per day during therapy and continued for 6 months after treatment is complete; similar medication can be used if intolerant of acyclovir
12-week course
References
- Keating MJ, Flinn I, Jain V, Binet JL, Hillmen P, Byrd J, Albitar M, Brettman L, Santabarbara P, Wacker B, Rai KR. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood. 2002 May 15;99(10):3554-61. link to original article contains dosing details in abstract PubMed
- Rai KR, Freter CE, Mercier RJ, Cooper MR, Mitchell BS, Stadtmauer EA, Santábarbara P, Wacker B, Brettman L. Alemtuzumab in previously treated chronic lymphocytic leukemia patients who also had received fludarabine. J Clin Oncol. 2002 Sep 15;20(18):3891-7. link to original article contains dosing details in abstract PubMed
- Lozanski G, Heerema NA, Flinn IW, Smith L, Harbison J, Webb J, Moran M, Lucas M, Lin T, Hackbarth ML, Proffitt JH, Lucas D, Grever MR, Byrd JC. Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions. Blood. 2004 May 1;103(9):3278-81. Epub 2004 Jan 15. link to original article contains dosing details in abstract PubMed
Alemtuzumab & Rituximab
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Faderl et al. 2003 | NR | Phase 2 |
Targeted therapy
- Alemtuzumab (Campath) 3 mg IV once on day 1, then 10 mg IV once on day 2, then 30 mg IV once on day 3 of week 1, then 30 mg IV once per day on days 10, 12, 17, 19, 24, 26 (i.e. days 3 and 5 of weeks 2 to 4)
- Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1, 8, 15, 22
- For patients with WBC count greater than 50 x 109/L, the first dose was split into 100 mg/m2 IV once on day 1, then 275 mg/m2 IV once on day 2
Supportive therapy
- Prophylactic Trimethoprim-Sulfamethoxazole (Bactrim DS), given during therapy and continuing at a minimum until 2 months after treatment is complete
- Prophylactic Valacyclovir (Valtrex) (or equivalent), given during therapy and continuing at a minimum until 2 months after treatment is complete
28-day cycle for 1 to 2 cycles depending on response and toxicity
References
- Faderl S, Thomas DA, O'Brien S, Garcia-Manero G, Kantarjian HM, Giles FJ, Koller C, Ferrajoli A, Verstovsek S, Pro B, Andreeff M, Beran M, Cortes J, Wierda W, Tran N, Keating MJ. Experience with alemtuzumab plus rituximab in patients with relapsed and refractory lymphoid malignancies. Blood. 2003 May 1;101(9):3413-5. Epub 2003 Jan 9. link to original article contains dosing details in abstract PubMed
Bendamustine & Ofatumumab
BendOfa: Bendamustine & Ofatumumab
Regimen
Study | Dates of enrollment | Evidence | Efficacy |
---|---|---|---|
Cortelezzi et al. 2013 (GIMEMA CLL0809) | 2010-2011 | Phase 2 | ORR: 72% (95% CI, 57–84%) |
Chemotherapy
- Bendamustine 70 mg/m2 IV once per day on days 1 & 2
Targeted therapy
- Ofatumumab (Arzerra) as follows:
- Cycle 1: 300 mg IV once on day 1, then 1000 mg IV once on day 7
- Cycle 2 onwards: 1000 mg IV once on day 1
Supportive therapy
- Acetaminophen (Tylenol) 1000 mg PO once per infusion, prior to ofatumumab
- Diphenhydramine (Benadryl) 50 mg PO once per infusion, prior to ofatumumab
- Methylprednisolone (Solumedrol) 40 mg IV once per infusion, prior to ofatumumab
- Allopurinol (Zyloprim) or Rasburicase (Elitek) required for prophylaxis against TLS; dose not specified
- Trimethoprim-Sulfamethoxazole (Bactrim DS) required; dose not specified
- Acyclovir (Zovirax) required; dose not specified
28-day cycle up to 6 cycles
References
- GIMEMA CLL0809: Cortelezzi A, Sciumè M, Liberati AM, Vincenti D, Cuneo A, Reda G, Laurenti L, Zaja F, Marasca R, Chiarenza A, Gritti G, Orsucci L, Storti S, Angelucci E, Cascavilla N, Gobbi M, Mauro FR, Morabito F, Fabris S, Piciocchi A, Vignetti M, Neri A, Rossi D, Giannarelli D, Guarini A, Foà R. Bendamustine in combination with ofatumumab in relapsed or refractory chronic lymphocytic leukemia: a GIMEMA multicenter phase II trial. Leukemia. 2014 Mar;28(3):642-8. Epub 2013 Nov 13. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
CFAR
CFAR: Cyclophosphamide, Fludarabine, Alemtuzumab, Rituximab
Regimen
Study | Dates of enrollment | Evidence | Efficacy |
---|---|---|---|
Badoux et al. 2011 (MDACC DM02-593) | 2002-2006 | Phase 2 | ORR: 65% |
Chemotherapy
- Cyclophosphamide (Cytoxan) 250 mg/m2 IV once per day on days 3 to 5
- Fludarabine (Fludara) 25 mg/m2 IV once per day on days 3 to 5
Targeted therapy
- Alemtuzumab (Campath) 30 mg IV once per day on days 1, 3, 5
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 2
- Cycles 2 to 6: 500 mg/m2 IV once on day 2
Supportive therapy
- Allopurinol (Zyloprim) as follows:
- Cycle 1: 300 mg PO once per day on days 1 to 7
- Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg PO twice per day
- Antiviral prophylaxis with ONE of the following:
- Valacyclovir (Valtrex) 500 mg PO once per day
- Valganciclovir (Valcyte) 450 mg PO twice per day
- Pegfilgrastim (Neulasta) 6 mg SC once on day 6
- At physician's discretion:
- Acetaminophen (Tylenol) 650 mg PO once per day on days 1, 2, 3, 5; 30 minutes prior to rituximab/Alemtuzumab (Campath)
- Diphenhydramine (Benadryl) 25 to 50 mg IV or PO once per day on days 1, 2, 3, 5; 30 minutes prior to rituximab/Alemtuzumab (Campath)
- Hydrocortisone (Cortef) 100 mg IV once per day on days 1, 2, 3, 5; 30 minutes prior to alemtuzumab
28-day cycle for 6 cycles
References
- MDACC DM02-593: Badoux XC, Keating MJ, Wang X, O'Brien SM, Ferrajoli A, Faderl S, Burger J, Koller C, Lerner S, Kantarjian H, Wierda WG. Cyclophosphamide, fludarabine, alemtuzumab, and rituximab as salvage therapy for heavily pretreated patients with chronic lymphocytic leukemia. Blood. 2011 Aug 25;118(8):2085-93. Epub 2011 Jun 13. link to original article contains dosing details in abstract link to PMC article PubMed Clinical Trial Registry
DFCR
DFCR: Duvelisib, Fludarabine, Cyclophosphamide, Rituximab
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Davids et al. 2020 (DFCI 14-193) | 2014-2016 | Phase 1b/2 |
Note: This is the phase 2 dosing.
Targeted therapy
- Duvelisib (Copiktra) 25 mg PO twice per day
- 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:
- Cycles 1 to 6: 25 mg/m2 IV once per day on days 1 to 3
- Cyclophosphamide (Cytoxan) as follows:
- Cycles 1 to 6: 250 mg/m2 IV once per day on days 1 to 3
28-day cycle for up to 26 cycles (2 years)
References
- DFCI 14-193: Davids MS, Fisher DC, Tyekucheva S, McDonough M, Hanna J, Lee B, Francoeur K, Montegaard J, Odejide O, Armand P, Arnason J, Brown JR. A phase 1b/2 study of duvelisib in combination with FCR (DFCR) for frontline therapy for younger CLL patients. Leukemia. 2021 Apr;35(4):1064-1072. Epub 2020 Aug 20. link to original article link to PMC article contains dosing details in manuscript PubMed Clinical Trial Registry
Fludarabine & Alemtuzumab
FluCam: Fludarabine & Campath (Alemtuzumab)
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Elter et al. 2005 | NR | Phase 2 |
Chemotherapy
- Fludarabine (Fludara) 30 mg/m2 IV once per day on days 1 to 3
Targeted therapy
- Alemtuzumab (Campath) as follows:
- Cycle 1: 3 mg IV once on day 1, then 10 mg IV once on day 2, then 30 mg IV once on day 3
- Cycles 2 to 6: 30 mg IV once per day on days 1 to 3
Supportive therapy
- Trimethoprim/Sulfamethoxazole 960 mg (paper did not specify which component was 960 mg) PO once per day, started on day 1 and continued at least 2 months after treatment is complete
- Valacyclovir (Valtrex) 500 mg PO twice per day, started on day 1 and continued at least 2 months after treatment is complete
- If patients experienced CMV (cytomegalovirus) reactivation, valacyclovir was replaced by (val)ganciclovir 500 mg PO or IV three times per day
- Fluconazole (Diflucan) 100 mg PO once per day, started if patients had evidence of fungal infection, continued until resolution
- Acetaminophen (Tylenol) 1000 mg PO once on day 1, prior to first dose of alemtuzumab, then with subsequent doses if clinically indicated
- Clemastine (Tavist) 2 mg IV once on day 1, prior to first dose of alemtuzumab, then with subsequent doses if clinically indicated
- Prednisone (Sterapred) 100 mg IV once on day 1, prior to first dose of alemtuzumab, then with subsequent doses if clinically indicated
- For patients with WBC count greater than 50 x 109/L, bulky disease, or history of hyperuricemia: Allopurinol (Zyloprim) 300 mg PO once on day 1, prior to first dose of alemtuzumab, and used later if clinically indicated
28-day cycle for 6 cycles
References
- Elter T, Borchmann P, Schulz H, Reiser M, Trelle S, Schnell R, Jensen M, Staib P, Schinköthe T, Stützer H, Rech J, Gramatzki M, Aulitzky W, Hasan I, Josting A, Hallek M, Engert A. Fludarabine in combination with alemtuzumab is effective and feasible in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: results of a phase II trial. J Clin Oncol. 2005 Oct 1;23(28):7024-31. Epub 2005 Sep 6. link to original article contains dosing details in abstract PubMed
Fludarabine & Ibrutinib
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Pleyer et al. 2020 (NIH 15-H-0172) | 2015-2019 | Phase 2 |
Chemotherapy
- Fludarabine (Fludara) as follows:
- Cycles 3 & 4: 25 mg/m2 IV once per day on days 1 to 5
Targeted therapy
- Ibrutinib (Imbruvica) 420 mg PO once per day
28-day cycles
References
- NIH 15-H-0172: Pleyer C, Tian X, Rampertaap S, Mu R, Soto S, Superata J, Gaglione E, Sun C, Lotter J, Stetler-Stevenson M, Yuan CM, Maric I, Pittaluga S, Rosenzweig S, Fleisher T, Wiestner A, Ahn IE. A phase II study of ibrutinib and short-course fludarabine in previously untreated patients with chronic lymphocytic leukemia. Am J Hematol. 2020 Nov;95(11):E310-E313. Epub 2020 Sep 8. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
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
- 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
- Update: Keating MJ, O'Brien S, Lerner S, Koller C, Beran M, Robertson LE, Freireich EJ, Estey E, Kantarjian H. Long-term follow-up of patients with chronic lymphocytic leukemia (CLL) receiving fludarabine regimens as initial therapy. Blood. 1998 Aug 15;92(4):1165-71. link to original article PubMed
HDMP-R
HDMP-R: High Dose, MethylPrednisolone, Rituximab
Regimen variant #1, 3 cycles
Study | Dates of enrollment | Evidence |
---|---|---|
Castro et al. 2008 | NR | Phase 2, <20 pts |
Glucocorticoid therapy
- Methylprednisolone (Solumedrol) 1000 mg/m2 IV over 90 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, 3, 5, 8, 17, 22
- Cycles 2 & 3: 375 mg/m2 IV once per day on days 1, 7, 14, 21
28-day cycle for 3 cycles
Regimen variant #2, 6 cycles
Study | Dates of enrollment | Evidence |
---|---|---|
Pileckyte et al. 2011 | NR in abstract | Phase 2 |
Glucocorticoid therapy
- Methylprednisolone (Solumedrol) 1000 mg/m2 IV over 4 hours once per day on days 1 to 5
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 50 mg IV once on day 1, then 150 mg IV once on day 2, then remainder of a 375 mg/m2 dose IV once on day 3, then 500 mg/m2 IV once on day 5
- Cycles 2 to 6: 500 mg/m2 IV once per day on days 1 & 5
Supportive therapy
- Trimethoprim/sulfamethoxazole "or an equivalent antibiotic throughout the treatment period and up to 6 months after the completion of therapy"
21-day cycle for 6 cycles
References
- Castro JE, Sandoval-Sus JD, Bole J, Rassenti L, Kipps TJ. Rituximab in combination with high-dose methylprednisolone for the treatment of fludarabine refractory high-risk chronic lymphocytic leukemia. Leukemia. 2008 Nov;22(11):2048-53. Epub 2008 Aug 28. link to original article link to PMC article contains dosing details in manuscript PubMed
- Pileckyte R, Jurgutis M, Valceckiene V, Stoskus M, Gineikiene E, Sejoniene J, Degulys A, Zvirblis T, Griskevicius L. Dose-dense high-dose methylprednisolone and rituximab in the treatment of relapsed or refractory high-risk chronic lymphocytic leukemia. Leuk Lymphoma. 2011 Jun;52(6):1055-65. link to original article contains dosing details in abstract PubMed
Ibrutinib & Ofatumumab
Regimen variant #1, concurrent ibrutinib and ofatumumab
Study | Dates of enrollment | Evidence |
---|---|---|
Jaglowski et al. 2015 (PCYC-1109-CA) | 2011-2012 | Phase 2 |
Prior treatment criteria
- Failure of two or more prior therapies, or Richter transformation
Targeted therapy
- Ibrutinib (Imbruvica) 420 mg PO once per day
- Ofatumumab (Arzerra) as follows:
- Cycle 1: 300 mg IV once on day 1, then 2000 mg IV once per day on days 8, 15, 22
- Cycle 2: 2000 mg IV once per day on days 1, 8, 15, 22
- Cycles 3 to 6: 2000 mg IV once on day 1
28-day cycles
Regimen variant #2, ibrutinib lead-in
Study | Dates of enrollment | Evidence |
---|---|---|
Jaglowski et al. 2015 (PCYC-1109-CA) | 2011-2012 | Phase 2 |
Prior treatment criteria
- Failure of two or more prior therapies, or Richter transformation
Targeted therapy
- Ibrutinib (Imbruvica) 420 mg PO once per day
- Ofatumumab (Arzerra) as follows:
- Cycle 2: 300 mg IV once on day 1, then 2000 mg IV once per day on days 8, 15, 22
- Cycle 3: 2000 mg IV once per day on days 1, 8, 15, 22
- Cycles 4 to 7: 2000 mg IV once on day 1
28-day cycles
Regimen variant #3, ofatumumab lead-in
Study | Dates of enrollment | Evidence |
---|---|---|
Jaglowski et al. 2015 (PCYC-1109-CA) | 2011-2012 | Phase 2 |
Prior treatment criteria
- Failure of two or more prior therapies, or Richter transformation
Targeted therapy
- Ibrutinib (Imbruvica) as follows:
- Cycle 3 onwards: 420 mg PO once per day
- Ofatumumab (Arzerra) as follows:
- Cycle 1: 300 mg IV once on day 1, then 2000 mg IV once per day on days 8, 15, 22
- Cycle 2: 2000 mg IV once per day on days 1, 8, 15, 22
- Cycles 3 to 6: 2000 mg IV once on day 1
28-day cycles
References
- PCYC-1109-CA: Jaglowski SM, Jones JA, Nagar V, Flynn JM, Andritsos LA, Maddocks KJ, Woyach JA, Blum KA, Grever MR, Smucker K, Ruppert AS, Heerema NA, Lozanski G, Stefanos M, Munneke B, West JS, Neuenburg JK, James DF, Hall N, Johnson AJ, Byrd JC. Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab in chronic lymphocytic leukemia: a phase 1b/2 study. Blood. 2015 Aug 13;126(7):842-50. Epub 2015 Jun 26. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
Ibrutinib & Rituximab
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Burger et al. 2014 (MDACC 2011-0785) | 2012 | Phase 2 |
Note: Only 4 patients in the published study were untreated.
Eligibility criteria
- Patients with high-risk CLL (del17p or TP53 mutation, PFS less than 36 months from initial therapy, or relapsed CLL with del11q)
Targeted therapy
- Ibrutinib (Imbruvica) 420 mg PO once per day
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15, 22
- Cycles 2 to 6: 375 mg/m2 IV once on day 1
28-day cycles
References
- MDACC 2011-0785: Burger JA, Keating MJ, Wierda WG, Hartmann E, Hoellenriegel J, Rosin NY, de Weerdt I, Jeyakumar G, Ferrajoli A, Cardenas-Turanzas M, Lerner S, Jorgensen JL, Nogueras-González GM, Zacharian G, Huang X, Kantarjian H, Garg N, Rosenwald A, O'Brien S. Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study. Lancet Oncol. 2014 Sep;15(10):1090-9. Epub 2014 Aug 20. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
- Update: Jain P, Keating MJ, Wierda WG, Sivina M, Thompson PA, Ferrajoli A, Estrov Z, Kantarjian H, O'Brien S, Burger JA. Long-term follow-up of treatment with ibrutinib and rituximab in patients with high-risk chronic lymphocytic leukemia. Clin Cancer Res. 2017 May 1;23(9):2154-2158. Epub 2016 Oct 19. link to original article link to PMC article PubMed
Ibrutinib, Venetoclax, Obinutuzumab
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Rogers et al. 2020 (OSU-14266) | 2015-2017 | Phase 2 |
Targeted therapy
- Ibrutinib (Imbruvica) as follows:
- Cycle 2 onwards: 420 mg PO once per day
- Venetoclax (Venclexta) as follows:
- Cycle 3: 20 mg PO once per day on days 1 to 7, then 50 mg PO once per day on days 8 to 14, then 100 mg PO once per day on days 15 to 21, then 200 mg PO once per day on days 22 to 28
- Cycles 4 to 14: 400 mg PO once per day
- Obinutuzumab (Gazyva) as follows:
- Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15
- Cycles 2 to 8: 1000 mg IV once on day 1
28-day cycles
References
- OSU-14266: Rogers KA, Huang Y, Ruppert AS, Abruzzo LV, Andersen BL, Awan FT, Bhat SA, Dean A, Lucas M, Banks C, Grantier C, Heerema NA, Lozanski G, Maddocks KJ, Valentine TR, Weiss DM, Jones JA, Woyach JA, Byrd JC. Phase II Study of Combination Obinutuzumab, Ibrutinib, and Venetoclax in Treatment-Naïve and Relapsed or Refractory Chronic Lymphocytic Leukemia. J Clin Oncol. 2020 Nov 1;38(31):3626-3637. Epub 2020 Aug 14. link to original article link to PMC article contains dosing details in manuscript PubMed Clinical Trial Registry
Idelalisib monotherapy
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Brown et al. 2014 (Gilead 101-02) | 2008-2011 | Phase 1, >20 pts |
Gopal et al. 2014 (DELTA) | 2011-2012 | Phase 2 (RT) |
References
- DELTA: Gopal AK, Kahl BS, de Vos S, Wagner-Johnston ND, Schuster SJ, Jurczak WJ, Flinn IW, Flowers CR, Martin P, Viardot A, Blum KA, Goy AH, Davies AJ, Zinzani PL, Dreyling M, Johnson D, Miller LL, Holes L, Li D, Dansey RD, Godfrey WR, Salles GA. PI3Kd inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014 Mar 13;370(11):1008-18. Epub 2014 Jan 22. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
- Update: Abstract: Ajay K. Gopal, MD, Brad S. Kahl, MD, Sven de Vos, MD, PhD, Nina D. Wagner-Johnston, MD, Stephen J. Schuster, MD, Wojciech Jurczak, MD, PhD, Ian W. Flinn, MD, PhD, Christopher R. Flowers, MD, Peter Martin, MD, Andreas Viardot, MD, Kristie A. Blum, MD, Andre Goy, MD, Andrew Davies, BM PhD, Pier Luigi Zinzani, MD, Martin H. Dreyling, MD, PhD, Leanne M. Holes, Bess Sorensen, PhD, Wayne R. Godfrey, MD and Gilles Andre Salles, MD, PhD. Mature Follow up from a Phase 2 Study of PI3K-Delta Inhibitor Idelalisib in Patients with Double (Rituximab and Alkylating agent)-Refractory Indolent B-Cell Non-Hodgkin Lymphoma (iNHL). ASH Annual Meeting 2014, Abstract 1708 link to abstract
- Gilead 101-02: Brown JR, Byrd JC, Coutre SE, Benson DM, Flinn IW, Wagner-Johnston ND, Spurgeon SE, Kahl BS, Bello C, Webb HK, Johnson DM, Peterman S, Li D, Jahn TM, Lannutti BJ, Ulrich RG, Yu AS, Miller LL, Furman RR. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110d, for relapsed/refractory chronic lymphocytic leukemia. Blood. 2014 May 29;123(22):3390-7. Epub 2014 Mar 10. link to original article link to PMC article PubMed Clinical Trial Registry
Lenalidomide monotherapy
Regimen variant #1
Study | Dates of enrollment | Evidence |
---|---|---|
Chanan-Khan et al. 2006 | 2004-2006 | Phase 2 |
Targeted therapy
- Lenalidomide (Revlimid) 5 mg PO once per day, escalated by 5 mg every 1 to 2 weeks to a target maximum dose of 25 mg PO once per day on days 1 to 21
Supportive therapy
- Allopurinol (Zyloprim) 300 mg PO once per day, starting 2 to 3 days prior to lenalidomide, and continued up to a total of 14 days
28-day cycles
Regimen variant #2
Study | Dates of enrollment | Evidence |
---|---|---|
Ferrajoli et al. 2008 (MDACC 2005-0175) | 2005-2007 | Phase 2 |
Targeted therapy
- Lenalidomide (Revlimid) as follows:
- Cycle 1: 10 mg PO once per day
- Cycle 2: 15 mg PO once per day
- Cycle 3: 20 mg PO once per day
- Cycle 4 onwards: 25 mg PO once per day
28-day cycles
Regimen variant #3
Study | Dates of enrollment | Evidence |
---|---|---|
Witzig et al. 2009 (CC-5013-NHL-001) | 2005-2006 | Phase 2, <20 patients in this subgroup |
Note: Patients studied in this trial and in this subgroup had a diagnosis of SLL.
References
- Chanan-Khan A, Miller KC, Musial L, Lawrence D, Padmanabhan S, Takeshita K, Porter CW, Goodrich DW, Bernstein ZP, Wallace P, Spaner D, Mohr A, Byrne C, Hernandez-Ilizaliturri F, Chrystal C, Starostik P, Czuczman MS. Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study. J Clin Oncol. 2006 Dec 1;24(34):5343-9. Epub 2006 Nov 6. link to original article contains dosing details in abstract PubMed
- MDACC 2005-0175: Ferrajoli A, Lee BN, Schlette EJ, O'Brien SM, Gao H, Wen S, Wierda WG, Estrov Z, Faderl S, Cohen EN, Li C, Reuben JM, Keating MJ. Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood. 2008 Jun 1;111(11):5291-7. Epub 2008 Mar 11. link to original article link to PMC article PubMed Clinical Trial Registry
- CC-5013-NHL-001: Witzig TE, Wiernik PH, Moore T, Reeder C, Cole C, Justice G, Kaplan H, Voralia M, Pietronigro D, Takeshita K, Ervin-Haynes A, Zeldis JB, Vose JM. Lenalidomide oral monotherapy produces durable responses in relapsed or refractory indolent non-Hodgkin's Lymphoma. J Clin Oncol. 2009 Nov 10;27(32):5404-9. Epub 2009 Oct 5. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
Lenalidomide & Ofatumumab
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Vitale et al. 2016 (MDACC 2009-0283) | 2010-2011 | Phase 2 |
Targeted therapy
- Lenalidomide (Revlimid) as follows:
- Cycle 1: 10 mg PO once per day on days 9 to 28
- Cycle 2 to 24: 10 mg PO once per day
- Ofatumumab (Arzerra) as follows:
- Cycle 1: 300 mg IV once on day 1, then 1000 mg IV once per day on days 8, 15, 22
- Cycles 3 to 6, 8, 10, 12, 14, 16, 18, 20, 22, 24: 1000 mg IV once on day 1
Supportive therapy
- Cycle 1: Allopurinol (Zyloprim) 300 mg PO once per day on days 1 to 14
- G-CSF use allowed per 2006 ASCO guidelines
- "No anti-infectious, venous thromboembolism (VTE), or TFR prophylaxis was mandated"
28-day cycle for 24 cycles
Subsequent treatment
- MDACC 2009-0283, patients with a sustained PR or CR: lenalidomide maintenance
References
- MDACC 2009-0283: Vitale C, Falchi L, Ten Hacken E, Gao H, Shaim H, Van Roosbroeck K, Calin G, O'Brien S, Faderl S, Wang X, Wierda WG, Rezvani K, Reuben JM, Burger JA, Keating MJ, Ferrajoli A. Ofatumumab and Lenalidomide for Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia: Correlation between Responses and Immune Characteristics. Clin Cancer Res. 2016 May 15;22(10):2359-67. Epub 2016 Jan 5. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
Lenalidomide & Rituximab (R2)
Regimen variant #1
Study | Dates of enrollment | Evidence |
---|---|---|
Chanan-Khan et al. 2006 | 2004-2006 | Phase 2 |
Note: this lenalidomide dosing was the result of a mid-protocol amendment due to TLS in two of the first 29 patients enrolled.
Targeted therapy
- Lenalidomide (Revlimid) 5 mg PO once per day, escalated by 5 mg every 1 to 2 weeks to a target maximum dose of 25 mg PO once per day on days 1 to 21
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15
- Cycle 2 onwards: 375 mg/m2 IV once per day on days 1 & 15
Supportive therapy
- Allopurinol (Zyloprim) 300 mg PO once per day, starting 2 to 3 days prior to chemotherapy, and continued up to a total of 14 days
28-day cycles
Regimen variant #2
Study | Dates of enrollment | Evidence |
---|---|---|
Badoux et al. 2013 (MDACC 2007-0208) | 2008-2009 | Phase 2 |
Targeted therapy
- Lenalidomide (Revlimid) as follows:
- Cycle 1: 10 mg PO once per day on days 9 to 28
- Cycle 2 onwards: 10 mg PO once per day on days 1 to 28
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15, 22
- Cycle 2: no rituximab given
- Cycles 3 to 12: 375 mg/m2 IV once on day 1
Supportive therapy
- Cycle 1: Allopurinol (Zyloprim) (dose/schedule not specified) on days 1 to 14
- No mandatory antibacterial, antiviral, DVT, or tumor flare prophylaxis
- Growth factor use allowed per 2006 ASCO guidelines
28-day cycle for 12 cycles
Subsequent treatment
- MDACC 2007-0208, responders: Lenalidomide maintenance could continue indefinitely
References
- Chanan-Khan A, Miller KC, Musial L, Lawrence D, Padmanabhan S, Takeshita K, Porter CW, Goodrich DW, Bernstein ZP, Wallace P, Spaner D, Mohr A, Byrne C, Hernandez-Ilizaliturri F, Chrystal C, Starostik P, Czuczman MS. Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study. J Clin Oncol. 2006 Dec 1;24(34):5343-9. Epub 2006 Nov 6. link to original article contains dosing details in manuscript PubMed
- MDACC 2007-0208: Badoux XC, Keating MJ, Wen S, Wierda WG, O'Brien SM, Faderl S, Sargent R, Burger JA, Ferrajoli A. Phase II Study of Lenalidomide and Rituximab As Salvage Therapy for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia. J Clin Oncol. 2013 Feb 10;31(5):584-91. Epub 2012 Dec 26. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
Obinutuzumab monotherapy
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Salles et al. 2012 (GAUGUIN) | 2008-2009 | Phase 1/2 |
Note: Dose here is the phase II dose reported in the Cartron et al. 2014 update.
Targeted therapy
- Obinutuzumab (Gazyva) as follows:
- Cycle 1: 1000 mg IV once per day on days 1, 8, 15
- Cycle 2 onwards: 1000 mg IV once on day 1
Supportive therapy
- Acetaminophen (Tylenol) 650 to 1000 mg PO once on cycle 1 day 1; 30 minutes prior to obinutuzumab, repeat for those at risk of tumor lysis or with history of reaction
- Antihistamine (no drug or dose specified) PO once on cycle 1 day 1; 30 minutes prior to obinutuzumab, repeat for those at risk of tumor lysis or with history of reaction
- For patients at "high risk" of severe infusion reaction, including those with a history of severe rituximab reactions: Corticosteroids (no drug/dose/route specified) once on cycle 1 day 1, prior to obinutuzumab21-day cycle for up to 8 cycles
References
- GAUGUIN: Salles G, Morschhauser F, Lamy T, Milpied N, Thieblemont C, Tilly H, Bieska G, Asikanius E, Carlile D, Birkett J, Pisa P, Cartron G. Phase 1 study results of the type II glycoengineered humanized anti-CD20 monoclonal antibody obinutuzumab (GA101) in B-cell lymphoma patients. Blood. 2012 May 31;119(22):5126-32. Epub 2012 Mar 19. link to original article PubMed Clinical Trial Registry
- Subgroup analysis: Morschhauser FA, Cartron G, Thieblemont C, Solal-Céligny P, Haioun C, Bouabdallah R, Feugier P, Bouabdallah K, Asikanius E, Lei G, Wenger M, Wassner-Fritsch E, Salles GA. Obinutuzumab (GA101) monotherapy in relapsed/refractory diffuse large B-cell lymphoma or mantle-cell lymphoma: results from the phase II GAUGUIN study. J Clin Oncol. 2013 Aug 10;31(23):2912-9. Epub 2013 Jul 8. link to original article contains dosing details in manuscript PubMed
- Subgroup analysis: Salles GA, Morschhauser F, Solal-Céligny P, Thieblemont C, Lamy T, Tilly H, Gyan E, Lei G, Wenger M, Wassner-Fritsch E, Cartron G. Obinutuzumab (GA101) in patients with relapsed/refractory indolent non-Hodgkin lymphoma: results from the phase II GAUGUIN study. J Clin Oncol. 2013 Aug 10;31(23):2920-6. Epub 2013 Jul 8. link to original article contains dosing details in manuscript PubMed
- Subgroup analysis: Cartron G, de Guibert S, Dilhuydy MS, Morschhauser F, Leblond V, Dupuis J, Mahe B, Bouabdallah R, Lei G, Wenger M, Wassner-Fritsch E, Hallek M. Obinutuzumab (GA101) in relapsed/refractory chronic lymphocytic leukemia: final data from the phase 1/2 GAUGUIN study. Blood. 2014 Oct 2;124(14):2196-202. Epub 2014 Aug 20. link to original article contains dosing details in manuscript PubMed
OFAR
OFAR: Oxaliplatin, Fludarabine, Ara-C (Cytarabine), Rituximab
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Tsimberidou et al. 2008 | 2004-2006 | Phase 1/2 |
Note: this is the dosing used in the phase 2 portion.
Chemotherapy
- Oxaliplatin (Eloxatin) 25 mg/m2 IV over 2 hours once per day on days 1 to 4
- Fludarabine (Fludara) 30 mg/m2 IV once per day on days 2 & 3, administered within 30 minutes of completion of oxaliplatin
- Cytarabine (Ara-C) 1000 mg/m2 IV over 2 hours once per day on days 2 & 3, 4 hours after fludarabine started
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV over 4 to 6 hours once on day 3
- Cycles 2 to 6: 375 mg/m2 IV over 4 to 6 hours once on day 1
Supportive therapy
- Pegfilgrastim (Neulasta) 6 mg SC once on day 6
- Herpes zoster and PCP (Pneumocystis jiroveci pneumonia) prophylaxis used
28-day cycle for up to 6 cycles
References
- Tsimberidou AM, Wierda WG, Plunkett W, Kurzrock R, O'Brien S, Wen S, Ferrajoli A, Ravandi-Kashani F, Garcia-Manero G, Estrov Z, Kipps TJ, Brown JR, Fiorentino A, Lerner S, Kantarjian HM, Keating MJ. Phase I-II study of oxaliplatin, fludarabine, cytarabine, and rituximab combination therapy in patients with Richter's syndrome or fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol. 2008 Jan 10;26(2):196-203. link to original article contains dosing details in manuscript PubMed
PCR
PCR: Pentostatin, Cyclophosphamide, Rituximab
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Lamanna et al. 2006 | 2001-2004 | Phase 2 |
Chemotherapy
- Pentostatin (Nipent) 4 mg/m2 IV once on day 1, given second
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1, given first
Targeted therapy
- Rituximab (Rituxan) given third, as follows:
- Cycles 2 to 6: 375 mg/m2 IV once on day 1
Supportive therapy
- At least 1.5 L of IVF
- Dexamethasone (Decadron) 20 mg (route not specified) once on day 1
- Granisetron 2 mg (route not specified) once on day 1
- Filgrastim (Neupogen) by the following weight-based criteria:
- Patients weighing up to 70 kg: 300 mcg SC once per day from day 3 until ANC greater than 5000/μL once or 1500/μL for 2 days
- Patients weighing more than 70 kg: 480 mcg SC once per day from day 3 until ANC greater than 5000/μL once or 1500/μL for 2 days
- Trimethoprim-Sulfamethoxazole (Bactrim DS) 1 DS tablet PO twice per day on MWF
- Acyclovir (Zovirax) 800 mg PO twice per day
21-day cycle for 6 cycles
References
- Lamanna N, Kalaycio M, Maslak P, Jurcic JG, Heaney M, Brentjens R, Zelenetz AD, Horgan D, Gencarelli A, Panageas KS, Scheinberg DA, Weiss MA. Pentostatin, cyclophosphamide, and rituximab is an active, well-tolerated regimen for patients with previously treated chronic lymphocytic leukemia. J Clin Oncol. 2006 Apr 1;24(10):1575-81. Epub 2006 Mar 6. link to original article contains dosing details in manuscript PubMed
R-BAC
R-BAC: Rituximab, Bendamustine, Ara-C (Cytarabine)
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Visco et al. 2013 | 2010-2012 | Pilot, <20 patients reported |
Targeted therapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 1
- Cycle 2 onwards: 500 mg/m2 IV once on day 1
Chemotherapy
- Bendamustine 70 mg/m2 IV once per day on days 1 & 2
- Cytarabine (Ara-C) 800 mg/m2 IV over 2 hours once per day on days 1 to 3, beginning 2 hours after bendamustine
Supportive therapy
- Primary prophylaxis with granulocyte colony-stimulating factor was routinely used starting from Day 5 after chemotherapy completion, and lasting for 3 to 6 days or until neutrophil count recovery.
28-day cycle for up to 4 cycles
References
- Visco C, Finotto S, Pomponi F, Sartori R, Laveder F, Trentin L, Paolini R, Di Bona E, Ruggeri M, Rodeghiero F. The combination of rituximab, bendamustine, and cytarabine for heavily pretreated relapsed/refractory cytogenetically high-risk patients with chronic lymphocytic leukemia. Am J Hematol. 2013 Apr;88(4):289-93. Epub 2013 Feb 28. link to original article contains dosing details in manuscript PubMed
Ruxolitinib monotherapy
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Jain et al. 2017 (MDACC 2013-0044) | 2014-2015 | Phase 2, <20 pts in this subgroup |
Note: this was a trial focused on symptom control, not efficacy.
Targeted therapy
- Ruxolitinib (Jakafi) 10 mg PO twice per day
References
- MDACC 2013-0044: Jain P, Keating M, Renner S, Cleeland C, Xuelin H, Gonzalez GN, Harris D, Li P, Liu Z, Veletic I, Rozovski U, Jain N, Thompson P, Bose P, DiNardo C, Ferrajoli A, O'Brien S, Burger J, Wierda W, Verstovsek S, Kantarjian H, Estrov Z. Ruxolitinib for symptom control in patients with chronic lymphocytic leukaemia: a single-group, phase 2 trial. Lancet Haematol. 2017 Feb;4(2):e67-e74. Epub 2017 Jan 11. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
Venetoclax monotherapy
Regimen variant #1, standard lead-in
FDA-recommended dose |
Study | Dates of enrollment | Evidence | Efficacy |
---|---|---|---|
Roberts et al. 2015 (M12-175) | 2011-2014 | Phase 1/2 (RT) | ORR: 79% |
Stilgenbauer et al. 2016 (M13-982) | 2013-2014 | Phase 2 (RT) | ORR: 79% (95% CI, 70.5-87) |
Jones et al. 2017 (M14-032 ibrutinib cohort) | 2014-2016 | Phase 2 (RT) | ORR: 65% (95% CI 53-74) |
Coutre et al. 2018 (M14-032 idelalisib cohort) | 2014-NR | Phase 2 (RT) | ORR: 67% |
This is the dosing schedule used in the phase II expansion cohort of M12-175. See papers for supportive care details during initial dosing.
Biomarker eligibility criteria
- M13-982: 17p deletion
Targeted therapy
- Venetoclax (Venclexta) as follows:
- Week 1: 20 mg PO once per day
- Week 2: 50 mg PO once per day
- Week 3: 100 mg PO once per day
- Week 4: 200 mg PO once per day
- Week 5 onwards: 400 mg PO once per day
Continued indefinitely
Regimen variant #2, modified lead-in
Study | Dates of enrollment | Evidence | Efficacy |
---|---|---|---|
Coutre et al. 2018 (M14-032 idelalisib cohort) | 2014-NR | Phase 2 | ORR: 67% |
Note: This dosing schedule was intended for high-risk patients with "clinical signs of progression during screening." See paper for supportive care details during initial dosing.
Targeted therapy
- Venetoclax (Venclexta) as follows:
- Day 1: 20 mg PO once per day
- Days 2 & 3: 50 mg PO once per day
- Days 4 to 7: 100 mg PO once per day
- Week 2: 200 mg PO once per day
- Week 3 onwards: 400 mg PO once per day
Continued indefinitely
References
- M12-175: Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF, Kipps TJ, Anderson MA, Brown JR, Gressick L, Wong S, Dunbar M, Zhu M, Desai MB, Cerri E, Heitner Enschede S, Humerickhouse RA, Wierda WG, Seymour JF. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016 Jan 28;374(4):311-22. Epub 2015 Dec 6. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
- M13-982: Stilgenbauer S, Eichhorst B, Schetelig J, Coutre S, Seymour JF, Munir T, Puvvada SD, Wendtner CM, Roberts AW, Jurczak W, Mulligan SP, Böttcher S, Mobasher M, Zhu M, Desai M, Chyla B, Verdugo M, Heitner Enschede S, Cerri E, Humerickhouse R, Gordon G, Hallek M, Wierda WG. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 2016 Jun;17(6):768-78. Epub 2016 May 10. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
- Update: Stilgenbauer S, Eichhorst B, Schetelig J, Hillmen P, Seymour JF, Coutre S, Jurczak W, Mulligan SP, Schuh A, Assouline S, Wendtner CM, Roberts AW, Davids MS, Bloehdorn J, Munir T, Böttcher S, Zhou L, Salem AH, Desai M, Chyla B, Arzt J, Kim SY, Verdugo M, Gordon G, Hallek M, Wierda WG. Venetoclax for patients with chronic lymphocytic leukemia with 17p deletion: results from the full population of a phase II pivotal trial. J Clin Oncol. 2018 Jul 1;36(19):1973-1980. Epub 2018 May 1. link to original article PubMed
- M14-032 ibrutinib cohort: Jones JA, Mato AR, Wierda WG, Davids MS, Choi M, Cheson BD, Furman RR, Lamanna N, Barr PM, Zhou L, Chyla B, Salem AH, Verdugo M, Humerickhouse RA, Potluri J, Coutre S, Woyach J, Byrd JC. Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial. Lancet Oncol. 2018 Jan;19(1):65-75. Epub 2017 Dec 12. link to original article link to PMC article PubMed Clinical Trial Registry
- M14-032 idelalisib cohort: Coutre S, Choi M, Furman RR, Eradat H, Heffner L, Jones JA, Chyla B, Zhou L, Agarwal S, Waskiewicz T, Verdugo M, Humerickhouse RA, Potluri J, Wierda WG, Davids MS. Venetoclax for patients with chronic lymphocytic leukemia who progressed during or after idelalisib therapy. Blood. 2018 Apr 12;131(15):1704-1711. Epub 2018 Jan 5. link to original article contains dosing details in supplement link to PMC article PubMed Clinical Trial Registry
Zanubrutinib & Obinutuzumab
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Tam et al. 2020 | 2016-NR | Phase 1b, >20 pts in this subgroup |
Targeted therapy
- Zanubrutinib (Brukinsa) 160 mg PO twice per day or 320 mg PO once per day
- Obinutuzumab (Gazyva) as follows:
- Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15
- Cycles 2 to 6: 1000 mg IV once on day 1
28-day cycles
References
- Tam CS, Quach H, Nicol A, Badoux X, Rose H, Prince HM, Leahy MF, Eek R, Wickham N, Patil SS, Huang J, Prathikanti R, Cohen A, Elstrom R, Reed W, Schneider J, Flinn IW. Zanubrutinib (BGB-3111) plus obinutuzumab in patients with chronic lymphocytic leukemia and follicular lymphoma. Blood Adv. 2020 Oct 13;4(19):4802-4811. link to original article link to PMC article contains dosing details in manuscript PubMed Clinical Trial Registry
Consolidation and/or maintenance after subsequent lines of therapy
FC, then allo HSCT
FC: Fludarabine & Cyclophosphamide
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Dreger et al. 2010 (GCLLSG CLL3X) | 2001-2007 | Phase 2 |
Chemotherapy
- Fludarabine (Fludara) 30 mg/m2 IV once per day on days -6 to -2
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once per day on days -6 to -2
Immunotherapy
- Allogeneic stem cells transfused on day 0
References
- GCLLSG CLL3X: Dreger P, Döhner H, Ritgen M, Böttcher S, Busch R, Dietrich S, Bunjes D, Cohen S, Schubert J, Hegenbart U, Beelen D, Zeis M, Stadler M, Hasenkamp J, Uharek L, Scheid C, Humpe A, Zenz T, Winkler D, Hallek M, Kneba M, Schmitz N, Stilgenbauer S; German CLL Study Group. Allogeneic stem cell transplantation provides durable disease control in poor-risk chronic lymphocytic leukemia: long-term clinical and MRD results of the German CLL Study Group CLL3X trial. Blood. 2010 Oct 7;116(14):2438-47. Epub 2010 Jul 1. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
- Update: Dreger P, Schnaiter A, Zenz T, Böttcher S, Rossi M, Paschka P, Bühler A, Dietrich S, Busch R, Ritgen M, Bunjes D, Zeis M, Stadler M, Uharek L, Scheid C, Hegenbart U, Hallek M, Kneba M, Schmitz N, Döhner H, Stilgenbauer S. TP53, SF3B1, and NOTCH1 mutations and outcome of allotransplantation for chronic lymphocytic leukemia: six-year follow-up of the GCLLSG CLL3X trial. Blood. 2013 Apr 18;121(16):3284-8. Epub 2013 Feb 22. link to original article PubMed
- Update: Krämer I, Stilgenbauer S, Dietrich S, Böttcher S, Zeis M, Stadler M, Bittenbring J, Uharek L, Scheid C, Hegenbart U, Ho A, Hallek M, Kneba M, Schmitz N, Döhner H, Dreger P. Allogeneic hematopoietic cell transplantation for high-risk CLL: 10-year follow-up of the GCLLSG CLL3X trial. Blood. 2017 Sep 21;130(12):1477-1480. Epub 2017 Jul 17. link to original article PubMed
Fludarabine & TBI, then allo HSCT
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Sorror et al. 2005 | 1997-2003 | Phase 2 |
Chemotherapy
- Fludarabine (Fludara) 30 mg/m2 IV once per day on days -4 to -2
Radiotherapy
- Total body irradiation (TBI) 2 Gy at a rate of 0.07 Gy/min on day 0
Immunotherapy
- Allogeneic stem cells transfused on day 0
GVHD prophylaxis
- Cyclosporine 6.25 mg/kg PO twice per day starting 4 to 6 hours after transplant, tapered at day 100 over 80 days (if no GVHD)
- Mycophenolate mofetil (CellCept) 15 mg/kg PO twice per day starting 4 to 6 hours after transplant, tapered at day 40 over 56 days (if no GVHD)
References
- Sorror ML, Maris MB, Sandmaier BM, Storer BE, Stuart MJ, Hegenbart U, Agura E, Chauncey TR, Leis J, Pulsipher M, McSweeney P, Radich JP, Bredeson C, Bruno B, Langston A, Loken MR, Al-Ali H, Blume KG, Storb R, Maloney DG. Hematopoietic cell transplantation after nonmyeloablative conditioning for advanced chronic lymphocytic leukemia. J Clin Oncol. 2005 Jun 1;23(16):3819-29. Epub 2005 Apr 4. link to original article PubMed
- Update: Sorror ML, Storer BE, Sandmaier BM, Maris M, Shizuru J, Maziarz R, Agura E, Chauncey TR, Pulsipher MA, McSweeney PA, Wade JC, Bruno B, Langston A, Radich J, Niederwieser D, Blume KG, Storb R, Maloney DG. Five-year follow-up of patients with advanced chronic lymphocytic leukemia treated with allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. J Clin Oncol. 2008 Oct 20;26(30):4912-20. Epub 2008 Sep 15. link to original article link to PMC article PubMed
Fludarabine, Busulfan, ATG, then allo HSCT
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Slavin et al. 1998 | NR | Phase 2 |
Schetelig et al. 2003 | 1998-2001 | Phase 2 |
Chemotherapy
- Fludarabine (Fludara) 30 mg/m2 IV once per day on days -10 to -5 (6 consecutive days)
- Busulfan (Myleran) 4 mg/kg/day PO on days -6 to -5 (2 consecutive days)
Immunosuppressive therapy
- ATG-Fresenius 10 mg/kg IV once per day on days -4 to -1 (4 consecutive days)
Immunotherapy
- Allogeneic stem cells transfused on day 0
References
- Slavin S, Nagler A, Naparstek E, Kapelushnik Y, Aker M, Cividalli G, Varadi G, Kirschbaum M, Ackerstein A, Samuel S, Amar A, Brautbar C, Ben-Tal O, Eldor A, Or R. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood. 1998 Feb 1;91(3):756-63. link to original article contains dosing details in manuscript PubMed
- Schetelig J, Thiede C, Bornhauser M, Schwerdtfeger R, Kiehl M, Beyer J, Sayer HG, Kroger N, Hensel M, Scheffold C, Held TK, Hoffken K, Ho AD, Kienast J, Neubauer A, Zander AR, Fauser AA, Ehninger G, Siegert W; Cooperative German Transplant Study Group. Evidence of a graft-versus-leukemia effect in chronic lymphocytic leukemia after reduced-intensity conditioning and allogeneic stem-cell transplantation: the Cooperative German Transplant Study Group. J Clin Oncol. 2003 Jul 15;21(14):2747-53. link to original article contains reference to protocol PubMed
Fludarabine, Cyclophosphamide, ATG, then allo HSCT
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Dreger et al. 2010 (GCLLSG CLL3X) | 2001-2007 | Phase 2 |
Chemotherapy
- Fludarabine (Fludara) 30 mg/m2 IV once per day on days -6 to -2 (5 consecutive days)
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once per day on days -6 to -2 (5 consecutive days)
Immunosuppressive therapy
- ATG-Fresenius 10 mg/kg/day IV on days -4 to -1 (4 consecutive days)
Immunotherapy
- Allogeneic stem cells transfused on day 0
References
- GCLLSG CLL3X: Dreger P, Döhner H, Ritgen M, Böttcher S, Busch R, Dietrich S, Bunjes D, Cohen S, Schubert J, Hegenbart U, Beelen D, Zeis M, Stadler M, Hasenkamp J, Uharek L, Scheid C, Humpe A, Zenz T, Winkler D, Hallek M, Kneba M, Schmitz N, Stilgenbauer S; German CLL Study Group. Allogeneic stem cell transplantation provides durable disease control in poor-risk chronic lymphocytic leukemia: long-term clinical and MRD results of the German CLL Study Group CLL3X trial. Blood. 2010 Oct 7;116(14):2438-47. Epub 2010 Jul 1. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
- Update: Dreger P, Schnaiter A, Zenz T, Böttcher S, Rossi M, Paschka P, Bühler A, Dietrich S, Busch R, Ritgen M, Bunjes D, Zeis M, Stadler M, Uharek L, Scheid C, Hegenbart U, Hallek M, Kneba M, Schmitz N, Döhner H, Stilgenbauer S. TP53, SF3B1, and NOTCH1 mutations and outcome of allotransplantation for chronic lymphocytic leukemia: six-year follow-up of the GCLLSG CLL3X trial. Blood. 2013 Apr 18;121(16):3284-8. Epub 2013 Feb 22. link to original article PubMed
- Update: Krämer I, Stilgenbauer S, Dietrich S, Böttcher S, Zeis M, Stadler M, Bittenbring J, Uharek L, Scheid C, Hegenbart U, Ho A, Hallek M, Kneba M, Schmitz N, Döhner H, Dreger P. Allogeneic hematopoietic cell transplantation for high-risk CLL: 10-year follow-up of the GCLLSG CLL3X trial. Blood. 2017 Sep 21;130(12):1477-1480. Epub 2017 Jul 17. link to original article PubMed
Observation
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Greil et al. 2016 (AGMT CLL-8a) | 2010-2013 | Phase 3 (C) | Rituximab | Inferior PFS |
van Oers et al. 2015 (PROLONG) | 2010-2014 | Phase 3 (C) | Ofatumumab | Inferior PFS |
No further treatment offered to patients in their second or third CR or PR; prior treatment was not specified in PROLONG.
Preceding treatment
- AGMT CLL-8a: Rituximab-containing chemoimmunotherapy
References
- PROLONG: van Oers MH, Kuliczkowski K, Smolej L, Petrini M, Offner F, Grosicki S, Levin MD, Gupta I, Phillips J, Williams V, Manson S, Lisby S, Geisler C; PROLONG study investigators. Ofatumumab maintenance versus observation in relapsed chronic lymphocytic leukaemia (PROLONG): an open-label, multicentre, randomised phase 3 study. Lancet Oncol. 2015 Oct;16(13):1370-9. Epub 2015 Sep 13. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
- Update: van Oers M, Smolej L, Petrini M, Offner F, Grosicki S, Levin MD, Davis J, Banerjee H, Stefanelli T, Hoever P, Geisler C. Ofatumumab maintenance prolongs progression-free survival in relapsed chronic lymphocytic leukemia: final analysis of the PROLONG study. Blood Cancer J. 2019 Dec 4;9(12):98. link to original article link to PMC article PubMed
- AGMT CLL-8a: Greil R, Obrtlíková P, Smolej L, Kozák T, Steurer M, Andel J, Burgstaller S, Mikušková E, Gercheva L, Nösslinger T, Papajík T, Ladická M, Girschikofsky M, Hrubiško M, Jäger U, Fridrik M, Pecherstorfer M, Králiková E, Burcoveanu C, Spasov E, Petzer A, Mihaylov G, Raynov J, Oexle H, Zabernigg A, Flochová E, Palášthy S, Stehlíková O, Doubek M, Altenhofer P, Pleyer L, Melchardt T, Klingler A, Mayer J, Egle A. Rituximab maintenance versus observation alone in patients with chronic lymphocytic leukaemia who respond to first-line or second-line rituximab-containing chemoimmunotherapy: final results of the AGMT CLL-8a Mabtenance randomised trial. Lancet Haematol. 2016 Jul;3(7):e317-29. Epub 2016 Jun 16. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
Ofatumumab monotherapy
Regimen variant #1
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
van Oers et al. 2015 (PROLONG) | 2010-2014 | Phase 3 (E-RT-esc) | Observation | Superior PFS Median PFS: 29.4 vs 15.2 mo (HR 0.50, 95% CI 0.38-0.66) |
Note: Treatment offered to patients in their second or third CR or PR; prior treatment was not specified.
Targeted therapy
- Ofatumumab (Arzerra) as follows:
- Cycle 1: 300 mg IV once on day 1, then 1000 mg IV once on day 7
- Cycles 2 to 13: 1000 mg IV once on day 1
Supportive therapy
- Acetaminophen (Tylenol) 1000 mg PO once per infusion, 30 to 120 minutes prior to ofatumumab
- Diphenhydramine (Benadryl) (or equivalent antihistamine) 50 mg IV or PO once per infusion, 30 to 120 minutes prior to ofatumumab
- Prednisolone (Millipred) (or equivalent glucocorticoid) 50 mg IV once per infusion, 30 to 120 minutes prior to ofatumumab
8-week cycle for up to 13 cycles (2 years)
Regimen variant #2
Study | Dates of enrollment | Evidence |
---|---|---|
Österborg et al. 2015 (GEN416) | 2009-2011 | Phase 2 |
Preceding treatment
- Ofatumumab x 8
Targeted therapy
- Ofatumumab (Arzerra) 2000 mg IV once on day 1
Supportive therapy
- Acetaminophen (Tylenol) 1000 mg PO once on day 1, prior to ofatumumab
- Cetirizine (Zyrtec) (or equivalent antihistamine) 10 mg PO once on day 1, prior to ofatumumab
Monthly cycle for up to 24 cycles (2 years)
References
- GEN416: Österborg A, Wierda WG, Mayer J, Hess G, Hillmen P, Schetelig J, Schuh A, Smolej L, Beck C, Dreyfus B, Hellman A, Kozlowski P, Pfreundschuh M, Rizzi R, Spacek M, Phillips JL, Gupta IV, Williams V, Jewell RC, Nebot N, Lisby S, Dyer MJ. Ofatumumab retreatment and maintenance in fludarabine-refractory chronic lymphocytic leukaemia patients. Br J Haematol. 2015 Jul;170(1):40-9. Epub 2015 Mar 30. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
- PROLONG: van Oers MH, Kuliczkowski K, Smolej L, Petrini M, Offner F, Grosicki S, Levin MD, Gupta I, Phillips J, Williams V, Manson S, Lisby S, Geisler C; PROLONG study investigators. Ofatumumab maintenance versus observation in relapsed chronic lymphocytic leukaemia (PROLONG): an open-label, multicentre, randomised phase 3 study. Lancet Oncol. 2015 Oct;16(13):1370-9. Epub 2015 Sep 13. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
Placebo
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Chanan-Khan et al. 2017 (CONTINUUM) | 2009-2015 | Phase 3 (C) | Lenalidomide | Did not meet primary endpoint of OS |
No active antineoplastic treatment offered to patients with at least partial response to second-line therapy.
References
- CONTINUUM: Chanan-Khan AA, Zaritskey A, Egyed M, Vokurka S, Semochkin S, Schuh A, Kassis J, Simpson D, Zhang J, Purse B, Foà R. Lenalidomide maintenance therapy in previously treated chronic lymphocytic leukaemia (CONTINUUM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Haematol. 2017 Nov;4(11):e534-e543. Epub 2017 Sep 25. link to original article PubMed Clinical Trial Registry
Rituximab monotherapy
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Greil et al. 2016 (AGMT CLL-8a) | 2010-2013 | Phase 3 (E-esc) | Observation | Superior PFS Median PFS: 47 vs 35.5 mo (HR 0.50, 95% CI 0.33-0.75) |
Preceding treatment
Targeted therapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
3-month cycle for 8 cycles (2 years)
References
- AGMT CLL-8a: Greil R, Obrtlíková P, Smolej L, Kozák T, Steurer M, Andel J, Burgstaller S, Mikušková E, Gercheva L, Nösslinger T, Papajík T, Ladická M, Girschikofsky M, Hrubiško M, Jäger U, Fridrik M, Pecherstorfer M, Králiková E, Burcoveanu C, Spasov E, Petzer A, Mihaylov G, Raynov J, Oexle H, Zabernigg A, Flochová E, Palášthy S, Stehlíková O, Doubek M, Altenhofer P, Pleyer L, Melchardt T, Klingler A, Mayer J, Egle A. Rituximab maintenance versus observation alone in patients with chronic lymphocytic leukaemia who respond to first-line or second-line rituximab-containing chemoimmunotherapy: final results of the AGMT CLL-8a Mabtenance randomised trial. Lancet Haematol. 2016 Jul;3(7):e317-29. Epub 2016 Jun 16. link to original article contains dosing details in abstract PubMed Clinical Trial Registry
Prognosis
These are various staging and risk prediction systems that are in approximate chronological order.
Original Rai staging (1975)
- Stage 0: bone marrow and blood lymphocytosis only
- Stage I: lymphocytosis with enlarged nodes
- Stage II: lymphocytosis with enlarged spleen or liver or both
- Stage III: lymphocytosis with anemia
- Stage IV: lymphocytosis with thrombocytopenia
- Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. Clinical staging of chronic lymphocytic leukemia. Blood. 1975 Aug;46(2):219-34. link to original article PubMed
Binet staging (1981)
- Group A: no anemia, no thrombocytopenia, less than three involved areas
- Group B: no anemia, no thrombocytopenia, three or more involved areas (counting as one each of the following: axillary, cervical, inguinal, lymph nodes, whether unilateral or bilateral, spleen and liver)
- Group C: anemia (hemoglobin less than 10 g/dL) and/or thrombocytopenia (platelets less than 100 x 109/L)
- Binet JL, Auquier A, Dighiero G, Chastang C, Piguet H, Goasguen J, Vaugier G, Potron G, Colona P, Oberling F, Thomas M, Tchernia G, Jacquillat C, Boivin P, Lesty C, Duault MT, Monconduit M, Belabbes S, Gremy F. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer. 1981 Jul 1;48(1):198-206. link to original article PubMed
Risk by cytogenetics
- Classic NEJM paper establishing abnormal karyotype as an adverse prognostic marker
- Han T, Ozer H, Sadamori N, Emrich L, Gomez GA, Henderson ES, Bloom ML, Sandberg AA. Prognostic importance of cytogenetic abnormalities in patients with chronic lymphocytic leukemia. N Engl J Med. 1984 Feb 2;310(5):288-92. to original article PubMed
- Large retrospective series looking at cytogenetic complexity
- Baliakas P, Jeromin S, Iskas M, Puiggros A, Plevova K, Nguyen-Khac F, Davis Z, Rigolin GM, Visentin A, Xochelli A, Delgado J, Baran-Marszak F, Stalika E, Abrisqueta P, Durechova K, Papaioannou G, Eclache V, Dimou M, Iliakis T, Collado R, Doubek M, Calasanz MJ, Ruiz-Xiville N, Moreno C, Jarosova M, Leeksma AC, Panayiotidis P, Podgornik H, Cymbalista F, Anagnostopoulos A, Trentin L, Stavroyianni N, Davi F, Ghia P, Kater AP, Cuneo A, Pospisilova S, Espinet B, Athanasiadou A, Oscier D, Haferlach C, Stamatopoulos K; ERIC, the European Research Initiative on CLL. Cytogenetic complexity in chronic lymphocytic leukemia: definitions, associations, and clinical impact. Blood. 2019 Mar 14;133(11):1205-1216. Epub 2019 Jan 2. link to original article PubMed
Risk by lymphocyte doubling time
- Montserrat E, Sanchez-Bisono J, Viñolas N, Rozman C. Lymphocyte doubling time in chronic lymphocytic leukaemia: analysis of its prognostic significance. Br J Haematol. 1986 Mar;62(3):567-75. link to original article PubMed
- Molica S, Alberti A. Prognostic value of the lymphocyte doubling time in chronic lymphocytic leukemia. Cancer. 1987 Dec 1;60(11):2712-6. link to original article PubMed
Risk by FISH
- Classic 2000 NEJM paper establishing that 17p deletion has the worst prognosis:
- Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L, Döhner K, Bentz M, Lichter P. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000 Dec 28;343(26):1910-6. link to original article PubMed
- This article and abstract explore the significance of 13q deletions in more detail:
- Van Dyke DL, Shanafelt TD, Call TG, Zent CS, Smoley SA, Rabe KG, Schwager SM, Sonbert JC, Slager SL, Kay NE. A comprehensive evaluation of the prognostic significance of 13q deletions in patients with B-chronic lymphocytic leukaemia. Br J Haematol. 2010 Feb;148(4):544-50. Epub 2009 Nov 6. link to original article link to PMC article PubMed
- Abstract: Claudia Haferlach, Melanie Zenger, Vera Grossmann, Frank Dicker, Sabine Jeromin, Alexander Kohlmann, Susanne Schnittger, Wolfgang Kern, Torsten Haferlach. The Impact of Homozygosity and Size of the 13q Deletion in Patients with CLL. Blood 2012 120:3892 abstract 3892 link to abstract
Risk by TP53 mutation
- Zenz T, Eichhorst B, Busch R, Denzel T, Häbe S, Winkler D, Bühler A, Edelmann J, Bergmann M, Hopfinger G, Hensel M, Hallek M, Döhner H, Stilgenbauer S. TP53 mutation and survival in chronic lymphocytic leukemia. J Clin Oncol. 2010 Oct 10;28(29):4473-9. Epub 2010 Aug 9. link to original article PubMed
Risk by CD38 expression
- Damle RN, Wasil T, Fais F, Ghiotto F, Valetto A, Allen SL, Buchbinder A, Budman D, Dittmar K, Kolitz J, Lichtman SM, Schulman P, Vinciguerra VP, Rai KR, Ferrarini M, Chiorazzi N. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood. 1999 Sep 15;94(6):1840-7. link to original article PubMed
- Review: Malavasi F, Deaglio S, Damle R, Cutrona G, Ferrarini M, Chiorazzi N. CD38 and chronic lymphocytic leukemia: a decade later. Blood. 2011 Sep 29;118(13):3470-8. link to original article link to PMC article PubMed
Risk by ZAP-70 expression (2003)
- Crespo M, Bosch F, Villamor N, Bellosillo B, Colomer D, Rozman M, Marcé S, López-Guillermo A, Campo E, Montserrat E. ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med. 2003 May 1;348(18):1764-75. link to original article PubMed
Prognostic scoring system using molecular and cytogenetic features (2012)
- Rossi D, Rasi S, Spina V, Bruscaggin A, Monti S, Ciardullo C, Deambrogi C, Khiabanian H, Serra R, Bertoni F, Forconi F, Laurenti L, Marasca R, Dal-Bo M, Rossi FM, Bulian P, Nomdedeu J, Del Poeta G, Gattei V, Pasqualucci L, Rabadan R, Foà R, Dalla-Favera R, Gaidano G. Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia. Blood. 2013 Feb 21;121(8):1403-12. Epub 2012 Dec 13. link to original article link to PMC article PubMed
CLL-IPI (2016)
- International CLL-IPI working group. An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncol. 2016 Jun;17(6):779-90. Epub 2016 May 13. link to original article PubMed
Prognostic scoring system using clinical features (2019)
- Soumerai JD, Ni A, Darif M, Londhe A, Xing G, Mun Y, Kay NE, Shanafelt TD, Rabe KG, Byrd JC, Chanan-Khan AA, Furman RR, Hillmen P, Jones J, Seymour JF, Sharman JP, Ferrante L, Mobasher M, Stark T, Reddy V, Dreiling LK, Bhargava P, Howes A, James DF, Zelenetz AD. Prognostic risk score for patients with relapsed or refractory chronic lymphocytic leukaemia treated with targeted therapies or chemoimmunotherapy: a retrospective, pooled cohort study with external validations. Lancet Haematol. 2019 Jul;6(7):e366-e374. Epub 2019 May 17. Erratum in: Lancet Haematol. 2019 Jul;6(7):e348. link to original article link to PMC article PubMed