Chronic lymphocytic leukemia

Page editor		Section editor
	Jon Arnason, MD Beth Israel Deaconess Medical Center Boston, MA, USA LinkedIn		Sanjai Sharma, MD Sequoia Regional Cancer Center Visalia, CA, USA LinkedIn

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. For placebo or observational studies in this condition, other than watchful waiting, please visit this 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 patients with CLL or in mixed populations of patients with CLL and SLL.

• We have moved How I Treat articles to a dedicated page.

86 regimens on this page 133 variants on this page

Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

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 PubMed

ESMO

• 2021: Eichhorst et al. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
  • 2015: Eichhorst et al. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
  • 2011: Eichhorst et al. Chronic lymphocytic leukemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
  • 2010: Eichhorst et al. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
  • 2009: Eichhorst et al. Chronic lymphocytic leukemia: ESMO minimum clinical recommendations for diagnosis, treatment and follow-up PubMed
  • 2008: Eichhorst et al. Chronic lymphocytic leukemia: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
  • 2007: Hallek. Chronic lymphocytic leukemia: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
  • 2005: Hallek et al. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of chronic lymphocytic leukemia PubMed
• 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
• 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) link to PMC 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
• 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 PubMed
• 1996: Cheson et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment PubMed

NCCN

• NCCN Guidelines - Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
  • 2020: Wierda et al. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 4.2020, NCCN Clinical Practice Guidelines in Oncology. PubMed
  • 2015: Zelenetz et al. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 1.2015 link to PMC article 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 (primary endpoint) 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

1. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT02475681
2. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT02029443

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 (primary endpoint) 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

1. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT02475681

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 (primary endpoint) 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) as follows:
  • Starting dose: 3 mg IV once per day
  • Once tolerated in terms of infusion reactions: 10 mg IV once per day
  • Once 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

1. 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 dosing details in abstract have been reviewed by our editors PubMed NCT00046683

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 (co-primary endpoint) 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 (secondary endpoint) Median PFS: 16.5 vs 9.6 mo Superior ORR (primary endpoint)

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.

Chemotherapy

• Bendamustine 100 mg/m² IV once per day on days 1 & 2

28-day cycle for 6 cycles

References

1. Knauf WU, Lissichkov T, Aldaoud A, Liberati A, Loscertales J, Herbrecht R, Juliusson G, Postner G, Gercheva L, Goranov S, Becker M, Fricke HJ, Huguet F, Del Giudice I, Klein P, Tremmel L, Merkle K, Montillo M. Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009 Sep 10;27(26):4378-84. Epub 2009 Aug 3. link to original article dosing details in manuscript have been reviewed by our editors PubMed
   1. Update: Knauf WU, Lissitchkov T, Aldaoud A, Liberati AM, Loscertales J, Herbrecht R, Juliusson G, Postner G, Gercheva L, Goranov S, Becker M, Fricke HJ, Huguet F, Del Giudice I, Klein P, Merkle K, Montillo M. Bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukaemia: updated results of a randomized phase III trial. Br J Haematol. 2012 Oct;159(1):67-77. Epub 2012 Aug 4. link to original article PubMed
2. 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
3. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT01109264

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	Inconclusive whether non-inferior PFS (primary endpoint) Median PFS: 41.7 vs 55.2 mo (HR 1.64, 90.4% CI 1.31-2.06)
Michallet et al. 2018 (MABLE)	2010-2014	Phase 3b (E-switch-ic)	R-Clb	Superior PFS (secondary endpoint) Median PFS: 39.6 vs 29.9 mo (HR 0.52, 95% CI 0.34-0.81)
Woyach et al. 2018 (Alliance A041202)	2013-2016	Phase 3 (C)	1. Ibrutinib 2. Ibrutinib & Rituximab	Inferior PFS
Eichhorst et al. 2023 (GAIA)	2016-12-13 to 2019-10-13	Phase 3 (C)	1. Venetoclax & Obinutuzumab 2. Ibrutinib, Venetoclax, Obinutuzumab	Inferior PFS
			3. Venetoclax & Rituximab	Did not meet primary endpoint of PFS
Tam et al. 2022 (SEQUOIACLL)	2017-2019	Phase 3 (C)	Zanubrutinib	Inferior PFS

Eligibility criteria

• GAIA: Older than 65 years old

Biomarker eligibility criteria

• SEQUOIA_CLL: 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 up to 6: 500 mg/m² IV once on day 1

28-day cycle for up to 6 cycles

Regimen variant #2, 6 cycles with escalation

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Woyach et al. 2018 (Alliance A041202)	2013-2016	Phase 3 (C)	1. Ibrutinib 2. Ibrutinib & Rituximab	Inferior PFS

Chemotherapy

• Bendamustine as follows:
  • Cycle 1: 70 mg/m² IV once per day on days 1 & 2
  • Cycles 2 to 6: 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
  • Cycle 2 up to 6: 500 mg/m² IV once on day 1

28-day cycle for 6 cycles

Regimen variant #3, 6 cycles with maintenance rituximab

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Wang et al. 2022 (SHINE)	2013-05 to 2014-11	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) as follows:
  • Cycles 1 to 6: 375 mg/m² IV once on day 1
  • Cycles 7 to 18: 375 mg/m² IV once on day 1

28-day cycle for 6 cycles, then 8-week cycle for 12 cycles

References

1. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT00274989
2. 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
3. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT00769522
4. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01056510
5. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01886872
   1. Update: Woyach JA, Perez Burbano G, Ruppert AS, Miller C, Heerema NA, Zhao W, Wall A, Ding W, Bartlett NL, Brander DM, Barr PM, Rogers KA, Parikh SA, Stephens DM, Brown JR, Lozanski G, Blachly J, Nattam S, Larson RA, Erba H, Litzow M, Luger S, Owen C, Kuzma C, Abramson JS, Little RF, Dinner S, Stone RM, Uy G, Stock W, Mandrekar SJ, Byrd JC. Follow-up from the A041202 study shows continued efficacy of ibrutinib regimens for older adults with CLL. Blood. 2024 Apr 18;143(16):1616-1627. link to original article link to PMC article PubMed
6. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT01776840
7. SEQUOIA_CLL: 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 dosing details in manuscript have been reviewed by our editors PubMed NCT03336333
   1. HRQoL analysis: Ghia P, Barnes G, Yang K, Tam CS, Robak T, Brown JR, Kahl BS, Tian T, Szeto A, Paik JC, Shadman M. Health-related quality-of-life in treatment-naive CLL/SLL patients treated with zanubrutinib versus bendamustine plus rituximab. Curr Med Res Opin. 2023 Nov;39(11):1505-1511. Epub 2023 Oct 12. link to original article PubMed
8. GAIA: Eichhorst B, Niemann CU, Kater AP, Fürstenau M, von Tresckow J, Zhang C, Robrecht S, Gregor M, Juliusson G, Thornton P, Staber PB, Tadmor T, Lindström V, da Cunha-Bang C, Schneider C, Poulsen CB, Illmer T, Schöttker B, Nösslinger T, Janssens A, Christiansen I, Baumann M, Frederiksen H, van der Klift M, Jäger U, Leys MBL, Hoogendoorn M, Lotfi K, Hebart H, Gaska T, Koene H, Enggaard L, Goede J, Regelink JC, Widmer A, Simon F, De Silva N, Fink AM, Bahlo J, Fischer K, Wendtner CM, Kreuzer KA, Ritgen M, Brüggemann M, Tausch E, Levin MD, van Oers M, Geisler C, Stilgenbauer S, Hallek M; GCLLSG, the HOVON and Nordic CLL Study Groups, the SAKK, the Israeli CLL Association, and Cancer Trials Ireland. First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia. N Engl J Med. 2023 May 11;388(19):1739-1754. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT02950051
   1. Update: Fürstenau M, Kater AP, Robrecht S, von Tresckow J, Zhang C, Gregor M, Thornton P, Staber PB, Tadmor T, Lindström V, Juliusson G, Janssens A, Levin MD, da Cunha-Bang C, Schneider C, Goldschmidt N, Vandenberghe E, Rossi D, Benz R, Nösslinger T, Heintel D, Poulsen CB, Christiansen I, Frederiksen H, Enggaard L, Posthuma EFM, Issa DE, Visser HPJ, Bellido M, Kutsch N, Dürig J, Stehle A, Vöhringer M, Böttcher S, Schulte C, Simon F, Fink AM, Fischer K, Holmes EE, Kreuzer KA, Ritgen M, Brüggemann M, Tausch E, Stilgenbauer S, Hallek M, Niemann CU, Eichhorst B. First-line venetoclax combinations versus chemoimmunotherapy in fit patients with chronic lymphocytic leukaemia (GAIA/CLL13): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2024 Jun;25(6):744-759. Erratum in: Lancet Oncol. 2024 Jul;25(7):e284. link to original article PubMed
9. ACE-CL-311: NCT03836261
10. BRUIN CLL-313: NCT05023980
11. CRISTALLO: NCT04285567

Bendamustine & Rituximab (BR) & Ibrutinib

BR & Ibrutinib: Bendamustine, Rituximab, Ibrutinib

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Wang et al. 2022 (SHINE)	2013-05 to 2014-11	Phase 3 (E-esc)	BR	Seems to have superior PFS (primary endpoint) 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 6: 375 mg/m² IV once on day 1
  • Cycles 7 to 18: 375 mg/m² IV once on day 1
• Ibrutinib (Imbruvica) as follows:
  • Cycles 1 to 6: 560 mg PO once per day on days 1 to 28
  • Cycle 7 onwards: 560 mg PO once per day on days 1 to 56

28-day cycle for 6 cycles, then 8-week cycles

References

1. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT01776840

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 (primary endpoint)
			2. CMC	Seems to have inferior CR rate (primary endpoint)

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

1. PALG CLL2: Robak T, Blonski JZ, Gora-Tybor J, Jamroziak K, Dwilewicz-Trojaczek J, Tomaszewska A, Konopka L, Ceglarek B, Dmoszynska A, Kowal M, Kloczko J, Stella-Holowiecka B, Sulek K, Calbecka M, Zawilska K, Kuliczkowski K, Skotnicki AB, Warzocha K, Kasznicki M; 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 dosing details in manuscript have been reviewed by our editors PubMed
   1. 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
2. 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 dosing details in manuscript have been reviewed by our editors 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 (secondary endpoint) Median OS: NYR vs NYR (HR 0.41, 95% CI 0.23-0.74) Superior PFS (primary endpoint) Median PFS: 26.7 vs 11.1 mo (HR 0.18, 95% CI 0.13-0.24)
			2. Chlorambucil & Rituximab	Superior PFS (primary endpoint) (HR 0.39, 95% CI 0.31-0.49)
Moreno et al. 2018 (iLLUMINATE)	2014-10-06 to 2015-10-12	Phase 3 (C)	Ibrutinib & Obinutuzumab	Inferior PFS
Sharman et al. 2020 (ELEVATE TN)	2015-2017	Phase 3 (C)	1. Acalabrutinib 2. Acalabrutinib & Obinutuzumab	Inferior PFS
Kater et al. 2022 (GLOW)	2018-05 to 2019-04	Phase 3 (C)	Ibrutinib & Venetoclax	Inferior PFS

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)	2015-08-07 to 2016-08-04	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

1. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT01010061
   1. Update: Goede V, Fischer K, Engelke A, Schlag R, Lepretre S, Casado Montero LF, Montillo M, Fegan C, Asikanius E, Humphrey K, Fingerle-Rowson G, Hallek M. Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study. Leukemia. 2015 Jul;29(7):1602-4. Epub 2015 Jan 30. link to original article PubMed
2. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT02264574
3. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT02242942
   1. 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
   2. 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
4. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT02475681
5. GLOW: Kater AP, Owen C, Moreno C, Follows G, Munir T, Levin MD, Benjamini O, Janssens A, Osterborg A, Robak T, Simkovic M, Stevens D, Voloshin S, Vorobyev V, Ysebaert L, Qin R, Steele AJ, Schuier N, Baeten K, Caces DB, Niemann CU. Fixed-Duration Ibrutinib-Venetoclax in Patients with Chronic Lymphocytic Leukemia and Comorbidities. NEJM Evid. 2022 Jul;1(7):EVIDoa2200006. Epub 2022 May 13. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT03462719
   1. Update: Niemann CU, Munir T, Moreno C, Owen C, Follows GA, Benjamini O, Janssens A, Levin MD, Robak T, Simkovic M, Voloshin S, Vorobyev V, Yagci M, Ysebaert L, Qi K, Qi Q, Sinet P, Parisi L, Srinivasan S, Schuier N, Baeten K, Howes A, Caces DB, Kater AP. Fixed-duration ibrutinib-venetoclax versus chlorambucil-obinutuzumab in previously untreated chronic lymphocytic leukaemia (GLOW): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2023 Dec;24(12):1423-1433. Epub 2023 Nov 6. link to original article PubMed
6. UNITY-CLL: NCT02612311

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 (primary endpoint) 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
  • Cycles 2 to 3 up to 12: 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

1. 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 dosing details in abstract have been reviewed by our editors PubMed NCT00748189
   1. Update: Offner F, Robak T, Janssens A, Govind Babu K, Kloczko J, Grosicki S, Mayer J, Panagiotidis P, Schuh A, Pettitt A, Montillo M, Werner O, Vincent G, Khanna S, Hillmen P. A five-year follow-up of untreated patients with chronic lymphocytic leukaemia treated with ofatumumab and chlorambucil: final analysis of the Complement 1 phase 3 trial. Br J Haematol. 2020 Sep;190(5):736-740. Epub 2020 Mar 31. link to original article PubMed

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 (primary endpoint) Median PFS: 16.3 vs 11.1 mo (HR 0.44, 95% CI 0.34-0.57)
			2. Chlorambucil & Obinutuzumab	Inferior PFS (primary endpoint)
Awaiting publication (D822BC00001)	2020-2024	Phase 3 (C)	Acalabrutinib	TBD if different primary endpoint of PFS

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 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
  • Cycles 4 to 8: 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 (secondary endpoint)

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 consolidation x up to 6 cycles
• MABLE, patients not achieving CR: Optional chlorambucil consolidation x up to 6 cycles or until CR

References

1. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT01010061
   1. Update: Goede V, Fischer K, Engelke A, Schlag R, Lepretre S, Casado Montero LF, Montillo M, Fegan C, Asikanius E, Humphrey K, Fingerle-Rowson G, Hallek M. Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study. Leukemia. 2015 Jul;29(7):1602-4. Epub 2015 Jan 30. link to original article PubMed
2. 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 dosing details in manuscript have been reviewed by our editors PubMed EudraCT 2008-001612-20
3. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00532129
4. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01056510
5. D822BC00001: contains dosing details on CT.gov NCT04075292

Cladribine monotherapy

Regimen variant #1, 0.6 mg/kg

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Robak et al. 2006 (PALG CLL2)	1998-2003	Phase 3 (C)	1. CC	Might have inferior CR rate
			2. CMC	Inferior CR rate

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

Regimen variant #3, 5 mg/m²

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Mulligan et al. 2014	1997-2004	Phase 3 (E-switch-ic)	1. Chlorambucil 2. Fludarabine	Did not meet primary endpoint of ORR Superior PFS (secondary endpoint)

Chemotherapy

• Cladribine (Leustatin) 5 mg/m² SC or IV over 2 hours once per day on days 1 to 5

28-day cycle for up to 6 cycles

Regimen variant #4, 10 mg/m²

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Mulligan et al. 2014	1997-2004	Phase 3 (E-switch-ic)	1. Chlorambucil 2. Fludarabine	Did not meet primary endpoint of ORR Superior PFS (secondary endpoint)

Chemotherapy

• Cladribine (Leustatin) 10 mg/m² PO once per day on days 1 to 5

28-day cycle for up to 6 cycles

References

1. Saven A, Lemon RH, Kosty M, Beutler E, Piro LD. 2-Chlorodeoxyadenosine activity in patients with untreated chronic lymphocytic leukemia. J Clin Oncol. 1995 Mar;13(3):570-4. link to original article dosing details in abstract have been reviewed by our editors PubMed
2. 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 dosing details in manuscript have been reviewed by our editors PubMed
   1. 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
3. 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 dosing details in manuscript have been reviewed by our editors PubMed

FCA

FCA: Fludarabine, Cyclophosphamide, Alemtuzumab
FCCam: Fludarabine, Cyclophosphamide, Campath (Alemtuzumab)

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Geisler et al. 2014 (HOVON-68)	2006-2010	Phase 3 (E-esc)	FC	Superior PFS (primary endpoint) PFS36: 53% vs 37%

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
  • Cycles 2 to 6: 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

Regimen variant #2

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
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.

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) 30 mg SC once per day on day 1 to 3

28-day cycle for 6 cycles

References

1. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT00564512
2. 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 dosing details in manuscript have been reviewed by our editors PubMed NTR529

FCR

FCR: Fludarabine, Cyclophosphamide, Rituximab
R-FC: Rituximab, Fludarabine, Cyclophosphamide

Regimen variant #1, 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 #2, 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 (primary endpoint)
Hillmen et al. 2023 (FLAIR)	2014-09-19 to 2018-07-19	Phase 3 (C)	Ibrutinib & Rituximab	Inferior PFS
Hillmen et al. 2023 (FLAIR part 2)	2017-07-20 to 2021-03-24	Phase 3 (C)	1. Ibrutinib & Venetoclax	Inferior PFS/OS
			2. Ibrutinib	Not reported

Note: in contrast to other variants, FC was given over 5 days not 3. ARCTIC should not be confused with the trial by the same name in NSCLC. FLAIR was a platform trial with distinct enrollments, such that Hillmen et al. 2023 is labeled as FLAIR part 2.

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

Regimen variant #3, 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 #4, 25/250/375-500, IV FC

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 PFS (primary endpoint) PFS36: 65% vs 45% (HR 0.56, 95% CI 0.46-0.69) Superior OS1 (secondary endpoint) 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)	Watchful waiting	Superior EFS (primary endpoint) 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
Assouline et al. 2016 (SAWYER)	2012-08-20 to 2013-06-17	Randomized Phase 1b (C)	FCR (SC Rituximab)	Not reported
Shanafelt et al. 2019 (ECOG E1912)	2014-2016	Phase 3 (C)	Ibrutinib & Rituximab	Inferior OS
Eichhorst et al. 2023 (GAIA)	2016-12-13 to 2019-10-13	Phase 3 (C)	1. Venetoclax & Obinutuzumab 2. Ibrutinib, Venetoclax, Obinutuzumab	Inferior PFS
			3. Venetoclax & Rituximab	Did not meet primary endpoint of PFS

¹Reported efficacy for GCLLSG CLL8 is based on the 2016 update.
Note: ECOG E1912 used alternate rituximab dosing in cycle 1: 50 mg/m² IV once on day 1, then 325 mg/m² IV once on day 2.

Eligibility criteria

• GAIA: 65 years old or younger

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
  • Cycles 2 to 6: 500 mg/m² IV once on day 1

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 #5, 25/250/375-500, PO FC

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Lepretre et al. 2012 (GOELAMS CLL2007FMP)	2007-2009	Phase 3 (C)	FCCam	Did not meet primary endpoint of PFS36

Chemotherapy

• Fludarabine (Fludara) 25 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 0
  • Cycles 2 to 6: 500 mg/m² IV once on day 1

28-day cycle for 6 cycles

Regimen variant #6, 25/250/500

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Awan et al. 2014 (LUCID)	2006 to not reported	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 equivalent
• Acyclovir (Zovirax) 400 mg PO twice per day or equivalent
• Growth factors at physician discretion

28-day cycle for 6 cycles

Regimen variant #7, 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

References

1. Keating MJ, O'Brien S, Albitar M, Lerner S, Plunkett W, Giles F, Andreeff M, Cortes J, Faderl S, Thomas D, Koller C, Wierda W, Detry MA, Lynn A, Kantarjian H. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol. 2005 Jun 20;23(18):4079-88. Epub 2005 Mar 14. link to original article dosing details in manuscript have been reviewed by our editors PubMed
   1. 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
   2. 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
   3. Update: Thompson PA, Bazinet A, Wierda WG, Tam CS, O'Brien SM, Saha S, Peterson CB, Plunkett W, Keating MJ. Sustained remissions in CLL after frontline FCR treatment with very-long-term follow-up. Blood. 2023 Nov 23;142(21):1784-1788. link to original article PubMed
2. Tam CS, Wolf M, Prince HM, Januszewicz EH, Westerman D, Lin KI, Carney D, Seymour JF. Fludarabine, cyclophosphamide, and rituximab for the treatment of patients with chronic lymphocytic leukemia or indolent non-Hodgkin lymphoma. Cancer. 2006 Jun 1;106(11):2412-20. link to original article dosing details in manuscript have been reviewed by our editors PubMed
3. 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 dosing details in manuscript have been reviewed by our editors PubMed
   1. 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
4. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT00281918
   1. Update: Fischer K, Bahlo J, Fink AM, Goede V, Herling CD, Cramer P, Langerbeins P, von Tresckow J, Engelke A, Maurer C, Kovacs G, Herling M, Tausch E, Kreuzer KA, Eichhorst B, Böttcher S, Seymour JF, Ghia P, Marlton P, Kneba M, Wendtner CM, Döhner H, Stilgenbauer S, Hallek M. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016 Jan 14;127(2):208-15. Epub 2015 Oct 20. link to original article PubMed
   2. HRQoL analysis: Kutsch N, Busch R, Bahlo J, Mayer J, Hensel M, Hopfinger G, Hess G, von Grünhagen U, Wendtner CM, Maria Fink A, Fischer K, Hallek M, Eichhorst B. FCR front-line therapy and quality of life in patients with chronic lymphocytic leukemia. Leuk Lymphoma. 2017 Feb;58(2):399-407. Epub 2016 Jun 29. link to original article PubMed
5. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT00564512
6. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT00275054
7. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT00391066
8. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT01292603
9. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT00769522
10. 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 dosing details in manuscript have been reviewed by our editors PubMed ISRCTN42165735
11. 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 dosing details in supplement have been reviewed by our editors PubMed ISRCTN16544962
12. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT00645606
13. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT02048813
    1. 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
14. FLAIR: Hillmen P, Pitchford A, Bloor A, Broom A, Young M, Kennedy B, Walewska R, Furtado M, Preston G, Neilson JR, Pemberton N, Sidra G, Morley N, Cwynarski K, Schuh A, Forconi F, Elmusharaf N, Paneesha S, Fox CP, Howard DR, Hockaday A, Brown JM, Cairns DA, Jackson S, Greatorex N, Webster N, Shingles J, Dalal S, Patten PEM, Allsup D, Rawstron A, Munir T. Ibrutinib and rituximab versus fludarabine, cyclophosphamide, and rituximab for patients with previously untreated chronic lymphocytic leukaemia (FLAIR): interim analysis of a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2023 May;24(5):535-552. link to original article dosing details in manuscript have been reviewed by our editors PubMed ISRCTN01844152
15. GAIA: Eichhorst B, Niemann CU, Kater AP, Fürstenau M, von Tresckow J, Zhang C, Robrecht S, Gregor M, Juliusson G, Thornton P, Staber PB, Tadmor T, Lindström V, da Cunha-Bang C, Schneider C, Poulsen CB, Illmer T, Schöttker B, Nösslinger T, Janssens A, Christiansen I, Baumann M, Frederiksen H, van der Klift M, Jäger U, Leys MBL, Hoogendoorn M, Lotfi K, Hebart H, Gaska T, Koene H, Enggaard L, Goede J, Regelink JC, Widmer A, Simon F, De Silva N, Fink AM, Bahlo J, Fischer K, Wendtner CM, Kreuzer KA, Ritgen M, Brüggemann M, Tausch E, Levin MD, van Oers M, Geisler C, Stilgenbauer S, Hallek M; GCLLSG, the HOVON and Nordic CLL Study Groups, the SAKK, the Israeli CLL Association, and Cancer Trials Ireland. First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia. N Engl J Med. 2023 May 11;388(19):1739-1754. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT02950051
    1. Update: Fürstenau M, Kater AP, Robrecht S, von Tresckow J, Zhang C, Gregor M, Thornton P, Staber PB, Tadmor T, Lindström V, Juliusson G, Janssens A, Levin MD, da Cunha-Bang C, Schneider C, Goldschmidt N, Vandenberghe E, Rossi D, Benz R, Nösslinger T, Heintel D, Poulsen CB, Christiansen I, Frederiksen H, Enggaard L, Posthuma EFM, Issa DE, Visser HPJ, Bellido M, Kutsch N, Dürig J, Stehle A, Vöhringer M, Böttcher S, Schulte C, Simon F, Fink AM, Fischer K, Holmes EE, Kreuzer KA, Ritgen M, Brüggemann M, Tausch E, Stilgenbauer S, Hallek M, Niemann CU, Eichhorst B. First-line venetoclax combinations versus chemoimmunotherapy in fit patients with chronic lymphocytic leukaemia (GAIA/CLL13): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2024 Jun;25(6):744-759. Erratum in: Lancet Oncol. 2024 Jul;25(7):e284. link to original article PubMed
16. FLAIR part 2: Munir T, Cairns DA, Bloor A, Allsup D, Cwynarski K, Pettitt A, Paneesha S, Fox CP, Eyre TA, Forconi F, Elmusharaf N, Kennedy B, Gribben J, Pemberton N, Sheehy O, Preston G, Schuh A, Walewska R, Duley L, Howard D, Hockaday A, Jackson S, Greatorex N, Girvan S, Bell S, Brown JM, Webster N, Dalal S, de Tute R, Rawstron A, Patten PEM, Hillmen P; National Cancer Research Institute Chronic Lymphocytic Leukemia Subgroup. Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease. N Engl J Med. 2024 Jan 25;390(4):326-337. Epub 2023 Dec 10. link to original article dosing details in supplement have been reviewed by our editors PubMed ISRCTN01844152
17. ACE-CL-311: NCT03836261
18. CRISTALLO: NCT04285567

FCR (SC Rituximab)

FCR: Fludarabine, Cyclophosphamide, Rituximab hyaluronidase

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Assouline et al. 2016 (SAWYER)	2012-08-20 to 2013-06-17	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

1. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT01292603

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 PFS (primary endpoint) Median PFS: 23.7 vs 16.5 mo (HR 0.61, 95% CI 0.47-0.80) Superior OS (secondary endpoint) 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

1. 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 dosing details in abstract have been reviewed by our editors PubMed NCT00086580

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 to not reported	Phase 3 (E-RT-switch-ooc)	Chlorambucil	Superior PFS (primary endpoint) PFS18: 90% vs 52% (HR 0.16, 95% CI 0.09-0.28) Superior OS1 (secondary endpoint) 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)	1. BR	Superior PFS2 (primary endpoint) Median PFS: NYR vs 44 mo (HR 0.36, 95% CI 0.25-0.51)
			2. Ibrutinib & Rituximab	Did not meet primary endpoint of PFS2 Median PFS: NYR vs NYR (HR 1.01, 95% CI 0.68-1.52)
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 (primary endpoint) 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 if different primary endpoint of PFS
Awaiting publication (GCLLSG CLL17)	2021-2027	Phase 3 (C)	1. VG 2. VI	TBD if different primary endpoint of PFS
Awaiting publication (BRUIN CLL-314)	2022-2028	Phase 3 (C)	Pirtobrutinib	TBD if different primary endpoint of ORR

¹Reported efficacy for RESONATE-2 is based on the 2019 update.
²Reported efficacy for Alliance A041202 is based on the 2024 update.
Note: 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

Targeted therapy

• Ibrutinib (Imbruvica) 420 mg PO once per day on days 1 to 28

28-day cycles

References

1. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01105247
   1. 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
   2. 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
   3. 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
2. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01500733
3. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01722487
   1. Update: Barr PM, Robak T, Owen C, Tedeschi A, Bairey O, Bartlett NL, Burger JA, Hillmen P, Coutre S, Devereux S, Grosicki S, McCarthy H, Li J, Simpson D, Offner F, Moreno C, Zhou C, Styles L, James D, Kipps TJ, Ghia P. Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: extended phase 3 results from RESONATE-2. Haematologica. 2018 Sep;103(9):1502-1510. Epub 2018 Jun 7. link to original article link to PMC article PubMed
   2. Update: Burger JA, Barr PM, Robak T, Owen C, Ghia P, Tedeschi A, Bairey O, Hillmen P, Coutre SE, Devereux S, Grosicki S, McCarthy H, Simpson D, Offner F, Moreno C, Dai S, Lal I, Dean JP, Kipps TJ. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia. 2020 Mar;34(3):787-798. Epub 2019 Oct 18. link to original article link to PMC article PubMed
4. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01886872
   1. Update: Woyach JA, Perez Burbano G, Ruppert AS, Miller C, Heerema NA, Zhao W, Wall A, Ding W, Bartlett NL, Brander DM, Barr PM, Rogers KA, Parikh SA, Stephens DM, Brown JR, Lozanski G, Blachly J, Nattam S, Larson RA, Erba H, Litzow M, Luger S, Owen C, Kuzma C, Abramson JS, Little RF, Dinner S, Stone RM, Uy G, Stock W, Mandrekar SJ, Byrd JC. Follow-up from the A041202 study shows continued efficacy of ibrutinib regimens for older adults with CLL. Blood. 2024 Apr 18;143(16):1616-1627. link to original article link to PMC article PubMed
5. 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 dosing details in abstract have been reviewed by our editors link to PMC article PubMed NCT02007044
6. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT02863718
7. BRUIN CLL-314: NCT05254743
8. GCLLSG CLL17: NCT04608318
9. SYMPATICO: NCT03112174

Ibrutinib & Obinutuzumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Moreno et al. 2018 (iLLUMINATE)	2014-10-06 to 2015-10-12	Phase 3 (E-RT-switch-ooc)	G-Clb	Superior PFS (primary endpoint) 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

1. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT02264574
2. ECOG-ACRIN EA9161: NCT03701282
3. Alliance A041702: NCT03737981

Ibrutinib & Rituximab

Regimen variant #1, limited duration

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hillmen et al. 2023 (FLAIR)	2014-09-19 to 2018-07-19	Phase 3 (E-switch-ooc)	FCR	Superior PFS (primary endpoint) Median PFS: NYR vs 67 mo (HR 0.44, 95% CI 0.32-0.60)

Targeted therapy

• Ibrutinib (Imbruvica) 420 mg PO once per day on days 1 to 28
• 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 up to 78 cycles (6 years)

Regimen variant #2, indefinite

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Shanafelt et al. 2019 (ECOG E1912)	2014-2016	Phase 3 (E-RT-switch-ooc)	FCR	Superior PFS (primary endpoint) PFS36: 89.4% vs 72.9% (HR 0.35, 95% CI 0.22-0.56) Superior OS1 (secondary endpoint) 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 on days 1 to 28
• 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

1. 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 link to PMC article PubMed NCT01886872
   1. Update: Woyach JA, Perez Burbano G, Ruppert AS, Miller C, Heerema NA, Zhao W, Wall A, Ding W, Bartlett NL, Brander DM, Barr PM, Rogers KA, Parikh SA, Stephens DM, Brown JR, Lozanski G, Blachly J, Nattam S, Larson RA, Erba H, Litzow M, Luger S, Owen C, Kuzma C, Abramson JS, Little RF, Dinner S, Stone RM, Uy G, Stock W, Mandrekar SJ, Byrd JC. Follow-up from the A041202 study shows continued efficacy of ibrutinib regimens for older adults with CLL. Blood. 2024 Apr 18;143(16):1616-1627. link to original article link to PMC article PubMed
2. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT02048813
   1. 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
3. FLAIR: Hillmen P, Pitchford A, Bloor A, Broom A, Young M, Kennedy B, Walewska R, Furtado M, Preston G, Neilson JR, Pemberton N, Sidra G, Morley N, Cwynarski K, Schuh A, Forconi F, Elmusharaf N, Paneesha S, Fox CP, Howard DR, Hockaday A, Brown JM, Cairns DA, Jackson S, Greatorex N, Webster N, Shingles J, Dalal S, Patten PEM, Allsup D, Rawstron A, Munir T. Ibrutinib and rituximab versus fludarabine, cyclophosphamide, and rituximab for patients with previously untreated chronic lymphocytic leukaemia (FLAIR): interim analysis of a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2023 May;24(5):535-552. link to original article dosing details in manuscript have been reviewed by our editors PubMed ISRCTN01844152

Ibrutinib & Venetoclax

VI: Ventoclax & Ibrutinib

Regimen variant #1, 15 cycles

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kater et al. 2022 (GLOW)	2018-05 to 2019-04	Phase 3 (E-switch-ooc)	GClb	Superior PFS1 (primary endpoint) PFS42: 74.6% vs 24.8% (HR 0.21, 95% CI 0.14-0.33)

¹Reported efficacy is based on the 2023 update.

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 on days 1 to 28
• 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 on days 1 to 28

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 on days 1 to 28
• 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 24: 400 mg PO once per day on days 1 to 28

28-day cycle for up to 24 cycles

Regimen variant #3, MRD-guided discontinuation

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hillmen et al. 2023 (FLAIR part 2)	2017-07-20 to 2021-03-24	Phase 3 (E-switch-ooc)	1. FCR	Superior PFS (primary endpoint) PFS36: 97.2% vs 76.8%% (HR 0.13, 95% CI 0.07-0.24) Superior OS (secondary endpoint) OS36: 98% vs 93% (HR 0.31, 95% CI 0.15-0.67)
			2. Ibrutinib	Not reported

Note: See paper for details regarding MRD-guided discontinuation.

Targeted therapy

• Ibrutinib (Imbruvica) 420 mg PO once per day on days 1 to 28
• 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 up to 78: 400 mg PO once per day on days 1 to 28

28-day cycle for up to 78 cycles

References

1. 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 dosing details in abstract have been reviewed by our editors PubMed NCT02756897
2. GLOW: Kater AP, Owen C, Moreno C, Follows G, Munir T, Levin MD, Benjamini O, Janssens A, Osterborg A, Robak T, Simkovic M, Stevens D, Voloshin S, Vorobyev V, Ysebaert L, Qin R, Steele AJ, Schuier N, Baeten K, Caces DB, Niemann CU. Fixed-Duration Ibrutinib-Venetoclax in Patients with Chronic Lymphocytic Leukemia and Comorbidities. NEJM Evid. 2022 Jul;1(7):EVIDoa2200006. Epub 2022 May 13. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT03462719
   1. Update: Niemann CU, Munir T, Moreno C, Owen C, Follows GA, Benjamini O, Janssens A, Levin MD, Robak T, Simkovic M, Voloshin S, Vorobyev V, Yagci M, Ysebaert L, Qi K, Qi Q, Sinet P, Parisi L, Srinivasan S, Schuier N, Baeten K, Howes A, Caces DB, Kater AP. Fixed-duration ibrutinib-venetoclax versus chlorambucil-obinutuzumab in previously untreated chronic lymphocytic leukaemia (GLOW): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2023 Dec;24(12):1423-1433. Epub 2023 Nov 6. link to original article PubMed
3. FLAIR part 2: Munir T, Cairns DA, Bloor A, Allsup D, Cwynarski K, Pettitt A, Paneesha S, Fox CP, Eyre TA, Forconi F, Elmusharaf N, Kennedy B, Gribben J, Pemberton N, Sheehy O, Preston G, Schuh A, Walewska R, Duley L, Howard D, Hockaday A, Jackson S, Greatorex N, Girvan S, Bell S, Brown JM, Webster N, Dalal S, de Tute R, Rawstron A, Patten PEM, Hillmen P; National Cancer Research Institute Chronic Lymphocytic Leukemia Subgroup. Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease. N Engl J Med. 2024 Jan 25;390(4):326-337. Epub 2023 Dec 10. link to original article dosing details in supplement have been reviewed by our editors PubMed ISRCTN01844152

Ibrutinib, Venetoclax, Obinutuzumab

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Eichhorst et al. 2023 (GAIA)	2016-12-13 to 2019-10-13	Phase 3 (E-switch-ooc)	1a. BR 1b. FCR	Superior PFS2 (co-primary endpoint) PFS48: 85.5% vs 62% (HR 0.30, 97.5% CI 0.19-0.47)
			2. Venetoclax & Obinutuzumab	Might have superior PFS2 (co-primary endpoint) PFS48: 85.5% vs 81.8% (HR 0.63, 97.5% CI 0.39-1.02)
			3. Venetoclax & Rituximab	Superior PFS2 (co-primary endpoint) PFS48: 85.5% vs 70.1% (HR 0.38, 97.5% CI 0.24-0.59)

¹Reported efficacy is based on the 2021 update.
Note: Obinutuzumab is only given for the first six cycles.

Targeted therapy

• Ibrutinib (Imbruvica) 420 mg PO once per day on days 1 to 28
• 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 up to 36 cycles

Regimen variant #2

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 on days 1 to 28
• 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

1. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT02427451
2. GAIA: Eichhorst B, Niemann CU, Kater AP, Fürstenau M, von Tresckow J, Zhang C, Robrecht S, Gregor M, Juliusson G, Thornton P, Staber PB, Tadmor T, Lindström V, da Cunha-Bang C, Schneider C, Poulsen CB, Illmer T, Schöttker B, Nösslinger T, Janssens A, Christiansen I, Baumann M, Frederiksen H, van der Klift M, Jäger U, Leys MBL, Hoogendoorn M, Lotfi K, Hebart H, Gaska T, Koene H, Enggaard L, Goede J, Regelink JC, Widmer A, Simon F, De Silva N, Fink AM, Bahlo J, Fischer K, Wendtner CM, Kreuzer KA, Ritgen M, Brüggemann M, Tausch E, Levin MD, van Oers M, Geisler C, Stilgenbauer S, Hallek M; GCLLSG, the HOVON and Nordic CLL Study Groups, the SAKK, the Israeli CLL Association, and Cancer Trials Ireland. First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia. N Engl J Med. 2023 May 11;388(19):1739-1754. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT02950051
   1. Update: Fürstenau M, Kater AP, Robrecht S, von Tresckow J, Zhang C, Gregor M, Thornton P, Staber PB, Tadmor T, Lindström V, Juliusson G, Janssens A, Levin MD, da Cunha-Bang C, Schneider C, Goldschmidt N, Vandenberghe E, Rossi D, Benz R, Nösslinger T, Heintel D, Poulsen CB, Christiansen I, Frederiksen H, Enggaard L, Posthuma EFM, Issa DE, Visser HPJ, Bellido M, Kutsch N, Dürig J, Stehle A, Vöhringer M, Böttcher S, Schulte C, Simon F, Fink AM, Fischer K, Holmes EE, Kreuzer KA, Ritgen M, Brüggemann M, Tausch E, Stilgenbauer S, Hallek M, Niemann CU, Eichhorst B. First-line venetoclax combinations versus chemoimmunotherapy in fit patients with chronic lymphocytic leukaemia (GAIA/CLL13): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2024 Jun;25(6):744-759. Erratum in: Lancet Oncol. 2024 Jul;25(7):e284. link to original article PubMed

Obinutuzumab monotherapy

Regimen variant #1, standard-dose (1000 mg)

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Byrd et al. 2015 (GAGE)	2011 to not reported	Randomized Phase 2 (C)	Obinutuzumab; high-dose	Might have inferior ORR

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 up to 8: 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 for up to 8 cycles

Regimen variant #2, high-dose (2000 mg), option A

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Byrd et al. 2015 (GAGE)	2011 to not reported	Randomized Phase 2 (E-esc)	Obinutuzumab; standard-dose	Might have superior ORR (primary endpoint)

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 on day 3, then 2000 mg IV once per day on days 8 & 15
  • Cycles 2 up to 8: 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 for up to 8 cycles

Regimen variant #3, high-dose (2000 mg), option B

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Byrd et al. 2015 (GAGE)	2011 to not reported	Randomized Phase 2 (E-esc)	Obinutuzumab; standard-dose	Might have superior ORR (primary endpoint)

Targeted therapy

• Obinutuzumab (Gazyva) as follows:
  • Cycle 1: 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
  • Cycles 2 up to 8: 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 for up to 8 cycles

References

1. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01414205

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)	2015-08-07 to 2016-08-04	Phase 3 (E-RT-switch-ooc)	Chlorambucil & Obinutuzumab	Superior PFS1 (primary endpoint) Median PFS: NYR vs 36.4 mo (HR 0.33, 95% CI 0.25-0.45)
Eichhorst et al. 2023 (GAIA)	2016-12-13 to 2019-10-13	Phase 3 (E-switch-ooc)	1a. BR 1b. FCR	Superior PFS2 (co-primary endpoint) PFS48: 81.8% vs 62% (HR 0.47, 97.5% CI 0.32-0.69)
			2. Ibrutinib, Venetoclax, Obinutuzumab	Might have inferior PFS2
			3. Venetoclax & Rituximab	Superior PFS2 (co-primary endpoint) PFS48: 81.8% vs 70.1% (HR 0.57, 97.5% CI 0.38-0.84)
Awaiting publication (GCLLSG CLL16)	2022-2026	Phase 3 (C)	GAVE	TBD if different primary endpoint of PFS
Awaiting publication (MAJIC)	2022-2029	Phase 3 (C)	Acalabrutinib & Venetoclax	TBD if different primary endpoint of PFS

¹Reported efficacy is based on the 2021 update.
²Reported efficacy is based on the 2024 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

1. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT02242942
   1. 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
   2. 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
2. GAIA: Eichhorst B, Niemann CU, Kater AP, Fürstenau M, von Tresckow J, Zhang C, Robrecht S, Gregor M, Juliusson G, Thornton P, Staber PB, Tadmor T, Lindström V, da Cunha-Bang C, Schneider C, Poulsen CB, Illmer T, Schöttker B, Nösslinger T, Janssens A, Christiansen I, Baumann M, Frederiksen H, van der Klift M, Jäger U, Leys MBL, Hoogendoorn M, Lotfi K, Hebart H, Gaska T, Koene H, Enggaard L, Goede J, Regelink JC, Widmer A, Simon F, De Silva N, Fink AM, Bahlo J, Fischer K, Wendtner CM, Kreuzer KA, Ritgen M, Brüggemann M, Tausch E, Levin MD, van Oers M, Geisler C, Stilgenbauer S, Hallek M; GCLLSG, the HOVON and Nordic CLL Study Groups, the SAKK, the Israeli CLL Association, and Cancer Trials Ireland. First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia. N Engl J Med. 2023 May 11;388(19):1739-1754. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT02950051
   1. Update: Fürstenau M, Kater AP, Robrecht S, von Tresckow J, Zhang C, Gregor M, Thornton P, Staber PB, Tadmor T, Lindström V, Juliusson G, Janssens A, Levin MD, da Cunha-Bang C, Schneider C, Goldschmidt N, Vandenberghe E, Rossi D, Benz R, Nösslinger T, Heintel D, Poulsen CB, Christiansen I, Frederiksen H, Enggaard L, Posthuma EFM, Issa DE, Visser HPJ, Bellido M, Kutsch N, Dürig J, Stehle A, Vöhringer M, Böttcher S, Schulte C, Simon F, Fink AM, Fischer K, Holmes EE, Kreuzer KA, Ritgen M, Brüggemann M, Tausch E, Stilgenbauer S, Hallek M, Niemann CU, Eichhorst B. First-line venetoclax combinations versus chemoimmunotherapy in fit patients with chronic lymphocytic leukaemia (GAIA/CLL13): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2024 Jun;25(6):744-759. Erratum in: Lancet Oncol. 2024 Jul;25(7):e284. link to original article PubMed
3. EVOLVE CLL/SLL: NCT04269902
4. GCLLSG CLL16: NCT05197192
5. MAJIC: NCT05057494

Watchful waiting

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Dighiero et al. 1998 (FRE-CLL-85)	1980-1985	Phase 3 (C)	Chlorambucil	Seems to have inferior PFS
Dighiero et al. 1998 (FRE-CLL-90)	1985-1990	Phase 3 (C)	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 if different primary endpoint of EFS

References

1. 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 PubMed
2. FRE-CLL-90: Dighiero G, Maloum K, Desablens B, Cazin B, Navarro M, Leblay R, Leporrier M, Jaubert J, Lepeu G, Dreyfus B, Binet JL, Travade P; French Cooperative Group on Chronic Lymphocytic Leukemia. Chlorambucil in indolent chronic lymphocytic leukemia. N Engl J Med. 1998 May 21;338(21):1506-14. link to original article PubMed
3. 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 NCT00275054
4. GCLLSG CLL1: Hoechstetter MA, Busch R, Eichhorst B, Bühler A, Winkler D, Eckart MJ, Vehling-Kaiser U, Schimke H, Jäger U, Hurtz HJ, Hopfinger G, Hartmann F, Fuss H, Abenhardt W, Blau I, Freier W, Müller L, Goebeler M, Wendtner CM, Bahlo J, Fischer K, Bentz M, Emmerich B, Döhner H, Hallek M, Stilgenbauer S. Early, risk-adapted treatment with fludarabine in Binet stage A chronic lymphocytic leukemia patients: results of the CLL1 trial of the German CLL study group. Leukemia. 2017 Dec;31(12):2833-2837. Epub 2017 Aug 14. link to original article PubMed NCT00262782
5. 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 PubMed NCT02863718
6. GLLC-EARLY: NCT04178798

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 (primary endpoint) Median PFS: NYR vs NYR (HR 0.42, 95% CI 0.28-0.63)

Biomarker eligibility criteria

• SEQUOIA_CLL: No 17p deletion

Targeted therapy

• Zanubrutinib (Brukinsa) 160 mg PO twice per day on days 1 to 28

28-day cycles

References

1. SEQUOIA_CLL: 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 dosing details in manuscript have been reviewed by our editors PubMed NCT03336333

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

1. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT00292760

AVO

AVO: Acalabrutinib, Venetoclax, Obinutuzumab

Regimen

Study	Dates of enrollment	Evidence
Davids et al. 2021 (DFCI 18-226)	2018-2019	Phase 2

Targeted therapy

• Acalabrutinib (Calquence) 100 mg PO twice per day on days 1 to 28
• Venetoclax (Venclexta) as follows:
  • Cycle 4: 20 mg PO once on day 1, then 50 mg PO once per day on days 2 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
  • Cycle 5 onwards: 400 mg PO once per day on days 1 to 28
• 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

1. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT03580928

Bendamustine & Obinutuzumab

G-B: Gazyva (Obinutuzumab), Bendamustine

Regimen

Study	Dates of enrollment	Evidence	Efficacy
Brown et al. 2015 (GALTON)	2011 to not reported	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

1. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01300247
2. 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 dosing details in abstract have been reviewed by our editors PubMed NCT02320487

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

1. 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 dosing details in manuscript have been reviewed by our editors PubMed

G-FC

G-FC: Gazyva (Obinutuzumab), Fludarabine, Cyclophosphamide

Regimen

Study	Dates of enrollment	Evidence
Brown et al. 2015 (GALTON)	2011 to not reported	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

1. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01300247

HDMP-R

HDMP-R: High Dose, MethylPrednisolone & Rituximab

Regimen

Study	Dates of enrollment	Evidence
Castro et al. 2009	Not reported	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

1. 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 dosing details in abstract have been reviewed by our editors link to PMC article PubMed

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:
  • Lead-in: 420 mg PO once per day on days 1 to 7
  • Cycle 1 onwards: 420 mg PO once per day on days 1 to 28
• 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

7-day lead-in, then 28-day cycles (see note)

References

1. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT02251548

Lenalidomide & Rituximab (R²)

Regimen variant #1

Study	Dates of enrollment	Evidence
James et al. 2014 (CRC014)	2008 to not reported	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
  • Cycles 3 up to 7: 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
  • Cycles 3 up to 7: 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 course, 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

1. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00628238
2. 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 dosing details in abstract have been reviewed by our editors link to PMC article PubMed NCT00695786

O-FC

O-FC: Ofatumumab, Fludarabine, Cyclophosphamide

Regimen

Study	Dates of enrollment	Evidence
Wierda et al. 2011 (407 Study)	2007 to not reported	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
  • Cycles 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

1. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00410163

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

1. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT01024010
2. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01681563
3. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT01024010

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	Not reported	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 to not reported	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

1. 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 dosing details in abstract have been reviewed by our editors link to PMC article PubMed
2. 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
3. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00496873

RCC

RCC: Rituximab, Cladribine, Cyclophosphamide

Regimen

Study	Dates of enrollment	Evidence
Robak et al. 2018 (PALG CLL4)	2009-07 to 2011-12	Non-randomized part of phase 3b RCT

Targeted therapy

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

Chemotherapy

• Cladribine (Leustatin) 0.12 mg/kg IV once per day on days 2 to 4
• Cyclophosphamide (Cytoxan) 250 mg/m² IV over 15 to 30 minutes once per day on days 2 to 4

28-day cycle for 6 cycles

Subsequent treatment

• Observation versus Rituximab maintenance

References

1. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT00718549

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 on day 1
  • In Hainsworth et al. 2003, optional alternate initial dosing for patients with WBC count more 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 on day 1; 30 minutes prior to rituximab
• Diphenhydramine (Benadryl) 50 mg PO or IV once on day 1; 30 minutes prior to rituximab
• In Hainsworth et al. 2003, if WBC count more 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 on day 1; 30 minutes prior to rituximab
  • Ranitidine (Zantac) 50 mg IV once on day 1; 30 minutes prior to rituximab

7-day cycle for 4 cycles

Subsequent treatment

• Hainsworth et al. 2003, SD or better: Rituximab maintenance
• RESORT substudy, PR/CR: Indefinite rituximab continuation versus salvage rituximab at time of progression

References

1. Hainsworth JD, Litchy S, Barton JH, Houston GA, Hermann RC, Bradof JE, Greco FA; Minnie Pearl Cancer Research Network. Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol. 2003 May 1;21(9):1746-51. link to original article dosing details in manuscript have been reviewed by our editors PubMed
2. 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 dosing details in abstract have been reviewed by our editors link to PMC article PubMed NCT01406782

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

Continued indefinitely

References

1. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT02131584

Zanubrutinib & Obinutuzumab

Regimen

Study	Dates of enrollment	Evidence
Tam et al. 2020	2016 to not reported	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

1. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT02569476

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

• First-line 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)	Not reported	Phase 3 (E-esc)	Observation	Superior PFS1 (primary endpoint)

¹Reported efficacy is based on the 2009 update.
Note: this study closed early due to high rates of infections in the experimental arm. Alemtuzumab dose is increased only if tolerated.

Preceding treatment

• First-line F x 6 or FC x 6

Targeted therapy

• Alemtuzumab (Campath) as follows:
  • Cycle 1: 3 mg SC once on day 1, then 10 mg SC once on day 2, then 30 mg SC once on day 5
  • Cycles 2 to 12: 30 mg SC once per day on days 1, 3, 5 (three times per week)

7-day cycle for 12 cycles

References

1. 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 dosing details in manuscript have been reviewed by our editors PubMed
   1. 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
2. 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 dosing details in abstract have been reviewed by our editors 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 (primary endpoint) Median PFS: NYR vs 13.3 mo (HR 0.17, 95% CI 0.07-0.38)

Note that while the NCT01556776 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". Lenalidomide dose is only increased if tolerated.

Preceding treatment

• GCLLSG CLLM1: First-line chemoimmunotherapy

Targeted therapy

• Lenalidomide (Revlimid) as follows:
  • Cycle 1: 5 mg PO once per day on days 1 to 28
  • Cycles 2 to 6: 10 mg PO once per day on days 1 to 28
  • Cycle 7 onwards: 15 mg PO once per day on days 1 to 28

28-day cycles

References

1. 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 dosing details in abstract have been reviewed by our editors PubMed NCT01556776

Ofatumumab monotherapy

Regimen

Study	Dates of enrollment	Evidence
Strati et al. 2016 (MC0983 arm 2)	2011-2012	Phase 2

Preceding treatment

• First-line PCO x 6

Targeted therapy

• Ofatumumab (Arzerra) 1000 mg IV once on day 1

28-day cycle for 6 cycles

References

1. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT01024010

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 (secondary endpoint)

Preceding treatment

• ML21445: First-line Clb-R

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV once on day 1

8-week cycle for 6 cycles

Regimen variant #2, 2 years, given q3mo

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Bosch et al. 2009	2005-11 to 2007-11	Phase 2
Robak et al. 2018 (PALG CLL4)	2009-07 to 2011-12	Phase 3b (E-esc)	Observation	Seems to have superior PFS
Greil et al. 2016 (AGMT CLL-8a)	2010-2013	Phase 3 (E-esc)	Observation	Superior PFS (primary endpoint) Median PFS: 47 vs 35.5 mo (HR 0.50, 95% CI 0.33-0.75)

Preceding treatment

• Bosch et al. 2009: First-line R-FCM
• PALG CLL4: First-line RCC x 6
• AGMT CLL-8a: First-line 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 (primary endpoint) Median PFS: 59.3 vs 49 mo (HR 0.55, 95% CI 0.40-0.75)

Note the higher dose used here.

Preceding treatment

• First-line 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)	Not reported	Phase 3 (E-esc)	Observation	Superior PFS (primary endpoint) Median PFS: 4.3 vs 1.3 y (HR 0.40, 95% CI 0.30-0.50)

ECOG E1496 included patients with SLL, but they were grouped into an "other" non-follicular lymphoma category.

Preceding treatment

• Hainsworth et al. 2003: First-line rituximab
• ECOG E1496: First-line CVP

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 (E-esc)	Rituximab salvage	Seems to have superior TTTF

Intended for patients with SLL.

Preceding treatment

• First-line Rituximab

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV once on day 1

13-week cycles

Regimen variant #6, indefinite 500 mg/m² q3mo

Study	Dates of enrollment	Evidence
Foon et al. 2009	2003-2007	Phase 2

Preceding treatment

• First-line FCR-Lite x 6

Targeted therapy

• Rituximab (Rituxan) 500 mg/m² IV once on day 1

3-month cycles

References

1. Hainsworth JD, Litchy S, Barton JH, Houston GA, Hermann RC, Bradof JE, Greco FA; Minnie Pearl Cancer Research Network. Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol. 2003 May 1;21(9):1746-51. link to original article PubMed
2. 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 dosing details in manuscript have been reviewed by our editors PubMed
   1. 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
3. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00003204
4. 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 dosing details in manuscript have been reviewed by our editors PubMed EudraCT 2005-001569-33
   1. Update: Abrisqueta P, Villamor N, Terol MJ, González-Barca E, González M, Ferrà C, Abella E, Delgado J, García-Marco JA, González Y, Carbonell F, Ferrer S, Monzó E, Jarque I, Muntañola A, Constants M, Escoda L, Calvo X, Bobillo S, Montoro JB, Montserrat E, Bosch F. Rituximab maintenance after first-line therapy with rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) for chronic lymphocytic leukemia. Blood. 2013 Dec 5;122(24):3951-9. Epub 2013 Oct 11. link to original article dosing details in manuscript have been reviewed by our editors PubMed
5. 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 dosing details in manuscript have been reviewed by our editors PubMed EudraCT 2008-001612-20
6. 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 dosing details in abstract have been reviewed by our editors link to PMC article PubMed NCT01406782
7. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT01118234
8. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT00645606
9. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT00718549

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 to not reported	Phase 1/2		ORR: 95%
Byrd et al. 2021 (ACE-CL-006)	2015-2017	Phase 3 (E-switch-ic)	Ibrutinib	Non-inferior PFS (primary endpoint) Median PFS: 38.4 vs 38.4 mo (HR 1.00, 95% CI 0.79-1.27)
Ghia et al. 2020 (ASCEND)	2017-02-21 to 2018-01-17	Phase 3 (E-RT-switch-ooc)	Investigator's choice of: 1a. BR 1b. Idelalisib & Rituximab	Superior PFS (primary endpoint) 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

Targeted therapy

• Acalabrutinib (Calquence) 100 mg PO twice per day

Continued indefinitely

References

1. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT02029443
2. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT02970318
3. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT02477696

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 (primary endpoint) Median PFS: 20.1 vs 14.8 mo (HR 0.87, 90% CI 0.60-1.27)

Chemotherapy

• Bendamustine 100 mg/m² IV once per day on days 1 & 2

28-day cycle for up to 8 cycles

Regimen variant #3, 120 mg/m²

Study	Dates of enrollment	Evidence
Friedberg et al. 2008	2003-09 to 2005-02	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

1. 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 dosing details in manuscript have been reviewed by our editors PubMed
2. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00069758
3. 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
4. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT01423032
5. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01188681

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 (primary endpoint)
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)	2017-02-21 to 2018-01-17	Phase 3 (C)	Acalabrutinib	Inferior PFS
Awaiting publication (BRUIN CLL-321)	2021-2024	Phase 3 (C)	Pirtobrutinib	TBD if different primary endpoint of PFS

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

28-day cycle for up to 6 cycles

References

1. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT00274989
2. 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
3. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT01611090
   1. 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
   2. 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
4. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT01569295
5. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01056510
6. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT02005471
   1. 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
   2. 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
   3. 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
7. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT02970318
8. BRUIN CLL-321: NCT04666038

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 to not reported	Phase 2
Chanan-Khan et al. 2015 (HELIOS)	2012-2014	Phase 3 (E-RT-esc)	BR	Superior PFS (primary endpoint) Median PFS: NYR vs 13.3 mo (HR 0.20, 95% CI 0.15-0.28) Superior OS1 (secondary endpoint) 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

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
• Ibrutinib (Imbruvica) 420 mg PO once per day on days 1 to 28

28-day cycles

References

1. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01292135
2. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT01611090
   1. 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
   2. 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 (primary endpoint) 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 on days 1 to 28

28-day cycles

References

1. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01569295

Duvelisib monotherapy

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Flinn et al. 2018 (DUO)	2014-01-21 to 2015-12-09	Phase 3 (E-RT-switch-ooc)	Ofatumumab	Superior PFS (primary endpoint) Median PFS: 13.3 vs 9.9 mo (HR 0.52)

Targeted therapy

• Duvelisib (Copiktra) 25 mg PO twice per day on days 1 to 28

28-day cycles

References

1. 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. Epub 2018 Oct 4. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT02004522

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 to not reported	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 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 (primary endpoint) 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

1. 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 dosing details in manuscript have been reviewed by our editors PubMed
   1. 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
2. Tam CS, Wolf M, Prince HM, Januszewicz EH, Westerman D, Lin KI, Carney D, Seymour JF. Fludarabine, cyclophosphamide, and rituximab for the treatment of patients with chronic lymphocytic leukemia or indolent non-Hodgkin lymphoma. Cancer. 2006 Jun 1;106(11):2412-20. link to original article dosing details in manuscript have been reviewed by our editors PubMed
3. 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 dosing details in manuscript have been reviewed by our editors PubMed content property of HemOnc.org NCT00090051
4. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT00391066

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 was 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 varying durations: 6 to 10 cycles (Johnson et al. 1996); 8 cycles (WiSP RI05)

References

1. 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 dosing details in manuscript have been reviewed by our editors PubMed
2. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT01423032

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, fewer than 20 pts
Byrd et al. 2014 (RESONATE)	2012-06 to 2013-04	Phase 3 (E-RT-switch-ooc)	Ofatumumab	Superior PFS1 (primary endpoint) 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 PFS (primary endpoint) PFS18: 74% vs 11.9% (HR 0.18, 95% CI 0.105-0.31) Superior OS (secondary endpoint) OS24: 79.8% vs 57.6% (HR 0.45, 95% CI 0.22-0.90)
Sharman et al. 2021 (GENUINE)	2015-02-06 to 2016-12-19	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

Targeted therapy

• Ibrutinib (Imbruvica) 420 mg PO once per day on days 1 to 28

28-day cycles

References

1. 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. Epub 2013 Jun 19. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01105247
   1. 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
   2. 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
   3. 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
2. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01578707
   1. 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
   2. 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
   3. 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
3. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01500733
4. 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 dosing details in abstract have been reviewed by our editors PubMed NCT01744691
5. 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
6. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01973387
7. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT02301156
8. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT02477696
9. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT03734016
   1. 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
   2. HRQoL analysis: Tam CS, Lamanna N, O'Brien SM, Qiu L, Yang K, Barnes G, Wu K, Salmi T, Brown JR. Health-related quality of life outcomes associated with zanubrutinib versus ibrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma: results from the ALPINE Trial. Curr Med Res Opin. 2023 Nov;39(11):1497-1503. Epub 2023 Oct 27. link to original article PubMed

Ibrutinib & Ublituximab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Sharman et al. 2021 (GENUINE)	2015-02-06 to 2016-12-19	Phase 3 (E-esc)	Ibrutinib	Seems to have superior ORR (primary endpoint)

Biomarker eligibility criteria

• 17p deletion, 11q deletion, or TP53 mutation

Targeted therapy

• Ibrutinib (Imbruvica) 420 mg PO once per day on days 1 to 28
• Ublituximab (Briumvi) as follows:
  • Cycle 1: 150 mg IV over 4 hours once on day 1, then 750 mg IV over 4 hours once on day 2, then 900 mg IV over 3 hours once per day on days 8 & 15
  • Cycles 2 to 5: 900 mg IV over 90 minutes once on day 1
  • Cycle 6 onwards: 900 mg IV once on day 1

28-day cycle for 5 cycles, then 12-week cycles

References

1. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT02301156

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 (primary endpoint) 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

1. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT01659021

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)	2012-05 to 2013-08	Phase 3 (E-RT-esc)	Rituximab	Superior PFS (primary endpoint) 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 on days 1 to 28
• 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 up to 18 cycles

Regimen variant #2, indefinite

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ghia et al. 2020 (ASCEND)	2017-02-21 to 2018-01-17	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 on days 1 to 28
• Rituximab (Rituxan) as follows:
  • Cycle 1: 375 mg/m² IV once on day 15
  • 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

28-day cycles

References

1. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01539512
   1. 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 link to PMC article PubMed
2. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT02970318
3. BRUIN CLL-321: NCT04666038

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.

Prior treatment criteria

• Fludarabine and ofatumumab exposure, with refractory disease

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 to not reported	Phase 2 (RT)
Österborg et al. 2016 (Novartis 114242)	2011 to not reported	Phase 3 (E-switch)	Physician's choice	Did not meet primary endpoint of PFS
Byrd et al. 2014 (RESONATE)	2012-06 to 2013-04	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)	2014-01-21 to 2015-12-09	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.

Prior treatment criteria

• Hx-CD20-406 & Novartis 114242: Fludarabine exposure, with refractory disease

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 to not reported	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

1. Coiffier B, Lepretre S, Pedersen LM, Gadeberg O, Fredriksen H, van Oers MH, Wooldridge J, Kloczko J, Holowiecki J, Hellmann A, Walewski J, Flensburg M, Petersen J, Robak T. Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1-2 study. Blood. 2008 Feb 1;111(3):1094-100. Epub 2007 Nov 14. link to original article PubMed
2. 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 dosing details in abstract have been reviewed by our editors link to PMC article PubMed NCT00349349
   1. 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
   2. 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
3. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01578707
   1. 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
   2. 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
   3. 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
4. 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
5. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT00802737
6. Novartis 114242: Österborg A, Udvardy M, Zaritskey A, Andersson PO, Grosicki S, Mazur G, Kaplan P, Steurer M, Schuh A, Montillo M, Kriachok 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 NCT01313689
   1. Update: Miklos U, Strugov V, Lewerin C, Grosicki S, Mazur G, Steurer M, Montillo M, Kriachok 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
7. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT01659021
8. 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 NCT01580228
9. 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. Epub 2018 Oct 4. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT02004522

O-FC

O-FC: Ofatumumab, Fludarabine, Cyclophosphamide

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Robak et al. 2016 (COMPLEMENT 2)	2008 to not reported	Phase 3 (E-RT-esc)	FC	Superior PFS (primary endpoint) 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

1. COMPLEMENT 2: Robak T, Warzocha K, Govind Babu K, Kulyaba Y, Kuliczkowski K, Abdulkadyrov K, Loscertales J, Kriachok I, Kłoczko J, Rekhtman G, Homenda W, Błoński JZ, McKeown A, Gorczyca MM, Carey JL, Chang CN, Lisby S, Gupta IV, Grosicki S. Ofatumumab plus fludarabine and cyclophosphamide in relapsed chronic lymphocytic leukemia: results from the COMPLEMENT 2 trial. Leuk Lymphoma. 2017 May;58(5):1084-1093. Epub 2016 Oct 12. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00824265

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 (primary endpoint)

Preceding treatment

• RESORT substudy: First-line Rituximab, with progression

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV once on day 1

7-day cycle for 4 cycles

Regimen variant #2, 8 doses

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Furman et al. 2014 (GS-US-312-0116)	2012-05 to 2013-08	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

1. 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 dosing details in manuscript have been reviewed by our editors PubMed
2. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01539512
   1. 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 link to PMC article PubMed
3. 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 dosing details in abstract have been reviewed by our editors link to PMC article PubMed NCT01406782
4. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01973387

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 if different primary endpoint of PFS

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
  • Weeks 5 up to 104: 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

1. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT02005471
   1. 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
   2. 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
   3. 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
2. BRUIN CLL-322: NCT04965493

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) Superior ORR (primary endpoint)

¹Reported efficacy is based on the 2022 update.

Prior treatment criteria

• ALPINE: At least 1 prior systemic therapy; prior BTKi not allowed

Targeted therapy

• Zanubrutinib (Brukinsa) 160 mg PO twice per day on days 1 to 28

28-day cycles

References

1. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT03734016
   1. 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
   2. HRQoL analysis: Tam CS, Lamanna N, O'Brien SM, Qiu L, Yang K, Barnes G, Wu K, Salmi T, Brown JR. Health-related quality of life outcomes associated with zanubrutinib versus ibrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma: results from the ALPINE Trial. Curr Med Res Opin. 2023 Nov;39(11):1497-1503. Epub 2023 Oct 27. 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	Not reported-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	Not reported	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

1. Keating MJ, Flinn I, Jain V, Binet JL, Hillmen P, Byrd J, Albitar M, Brettman L, Santabarbara P, Wacker B, Rai KR. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood. 2002 May 15;99(10):3554-61. link to original article dosing details in abstract have been reviewed by our editors PubMed
2. Rai KR, Freter CE, Mercier RJ, Cooper MR, Mitchell BS, Stadtmauer EA, Santábarbara P, Wacker B, Brettman L. Alemtuzumab in previously treated chronic lymphocytic leukemia patients who also had received fludarabine. J Clin Oncol. 2002 Sep 15;20(18):3891-7. link to original article dosing details in abstract have been reviewed by our editors PubMed
3. Lozanski G, Heerema NA, Flinn IW, Smith L, Harbison J, Webb J, Moran M, Lucas M, Lin T, Hackbarth ML, Proffitt JH, Lucas D, Grever MR, Byrd JC. Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions. Blood. 2004 May 1;103(9):3278-81. Epub 2004 Jan 15. link to original article dosing details in abstract have been reviewed by our editors PubMed

Alemtuzumab & Rituximab

Regimen

Study	Dates of enrollment	Evidence
Faderl et al. 2003	Not reported	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 more 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

1. Faderl S, Thomas DA, O'Brien S, Garcia-Manero G, Kantarjian HM, Giles FJ, Koller C, Ferrajoli A, Verstovsek S, Pro B, Andreeff M, Beran M, Cortes J, Wierda W, Tran N, Keating MJ. Experience with alemtuzumab plus rituximab in patients with relapsed and refractory lymphoid malignancies. Blood. 2003 May 1;101(9):3413-5. Epub 2003 Jan 9. link to original article dosing details in abstract have been reviewed by our editors 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
  • Cycles 2 to 6: 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 for up to 6 cycles

References

1. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT01244451

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

1. 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 dosing details in abstract have been reviewed by our editors link to PMC article PubMed NCT01082939

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

1. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT02158091

Fludarabine & Alemtuzumab

FluCam: Fludarabine & Campath (Alemtuzumab)

Regimen

Study	Dates of enrollment	Evidence
Elter et al. 2005	Not reported	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 more 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

1. Elter T, Borchmann P, Schulz H, Reiser M, Trelle S, Schnell R, Jensen M, Staib P, Schinköthe T, Stützer H, Rech J, Gramatzki M, Aulitzky W, Hasan I, Josting A, Hallek M, Engert A. Fludarabine in combination with alemtuzumab is effective and feasible in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: results of a phase II trial. J Clin Oncol. 2005 Oct 1;23(28):7024-31. Epub 2005 Sep 6. link to original article dosing details in abstract have been reviewed by our editors 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 on days 1 to 28

28-day cycles

References

1. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT02514083

Fludarabine & Prednisone

Regimen

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

Chemotherapy

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

Glucocorticoid therapy

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

28-day cycles

References

1. O'Brien S, Kantarjian H, Beran M, Smith T, Koller C, Estey E, Robertson LE, Lerner S, Keating M. Results of fludarabine and prednisone therapy in 264 patients with chronic lymphocytic leukemia with multivariate analysis-derived prognostic model for response to treatment. Blood. 1993 Sep 15;82(6):1695-700. link to original article dosing details in abstract have been reviewed by our editors PubMed
   1. Update: Keating MJ, O'Brien S, Lerner S, Koller C, Beran M, Robertson LE, Freireich EJ, Estey E, Kantarjian H. Long-term follow-up of patients with chronic lymphocytic leukemia (CLL) receiving fludarabine regimens as initial therapy. Blood. 1998 Aug 15;92(4):1165-71. link to original article PubMed

HDMP-R

HDMP-R: High Dose, MethylPrednisolone, Rituximab

Regimen variant #1, 3 cycles

Study	Dates of enrollment	Evidence
Castro et al. 2008	Not reported	Phase 2, fewer than 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 (LT-CLL-001)	2007-09 to 2009-01	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

1. 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 dosing details in manuscript have been reviewed by our editors PubMed
2. LT-CLL-001: 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 dosing details in abstract have been reviewed by our editors PubMed NCT00558181

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 on days 1 to 28
• 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 on days 1 to 28
• 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 on days 1 to 28
• 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

1. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01217749

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 on days 1 to 28
• 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

1. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01520519
   1. 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 on days 1 to 28
• 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 on days 1 to 28
• 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

1. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT02427451

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)

Targeted therapy

• Idelalisib (Zydelig) 150 mg PO twice per day

Continued indefinitely

References

1. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01282424
   1. 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.
2. 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 NCT00710528

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 on days 1 to 28
  • Cycle 2: 15 mg PO once per day on days 1 to 28
  • Cycle 3: 20 mg PO once per day on days 1 to 28
  • Cycle 4 onwards: 25 mg PO once per day on days 1 to 28

28-day cycles

Regimen variant #3

Study	Dates of enrollment	Evidence
Witzig et al. 2009 (CC-5013-NHL-001)	2005-2006	Phase 2, fewer than 20 patients in this subgroup

Note: Patients studied in this trial and in this subgroup had a diagnosis of SLL.

Targeted therapy

• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21

28-day cycles

References

1. Chanan-Khan A, Miller KC, Musial L, Lawrence D, Padmanabhan S, Takeshita K, Porter CW, Goodrich DW, Bernstein ZP, Wallace P, Spaner D, Mohr A, Byrne C, Hernandez-Ilizaliturri F, Chrystal C, Starostik P, Czuczman MS. Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study. J Clin Oncol. 2006 Dec 1;24(34):5343-9. Epub 2006 Nov 6. link to original article dosing details in manuscript have been reviewed by our editors PubMed
2. 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 NCT00267059
3. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT00179673

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
  • Cycles 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

1. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01002755

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
  • Cycles 2 to 12: 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

1. Chanan-Khan A, Miller KC, Musial L, Lawrence D, Padmanabhan S, Takeshita K, Porter CW, Goodrich DW, Bernstein ZP, Wallace P, Spaner D, Mohr A, Byrne C, Hernandez-Ilizaliturri F, Chrystal C, Starostik P, Czuczman MS. Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study. J Clin Oncol. 2006 Dec 1;24(34):5343-9. Epub 2006 Nov 6. link to original article dosing details in manuscript have been reviewed by our editors PubMed
2. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00759603

Lisocabtagene maraleucel monotherapy

Regimen

Study	Dates of enrollment	Evidence
Siddiqi et al. 2023 (TRANSCEND CLL 004)	2018-01-02 to 2022-06-16	Phase 1/2

Note: this is the dose-level 2 of the phase 1/2 trial.

Immunotherapy

• Lisocabtagene maraleucel (Breyanzi) target dose of 100 x 10⁶ CAR T cells IV once on day 0

One course

References

1. TRANSCEND CLL 004:Siddiqi T, Maloney DG, Kenderian SS, Brander DM, Dorritie K, Soumerai J, Riedell PA, Shah NN, Nath R, Fakhri B, Stephens DM, Ma S, Feldman T, Solomon SR, Schuster SJ, Perna SK, Tuazon SA, Ou SS, Papp E, Peiser L, Chen Y, Wierda WG. Lisocabtagene maraleucel in chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1-2 study. Lancet. 2023 Aug 19;402(10402):641-654. Epub 2023 Jun 5. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT03331198

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 obinutuzumab

21-day cycle for up to 8 cycles

References

1. 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 NCT00517530
   1. 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 dosing details in manuscript have been reviewed by our editors PubMed
   2. 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 dosing details in manuscript have been reviewed by our editors PubMed
   3. 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 dosing details in manuscript have been reviewed by our editors PubMed

OFAR

OFAR: Oxaliplatin, Fludarabine, Ara-C (Cytarabine), Rituximab

Regimen

Study	Dates of enrollment	Evidence	Efficacy
Tsimberidou et al. 2008	2004-2006	Phase 1/2	Likely has true ORR > 20%

Note: the manuscript does not specify what sequence the rituximab is given in.

Chemotherapy

• Oxaliplatin (Eloxatin) 25 mg/m² IV over 2 hours once per day on days 1 to 4, given first (see note)
• Fludarabine (Fludara) 30 mg/m² IV once per day on days 2 & 3, given second, within 30 minutes of completion of oxaliplatin (see note)
• Cytarabine (Ara-C) 1000 mg/m² IV over 2 hours once per day on days 2 & 3, given third, 4 hours after start of fludarabine (see note)

Targeted therapy

• Rituximab (Rituxan) as follows (see note):
  • 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

1. Tsimberidou AM, Wierda WG, Plunkett W, Kurzrock R, O'Brien S, Wen S, Ferrajoli A, Ravandi-Kashani F, Garcia-Manero G, Estrov Z, Kipps TJ, Brown JR, Fiorentino A, Lerner S, Kantarjian HM, Keating MJ. Phase I-II study of oxaliplatin, fludarabine, cytarabine, and rituximab combination therapy in patients with Richter's syndrome or fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol. 2008 Jan 10;26(2):196-203. link to original article dosing details in abstract have been reviewed by our editors 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:
  • 70 kg or less: 300 mcg SC once per day from day 3 until ANC greater than 5000/μL once or 1500/μL for 2 days
  • 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

1. Lamanna N, Kalaycio M, Maslak P, Jurcic JG, Heaney M, Brentjens R, Zelenetz AD, Horgan D, Gencarelli A, Panageas KS, Scheinberg DA, Weiss MA. Pentostatin, cyclophosphamide, and rituximab is an active, well-tolerated regimen for patients with previously treated chronic lymphocytic leukemia. J Clin Oncol. 2006 Apr 1;24(10):1575-81. Epub 2006 Mar 6. link to original article dosing details in manuscript have been reviewed by our editors PubMed

Pirtobrutinib monotherapy

Regimen

Study	Dates of enrollment	Evidence
Mato et al. 2023 (BRUINCLL)	2019-03-21 to 2022-07-29	Phase 1/2 (RT)

Note: This was the RP2D.

Targeted therapy

• Pirtobrutinib (Jaypirca) 200 mg PO once per day

Continued indefinitely

References

1. BRUIN_CLL: Mato AR, Woyach JA, Brown JR, Ghia P, Patel K, Eyre TA, Munir T, Lech-Maranda E, Lamanna N, Tam CS, Shah NN, Coombs CC, Ujjani CS, Fakhri B, Cheah CY, Patel MR, Alencar AJ, Cohen JB, Gerson JN, Flinn IW, Ma S, Jagadeesh D, Rhodes JM, Hernandez-Ilizaliturri F, Zinzani PL, Seymour JF, Balbas M, Nair B, Abada P, Wang C, Ruppert AS, Wang D, Tsai DE, Wierda WG, Jurczak W. Pirtobrutinib after a Covalent BTK Inhibitor in Chronic Lymphocytic Leukemia. N Engl J Med. 2023 Jul 6;389(1):33-44. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT03740529

R-BAC

R-BAC: Rituximab, Bendamustine, Ara-C (Cytarabine)

Regimen

Study	Dates of enrollment	Evidence
Visco et al. 2013	2010-2012	Pilot, fewer than 20 patients reported

Targeted therapy

• Rituximab (Rituxan) as follows:
  • Cycle 1: 375 mg/m² IV once on day 1
  • Cycles 2 to 4: 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

1. 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 dosing details in manuscript have been reviewed by our editors PubMed

Ruxolitinib monotherapy

Regimen

Study	Dates of enrollment	Evidence
Jain et al. 2017 (MDACC 2013-0044)	2014-2015	Phase 2, fewer than 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

Continued indefinitely

References

1. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT02131584

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 to not reported	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:
  • Cycle 1: 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 2 onwards: 400 mg PO once per day on days 1 to 28

28-day cycles

Regimen variant #2, modified lead-in

Study	Dates of enrollment	Evidence	Efficacy
Coutre et al. 2018 (M14-032 idelalisib cohort)	2014 to not reported	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:
  • Cycle 1: 20 mg PO once on day 1, then 50 mg PO once per day on days 2 & 3, then 100 mg PO once per day on days 4 to 7, then 200 mg PO once per day on days 8 to 14, then 400 mg PO once per day on days 15 to 28
  • Cycle 2 onwards: 400 mg PO once per day on days 1 to 28

28-day cycles

References

1. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01328626
2. 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 dosing details in abstract have been reviewed by our editors PubMed NCT01889186
   1. 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
3. 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 NCT02141282
4. 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 dosing details in supplement have been reviewed by our editors link to PMC article PubMed NCT02141282

Zanubrutinib & Obinutuzumab

Regimen

Study	Dates of enrollment	Evidence
Tam et al. 2020	2016 to not reported	Phase 1b, >20 pts in this subgroup

Targeted therapy

• Zanubrutinib (Brukinsa) 160 mg PO twice per day or 320 mg PO once per day on days 1 to 28
• 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

1. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT02569476

Consolidation and/or maintenance after subsequent lines of therapy

Busulfan & Fludarabine, then allo HSCT

Regimen

Study	Dates of enrollment	Evidence
Slavin et al. 1998	Not reported	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)

GVHD prophylaxis

• 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

One course

References

1. 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 dosing details in manuscript have been reviewed by our editors PubMed
2. 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

Cyclophosphamide & Fludarabine (FC), then allo HSCT

FluCy: 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 (5 consecutive days)
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once per day on days -6 to -2 (5 consecutive days)

GVHD prophylaxis

• ATG-Fresenius by the following donor-based criteria:
  • Unrelated donors: 10 mg/kg/day IV on days -4 to -1 (4 consecutive days)

Immunotherapy

• Allogeneic stem cells transfused on day 0

One course

References

1. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT00281983
   1. 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
   2. 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) 200 cGy at a rate of 7 cGy/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)

One course

References

1. 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 dosing details in manuscript have been reviewed by our editors PubMed
   1. 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

Lenalidomide monotherapy

Regimen

Study	Dates of enrollment	Evidence
Badoux et al. 2013 (MDACC 2007-0208)	2008-2009	Phase 2
Vitale et al. 2016 (MDACC 2009-0283)	2010-2011	Phase 2

Preceding treatment

• MDACC 2007-0208: Salvage R² x 12
• MDACC 2009-0283: Salvage Lenalidomide & Ofatumumab x 24

Targeted therapy

• Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 28

28-day cycles

References

1. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00759603
2. 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01002755

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 (primary endpoint) 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

• Second-line 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

1. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT00802737
2. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT00802737

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 (primary endpoint) Median PFS: 47 vs 35.5 mo (HR 0.50, 95% CI 0.33-0.75)

Preceding treatment

• Second-line rituximab-containing chemoimmunotherapy

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV once on day 1

3-month cycle for 8 cycles (2 years)

References

1. 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 dosing details in manuscript have been reviewed by our editors PubMed NCT01118234

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

1. 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)

1. 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

1. 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

1. 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 link to PMC article PubMed

Risk by lymphocyte doubling time

1. 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
2. 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:

1. 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:

1. 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
2. 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

1. 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

1. 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
2. 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)

1. 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)

1. 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)

• QxMD calculator

1. 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)

1. 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