Chronic lymphocytic leukemia

Back to Top
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. Please see the indolent lymphoma page for other regimens that have been tested in the broader population.
*We have moved How I Treat articles to a dedicated page.
Last updated on 2024-12-02:91 regimens on this page
134 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 EuroPMC
==ESMO==
*2024: Eichhorst et al. ESMO Clinical Practice Guideline interim update on new targeted therapies in the first line and at relapse of chronic lymphocytic leukaemia EuroPMC
**2021: Eichhorst et al. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2015: Eichhorst et al. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2011: Eichhorst et al. Chronic lymphocytic leukemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2010: Eichhorst et al. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2009: Eichhorst et al. Chronic lymphocytic leukemia: ESMO minimum clinical recommendations for diagnosis, treatment and follow-up EuroPMC
**2008: Eichhorst et al. Chronic lymphocytic leukemia: ESMO clinical recommendations for diagnosis, treatment and follow-up EuroPMC
**2007: Hallek. Chronic lymphocytic leukemia: ESMO clinical recommendations for diagnosis, treatment and follow-up EuroPMC
**2005: Hallek et al. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of chronic lymphocytic leukemia EuroPMC
*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 EuroPMC
*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 EuroPMC
==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 EuroPMC
*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 EuroPMC
*1996: Cheson et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment EuroPMC
==NCCN==
*NCCN Guidelines - Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
**2024: Wierda et al. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology EuroPMC
**2020: Wierda et al. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 4.2020, NCCN Clinical Practice Guidelines in Oncology EuroPMC
**2015: Zelenetz et al. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 1.2015 link to PMC article EuroPMC
=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
Sharman et al. 2020 (ELEVATE TN) 	2015-2017 	Phase 3 (E-RT-switch-ooc)	2. Chlorambucil & Obinutuzumab 	Longer 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===
# 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 EuroPMC NCT02475681
# 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 EuroPMC 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
Sharman et al. 2020 (ELEVATE TN)	2015-2017 	Phase 3 (E-RT-switch-ooc)	2. Chlorambucil & Obinutuzumab	Longer 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===
# 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 EuroPMC 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	Longer 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===
# 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 EuroPMC 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	Longer PFS (co-primary endpoint)Median PFS: 21.6 vs 8.3 mo(HR not reported)
Zhou et al. 2022 (SIM-79-001)	2009-2016 	Phase 3 (E-switch-ic) 	Chlorambucil	Longer PFS (secondary endpoint)Median PFS: 16.5 vs 9.6 mo(HR not reported)Higher 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===
# 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 EuroPMC
## 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 EuroPMC
# 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 EuroPMC
#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 EuroPMC 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 PFS1 (primary endpoint)Median PFS: 42.3 vs 57.6 mo(HR 1.59, 95% CI 1.27-2.00)
Michallet et al. 2018 (MABLE) 	2010-2014 	Phase 3b (E-switch-ic)	R-Clb 	Longer 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. Ibrutinib2. Ibrutinib & Rituximab 	Shorter PFS
Eichhorst et al. 2023 (GAIA) 	2016-12-13 to 2019-10-13	Phase 3 (C) 	1. Venetoclax & Obinutuzumab2. Ibrutinib, Venetoclax, Obinutuzumab	Shorter PFS
Eichhorst et al. 2023 (GAIA) 	2016-12-13 to 2019-10-13	Phase 3 (C) 	3. Venetoclax & Rituximab 	Did not meet primary endpoint of PFS
Tam et al. 2022 (SEQUOIACLL) 	2017-2019 	Phase 3 (C) 	Zanubrutinib 	Shorter PFSMedian PFS: NYR vs NYR (HR 2.38, 95% CI 1.59-3.57)
1Reported efficacy for GCLLSG CLL10 is based on the 2020 update.
====Eligibility criteria====
*GAIA: Older than 65 years old
====Biomarker eligibility criteria====
*SEQUOIACLL: No 17p deletion
====Chemotherapy====
*Bendamustine 90 mg/m2 IV once per day on days 1 & 2
====Targeted therapy====
*Rituximab (Rituxan) as follows:
**Cycle 1: 375 mg/m2 IV once on day 0 or 1
**Cycle 2 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. Ibrutinib2. Ibrutinib & Rituximab	Shorter 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 shorter PFSMedian PFS: 52.9 vs 80.6 mo(HR 1.33, 95% CI 1.04-1.69)
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===
# 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 EuroPMC NCT00274989
# 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 EuroPMC
# 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 EuroPMC NCT00769522
##Update: Kutsch N, Bahlo J, Robrecht S, Franklin J, Zhang C, Maurer C, De Silva N, Lange E, Weide R, Kiehl MG, Sökler M, Schlag R, Vehling-Kaiser U, Köchling G, Plöger C, Gregor M, Plesner T, Herling M, Fischer K, Döhner H, Kneba M, Wendtner CM, Klapper W, Kreuzer KA, Böttcher S, Stilgenbauer S, Fink AM, Hallek M, Eichhorst B. Long Term Follow-up Data and Health-Related Quality of Life in Frontline Therapy of Fit Patients Treated With FCR Versus BR (CLL10 Trial of the GCLLSG). Hemasphere. 2020 Jan 27;4(1):e336. link to original article link to PMC article EuroPMC
# 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 EuroPMC NCT01056510
# 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 EuroPMC NCT01886872
##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 EuroPMC
# 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 EuroPMC NCT01776840
# SEQUOIACLL: Tam CS, Brown JR, Kahl BS, Ghia P, Giannopoulos K, Jurczak W, Šimkovič M, Shadman M, Österborg A, Laurenti L, Walker P, Opat S, Chan H, Ciepluch H, Greil R, Tani M, Trněný M, Brander DM, Flinn IW, Grosicki S, Verner E, Tedeschi A, Li J, Tian T, Zhou L, Marimpietri C, Paik JC, Cohen A, Huang J, Robak T, Hillmen P. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022 Aug;23(8):1031-1043. Epub 2022 Jul 7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03336333
##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 EuroPMC
#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 EuroPMC NCT02950051
##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 EuroPMC
# ACE-CL-311: NCT03836261
# BRUIN CLL-313: NCT05023980
# 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 longer 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===
# 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 EuroPMC 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 higher CR rate (primary endpoint)
Robak et al. 2006 (PALG CLL2)	1998-2003 	Phase 3 (E-esc)	2. CMC 	Seems to have lower 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===
# 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 EuroPMC
## 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 EuroPMC
# 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 EuroPMC
==Chlorambucil & Obinutuzumab (GClb)==
GClb: GA101 (Obinutuzumab) & Chlorambucil
Clb-Obi: Chlorambucil & Obinutuzumab
===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 	Longer OS (secondary endpoint)Median OS: NYR vs NYR(HR 0.41, 95% CI 0.23-0.74)Longer PFS (primary endpoint)Median PFS: 26.7 vs 11.1 mo(HR 0.18, 95% CI 0.13-0.24)
Goede et al. 2014 (GCLLSG CLL11)	2010-2012 	Phase 3 (E-RT-esc)	2. Chlorambucil & Rituximab 	Longer 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 	Shorter PFSMedian PFS: 19 vs NYR mo(HR 4.35, 95% CI 2.70-6.67)
Sharman et al. 2020 (ELEVATE TN)	2015-2017 	Phase 3 (C) 	1. Acalabrutinib2. Acalabrutinib & Obinutuzumab	Shorter PFS
Kater et al. 2022 (GLOW) 	2018-05 to 2019-04 	Phase 3 (C) 	Ibrutinib & Venetoclax 	Shorter PFS1 (primary endpoint)PFS42: 24.8% vs 74.6%(HR 4.76, 95% CI 3.03-7.14)
1Reported efficacy for GLOW 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
====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	Shorter PFS1 (primary endpoint)Median PFS: 36.4 vs 76.2 mo(HR 2.50, 95% CI 1.92-3.23)Might have shorter OS1 (secondary endpoint)OS72: 69.2% vs 78.7%(HR 1.45, 95% CI 0.99-2.08)
1Reported efficacy is based on the 2024 update.
Note: Obinutuzumab was only given for the first six cycles.
====Chemotherapy====
*Chlorambucil (Leukeran) 0.5 mg/kg PO once per day on days 1 & 15
====Targeted therapy====
*Obinutuzumab (Gazyva) as follows:
**Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15 
**Cycles 2 to 6: 1000 mg IV once on day 1
28-day cycle for 12 cycles
===References===
# GCLLSG CLL11: Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, Chagorova T, de la Serna J, Dilhuydy MS, Illmer T, Opat S, Owen CJ, Samoylova O, Kreuzer KA, Stilgenbauer S, Döhner H, Langerak AW, Ritgen M, Kneba M, Asikanius E, Humphrey K, Wenger M, Hallek M. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014 Mar 20;370(12):1101-10. Epub 2014 Jan 8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01010061
## 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 EuroPMC
# 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 EuroPMC NCT02264574
# 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 EuroPMC NCT02242942
## 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 EuroPMC
##HRQoL analysis: Al-Sawaf O, Gentile B, Devine J, Zhang C, Sail K, Tandon M, Fink AM, Kutsch N, Wendtner CM, Eichhorst B, Hallek M, Fischer K. Health-related quality of life with fixed-duration venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: Results from the randomized, phase 3 CLL14 trial. Am J Hematol. 2021 Sep 1;96(9):1112-1119. Epub 2021 Jun 22. link to original article EuroPMC
## 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 EuroPMC
##Update: Al-Sawaf O, Zhang C, Jin HY, Robrecht S, Choi Y, Balasubramanian S, Kotak A, Chang YM, Fink AM, Tausch E, Schneider C, Ritgen M, Kreuzer KA, Chyla B, Paulson JN, Pallasch CP, Frenzel LP, Peifer M, Eichhorst B, Stilgenbauer S, Jiang Y, Hallek M, Fischer K. Transcriptomic profiles and 5-year results from the randomized CLL14 study of venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab in chronic lymphocytic leukemia. Nat Commun. 2023 Apr 18;14(1):2147. Erratum in: Nat Commun. 2023 Oct 23;14(1):6724. link to original article link to PMC article EuroPMC
## Update: Al-Sawaf O, Robrecht S, Zhang C, Olivieri S, Chang YM, Fink AM, Tausch E, Schneider C, Ritgen M, Kreuzer KA, Sivchev L, Niemann CU, Schwarer A, Loscertales J, Weinkove R, Strumberg D, Kilfoyle A, Manzoor BS, Jawaid D, Emechebe N, Devine J, Boyer M, Runkel ED, Eichhorst B, Stilgenbauer S, Jiang Y, Hallek M, Fischer K. Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 6-year results of the randomized phase 3 CLL14 study. Blood. 2024 Oct 31;144(18):1924-1935. link to original article link to PMC article EuroPMC
# 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 EuroPMC NCT02475681
# 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 EuroPMC NCT03462719
##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 EuroPMC
# 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	Longer 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===
# 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 EuroPMC NCT00748189
## 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 EuroPMC
==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 	Longer PFS (primary endpoint)Median PFS: 16.3 vs 11.1 mo(HR 0.44, 95% CI 0.34-0.57)
Goede et al. 2014 (GCLLSG CLL11) 	2010-2012 	Phase 3 (E-esc)	2. Chlorambucil & Obinutuzumab	Shorter 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 	Shorter PFS (secondary endpoint)Median PFS: 29.9 vs 39.6 mo(HR 1.92, 95% CI 1.23-2.94)
====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===
# 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 EuroPMC NCT01010061
## 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 EuroPMC
# 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 EuroPMC EudraCT 2008-001612-20
# NCRI CLL08: Hillmen P, Gribben JG, Follows GA, Milligan D, Sayala HA, Moreton P, Oscier DG, Dearden CE, Kennedy DB, Pettitt AR, Nathwani A, Varghese A, Cohen D, Rawstron A, Oertel S, Pocock CF. Rituximab plus chlorambucil as first-line treatment for chronic lymphocytic leukemia: Final analysis of an open-label phase II study. J Clin Oncol. 2014 Apr 20;32(12):1236-41. Epub 2014 Mar 17. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00532129
# 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 EuroPMC NCT01056510
#D822BC00001: dosing details on CT.gov have been reviewed by our editors 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 lower CR rate
Robak et al. 2006 (PALG CLL2)	1998-2003 	Phase 3 (C)	2. CMC 	Lower 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	Efficacy
Saven et al. 1995	1988-1993 	Phase 2 	ORR: 85%, 95% CI 62.1-96.8
====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. Chlorambucil2. Fludarabine	Did not meet primary endpoint of ORRLonger 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. Chlorambucil2. Fludarabine	Did not meet primary endpoint of ORRLonger 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===
# 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 EuroPMC
# 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 EuroPMC
## 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 EuroPMC
# 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 EuroPMC
==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 	Longer PFS (primary endpoint)PFS36: 53% vs 37%(HR 0.68, 95% CI 0.51-0.91)
====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===
# 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 EuroPMC NCT00564512
# 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 EuroPMC 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 	Higher CR rate (primary endpoint)
Hillmen et al. 2023 (FLAIR) 	2014-09-19 to 2018-07-19	Phase 3 (C) 	Ibrutinib & Rituximab 	Shorter PFSMedian PFS: 67 vs NYR mo(HR 2.27, 95% CI 1.67-3.12)
Hillmen et al. 2023 (FLAIR part 2)	2017-07-20 to 2021-03-24	Phase 3 (C) 	1. Ibrutinib & Venetoclax	Shorter PFS/OS
Hillmen et al. 2023 (FLAIR part 2)	2017-07-20 to 2021-03-24	Phase 3 (C) 	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 	Longer PFS (primary endpoint)PFS36: 65% vs 45%(HR 0.56, 95% CI 0.46-0.69)Longer 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 	Longer 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 PFS2 (primary endpoint)Median PFS: 57.6 vs 42.3 mo(HR 0.63, 95% CI 0.50-0.79) 	
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 	Shorter PFS (primary endpoint)PFS36: 72.9% vs 89.4%(HR 2.86, 95% CI 1.79-4.55)Shorter OS3 (secondary endpoint)OS60: 89% vs 95%(HR 2.13, 95% CI 1.12-4.00) 	
Eichhorst et al. 2023 (GAIA) 	2016-12-13 to 2019-10-13	Phase 3 (C) 	1. Venetoclax & Obinutuzumab2. Ibrutinib, Venetoclax, Obinutuzumab	Shorter PFS 	
Eichhorst et al. 2023 (GAIA) 	2016-12-13 to 2019-10-13	Phase 3 (C) 	3. Venetoclax & Rituximab 	Did not meet primary endpoint of PFS 	
1Reported efficacy for GCLLSG CLL8 is based on the 2016 update.
2Reported efficacy for GCLLSG CLL10 is based on the 2020 update.
3Reported efficacy for ECOG E1912 is based on the 2022 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 rateCR rate: 15% vs 16%
====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===
# 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 EuroPMC
## 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 EuroPMC
## 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 EuroPMC
##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 EuroPMC
# 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 EuroPMC
# 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 EuroPMC
## 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 EuroPMC
# 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 EuroPMC NCT00281918
## 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 EuroPMC
## 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 EuroPMC
# 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 EuroPMC NCT00564512
# 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 EuroPMC NCT00275054
# 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 EuroPMC NCT00391066
# 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 EuroPMC NCT01292603
# 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 EuroPMC NCT00769522
##Update: Kutsch N, Bahlo J, Robrecht S, Franklin J, Zhang C, Maurer C, De Silva N, Lange E, Weide R, Kiehl MG, Sökler M, Schlag R, Vehling-Kaiser U, Köchling G, Plöger C, Gregor M, Plesner T, Herling M, Fischer K, Döhner H, Kneba M, Wendtner CM, Klapper W, Kreuzer KA, Böttcher S, Stilgenbauer S, Fink AM, Hallek M, Eichhorst B. Long Term Follow-up Data and Health-Related Quality of Life in Frontline Therapy of Fit Patients Treated With FCR Versus BR (CLL10 Trial of the GCLLSG). Hemasphere. 2020 Jan 27;4(1):e336. link to original article link to PMC article EuroPMC
# 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 EuroPMC ISRCTN42165735
# ARCTIC: Howard DR, Munir T, McParland L, Rawstron AC, Milligan D, Schuh A, Hockaday A, Allsup DJ, Marshall S, Duncombe AS, O'Dwyer JL, Smith AF, Longo R, Varghese A, Hillmen P. Results of the randomized phase IIB ARCTIC trial of low-dose rituximab in previously untreated CLL. Leukemia. 2017 Nov;31(11):2416-2425. Epub 2017 Mar 24. link to original article dosing details in supplement have been reviewed by our editors EuroPMC ISRCTN16544962
# CLL 2007 SA: Dartigeas C, Van Den Neste E, Léger J, Maisonneuve H, Berthou C, Dilhuydy MS, De Guibert S, Leprêtre S, Béné MC, Nguyen-Khac F, Letestu R, Cymbalista F, Rodon P, Aurran-Schleinitz T, Vilque JP, Tournilhac O, Mahé B, Laribi K, Michallet AS, Delmer A, Feugier P, Lévy V, Delépine R, Colombat P, Leblond V; CLL 2007 SA investigators; FILO. Rituximab maintenance versus observation following abbreviated induction with chemoimmunotherapy in elderly patients with previously untreated chronic lymphocytic leukaemia (CLL 2007 SA): an open-label, randomised phase 3 study. Lancet Haematol. 2018 Feb;5(2):e82-e94. Epub 2017 Dec 20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00645606
# 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 EuroPMC NCT02048813
##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 EuroPMC
#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 EuroPMC ISRCTN01844152
#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 EuroPMC NCT02950051
##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 EuroPMC
#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 EuroPMC ISRCTN01844152
# ACE-CL-311: NCT03836261
# 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===
# 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 EuroPMC 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	Longer PFS (primary endpoint)Median PFS: 23.7 vs 16.5 mo(HR 0.61, 95% CI 0.47-0.80)Longer 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===
# 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 EuroPMC 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 	Longer PFS1 (primary endpoint)PFS84: 59% vs 9%(HR 0.15, 95% CI 0.11-0.22)Longer OS2 (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 	Longer PFS3 (primary endpoint)Median PFS: NYR vs 44 mo(HR 0.36, 95% CI 0.25-0.51)
Woyach et al. 2018 (Alliance A041202) 	2013-2016 	Phase 3 (E-switch-ooc) 	2. Ibrutinib & Rituximab	Did not meet primary endpoint of PFS2Median 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 	Longer EFS4 (primary endpoint)Median EFS: NYR vs 51.6 mo(HR 0.276, 95% CI 0.19-0.41)
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. VG2. 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 PFS efficacy for RESONATE-2 is based on the 2022 update.
2Reported OS efficacy for RESONATE-2 is based on the 2019 update.
3Reported efficacy for Alliance A041202 is based on the 2024 update.
4Reported efficacy for CLL12 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===
# 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 EuroPMC NCT01105247
## 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 EuroPMC
## 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 EuroPMC
## 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 EuroPMC
# 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 EuroPMC NCT01500733
# 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 EuroPMC NCT01722487
## 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 EuroPMC
## 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 EuroPMC
##Update: Barr PM, Owen C, Robak T, Tedeschi A, Bairey O, Burger JA, Hillmen P, Coutre SE, Dearden C, Grosicki S, McCarthy H, Li JY, Offner F, Moreno C, Zhou C, Hsu E, Szoke A, Kipps TJ, Ghia P. Up to 8-year follow-up from RESONATE-2: first-line ibrutinib treatment for patients with chronic lymphocytic leukemia. Blood Adv. 2022 Jun 14;6(11):3440-3450. link to original article link to PMC article EuroPMC
# 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 EuroPMC NCT01886872
##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 EuroPMC
# 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 EuroPMC NCT02007044
#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 EuroPMC NCT02863718
##Update: Langerbeins P, Robrecht S, Nieper P, Cramer P, Fürstenau M, Al-Sawaf O, Simon F, Fink AM, Kreuzer KA, Vehling-Kaiser U, Tausch E, Schneider C, Müller L, Eckart MJ, Schlag R, Freier W, Gaska T, Balser C, Reiser M, Stauch M, Zahn MO, Dörfel S, Staib P, Behlendorf T, Hensel M, Hebart H, Klaproth H, Block A, Liersch R, Hauch U, Heinrich B, Wendtner CM, Fischer K, Stilgenbauer S, Eichhorst B, Hallek M. Ibrutinib in Early-Stage Chronic Lymphocytic Leukemia: The Randomized, Placebo-Controlled, Double-Blind, Phase III CLL12 Trial. J Clin Oncol. 2025 Feb;43(4):392-402. link to original article link to EuroPMC
#BRUIN CLL-314: NCT05254743
# GCLLSG CLL17: NCT04608318
# 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 	Longer PFS (primary endpoint)Median PFS: NYR vs 19 mo(HR 0.23, 95% CI 0.15-0.37)
Awaiting publication (Alliance A041702) 	2019-2027 	Phase 3 (C) 	Ibrutinib, Venetoclax, Obinutuzumab	TBD if different primary endpoint of PFS
Awaiting publication (ECOG-ACRIN EA9161)	2019-2028 	Phase 3 (C) 	Ibrutinib, Venetoclax, Obinutuzumab	TBD if different primary endpoint of PFS
====Targeted therapy====
*Ibrutinib (Imbruvica) 420 mg PO once per day
*Obinutuzumab (Gazyva) as follows:
**Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15
**Cycles 2 to 6: 1000 mg IV once on day 1
28-day cycles
===References===
# iLLUMINATE: Moreno C, Greil R, Demirkan F, Tedeschi A, Anz B, Larratt L, Simkovic M, Samoilova O, Novak J, Ben-Yehuda D, Strugov V, Gill D, Gribben JG, Hsu E, Lih CJ, Zhou C, Clow F, James DF, Styles L, Flinn IW. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019 Jan;20(1):43-56. Epub 2018 Nov 30. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02264574
# ECOG-ACRIN EA9161: NCT03701282
# 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 	Longer 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 	Longer PFS (primary endpoint)PFS36: 89.4% vs 72.9%(HR 0.35, 95% CI 0.22-0.56)Longer 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===
# 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 EuroPMC NCT01886872
##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 EuroPMC
# 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 EuroPMC NCT02048813
##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 EuroPMC
#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 EuroPMC 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 	Longer 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 	Longer PFS (primary endpoint)PFS36: 97.2% vs 76.8%%(HR 0.13, 95% CI 0.07-0.24)Longer OS (secondary endpoint)OS36: 98% vs 93%(HR 0.31, 95% CI 0.15-0.67)
Hillmen et al. 2023 (FLAIR part 2)	2017-07-20 to 2021-03-24	Phase 3 (E-switch-ooc)	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===
# 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 EuroPMC NCT02756897
# 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 EuroPMC NCT03462719
##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 EuroPMC
#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 EuroPMC 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. BR1b. FCR 	Longer PFS1 (co-primary endpoint)PFS48: 85.5% vs 62%(HR 0.30, 97.5% CI 0.19-0.47)
Eichhorst et al. 2023 (GAIA)	2016-12-13 to 2019-10-13	Phase 3 (E-switch-ooc)	2. Venetoclax & Obinutuzumab	Might have longer PFS1 (co-primary endpoint)PFS48: 85.5% vs 81.8%(HR 0.63, 97.5% CI 0.39-1.02)
Eichhorst et al. 2023 (GAIA)	2016-12-13 to 2019-10-13	Phase 3 (E-switch-ooc)	3. Venetoclax & Rituximab 	Longer PFS1 (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===
# 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 EuroPMC NCT02427451
#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 EuroPMC NCT02950051
##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 EuroPMC
==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 lower 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 higher 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 higher 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===
# 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 EuroPMC NCT01414205
==Venetoclax & Obinutuzumab==
VG: Venetoclax & Gazyva (Obinutuzumab)
VO: Venetoclax & Obinutuzumab
GVE: Gazyva (Obinutuzumab) & VEnetoclax
Ven-Obi: Venetoclax & Obinutuzumab
===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 	Longer PFS1 (primary endpoint)Median PFS: 76.2 vs 36.4 mo(HR 0.40, 95% CI 0.31-0.52)Might have longer OS1 (secondary endpoint)OS72: 78.7% vs 69.2%(HR 0.69, 95% CI 0.48-1.01)
Eichhorst et al. 2023 (GAIA) 	2016-12-13 to 2019-10-13	Phase 3 (E-switch-ooc) 	1a. BR1b. FCR 	Longer PFS2 (co-primary endpoint)PFS48: 81.8% vs 62%(HR 0.47, 97.5% CI 0.32-0.69)
Eichhorst et al. 2023 (GAIA) 	2016-12-13 to 2019-10-13	Phase 3 (E-switch-ooc) 	2. Ibrutinib, Venetoclax, Obinutuzumab	Might have shorter PFS2
Eichhorst et al. 2023 (GAIA) 	2016-12-13 to 2019-10-13	Phase 3 (E-switch-ooc) 	3. Venetoclax & Rituximab 	Longer 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 for GCLLSG CLL14 is based on the 2024 update.
2Reported efficacy for GAIA 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===
# 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 EuroPMC NCT02242942
## 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 EuroPMC
##HRQoL analysis: Al-Sawaf O, Gentile B, Devine J, Zhang C, Sail K, Tandon M, Fink AM, Kutsch N, Wendtner CM, Eichhorst B, Hallek M, Fischer K. Health-related quality of life with fixed-duration venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: Results from the randomized, phase 3 CLL14 trial. Am J Hematol. 2021 Sep 1;96(9):1112-1119. Epub 2021 Jun 22. link to original article EuroPMC
## 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 EuroPMC
##Update: Al-Sawaf O, Zhang C, Jin HY, Robrecht S, Choi Y, Balasubramanian S, Kotak A, Chang YM, Fink AM, Tausch E, Schneider C, Ritgen M, Kreuzer KA, Chyla B, Paulson JN, Pallasch CP, Frenzel LP, Peifer M, Eichhorst B, Stilgenbauer S, Jiang Y, Hallek M, Fischer K. Transcriptomic profiles and 5-year results from the randomized CLL14 study of venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab in chronic lymphocytic leukemia. Nat Commun. 2023 Apr 18;14(1):2147. Erratum in: Nat Commun. 2023 Oct 23;14(1):6724. link to original article link to PMC article EuroPMC
## Update: Al-Sawaf O, Robrecht S, Zhang C, Olivieri S, Chang YM, Fink AM, Tausch E, Schneider C, Ritgen M, Kreuzer KA, Sivchev L, Niemann CU, Schwarer A, Loscertales J, Weinkove R, Strumberg D, Kilfoyle A, Manzoor BS, Jawaid D, Emechebe N, Devine J, Boyer M, Runkel ED, Eichhorst B, Stilgenbauer S, Jiang Y, Hallek M, Fischer K. Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 6-year results of the randomized phase 3 CLL14 study. Blood. 2024 Oct 31;144(18):1924-1935. link to original article link to PMC article EuroPMC
#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 EuroPMC NCT02950051
##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 EuroPMC
#EVOLVE CLL/SLL: NCT04269902
#GCLLSG CLL16: NCT05197192
#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 shorter PFS
Dighiero et al. 1998 (FRE-CLL-90) 	1985-1990 	Phase 3 (C)	Chlorambucil & Prednisone	Shorter PFS
Hoechstetter et al. 2017 (GCLLSG CLL1)	1997-2004 	Phase 3 (C)	Fludarabine 	Shorter PFS (co-primary endpoint)Median PFS: 12.9 vs 30.1 mo(HR not reported, p<0.001)
Herling et al. 2020 (GCLLSG CLL7) 	2005-2010 	Phase 3 (C)	FCR 	Shorter EFS (primary endpoint)Median EFS: 18.5 vs NYR mo(HR 4.55, 95% CI 3.03-6.67)
Langerbeins et al. 2022 (CLL12) 	2014-2019 	Phase 3 (C)	Ibrutinib 	Shorter EFS1 (primary endpoint)Median EFS: 51.6 vs NYR mo(HR 3.62, 95% CI 2.44-5.26)
Awaiting publication (GLLC-EARLY) 	2019-2024 	Phase 3 (C)	Acalabrutinib 	TBD if different primary endpoint of EFS
1Reported efficacy for CLL12 is based on the 2024 update.
===References===
# FRE-CLL-85: Dighiero G, Maloum K, Desablens B, Cazin B, Navarro M, Leblay R, Leporrier M, Jaubert J, Lepeu G, Dreyfus B, Binet JL, Travade P; French Cooperative Group on Chronic Lymphocytic Leukemia. Chlorambucil in indolent chronic lymphocytic leukemia. N Engl J Med. 1998 May 21;338(21):1506-14. link to original article EuroPMC
# 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 EuroPMC
# 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 EuroPMC NCT00275054
#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 EuroPMC NCT00262782
#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 EuroPMC NCT02863718
##Update: Langerbeins P, Robrecht S, Nieper P, Cramer P, Fürstenau M, Al-Sawaf O, Simon F, Fink AM, Kreuzer KA, Vehling-Kaiser U, Tausch E, Schneider C, Müller L, Eckart MJ, Schlag R, Freier W, Gaska T, Balser C, Reiser M, Stauch M, Zahn MO, Dörfel S, Staib P, Behlendorf T, Hensel M, Hebart H, Klaproth H, Block A, Liersch R, Hauch U, Heinrich B, Wendtner CM, Fischer K, Stilgenbauer S, Eichhorst B, Hallek M. Ibrutinib in Early-Stage Chronic Lymphocytic Leukemia: The Randomized, Placebo-Controlled, Double-Blind, Phase III CLL12 Trial. J Clin Oncol. 2025 Feb;43(4):392-402. link to original article link to EuroPMC
#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 	Longer PFS (primary endpoint)Median PFS: NYR vs NYR(HR 0.42, 95% CI 0.28-0.63)
====Biomarker eligibility criteria====
*SEQUOIACLL: No 17p deletion
====Targeted therapy====
*Zanubrutinib (Brukinsa) 160 mg PO twice per day on days 1 to 28
28-day cycles
===References===
# SEQUOIACLL: Tam CS, Brown JR, Kahl BS, Ghia P, Giannopoulos K, Jurczak W, Šimkovič M, Shadman M, Österborg A, Laurenti L, Walker P, Opat S, Chan H, Ciepluch H, Greil R, Tani M, Trněný M, Brander DM, Flinn IW, Grosicki S, Verner E, Tedeschi A, Li J, Tian T, Zhou L, Marimpietri C, Paik JC, Cohen A, Huang J, Robak T, Hillmen P. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022 Aug;23(8):1031-1043. Epub 2022 Jul 7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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===
# 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 EuroPMC 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===
# 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 EuroPMC 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===
# 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 EuroPMC NCT01300247
# 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 EuroPMC 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===
# 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 EuroPMC
==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===
# 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 EuroPMC 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===
# 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 EuroPMC
==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===
#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 EuroPMC NCT02251548
==Lenalidomide & Rituximab (R2)==
===Regimen===
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
===References===
# CRC014: James DF, Werner L, Brown JR, Wierda WG, Barrientos JC, Castro JE, Greaves A, Johnson AJ, Rassenti LZ, Rai KR, Neuberg D, Kipps TJ. Lenalidomide and rituximab for the initial treatment of patients with chronic lymphocytic leukemia: a multicenter clinical-translational study from the Chronic Lymphocytic Leukemia Research Consortium. J Clin Oncol. 2014 Jul 1;32(19):2067-73. Epub 2014 May 27. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00628238
==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===
# 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 EuroPMC 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===
# 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 EuroPMC NCT01024010
# 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 EuroPMC NCT01681563
# 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 EuroPMC NCT01024010
==PCR==
PCR: Pentostatin, Cyclophosphamide, Rituximab
===Regimen===
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
===References===
# Kay NE, Geyer SM, Call TG, Shanafelt TD, Zent CS, Jelinek DF, Tschumper R, Bone ND, Dewald GW, Lin TS, Heerema NA, Smith L, Grever MR, Byrd JC. Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia. Blood. 2007 Jan 15;109(2):405-11. Epub 2006 Sep 28. link to original article dosing details in abstract have been reviewed by our editors link to PMC article EuroPMC
# 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 EuroPMC
==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===
# 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 EuroPMC NCT00718549
==Rituximab monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Hainsworth et al. 2003	2000-2001 	Phase 2
====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
===References===
# Hainsworth JD, Litchy S, Barton JH, Houston GA, Hermann RC, Bradof JE, Greco FA; Minnie Pearl Cancer Research Network. Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol. 2003 May 1;21(9):1746-51. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==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===
# 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 EuroPMC 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===
#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 EuroPMC 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	Longer PFS1 (primary endpoint)Median PFS: NYR vs 20.6 mo(HR not reported)
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===
# 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 EuroPMC
## 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 EuroPMC
# 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 EuroPMC
==Lenalidomide monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Fink et al. 2017 (GCLLSG CLLM1)	2012-2016 	Phase 3 (E-esc)	Observation	Longer 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===
# 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 EuroPMC 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===
# 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 EuroPMC 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 longer 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	Longer PFS (primary endpoint)Median PFS: NYR vs 2.1 years(HR 0.42, 95% CI 0.19-0.93)
Greil et al. 2016 (AGMT CLL-8a)	2010-2013 	Phase 3 (E-esc) 	Observation	Longer 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	Longer 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 	 	
====Preceding treatment====
*Hainsworth et al. 2003: First-line rituximab
====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 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===
# 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 EuroPMC
# 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 EuroPMC
## 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 EuroPMC
# 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 EuroPMC EudraCT 2005-001569-33
## Update: Abrisqueta P, Villamor N, Terol MJ, González-Barca E, González M, Ferrà C, Abella E, Delgado J, García-Marco JA, González Y, Carbonell F, Ferrer S, Monzó E, Jarque I, Muntañola A, Constants M, Escoda L, Calvo X, Bobillo S, Montoro JB, Montserrat E, Bosch F. Rituximab maintenance after first-line therapy with rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) for chronic lymphocytic leukemia. Blood. 2013 Dec 5;122(24):3951-9. Epub 2013 Oct 11. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 EuroPMC EudraCT 2008-001612-20
# AGMT CLL-8a: Greil R, Obrtlíková P, Smolej L, Kozák T, Steurer M, Andel J, Burgstaller S, Mikušková E, Gercheva L, Nösslinger T, Papajík T, Ladická M, Girschikofsky M, Hrubiško M, Jäger U, Fridrik M, Pecherstorfer M, Králiková E, Burcoveanu C, Spasov E, Petzer A, Mihaylov G, Raynov J, Oexle H, Zabernigg A, Flochová E, Palášthy S, Stehlíková O, Doubek M, Altenhofer P, Pleyer L, Melchardt T, Klingler A, Mayer J, Egle A. Rituximab maintenance versus observation alone in patients with chronic lymphocytic leukaemia who respond to first-line or second-line rituximab-containing chemoimmunotherapy: final results of the AGMT CLL-8a Mabtenance randomised trial. Lancet Haematol. 2016 Jul;3(7):e317-29. Epub 2016 Jun 16. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01118234
# 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 EuroPMC NCT00645606
# 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 EuroPMC 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. BR1b. Idelalisib & Rituximab	Longer 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===
# 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 EuroPMC NCT02029443
# 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 EuroPMC NCT02970318
##Update: Ghia P, Pluta A, Wach M, Lysak D, Šimkovič M, Kriachok I, Illés Á, de la Serna J, Dolan S, Campbell P, Musuraca G, Jacob A, Avery EJ, Lee JH, Usenko G, Wang MH, Yu T, Jurczak W. Acalabrutinib Versus Investigator's Choice in Relapsed/Refractory Chronic Lymphocytic Leukemia: Final ASCEND Trial Results. Hemasphere. 2022 Nov 14;6(12):e801. link to original article link to PMC article EuroPMC
# 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 EuroPMC 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 shorter PFSMedian PFS: 10.2 vs 15.9 mo(HR not reported)
====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
===References===
# 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 EuroPMC
# 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 EuroPMC NCT01423032
# 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 EuroPMC 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 	Higher CR rate1 (primary endpoint)
Chanan-Khan et al. 2015 (HELIOS) 	2012-2014 	Phase 3 (C) 	BR & Ibrutinib 	Shorter PFS (primary endpoint)Median PFS: 13.3 vs NYR mo(HR 5.00, 95% CI 3.57-6.67)Shorter OS2 (secondary endpoint)Median OS: NYR vs NYR(HR 1.64, 95% CI 1.22-2.20)
Zelenetz et al. 2017 (Tugela) 	2012-2014 	Phase 3 (C) 	BR & Idelalisib 	Shorter PFSMedian PFS: 11.1 vs 20.8 mo(HR 3.03, 95% CI 2.27-4.00)
Seymour et al. 2018 (MURANO) 	2014-03-31 to 2015-09-23	Phase 3 (C) 	Venetoclax & Rituximab	Shorter PFS (primary endpoint)PFS24: 36.3% vs 84.9%(HR 5.88, 95% CI 4.00-9.09)Shorter OS3 (secondary endpoint)OS48: 66.8% vs 85.3%(HR 2.44, 95% CI 1.54-3.85)
Ghia et al. 2020 (ASCEND) 	2017-02-21 to 2018-01-17	Phase 3 (C) 	Acalabrutinib 	Shorter PFSMedian PFS: 16.5 vs NYR mo(HR 3.23, 95% CI 2.04-5.00)
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.
3Reported efficacy for OS in MURANO 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===
# 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 EuroPMC NCT00274989
# 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 EuroPMC
# 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 EuroPMC NCT01611090
## 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 EuroPMC
## 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 EuroPMC
# 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 EuroPMC NCT01569295
##HRQoL analysis: Montillo M, Illés Á, Robak T, Pristupa AS, Wach M, Egyed M, Delgado J, Jurczak W, Morschhauser F, Schuh A, Eradat H, Shreay S, Barrientos JC, Zelenetz AD. Idelalisib addition has neutral to beneficial effects on quality of life in bendamustine/rituximab-treated patients: results of a phase 3, randomized, controlled trial. Health Qual Life Outcomes. 2019 Nov 15;17(1):173. link to original article link to PMC article EuroPMC
# 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 EuroPMC NCT01056510
# 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 EuroPMC NCT02005471
## 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 EuroPMC
## 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 EuroPMC
## 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 EuroPMC
# 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 EuroPMC NCT02970318
##Update: Ghia P, Pluta A, Wach M, Lysak D, Šimkovič M, Kriachok I, Illés Á, de la Serna J, Dolan S, Campbell P, Musuraca G, Jacob A, Avery EJ, Lee JH, Usenko G, Wang MH, Yu T, Jurczak W. Acalabrutinib Versus Investigator's Choice in Relapsed/Refractory Chronic Lymphocytic Leukemia: Final ASCEND Trial Results. Hemasphere. 2022 Nov 14;6(12):e801. link to original article link to PMC article EuroPMC
#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 	Longer PFS (primary endpoint)Median PFS: NYR vs 13.3 mo(HR 0.20, 95% CI 0.15-0.28)Longer 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===
# 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 EuroPMC NCT01292135
# 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 EuroPMC NCT01611090
## 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 EuroPMC
## 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 EuroPMC
==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 	Longer 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===
# 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 EuroPMC NCT01569295
##HRQoL analysis: Montillo M, Illés Á, Robak T, Pristupa AS, Wach M, Egyed M, Delgado J, Jurczak W, Morschhauser F, Schuh A, Eradat H, Shreay S, Barrientos JC, Zelenetz AD. Idelalisib addition has neutral to beneficial effects on quality of life in bendamustine/rituximab-treated patients: results of a phase 3, randomized, controlled trial. Health Qual Life Outcomes. 2019 Nov 15;17(1):173. link to original article link to PMC article EuroPMC
==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	Longer 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===
# 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 EuroPMC 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 rateCR rate: 15% vs 16%
====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 	Longer 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===
# 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 EuroPMC 
## 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 EuroPMC
# 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 EuroPMC
# 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 EuroPMC content property of HemOnc.org NCT00090051
# 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 EuroPMC 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 higher ORR
Niederle et al. 2013 (WiSP RI05)	2001-2006 	Phase 3 (C) 	Bendamustine	Seems to have non-inferior PFSMedian PFS: 14.8 vs 20.1 mo(HR 1.15, 90% CI 0.79-1.67)
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===
# 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 EuroPMC
# 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 EuroPMC 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 	Longer 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 	Longer PFS (primary endpoint)PFS18: 74% vs 11.9%(HR 0.18, 95% CI 0.105-0.31)Longer 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 lower ORR
Byrd et al. 2021 (ACE-CL-006) 	2015-2017 	Phase 3 (C) 	Acalabrutinib 	Non-inferior PFSMedian PFS: 38.4 vs 38.4 mo(HR 1.00, 95% CI 0.79-1.27)
Hillmen et al. 2022 (ALPINE) 	2018-2020 	Phase 3 (C) 	Zanubrutinib 	Shorter PFS2PFS36: 54.4% vs 65.4%(HR 1.47, 95% CI 1.19-1.85)Lower ORR2ORR: 75.4% vs 85.6%
1Reported efficacy for RESONATE is based on the second 2019 update.
2Reported efficacy for ALPINE is based on the 2024 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===
# 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 EuroPMC NCT01105247
## 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 EuroPMC
## 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 EuroPMC
## 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 EuroPMC
# 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 EuroPMC NCT01578707
## 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 EuroPMC
## 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 EuroPMC
## 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 EuroPMC
# 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 EuroPMC NCT01500733
# 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 EuroPMC NCT01744691
# 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 EuroPMC
# 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 EuroPMC NCT01973387
# 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 EuroPMC NCT02301156
# 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 EuroPMC NCT02477696
#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 EuroPMC NCT03734016
##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 EuroPMC
##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 EuroPMC
##Update: Brown JR, Eichhorst B, Lamanna N, O'Brien SM, Tam CS, Qiu L, Jurczak W, Zhou K, Šimkovič M, Mayer J, Gillespie-Twardy A, Ferrajoli A, Ganly PS, Weinkove R, Grosicki S, Mital A, Robak T, Osterborg A, Yimer HA, Wang M, Salmi T, Wang L, Li J, Wu K, Cohen A, Shadman M. Sustained benefit of zanubrutinib vs ibrutinib in patients with R/R CLL/SLL: final comparative analysis of ALPINE. Blood. 2024 Dec 26;144(26):2706-2717. link to original article EuroPMC
==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 higher 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===
# 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 EuroPMC 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	Longer 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===
# 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 EuroPMC 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 	Longer 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	Shorter PFSMedian PFS: 16.5 vs NYR mo(HR 3.23, 95% CI 2.04-5.00)
====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===
# 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 EuroPMC NCT01539512
## 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 EuroPMC
# 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 EuroPMC NCT02970318
##Update: Ghia P, Pluta A, Wach M, Lysak D, Šimkovič M, Kriachok I, Illés Á, de la Serna J, Dolan S, Campbell P, Musuraca G, Jacob A, Avery EJ, Lee JH, Usenko G, Wang MH, Yu T, Jurczak W. Acalabrutinib Versus Investigator's Choice in Relapsed/Refractory Chronic Lymphocytic Leukemia: Final ASCEND Trial Results. Hemasphere. 2022 Nov 14;6(12):e801. link to original article link to PMC article EuroPMC
#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 	Shorter PFS1Median PFS: 8.1 vs 44.1 mo(HR 6.67, 95% CI 5.00-9.09)
Jones et al. 2017 (GS-US-312-0119) 	2012-2014 	Phase 3 (C) 	Idelalisib & Ofatumumab	Shorter PFSMedian PFS: 8 vs 16.3 mo(HR 3.70, 95% CI 2.56-5.26)
Flinn et al. 2018 (DUO) 	2014-01-21 to 2015-12-09	Phase 3 (C) 	Duvelisib 	Shorter PFSMedian PFS: 9.9 vs 13.3 mo(HR 1.92)
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 
**Cycles 4 to 12: 2000 mg IV once on day 1
28-day cycle for 12 cycles
===References===
# Coiffier B, Lepretre S, Pedersen LM, Gadeberg O, Fredriksen H, van Oers MH, Wooldridge J, Kloczko J, Holowiecki J, Hellmann A, Walewski J, Flensburg M, Petersen J, Robak T. Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1-2 study. Blood. 2008 Feb 1;111(3):1094-100. Epub 2007 Nov 14. link to original article EuroPMC
# 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 EuroPMC NCT00349349
## 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 EuroPMC 
## 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 EuroPMC
# 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 EuroPMC NCT01578707
## 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 EuroPMC
## 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 EuroPMC
## 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 EuroPMC
# 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 EuroPMC
# 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 EuroPMC NCT00802737
# 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 articleEuroPMC NCT01313689
##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 EuroPMC
# 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 EuroPMC NCT01659021
# 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 EuroPMC NCT01580228
# 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 EuroPMC 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 	Longer 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===
# 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 EuroPMC NCT00824265
##HRQoL analysis: Robak T, Warzocha K, Govind Babu K, Kulyaba Y, Kuliczkowski K, Abdulkadyrov K, Loscertales J, Kryachok I, Kłoczko J, Rekhtman G, Homenda W, Błoński JZ, McKeown A, Chang CN, Bal V, Lisby S, Gupta IV, Grosicki S. Health-related quality of life and patient-reported outcomes of ofatumumab plus fludarabine and cyclophosphamide versus fludarabine and cyclophosphamide in the COMPLEMENT 2 trial of patients with relapsed CLL. Leuk Lymphoma. 2017 Jul;58(7):1598-1606. Epub 2016 Nov 10. link to original article EuroPMC
==Rituximab monotherapy==
===Regimen variant #1, 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	Shorter PFS (primary endpoint)PFS6: 46% vs 93%(aHR 6.67, 95% CI 3.57-12.50)
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 #2, 8 doses alternate schedule===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Huang et al. 2018 (CR102604)	2013-2015 	Phase 3 (C)	Ibrutinib 	Shorter PFS (primary endpoint)PFS18: 11.9% vs 74%(HR 5.56, 95% CI 3.23-9.52)Shorter OS (secondary endpoint)OS24: 57.6% vs 79.8%(HR 2.22, 95% CI 1.11-4.55)
====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===
# 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 EuroPMC NCT01539512
## 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 EuroPMC
# 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 EuroPMC 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 	Longer PFS (primary endpoint)PFS24: 84.9% vs 36.3%(HR 0.17, 95% CI 0.11-0.25)Longer 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:
**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
**Cycles 2 to 26: 400 mg PO once per day on days 1 to 28
*Rituximab (Rituxan) as follows:
**Cycle 2: 375 mg/m2 IV once on day 8
**Cycles 3 to 7: 500 mg/m2 IV once on day 8
28-day cycle for up to 26 cycles (2 years)
===References===
# MURANO: Seymour JF, Kipps TJ, Eichhorst B, Hillmen P, D'Rozario J, Assouline S, Owen C, Gerecitano J, Robak T, De la Serna J, Jaeger U, Cartron G, Montillo M, Humerickhouse R, Punnoose EA, Li Y, Boyer M, Humphrey K, Mobasher M, Kater AP. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018 Mar 22;378(12):1107-1120. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02005471
## 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 EuroPMC
## 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 EuroPMC
## 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 EuroPMC
# 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 	Longer PFS1 (secondary endpoint)PFS36: 65.4% vs 54.4%(HR 0.68, 95% CI 0.54-0.84)Higher ORR1 (primary endpoint)ORR: 85.6% vs 75.4%
1Reported efficacy is based on the 2024 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===
#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 EuroPMC NCT03734016
##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 EuroPMC
##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 EuroPMC
##Update: Brown JR, Eichhorst B, Lamanna N, O'Brien SM, Tam CS, Qiu L, Jurczak W, Zhou K, Šimkovič M, Mayer J, Gillespie-Twardy A, Ferrajoli A, Ganly PS, Weinkove R, Grosicki S, Mital A, Robak T, Osterborg A, Yimer HA, Wang M, Salmi T, Wang L, Li J, Wu K, Cohen A, Shadman M. Sustained benefit of zanubrutinib vs ibrutinib in patients with R/R CLL/SLL: final comparative analysis of ALPINE. Blood. 2024 Dec 26;144(26):2706-2717. link to original article EuroPMC
=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 to 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===
# 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 EuroPMC
# 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 EuroPMC
# 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 EuroPMC
==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===
# 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 EuroPMC
==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===
# 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 EuroPMC 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===
# 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 EuroPMC 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===
#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 EuroPMC 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===
# 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 EuroPMC
==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===
# 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 EuroPMC 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===
# 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 EuroPMC
## 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 EuroPMC
==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===
# 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 EuroPMC
# 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 EuroPMC 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===
# 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 EuroPMC 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===
# 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 EuroPMC NCT01520519
## 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 EuroPMC
==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===
# 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 EuroPMC NCT02427451
==Idelalisib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Brown et al. 2014 (Gilead 101-02)	2008-2011 	Phase 1, >20 pts
====Targeted therapy====
*Idelalisib (Zydelig) 150 mg PO twice per day
Continued indefinitely
===References===
# 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 EuroPMC 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
===References===
# Chanan-Khan A, Miller KC, Musial L, Lawrence D, Padmanabhan S, Takeshita K, Porter CW, Goodrich DW, Bernstein ZP, Wallace P, Spaner D, Mohr A, Byrne C, Hernandez-Ilizaliturri F, Chrystal C, Starostik P, Czuczman MS. Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study. J Clin Oncol. 2006 Dec 1;24(34):5343-9. Epub 2006 Nov 6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 EuroPMC NCT00267059
==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===
# 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 EuroPMC 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 
**Cycles 3 to 12: 375 mg/m2 IV once on day 1
====Supportive therapy====
*Cycle 1: Allopurinol (Zyloprim) (dose/schedule not specified) on days 1 to 14 
*No mandatory antibacterial, antiviral, DVT, or tumor flare prophylaxis
*Growth factor use allowed per 2006 ASCO guidelines 
28-day cycle for 12 cycles
====Subsequent treatment====
*MDACC 2007-0208, responders: Lenalidomide maintenance could continue indefinitely
===References===
# Chanan-Khan A, Miller KC, Musial L, Lawrence D, Padmanabhan S, Takeshita K, Porter CW, Goodrich DW, Bernstein ZP, Wallace P, Spaner D, Mohr A, Byrne C, Hernandez-Ilizaliturri F, Chrystal C, Starostik P, Czuczman MS. Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study. J Clin Oncol. 2006 Dec 1;24(34):5343-9. Epub 2006 Nov 6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 EuroPMC 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===
#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 EuroPMC 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===
# 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 EuroPMC NCT00517530
## 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 EuroPMC
## 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 EuroPMC
## 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 EuroPMC
==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===
# 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 EuroPMC
==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===
# 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 EuroPMC
==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===
#BRUINCLL: 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 EuroPMC 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===
# 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 EuroPMC
==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===
# 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 EuroPMC 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===
# 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 EuroPMC NCT01328626
# 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 EuroPMC NCT01889186
## 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 EuroPMC
# 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 EuroPMC NCT02141282
# 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 EuroPMC 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===
#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 EuroPMC 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
===References===
# Slavin S, Nagler A, Naparstek E, Kapelushnik Y, Aker M, Cividalli G, Varadi G, Kirschbaum M, Ackerstein A, Samuel S, Amar A, Brautbar C, Ben-Tal O, Eldor A, Or R. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood. 1998 Feb 1;91(3):756-63. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 EuroPMC
==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
===References===
# GCLLSG CLL3X: Dreger P, Döhner H, Ritgen M, Böttcher S, Busch R, Dietrich S, Bunjes D, Cohen S, Schubert J, Hegenbart U, Beelen D, Zeis M, Stadler M, Hasenkamp J, Uharek L, Scheid C, Humpe A, Zenz T, Winkler D, Hallek M, Kneba M, Schmitz N, Stilgenbauer S; German CLL Study Group. Allogeneic stem cell transplantation provides durable disease control in poor-risk chronic lymphocytic leukemia: long-term clinical and MRD results of the German CLL Study Group CLL3X trial. Blood. 2010 Oct 7;116(14):2438-47. Epub 2010 Jul 1. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00281983
## 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 EuroPMC
## 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 EuroPMC
==Fludarabine & TBI, then allo HSCT==
===Regimen===
Study 	Dates of enrollment	Evidence
Sorror et al. 2005	1997-2003 	Phase 2
===References===
# Sorror ML, Maris MB, Sandmaier BM, Storer BE, Stuart MJ, Hegenbart U, Agura E, Chauncey TR, Leis J, Pulsipher M, McSweeney P, Radich JP, Bredeson C, Bruno B, Langston A, Loken MR, Al-Ali H, Blume KG, Storb R, Maloney DG. Hematopoietic cell transplantation after nonmyeloablative conditioning for advanced chronic lymphocytic leukemia. J Clin Oncol. 2005 Jun 1;23(16):3819-29. Epub 2005 Apr 4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
==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===
# 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 EuroPMC NCT00759603
# 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 EuroPMC 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	Longer 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===
# 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 EuroPMC NCT00802737
# 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 EuroPMC NCT00802737
</div>
==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	Longer 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===
# 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 EuroPMC 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
# 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 EuroPMC
==Binet staging (1981)==
*Group A: no anemia, no thrombocytopenia, less than three involved areas
*Group B: no anemia, no thrombocytopenia, three or more involved areas (counting as one each of the following: axillary, cervical, inguinal, lymph nodes, whether unilateral or bilateral, spleen and liver)
*Group C: anemia (hemoglobin less than 10 g/dL) and/or thrombocytopenia (platelets less than 100 x 109/L)
# Binet JL, Auquier A, Dighiero G, Chastang C, Piguet H, Goasguen J, Vaugier G, Potron G, Colona P, Oberling F, Thomas M, Tchernia G, Jacquillat C, Boivin P, Lesty C, Duault MT, Monconduit M, Belabbes S, Gremy F. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer. 1981 Jul 1;48(1):198-206. link to original article EuroPMC
==Risk by cytogenetics==
*Classic NEJM paper establishing abnormal karyotype as an adverse prognostic marker
# Han T, Ozer H, Sadamori N, Emrich L, Gomez GA, Henderson ES, Bloom ML, Sandberg AA. Prognostic importance of cytogenetic abnormalities in patients with chronic lymphocytic leukemia. N Engl J Med. 1984 Feb 2;310(5):288-92. to original article EuroPMC
*Large retrospective series looking at cytogenetic complexity
# Baliakas P, Jeromin S, Iskas M, Puiggros A, Plevova K, Nguyen-Khac F, Davis Z, Rigolin GM, Visentin A, Xochelli A, Delgado J, Baran-Marszak F, Stalika E, Abrisqueta P, Durechova K, Papaioannou G, Eclache V, Dimou M, Iliakis T, Collado R, Doubek M, Calasanz MJ, Ruiz-Xiville N, Moreno C, Jarosova M, Leeksma AC, Panayiotidis P, Podgornik H, Cymbalista F, Anagnostopoulos A, Trentin L, Stavroyianni N, Davi F, Ghia P, Kater AP, Cuneo A, Pospisilova S, Espinet B, Athanasiadou A, Oscier D, Haferlach C, Stamatopoulos K; ERIC, the European Research Initiative on CLL. Cytogenetic complexity in chronic lymphocytic leukemia: definitions, associations, and clinical impact. Blood. 2019 Mar 14;133(11):1205-1216. Epub 2019 Jan 2. link to original article link to PMC article EuroPMC
==Risk by lymphocyte doubling time==
# Montserrat E, Sanchez-Bisono J, Viñolas N, Rozman C. Lymphocyte doubling time in chronic lymphocytic leukaemia: analysis of its prognostic significance. Br J Haematol. 1986 Mar;62(3):567-75. link to original article EuroPMC
# 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 EuroPMC
==Risk by FISH==
*Classic 2000 NEJM paper establishing that 17p deletion has the worst prognosis:
# Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L, Döhner K, Bentz M, Lichter P. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000 Dec 28;343(26):1910-6. link to original article EuroPMC
*This article and abstract explore the significance of 13q deletions in more detail:
# Van Dyke DL, Shanafelt TD, Call TG, Zent CS, Smoley SA, Rabe KG, Schwager SM, Sonbert JC, Slager SL, Kay NE. A comprehensive evaluation of the prognostic significance of 13q deletions in patients with B-chronic lymphocytic leukaemia. Br J Haematol. 2010 Feb;148(4):544-50. Epub 2009 Nov 6. link to original article link to PMC article EuroPMC 
# Abstract: Claudia Haferlach, Melanie Zenger, Vera Grossmann, Frank Dicker, Sabine Jeromin, Alexander Kohlmann, Susanne Schnittger, Wolfgang Kern, Torsten Haferlach. The Impact of Homozygosity and Size of the 13q Deletion in Patients with CLL. Blood 2012 120:3892 abstract 3892 link to abstract
==Risk by TP53 mutation==
# Zenz T, Eichhorst B, Busch R, Denzel T, Häbe S, Winkler D, Bühler A, Edelmann J, Bergmann M, Hopfinger G, Hensel M, Hallek M, Döhner H, Stilgenbauer S. TP53 mutation and survival in chronic lymphocytic leukemia. J Clin Oncol. 2010 Oct 10;28(29):4473-9. Epub 2010 Aug 9. link to original article EuroPMC
==Risk by CD38 expression==
# Damle RN, Wasil T, Fais F, Ghiotto F, Valetto A, Allen SL, Buchbinder A, Budman D, Dittmar K, Kolitz J, Lichtman SM, Schulman P, Vinciguerra VP, Rai KR, Ferrarini M, Chiorazzi N. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood. 1999 Sep 15;94(6):1840-7. link to original article EuroPMC
# 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 EuroPMC
==Risk by ZAP-70 expression (2003)==
# Crespo M, Bosch F, Villamor N, Bellosillo B, Colomer D, Rozman M, Marcé S, López-Guillermo A, Campo E, Montserrat E. ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med. 2003 May 1;348(18):1764-75. link to original article EuroPMC
==Prognostic scoring system using molecular and cytogenetic features (2012)==
# Rossi D, Rasi S, Spina V, Bruscaggin A, Monti S, Ciardullo C, Deambrogi C, Khiabanian H, Serra R, Bertoni F, Forconi F, Laurenti L, Marasca R, Dal-Bo M, Rossi FM, Bulian P, Nomdedeu J, Del Poeta G, Gattei V, Pasqualucci L, Rabadan R, Foà R, Dalla-Favera R, Gaidano G. Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia. Blood. 2013 Feb 21;121(8):1403-12. Epub 2012 Dec 13. link to original article link to PMC article EuroPMC
==CLL-IPI (2016)==
*QxMD calculator
# 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 EuroPMC
==Prognostic scoring system using clinical features (2019)==
# Soumerai JD, Ni A, Darif M, Londhe A, Xing G, Mun Y, Kay NE, Shanafelt TD, Rabe KG, Byrd JC, Chanan-Khan AA, Furman RR, Hillmen P, Jones J, Seymour JF, Sharman JP, Ferrante L, Mobasher M, Stark T, Reddy V, Dreiling LK, Bhargava P, Howes A, James DF, Zelenetz AD. Prognostic risk score for patients with relapsed or refractory chronic lymphocytic leukaemia treated with targeted therapies or chemoimmunotherapy: a retrospective, pooled cohort study with external validations. Lancet Haematol. 2019 Jul;6(7):e366-e374. Epub 2019 May 17. Erratum in: Lancet Haematol. 2019 Jul;6(7):e348. link to original article link to PMC article EuroPMC
Category:Chronic lymphocytic leukemia regimens
Category:Disease-specific pages
Category:Indolent lymphomas