Chronic lymphocytic leukemia

Section editor
	Sanjai Sharma, MD Sequoia Regional Cancer Center Visalia, CA

Are you looking for a regimen but can't find it here? It is possible that we've moved it to the historical regimens page. If you still can't find it, please let us know so we can add it!
Note: there are several regimens on this page that are specific to small lymphocytic lymphoma (SLL). The vast majority of the regimens here were evaluated in CLL or in mixed populations of CLL and SLL patients.

79 regimens on this page 116 variants on this page

Guidelines

ASBMT

• 2016: Kharfan-Dabaja et al. Clinical practice recommendations for use of allogeneic hematopoietic cell transplantation in chronic lymphocytic leukemia on behalf of the guidelines committee of the American Society for Blood and Marrow Transplantation

ESMO

• 2016: Ladetto et al. ESMO consensus conference on malignant lymphoma: general perspectives and recommendations for prognostic tools in mature B-cell lymphomas and chronic lymphocytic leukaemia PubMed
• 2015: Eichhorst et al. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
• 2013: Ghielmini et al. ESMO Guidelines consensus conference on malignant lymphoma 2011 part 1: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL) PubMed

"How I Treat"

• 2018: Brown How I treat CLL patients with ibrutinib PubMed

International Workshop on Chronic Lymphocytic Leukemia (iwCLL)

• 2018: Hallek et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL PubMed

Older

• 2008: Hallek et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines
• 1996: Cheson et al. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment PubMed

NCCN

• NCCN Guidelines - Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

First-line therapy, randomized data

Acalabrutinib monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Sharman et al. 2020 (ELEVATE TN)	2015-2017	Phase III (E-switch-ooc)	Chlorambucil & Obinutuzumab	Superior PFS

Chemotherapy

• Acalabrutinib (Calquence) 100 mg PO twice per day

Continued indefinitely

References

1. ELEVATE TN: Sharman JP, Egyed M, Jurczak W, Skarbnik A, Pagel JM, Flinn IW, Kamdar M, Munir T, Walewska R, Corbett G, Fogliatto LM, Herishanu Y, Banerji V, Coutre S, Follows G, Walker P, Karlsson K, Ghia P, Janssens A, Cymbalista F, Woyach JA, Salles G, Wierda WG, Izumi R, Munugalavadla V, Patel P, Wang MH, Wong S, Byrd JC. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020 Apr 18;395(10232):1278-1291. link to original article PubMed

Acalabrutinib & Obinutuzumab

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Sharman et al. 2020 (ELEVATE TN)	2015-2017	Phase III (E-switch-ooc)	Chlorambucil & Obinutuzumab	Superior PFS

Chemotherapy

• 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 on day 8, then 1000 mg IV once on day 15
  • Cycles 3 to 7: 1000 mg IV once on day 1

28-day cycles

References

1. ELEVATE TN: Sharman JP, Egyed M, Jurczak W, Skarbnik A, Pagel JM, Flinn IW, Kamdar M, Munir T, Walewska R, Corbett G, Fogliatto LM, Herishanu Y, Banerji V, Coutre S, Follows G, Walker P, Karlsson K, Ghia P, Janssens A, Cymbalista F, Woyach JA, Salles G, Wierda WG, Izumi R, Munugalavadla V, Patel P, Wang MH, Wong S, Byrd JC. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020 Apr 18;395(10232):1278-1291. link to original article PubMed

Alemtuzumab monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Hillmen et al. 2007 (CAM 307)	2001-2004	Phase III (E-RT-switch-ooc)	Chlorambucil	Superior PFS

This regimen was intended for patients who were at least 18 years old with flow cytometry–confirmed diagnosis of B-cell CLL, Rai stage I through IV with evidence of progression according to the National Cancer Institute Working Group (NCI-WG) 1996 criteria, no previous chemotherapy for CLL, a life expectancy of at least 12 weeks, WHO performance status of 0 to 2, and adequate renal and liver function.

Chemotherapy

• Alemtuzumab (Campath) as follows:
  • 3 mg IV once per day, then increased as tolerated in terms of infusion reactions to 10 mg IV once per day, and then to 30 mg IV once per day
  • Once 30 mg dose is tolerated: 30 mg IV over 2 hours, 3 times per week

Supportive medications

• See references for details, as they differ by paper.
• Diphenhydramine (Benadryl) 50 mg PO once per infusion, 30 minutes prior to Alemtuzumab (Campath)
• Acetaminophen (Tylenol) 650 mg PO once per infusion, 30 minutes prior to Alemtuzumab (Campath)
• Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg PO 3 times per week, starting on day 8, continuing at a minimum until 2 months after treatment is complete
• Famciclovir (Famvir) 250 mg PO twice per day, starting on day 8, continuing at a minimum until 2 months after treatment is complete

12- to 16-week course; total course varies depending on reference

References

1. Hillmen P, Skotnicki AB, Robak T, Jaksic B, Dmoszynska A, Wu J, Sirard C, Mayer J. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol. 2007 Dec 10;25(35):5616-23. Epub 2007 Nov 5. link to original article contains protocol PubMed

Bendamustine monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Knauf et al. 2009	2002-2006	Phase III (E-RT-switch-ic)	Chlorambucil	Superior PFS

This regimen was intended for previously untreated CLL patients up to 75 years of age with Binet stage B or C disease in need for treatment per the NCI-WG guidelines or IWCLL guidelines.

Chemotherapy

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

28-day cycle for 6 cycles

References

1. Knauf WU, Lissichkov T, Aldaoud A, Liberati A, Loscertales J, Herbrecht R, Juliusson G, Postner G, Gercheva L, Goranov S, Becker M, Fricke HJ, Huguet F, Del Giudice I, Klein P, Tremmel L, Merkle K, Montillo M. Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009 Sep 10;27(26):4378-84. Epub 2009 Aug 3. link to original article contains verified protocol PubMed
   1. Update: Knauf WU, Lissitchkov T, Aldaoud A, Liberati AM, Loscertales J, Herbrecht R, Juliusson G, Postner G, Gercheva L, Goranov S, Becker M, Fricke HJ, Huguet F, Del Giudice I, Klein P, Merkle K, Montillo M. Bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukaemia: updated results of a randomized phase III trial. Br J Haematol. 2012 Oct;159(1):67-77. Epub 2012 Aug 4. link to original article PubMed
2. Retrospective: Kolibaba KS, Sterchele JA, Joshi AD, Forsyth M, Alwon E, Beygi H, Kennealey GT. Demographics, treatment patterns, safety, and real-world effectiveness in patients aged 70 years and over with chronic lymphocytic leukemia receiving bendamustine with or without rituximab: a retrospective study. Ther Adv Hematol. 2013 Jun;4(3):157-71. link to PMC article PubMed

BR

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BR: Bendamustine & Rituximab
R-B: Rituximab & Bendamustine

Regimen

Study	Evidence	Comparator	Comparative Efficacy
Fischer et al. 2012 (GCLLSG CLL2M)	Phase II
Eichhorst et al. 2016 (GCLLSG CLL10)	Phase III (E-switch-ic)	FCR	Seems to have inferior PFS
Michallet et al. 2018 (MABLE)	Phase IIIb (E-switch-ic)	R-Clb	Superior PFS

Chemotherapy

• Bendamustine 90 mg/m² IV once per day on days 1 & 2
• Rituximab (Rituxan) as follows:
  • Cycle 1: 375 mg/m² IV once on day 0
  • Subsequent cycles: 500 mg/m² IV once on day 1

28-day cycle for up to 6 cycles

References

1. GCLLSG CLL2M: Fischer K, Cramer P, Busch R, Böttcher S, Bahlo J, Schubert J, Pflüger KH, Schott S, Goede V, Isfort S, von Tresckow J, Fink AM, Bühler A, Winkler D, Kreuzer KA, Staib P, Ritgen M, Kneba M, Döhner H, Eichhorst BF, Hallek M, Stilgenbauer S, Wendtner CM. Bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. 2012 Sep 10;30(26):3209-16. Epub 2012 Aug 6. link to original article contains verified protocol PubMed
2. Retrospective: Kolibaba KS, Sterchele JA, Joshi AD, Forsyth M, Alwon E, Beygi H, Kennealey GT. Demographics, treatment patterns, safety, and real-world effectiveness in patients aged 70 years and over with chronic lymphocytic leukemia receiving bendamustine with or without rituximab: a retrospective study. Ther Adv Hematol. 2013 Jun;4(3):157-71. link to PMC article PubMed
3. GCLLSG CLL10: Eichhorst B, Fink AM, Bahlo J, Busch R, Kovacs G, Maurer C, Lange E, Köppler H, Kiehl M, Sökler M, Schlag R, Vehling-Kaiser U, Köchling G, Plöger C, Gregor M, Plesner T, Trneny M, Fischer K, Döhner H, Kneba M, Wendtner CM, Klapper W, Kreuzer KA, Stilgenbauer S, Böttcher S, Hallek M; International Group of Investigators; GCLLSG. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016 Jul;17(7):928-42. Epub 2016 May 20. link to original article PubMed
4. MABLE: Michallet AS, Aktan M, Hiddemann W, Ilhan O, Johansson P, Laribi K, Meddeb B, Moreno C, Raposo J, Schuh A, Ünal A, Widenius T, Bernhardt A, Kellershohn K, Messeri D, Osborne S, Leblond V. Rituximab plus bendamustine or chlorambucil for chronic lymphocytic leukemia: primary analysis of the randomized, open-label MABLE study. Haematologica. 2018 Apr;103(4):698-706. Epub 2018 Feb 1. link to original article contains verified protocol link to PMC article PubMed

CC

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CC: Cladribine, Cyclophosphamide

Regimen variant #1, 0.36/650

Study	Evidence	Comparator	Comparative Efficacy
Robak et al. 2006 (PALG CLL2)	Phase III (E-esc)	1. Cladribine	Might have superior CR rate
		2. CMC	Seems to have inferior CR rate

Chemotherapy

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

Supportive medications

• 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	Evidence	Comparator	Comparative Efficacy
Robak et al. 2010 (PALG-CLL3)	Phase III (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 medications

• "No routine prophylaxis with antibiotics, antiviral agents, or growth factors."

28-day cycle for up to 6 cycles

References

1. PALG CLL2: Robak T, Blonski JZ, Gora-Tybor J, Jamroziak K, Dwilewicz-Trojaczek J, Tomaszewska A, Konopka L, Ceglarek B, Dmoszynska A, Kowal M, Kloczko J, Stella-Holowiecka B, Sulek K, Calbecka M, Zawilska K, Kuliczkowski K, Skotnicki AB, Warzocha K, Kasznicki M; PALG. Cladribine alone and in combination with cyclophosphamide or cyclophosphamide plus mitoxantrone in the treatment of progressive chronic lymphocytic leukemia: report of a prospective, multicenter, randomized trial of the Polish Adult Leukemia Group (PALG CLL2). Blood. 2006 Jul 15;108(2):473-9. Epub 2006 Mar 21. link to original article contains verified protocol PubMed
   1. Update: Robak T, Blonski JZ, Gora-Tybor J, Calbecka M, Dwilewicz-Trojaczek J, Boguradzki P, Dmoszynska A, Kowal M, Kloczko J, Piszcz J, Stella-Holowiecka B, Sulek K, Kuliczkowski K, Potoczek S, Warzocha K, Lech-Maranda E, Skotnicki AB, Piotrowska M, Moskwa A, Zawilska K, Jamroziak K. Long-term results of the Polish Adult Leukemia Group PALG-CLL2 phase III randomized study comparing cladribine-based combinations in chronic lymphocytic leukemia. Leuk Lymphoma. 2014 Mar;55(3):606-10. Epub 2013 Nov 14. link to original article PubMed
2. PALG-CLL3: Robak T, Jamroziak K, Gora-Tybor J, Stella-Holowiecka B, Konopka L, Ceglarek B, Warzocha K, Seferynska I, Piszcz J, Calbecka M, Kostyra A, Dwilewicz-Trojaczek J, Dmoszyñska A, Zawilska K, Hellmann A, Zdunczyk A, Potoczek S, Piotrowska M, Lewandowski K, Blonski JZ. Comparison of cladribine plus cyclophosphamide with fludarabine plus cyclophosphamide as first-line therapy for chronic lymphocytic leukemia: a phase III randomized study by the Polish Adult Leukemia Group (PALG-CLL3 Study). J Clin Oncol. 2010 Apr 10;28(11):1863-9. Epub 2010 Mar 8. link to original article contains verified protocol PubMed

Chlorambucil & Obinutuzumab

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GClb: GA101 (Obinutuzumab) & Chlorambucil

Regimen variant #1, 6 cycles

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Goede et al. 2014 (GCLLSG CLL11)	2010-2012	Phase III (E-RT-esc)	1. Chlorambucil	Superior OS
			2. Chlorambucil & Rituximab	Superior PFS

Chemotherapy

• Chlorambucil (Leukeran) 0.5 mg/kg PO once per day on days 1 & 15
• 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Fischer et al. 2019 (GCLLSG CLL14)	NR	Phase III (C)	Venetoclax & Obinutuzumab	Inferior PFS

Note: Obinutuzumab is only given for the first six cycles.

Chemotherapy

• Chlorambucil (Leukeran) 0.5 mg/kg PO once per day on days 1 & 15
• Obinutuzumab (Gazyva) as follows:
  • Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15
  • Cycles 2 to 6: 1000 mg IV once on day 1

28-day cycle for 12 cycles

References

1. GCLLSG CLL11: Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, Chagorova T, de la Serna J, Dilhuydy MS, Illmer T, Opat S, Owen CJ, Samoylova O, Kreuzer KA, Stilgenbauer S, Döhner H, Langerak AW, Ritgen M, Kneba M, Asikanius E, Humphrey K, Wenger M, Hallek M. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014 Mar 20;370(12):1101-10. Epub 2014 Jan 8. link to original article contains verified protocol PubMed
   1. Update: Goede V, Fischer K, Engelke A, Schlag R, Lepretre S, Montero LF, Montillo M, Fegan C, Asikanius E, Humphrey K, Fingerle-Rowson G, Hallek M. Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study. Leukemia. 2015 Jul;29(7):1602-4. Epub 2015 Jan 30. link to original article PubMed
2. iLLUMINATE: Moreno C, Greil R, Demirkan F, Tedeschi A, Anz B, Larratt L, Simkovic M, Samoilova O, Novak J, Ben-Yehuda D, Strugov V, Gill D, Gribben JG, Hsu E, Lih CJ, Zhou C, Clow F, James DF, Styles L, Flinn IW. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019 Jan;20(1):43-56. Epub 2018 Nov 30. link to original article contains protocol PubMed
3. GCLLSG CLL14: Fischer K, Al-Sawaf O, Bahlo J, Fink AM, Tandon M, Dixon M, Robrecht S, Warburton S, Humphrey K, Samoylova O, Liberati AM, Pinilla-Ibarz J, Opat S, Sivcheva L, Le Dû K, Fogliatto LM, Niemann CU, Weinkove R, Robinson S, Kipps TJ, Boettcher S, Tausch E, Humerickhouse R, Eichhorst B, Wendtner CM, Langerak AW, Kreuzer KA, Ritgen M, Goede V, Stilgenbauer S, Mobasher M, Hallek M. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019 Jun 6;380(23):2225-2236. Epub 2019 Jun 4. link to original article contains verified protocol PubMed

Chlorambucil & Ofatumumab

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Hillmen et al. 2015 (COMPLEMENT 1)	2008-2011	Phase III (E-RT-esc)	Chlorambucil	Superior PFS

Chemotherapy

• Chlorambucil (Leukeran) 10 mg/m² PO once per day on days 1 to 7
• Ofatumumab (Arzerra) as follows:
  • Cycle 1: 300 mg IV once on day 1, then 1000 mg IV once on day 8
  • Cycle 2 onwards: 1000 mg IV once on day 1

Supportive medications

• Premedication for Ofatumumab (Arzerra) included Acetaminophen (Tylenol), antihistamines, and glucocorticoids (no doses or further information provided)

28-day cycle for a minimum of 3 cycles, and then given until best response up to a maximum of 12 cycles

References

1. COMPLEMENT 1: Hillmen P, Robak T, Janssens A, Babu KG, Kloczko J, Grosicki S, Doubek M, Panagiotidis P, Kimby E, Schuh A, Pettitt AR, Boyd T, Montillo M, Gupta IV, Wright O, Dixon I, Carey JL, Chang CN, Lisby S, McKeown A, Offner F; COMPLEMENT 1 Study Investigators. Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial. Lancet. 2015 May 9;385(9980):1873-83. Epub 2015 Apr 13. link to original article contains protocol PubMed

Chlorambucil & Rituximab

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RClb: Rituximab & Chlorambucil
CLB-R: ChLoramBucil & Rituximab

Regimen variant #1, Clb 0.5 mg/kg q2wk

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Goede et al. 2014 (GCLLSG CLL11)	2010-2012	Phase III (E-esc)	1. Chlorambucil	Superior PFS
			2. Chlorambucil & Obinutuzumab	Inferior PFS

Chemotherapy

• Chlorambucil (Leukeran) 0.5 mg/kg PO once per day on days 1 & 15
• 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	Evidence
Foà et al. 2014 (ML21445)	Non-randomized portion of RCT

Chemotherapy

• Chlorambucil (Leukeran) 8 mg/m²/day PO once per day on days 1 to 7
• Rituximab (Rituxan) as follows:
  • Cycle 3: 375 mg/m² IV once on day 1
  • Subsequent cycles: 500 mg/m² IV once on day 1

28-day cycle for up to 8 cycles

Subsequent treatment

• Responders (PR or better): Observation versus Rituximab maintenance

Regimen variant #3, Clb 10 mg/m²/d, 1 week out of 4

Study	Evidence	Comparator	Comparative Efficacy
Hillmen et al. 2014 (NCRI CLL208)	Phase II
Michallet et al. 2018 (MABLE)	Phase IIIb (E-switch-ic)	BR	Inferior PFS

Chemotherapy

• Chlorambucil (Leukeran) 10 mg/m² PO once per day on days 1 to 7
• 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 could have up to 6 more cycles of chlorambucil alone
• MABLE: Patients not achieving CR could have up to 6 more cycles of chlorambucil alone or until CR

References

1. GCLLSG CLL11: Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, Chagorova T, de la Serna J, Dilhuydy MS, Illmer T, Opat S, Owen CJ, Samoylova O, Kreuzer KA, Stilgenbauer S, Döhner H, Langerak AW, Ritgen M, Kneba M, Asikanius E, Humphrey K, Wenger M, Hallek M. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014 Mar 20;370(12):1101-10. Epub 2014 Jan 8. link to original article contains verified protocol PubMed
   1. Update: Goede V, Fischer K, Engelke A, Schlag R, Lepretre S, Montero LF, Montillo M, Fegan C, Asikanius E, Humphrey K, Fingerle-Rowson G, Hallek M. Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study. Leukemia. 2015 Jul;29(7):1602-4. Epub 2015 Jan 30. link to original article PubMed
2. ML21445: Foà R, Del Giudice I, Cuneo A, Del Poeta G, Ciolli S, Di Raimondo F, Lauria F, Cencini E, Rigolin GM, Cortelezzi A, Nobile F, Callea V, Brugiatelli M, Massaia M, Molica S, Trentin L, Rizzi R, Specchia G, Di Serio F, Orsucci L, Ambrosetti A, Montillo M, Zinzani PL, Ferrara F, Morabito F, Mura MA, Soriani S, Peragine N, Tavolaro S, Bonina S, Marinelli M, De Propris MS, Starza ID, Piciocchi A, Alietti A, Runggaldier EJ, Gamba E, Mauro FR, Chiaretti S, Guarini A. Chlorambucil plus rituximab with or without maintenance rituximab as first-line treatment for elderly chronic lymphocytic leukemia patients. Am J Hematol. 2014 May;89(5):480-6. Epub 2014 Feb 18. link to original article contains verified protocol PubMed
3. NCRI CLL08: Hillmen P, Gribben JG, Follows GA, Milligan D, Sayala HA, Moreton P, Oscier DG, Dearden CE, Kennedy DB, Pettitt AR, Nathwani A, Varghese A, Cohen D, Rawstron A, Oertel S, Pocock CF. Rituximab plus chlorambucil as first-line treatment for chronic lymphocytic leukemia: Final analysis of an open-label phase II study. J Clin Oncol. 2014 Apr 20;32(12):1236-41. Epub 2014 Mar 17. link to original article contains verified protocol link to PMC article PubMed
4. MABLE: Michallet AS, Aktan M, Hiddemann W, Ilhan O, Johansson P, Laribi K, Meddeb B, Moreno C, Raposo J, Schuh A, Ünal A, Widenius T, Bernhardt A, Kellershohn K, Messeri D, Osborne S, Leblond V. Rituximab plus bendamustine or chlorambucil for chronic lymphocytic leukemia: primary analysis of the randomized, open-label MABLE study. Haematologica. 2018 Apr;103(4):698-706. Epub 2018 Feb 1. link to original article contains verified protocol link to PMC article PubMed

Cladribine monotherapy

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Regimen variant #1, 0.6 mg/kg

Study	Evidence	Comparator	Comparative Efficacy
Robak et al. 2006 (PALG CLL2)	Phase III (C)	1. CC	Might have inferior CR rate
		2. CMC	Inferior CR rate
Mulligan et al. 2014	Phase III (E-switch-ic)	1. Chlorambucil 2. Fludarabine	Superior PFS

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm. Dosing details for Mulligan et al. 2014 were not available in the abstract.

Chemotherapy

• Cladribine (Leustatin) 0.12 mg/kg IV over 2 hours once per day on days 1 to 5

Supportive medications

• 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	Evidence
Saven et al. 1995	Phase II

Chemotherapy

• Cladribine (Leustatin) 0.1 mg/m²/day IV continuous infusion on days 1 to 7 (total dose per cycle: 0.7 mg/m²)

28 to 35-day cycles, repeated until maximum response or limiting toxicity

References

1. Saven A, Lemon RH, Kosty M, Beutler E, Piro LD. 2-Chlorodeoxyadenosine activity in patients with untreated chronic lymphocytic leukemia. J Clin Oncol. 1995 Mar;13(3):570-4. link to original article contains protocol PubMed
2. PALG CLL2: Robak T, Blonski JZ, Gora-Tybor J, Jamroziak K, Dwilewicz-Trojaczek J, Tomaszewska A, Konopka L, Ceglarek B, Dmoszynska A, Kowal M, Kloczko J, Stella-Holowiecka B, Sulek K, Calbecka M, Zawilska K, Kuliczkowski K, Skotnicki AB, Warzocha K, Kasznicki M; Polish Adult Leukemia Group. Cladribine alone and in combination with cyclophosphamide or cyclophosphamide plus mitoxantrone in the treatment of progressive chronic lymphocytic leukemia: report of a prospective, multicenter, randomized trial of the Polish Adult Leukemia Group (PALG CLL2). Blood. 2006 Jul 15;108(2):473-9. Epub 2006 Mar 21. link to original article contains verified protocol PubMed
   1. Update: Robak T, Blonski JZ, Gora-Tybor J, Calbecka M, Dwilewicz-Trojaczek J, Boguradzki P, Dmoszynska A, Kowal M, Kloczko J, Piszcz J, Stella-Holowiecka B, Sulek K, Kuliczkowski K, Potoczek S, Warzocha K, Lech-Maranda E, Skotnicki AB, Piotrowska M, Moskwa A, Zawilska K, Jamroziak K. Long-term results of the Polish Adult Leukemia Group PALG-CLL2 phase III randomized study comparing cladribine-based combinations in chronic lymphocytic leukemia. Leuk Lymphoma. 2014 Mar;55(3):606-10. Epub 2013 Nov 14. link to original article PubMed
3. Mulligan SP, Karlsson K, Strömberg M, Jønsson V, Gill D, Hammerström J, Hertzberg M, McLennan R, Uggla B, Norman J, Wallvik J, Sundström G, Johansson H, Brandberg Y, Liliemark J, Juliusson G; Scandinavian Lymphoma Group; ALLG. Cladribine prolongs progression-free survival and time to second treatment compared to fludarabine and high-dose chlorambucil in chronic lymphocytic leukemia. Leuk Lymphoma. 2014 Dec;55(12):2769-77. Epub 2014 Apr 16. link to original article PubMed

CMC

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CMC: Cladribine, Mitoxantrone, Cyclophosphamide

Regimen

Study	Evidence	Comparator	Comparative Efficacy
Robak et al. 2006 (PALG CLL2)	Phase III (E-esc)	1. Cladribine	Superior CR rate
		2. CC	Seems to have superior CR rate

Chemotherapy

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

28-day cycle for up to 6 cycles

References

1. PALG CLL2: Robak T, Blonski JZ, Gora-Tybor J, Jamroziak K, Dwilewicz-Trojaczek J, Tomaszewska A, Konopka L, Ceglarek B, Dmoszynska A, Kowal M, Kloczko J, Stella-Holowiecka B, Sulek K, Calbecka M, Zawilska K, Kuliczkowski K, Skotnicki AB, Warzocha K, Kasznicki M; Polish Adult Leukemia Group. Cladribine alone and in combination with cyclophosphamide or cyclophosphamide plus mitoxantrone in the treatment of progressive chronic lymphocytic leukemia: report of a prospective, multicenter, randomized trial of the Polish Adult Leukemia Group (PALG CLL2). Blood. 2006 Jul 15;108(2):473-9. Epub 2006 Mar 21. link to original article contains protocol PubMed

FCA

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

Regimen

Study	Evidence	Comparator	Comparative Efficacy
Lepretre et al. 2012 (GOELAMS CLL2007FMP)	Phase III (E-switch-ic)	FCR	Did not meet primary endpoint of PFS36
Geisler et al. 2014 (HOVON-68)	Phase III (E-esc)	FC	Superior PFS

GOELAMS CLL2007FMP was halted prematurely due to excess mortality. In 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 of age, with WHO performance status less than 3 and no severe comorbidities, with high-risk CLL as defined by the presence of either unmutated IGHV, 17p deletion, 11q deletion, or trisomy 12 by FISH.

Chemotherapy

• Fludarabine (Fludara) 40 mg/m² PO once per day on days 1 to 3
• Cyclophosphamide (Cytoxan) 250 mg/m² PO once per day on days 1 to 3
• Alemtuzumab (Campath) as follows:
  • Cycle 1: 30 mg SC once per day on days -1, 0, and 1
  • Subsequent cycles: 30 mg SC once on day 1

Supportive medications

• Cotrimoxazole 400/80 mg PO once per day until 6 months after end of treatment
• Acyclovir (Zovirax) 400 mg PO three times per day until 3 months after end of treatment

OR

• Valacyclovir (Valtrex) 500 mg PO twice per day until 3 months after end of treatment

28-day cycle for 6 cycles

References

1. Lepretre S, Aurran T, Mahé B, Cazin B, Tournilhac O, Maisonneuve H, Casasnovas O, Delmer A, Leblond V, Royer B, Corront B, Chevret S, Delépine R, Vaudaux S, Van Den Neste E, Béné MC, Letestu R, Cymbalista F, Feugier P. Excess mortality after treatment with fludarabine and cyclophosphamide in combination with alemtuzumab in previously untreated patients with chronic lymphocytic leukemia in a randomized phase 3 trial. Blood. 2012 May 31;119(22):5104-10. Epub 2012 Feb 14. link to original article PubMed
2. Geisler CH, van T' Veer MB, Jurlander J, Walewski J, Tjønnfjord G, Itälä Remes M, Kimby E, Kozak T, Polliack A, Wu KL, Wittebol S, Abrahamse-Testroote MC, Doorduijn J, Ghidey Alemayehu W, van Oers MH. Frontline low-dose alemtuzumab with fludarabine and cyclophosphamide prolongs progression-free survival in high-risk CLL. Blood. 2014 May 22;123(21):3255-62. Epub 2014 Apr 15. link to original article contains verified protocol PubMed

FCM

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FCM: Fludarabine, Cyclophosphamide, Mitoxantrone

Regimen variant #1

Study	Evidence	Comparator	Comparative Efficacy
Hillmen et al. 2011 (NCRI CLL201)	Randomized Phase II (C)	FCM-R	Did not meet primary endpoint of ORR

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

Chemotherapy

• Fludarabine (Fludara) 24 mg/m² PO once per day on days 1 to 5
• Cyclophosphamide (Cytoxan) 150 mg/m² PO once per day on days 1 to 5
• Mitoxantrone (Novantrone) 6 mg/m² IV once on day 1

28-day cycle for 6 cycles

Regimen variant #2

Study	Evidence
Bosch et al. 2008	Phase II

Chemotherapy

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

Supportive medications

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

28-day cycle for 6 cycles

References

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

FCR

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

Regimen variant #1, 25/250/375-500

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Keating et al. 2005		Phase II
Hallek et al. 2010 (GCLLSG CLL8)	2003-2006	Phase III (E-RT-esc)	FC	Superior OS (*)	Equivalent HRQoL
Lepretre et al. 2012 (GOELAMS CLL2007FMP)		Phase III (C)	FCCam	Did not meet primary endpoint of PFS36
Schweighofer et al. 2013 (GCLLSG CLL7)		Phase III (E-esc)	Observation	Superior EFS
Eichhorst et al. 2016 (GCLLSG CLL10)		Phase III (C)	BR	Seems to have superior PFS
Shanafelt et al. 2019 (ECOG E1912)		Phase III (C)	Ibrutinib & Rituximab	Inferior OS

Note: reported efficacy for GCLLSG CLL8 is based on the updated 2016 results.

Chemotherapy

• Fludarabine (Fludara) 25 mg/m² IV once per day on days 1 to 3
• Cyclophosphamide (Cytoxan) 250 mg/m² IV once per day on days 1 to 3
• Rituximab (Rituxan) as follows:
  • Cycle 1: 375 mg/m² IV once on day 0
    • Alternate dosing in ECOG E1912: 50 mg/m² IV once on day 1, then 325 mg/m² IV once on day 2
  • Cycles 2 to 6: 500 mg/m² IV once on day 1

Supportive medications

• Note: these vary according to reference.
• Diphenhydramine (Benadryl) 25 mg IV once per infusion, 30 minutes prior to Rituximab (Rituxan)
• Acetaminophen (Tylenol) 650 mg PO once per infusion, 30 minutes prior to Rituximab (Rituxan)
• Cycle 1: Allopurinol (Zyloprim) 300 mg PO once per day on days 1 to 7
• Some patients received:
  • Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg PO twice per week
  • Valacyclovir (Valtrex) 500 mg PO once per day
• PCP (Pneumocystis jirovecii pneumonia) prophylaxis recommended for severe leukopenia greater than 7 days
• No routine prophylaxis with antiviral medications or G-CSF

28-day cycle for 6 cycles

Regimen variant #2, 25/250/500

Study	Evidence	Comparator	Comparative Efficacy
Awan et al. 2014 (LUCID)	Phase III (C)	FCR+L	Did not meet primary endpoint of CR rate

Chemotherapy

• Fludarabine (Fludara) as follows:
  • Cycle 1: 25 mg/m² IV over at least 10 to 30 minutes once per day on days 2 to 4
  • Cycle 2 to 6: 25 mg/m² IV over at least 10 to 30 minutes once per day on days 1 to 3
• Cyclophosphamide (Cytoxan) as follows:
  • Cycle 1: 250 mg/m² IV over at least 10 to 30 minutes once per day on days 2 to 4
  • Cycle 2 to 6: 250 mg/m² IV over at least 10 to 30 minutes once per day on days 1 to 3
• 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 medications

• Cotrimoxazole or equivalent
• Acyclovir (Zovirax) 400 mg PO twice per day or equivalent
• Growth factors at physician discretion

28-day cycle for 6 cycles

Regimen variant #3, 20/150/375-500 ("FCR-Lite")

Study	Evidence
Foon et al. 2009	Phase II

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
• 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 medications

• Diphenhydramine (Benadryl) 25 mg PO once per day on days 1 & 14, prior to Rituximab (Rituxan)
• Acetaminophen (Tylenol) 650 mg PO once per day on days 1 & 14, prior to Rituximab (Rituxan)
• Dexamethasone (Decadron) 10 mg IV or PO once per day on days 1 & 14, prior to Rituximab (Rituxan)
• 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
• Filgrastim (Neupogen) or Pegfilgrastim (Neulasta) 24 hours after chemo (details not provided)

28-day cycle for 6 cycles

Subsequent treatment

• Indefinite rituximab maintenance

Regimen variant #4, 40/250/375-500, oral FC

Study	Evidence
Dartigeas et al. 2017 (CLL 2007 SA)	Non-randomized portion of 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
• Rituximab (Rituxan) as follows:
  • Cycle 1: 375 mg/m² IV once on day 1, then 500 mg/m² IV once on day 14
  • Cycle 2: 500 mg/m² IV once per day on days 1 & 14
  • Cycles 3 & 4: 500 mg/m² IV once on day 1

1-month cycle for 4 cycles

Subsequent treatment

• Rituximab maintenance versus observation

Regimen variant #5, 25/250/375

Study	Evidence
Tam et al. 2006	Phase II

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

28-day cycle for up to 6 cycles or "attainment of maximum response"

Regimen variant #6, 24/150/375-500, oral FC

Study	Evidence	Comparator	Comparative Efficacy
Munir et al. 2017 (ADMIRE)	Randomized Phase IIB (C)	FCM-R	Did not meet primary endpoint of CR rate
Howard et al. 2017 (ARCTIC)	Randomized Phase IIB (C)	FCM-miniR	Superior CR rate

Note: in contrast to other variants, FC is given over 5 days not 3.

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

28-day cycle for 6 cycles

References

1. Keating MJ, O'Brien S, Albitar M, Lerner S, Plunkett W, Giles F, Andreeff M, Cortes J, Faderl S, Thomas D, Koller C, Wierda W, Detry MA, Lynn A, Kantarjian H. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol. 2005 Jun 20;23(18):4079-88. Epub 2005 Mar 14. link to original article contains verified protocol PubMed
   1. Update: Tam CS, O'Brien S, Wierda W, Kantarjian H, Wen S, Do KA, Thomas DA, Cortes J, Lerner S, Keating MJ. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood. 2008 Aug 15;112(4):975-80. Epub 2008 Apr 14. link to original article link to PMC article PubMed
   2. Update: Thompson PA, Tam CS, O'Brien SM, Wierda WG, Stingo F, Plunkett W, Smith SC, Kantarjian HM, Freireich EJ, Keating MJ. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood. 2016 Jan 21;127(3):303-9. Epub 2015 Oct 22. link to original article link to PMC article PubMed
2. Tam CS, Wolf M, Prince HM, Januszewicz EH, Westerman D, Lin KI, Carney D, Seymour JF. Fludarabine, cyclophosphamide, and rituximab for the treatment of patients with chronic lymphocytic leukemia or indolent non-Hodgkin lymphoma. Cancer. 2006 Jun 1;106(11):2412-20. link to original article contains verified protocol PubMed
3. Foon KA, Boyiadzis M, Land SR, Marks S, Raptis A, Pietragallo L, Meisner D, Laman A, Sulecki M, Butchko A, Schaefer P, Lenzer D, Tarhini A. Chemoimmunotherapy with low-dose fludarabine and cyclophosphamide and high dose rituximab in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009 Feb 1;27(4):498-503. Epub 2008 Dec 15. link to original article contains verified protocol PubMed
   1. Update: Foon KA, Mehta D, Lentzsch S, Kropf P, Marks S, Lenzner D, Pietragallo L, Sulecki M, Tarhini A, Boyiadzis M. Long-term results of chemoimmunotherapy with low-dose fludarabine, cyclophosphamide and high-dose rituximab as initial treatment for patients with chronic lymphocytic leukemia. Blood. 2012 Mar 29;119(13):3184-5. link to original article PubMed
4. GCLLSG CLL8: Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J, Hensel M, Hopfinger G, Hess G, von Grünhagen U, Bergmann M, Catalano J, Zinzani PL, Caligaris-Cappio F, Seymour JF, Berrebi A, Jäger U, Cazin B, Trneny M, Westermann A, Wendtner CM, Eichhorst BF, Staib P, Bühler A, Winkler D, Zenz T, Böttcher S, Ritgen M, Mendila M, Kneba M, Döhner H, Stilgenbauer S; International Group of Investigators; German Chronic Lymphocytic Leukaemia Study Group. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010 Oct 2;376(9747):1164-74. link to original article contains verified protocol PubMed
   1. Update: Fischer K, Bahlo J, Fink AM, Goede V, Herling CD, Cramer P, Langerbeins P, von Tresckow J, Engelke A, Maurer C, Kovacs G, Herling M, Tausch E, Kreuzer KA, Eichhorst B, Böttcher S, Seymour JF, Ghia P, Marlton P, Kneba M, Wendtner CM, Döhner H, Stilgenbauer S, Hallek M. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016 Jan 14;127(2):208-15. Epub 2015 Oct 20. link to original article PubMed
   2. HRQoL analysis: Kutsch N, Busch R, Bahlo J, Mayer J, Hensel M, Hopfinger G, Hess G, von Grünhagen U, Wendtner CM, Maria Fink A, Fischer K, Hallek M, Eichhorst B. FCR front-line therapy and quality of life in patients with chronic lymphocytic leukemia. Leuk Lymphoma. 2017 Feb;58(2):399-407. Epub 2016 Jun 29. link to original article PubMed
5. Lepretre S, Aurran T, Mahé B, Cazin B, Tournilhac O, Maisonneuve H, Casasnovas O, Delmer A, Leblond V, Royer B, Corront B, Chevret S, Delépine R, Vaudaux S, Van Den Neste E, Béné MC, Letestu R, Cymbalista F, Feugier P. Excess mortality after treatment with fludarabine and cyclophosphamide in combination with alemtuzumab in previously untreated patients with chronic lymphocytic leukemia in a randomized phase 3 trial. Blood. 2012 May 31;119(22):5104-10. Epub 2012 Feb 14. link to original article PubMed
6. Abstract: Carmen D Schweighofer, MD, Florence Cymbalista, MD, Carolin Müller, MD, Raymonde Busch, PhD, Raphael Porcher, PhD, Petra Langerbeins, MD, Bruno Cazin, MD, Anna-Maria Fink, MD, Brigitte Dreyfus, MD, Stefan Ibach, Stéphane Leprêtre, MD, Kirsten Fischer, MD, Ursula Vehling-Kaiser, MD, Barbara Eichhorst, MD, Manuela A. Bergmann, MD, Stephan Stilgenbauer, MD, Hartmut Döhner, MD, Veronique Leblond, MD, Michael Hallek, MD, and Vincent Levy, MD, PhD. Early Versus Deferred Treatment With Combined Fludarabine, Cyclophosphamide and Rituximab (FCR) Improves Event-Free Survival In Patients With High-Risk Binet Stage A Chronic Lymphocytic Leukemia – First Results Of a Randomized German-French Cooperative Phase III Trial. 2013 ASH Annual Symposium abstract 524 link to abstract
7. Awan FT, Hillmen P, Hellmann A, Robak T, Hughes SG, Trone D, Shannon M, Flinn IW, Byrd JC; LUCID trial investigators. A randomized, open-label, multicentre, phase 2/3 study to evaluate the safety and efficacy of lumiliximab in combination with fludarabine, cyclophosphamide and rituximab versus fludarabine, cyclophosphamide and rituximab alone in subjects with relapsed chronic lymphocytic leukaemia. Br J Haematol. 2014 Nov;167(4):466-77. Epub 2014 Aug 8. link to original article contains verified protocol PubMed
8. GCLLSG CLL10: Eichhorst B, Fink AM, Bahlo J, Busch R, Kovacs G, Maurer C, Lange E, Köppler H, Kiehl M, Sökler M, Schlag R, Vehling-Kaiser U, Köchling G, Plöger C, Gregor M, Plesner T, Trneny M, Fischer K, Döhner H, Kneba M, Wendtner CM, Klapper W, Kreuzer KA, Stilgenbauer S, Böttcher S, Hallek M; International Group of Investigators; German CLL Study Group. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016 Jul;17(7):928-42. Epub 2016 May 20. link to original article PubMed
9. ADMIRE: Munir T, Howard DR, McParland L, Pocock C, Rawstron AC, Hockaday A, Varghese A, Hamblin M, Bloor A, Pettitt A, Fegan C, Blundell J, Gribben JG, Phillips D, Hillmen P. Results of the randomized phase IIB ADMIRE trial of FCR with or without mitoxantrone in previously untreated CLL. Leukemia. 2017 Oct;31(10):2085-2093. Epub 2017 Apr 20. link to original article contains verified protocol PubMed
10. ARCTIC: Howard DR, Munir T, McParland L, Rawstron AC, Milligan D, Schuh A, Hockaday A, Allsup DJ, Marshall S, Duncombe AS, O'Dwyer JL, Smith AF, Longo R, Varghese A, Hillmen P. Results of the randomized phase IIB ARCTIC trial of low-dose rituximab in previously untreated CLL. Leukemia. 2017 Nov;31(11):2416-2425. Epub 2017 Mar 24. link to original article contains verified protocol in supplement PubMed
11. CLL 2007 SA: Dartigeas C, Van Den Neste E, Léger J, Maisonneuve H, Berthou C, Dilhuydy MS, De Guibert S, Leprêtre S, Béné MC, Nguyen-Khac F, Letestu R, Cymbalista F, Rodon P, Aurran-Schleinitz T, Vilque JP, Tournilhac O, Mahé B, Laribi K, Michallet AS, Delmer A, Feugier P, Lévy V, Delépine R, Colombat P, Leblond V; CLL 2007 SA investigators; FILO. Rituximab maintenance versus observation following abbreviated induction with chemoimmunotherapy in elderly patients with previously untreated chronic lymphocytic leukaemia (CLL 2007 SA): an open-label, randomised phase 3 study. Lancet Haematol. 2018 Feb;5(2):e82-e94. Epub 2017 Dec 20. link to original article contains protocol PubMed
12. ECOG E1912: Shanafelt TD, Wang XV, Kay NE, Hanson CA, O'Brien S, Barrientos J, Jelinek DF, Braggio E, Leis JF, Zhang CC, Coutre SE, Barr PM, Cashen AF, Mato AR, Singh AK, Mullane MP, Little RF, Erba H, Stone RM, Litzow M, Tallman M. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019 Aug 1;381(5):432-443. link to original article contains verified protocol PubMed

FCR (Rituximab Hycela)

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FCR: Fludarabine, Cyclophosphamide, Rituximab hyaluronidase

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Assouline et al. 2016 (SAWYER)	2012-2013	Randomized Phase 1b (E-RT-switch-ic)	FCR	Not reported

Note: other variants include oral fludarabine and/or cyclophosphamide; to be completed.

Chemotherapy

• Fludarabine (Fludara) 25 mg/m² IV once per day on days 1 to 3
• Cyclophosphamide (Cytoxan) 250 mg/m² IV once per day on days 1 to 3
• Rituximab (Rituxan) as follows:
  • Cycle 1: 375 mg/m² IV once on day 0
• Rituximab and hyaluronidase human (Rituxan Hycela) as follows:
  • Cycles 2 to 6: 1600 mg SC once on day 1

28-day cycle for up to 6 cycles

References

1. SAWYER: Assouline S, Buccheri V, Delmer A, Gaidano G, Trneny M, Berthillon N, Brewster M, Catalani O, Li S, McIntyre C, Sayyed P, Badoux X. Pharmacokinetics, safety, and efficacy of subcutaneous versus intravenous rituximab plus chemotherapy as treatment for chronic lymphocytic leukaemia (SAWYER): a phase 1b, open-label, randomised controlled non-inferiority trial. Lancet Haematol. 2016 Mar;3(3):e128-38. link to original article contains verified protocol PubMed

Fludarabine & Alemtuzumab

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Elter et al. 2011 (CAM 314)	Phase III (E-esc)	Fludarabine	Seems to have superior OS

Chemotherapy

• Fludarabine (Fludara)
• Alemtuzumab (Campath)

28-day cycle for up to 6 cycles

References

1. CAM 314: Elter T, Gercheva-Kyuchukova L, Pylylpenko H, Robak T, Jaksic B, Rekhtman G, Kyrcz-Krzemień S, Vatutin M, Wu J, Sirard C, Hallek M, Engert A. Fludarabine plus alemtuzumab versus fludarabine alone in patients with previously treated chronic lymphocytic leukaemia: a randomised phase 3 trial. Lancet Oncol. 2011 Dec;12(13):1204-13. Epub 2011 Oct 10. link to original article PubMed

Ibrutinib monotherapy

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Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
O'Brien et al. 2013 (PCYC-1102)	2010-2012	Phase Ib/II (RT)
Farooqui et al. 2014 (NHLBI 12-H-0035)		Phase II
Burger et al. 2015 (RESONATE-2)	2013-NR	Phase III (E-RT-switch-ooc)	Chlorambucil	Superior OS (*)
Langerbeins et al. 2015 (CLL12)		Phase III (E-esc)	Placebo	TBD
Woyach et al. 2018 (Alliance A041202)		Phase III (E-switch-ooc)	BR	Superior PFS
			Ibrutinib & Rituximab	Did not meet primary endpoint of PFS
Burger et al. 2018 (MDACC 2013-0703)		Phase III (C)	Ibrutinib & Rituximab	Did not meet primary endpoint of PFS

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. NHLBI 12-H-0035 was intended for patients with p.TP53 aberrations. RESONATE-2 was intended for patients older than 65 years. CLL12 was intended for patients with asymptomatic Binet stage A CLL. Reported efficacy for RESONATE-2 is based on the 2019 update.

Chemotherapy

• Ibrutinib (Imbruvica) 420 mg PO once per day

28-day cycles

References

1. PCYC-1102: O'Brien S, Furman RR, Coutre SE, Sharman JP, Burger JA, Blum KA, Grant B, Richards DA, Coleman M, Wierda WG, Jones JA, Zhao W, Heerema NA, Johnson AJ, Izumi R, Hamdy A, Chang BY, Graef T, Clow F, Buggy JJ, James DF, Byrd JC. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol. 2014 Jan;15(1):48-58. Epub 2013 Dec 10. link to original article contains verified protocol link to PMC article PubMed
   1. Update: Byrd JC, Furman RR, Coutre SE, Burger JA, Blum KA, Coleman M, Wierda WG, Jones JA, Zhao W, Heerema NA, Johnson AJ, Shaw Y, Bilotti E, Zhou C, James DF, O'Brien S. Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015 Apr 16;125(16):2497-506. Epub 2015 Feb 19. link to original article link to PMC article PubMed
   2. Update: O'Brien S, Furman RR, Coutre S, Flinn IW, Burger JA, Blum K, Sharman J, Wierda W, Jones J, Zhao W, Heerema NA, Johnson AJ, Luan Y, James DF, Chu AD, Byrd JC. Single-agent ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. Blood. 2018 Apr 26;131(17):1910-1919. Epub 2018 Feb 2. link to original article PubMed
2. NHLBI 12-H-0035: Farooqui MZ, Valdez J, Martyr S, Aue G, Saba N, Niemann CU, Herman SE, Tian X, Marti G, Soto S, Hughes TE, Jones J, Lipsky A, Pittaluga S, Stetler-Stevenson M, Yuan C, Lee YS, Pedersen LB, Geisler CH, Calvo KR, Arthur DC, Maric I, Childs R, Young NS, Wiestner A. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol. 2015 Feb;16(2):169-76. Epub 2014 Dec 31. link to original article contains protocol link to PMC article PubMed
3. RESONATE-2: Burger JA, Tedeschi A, Barr PM, Robak T, Owen C, Ghia P, Bairey O, Hillmen P, Bartlett NL, Li J, Simpson D, Grosicki S, Devereux S, McCarthy H, Coutre S, Quach H, Gaidano G, Maslyak Z, Stevens DA, Janssens A, Offner F, Mayer J, O'Dwyer M, Hellmann A, Schuh A, Siddiqi T, Polliack A, Tam CS, Suri D, Cheng M, Clow F, Styles L, James DF, Kipps TJ; RESONATE-2 Investigators. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015 Dec 17;373(25):2425-37. Epub 2015 Dec 6. link to original article contains verified protocol link to PMC article PubMed
   1. Update: Barr PM, Robak T, Owen C, Tedeschi A, Bairey O, Bartlett NL, Burger JA, Hillmen P, Coutre S, Devereux S, Grosicki S, McCarthy H, Li J, Simpson D, Offner F, Moreno C, Zhou C, Styles L, James D, Kipps TJ, Ghia P. Sustained efficacy and detailed clinical follow-up of first-line ibrutinib treatment in older patients with chronic lymphocytic leukemia: extended phase 3 results from RESONATE-2. Haematologica. 2018 Sep;103(9):1502-1510. Epub 2018 Jun 7. link to original article link to PMC article PubMed
   2. Update: Burger JA, Barr PM, Robak T, Owen C, Ghia P, Tedeschi A, Bairey O, Hillmen P, Coutre SE, Devereux S, Grosicki S, McCarthy H, Simpson D, Offner F, Moreno C, Dai S, Lal I, Dean JP, Kipps TJ. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia. 2020 Mar;34(3):787-798. Epub 2019 Oct 18. link to original article PubMed
4. Abstract: Petra Langerbeins, MD, Jasmin Bahlo, Christina Rhein, Paula Cramer, MD, Anna-Maria Fink, MD, Natali Pflug, MD, Julia von Tresckow, MD, Stephan Stilgenbauer, MD, Karl-Anton Kreuzer, Michael J. Eckart, MD, Ursula Vehling-Kaiser, MD, Rudolf Schlag, MD, Christina Balser, MD, Lothar Müller, MD, Clemens-Martin Wendtner, MD, Kirsten Fischer, MD, Barbara Eichhorst, MD and Michael Hallek, MD. Ibrutinib in Early Stage CLL: Preliminary Safety Results of a Placebo-Controlled Phase III Study. ASH Annual Meeting 2015 Abstract 2934. link to abstract
5. Alliance A041202: Woyach JA, Ruppert AS, Heerema NA, Zhao W, Booth AM, Ding W, Bartlett NL, Brander DM, Barr PM, Rogers KA, Parikh SA, Coutre S, Hurria A, Brown JR, Lozanski G, Blachly JS, Ozer HG, Major-Elechi B, Fruth B, Nattam S, Larson RA, Erba H, Litzow M, Owen C, Kuzma C, Abramson JS, Little RF, Smith SE, Stone RM, Mandrekar SJ, Byrd JC. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018 Dec 27;379(26):2517-2528. Epub 2018 Dec 1. link to original article contains protocol PubMed
6. MDACC 2013-0703: Burger JA, Sivina M, Jain N, Kim E, Kadia T, Estrov Z, Nogueras-Gonzalez GM, Huang X, Jorgensen J, Li J, Cheng M, Clow F, Ohanian M, Andreeff M, Mathew T, Thompson P, Kantarjian H, O'Brien S, Wierda WG, Ferrajoli A, Keating MJ. Randomized trial of ibrutinib vs ibrutinib plus rituximab in patients with chronic lymphocytic leukemia. Blood. 2019 Mar 7;133(10):1011-1019. Epub 2018 Dec 7. link to original article contains protocol link to PMC article PubMed

Ibrutinib & Obinutuzumab

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Moreno et al. 2018 (iLLUMINATE)	2014-2015	Phase III (E-RT-switch-ooc)	G-Clb	Superior PFS

Chemotherapy

• Ibrutinib (Imbruvica) 420 mg PO once per day
• Obinutuzumab (Gazyva) as follows:
  • Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15
  • Cycles 2 to 6: 1000 mg IV once on day 1

28-day cycles

References

1. iLLUMINATE: Moreno C, Greil R, Demirkan F, Tedeschi A, Anz B, Larratt L, Simkovic M, Samoilova O, Novak J, Ben-Yehuda D, Strugov V, Gill D, Gribben JG, Hsu E, Lih CJ, Zhou C, Clow F, James DF, Styles L, Flinn IW. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019 Jan;20(1):43-56. Epub 2018 Nov 30. link to original article contains protocol PubMed

Ibrutinib & Rituximab

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Shanafelt et al. 2019 (ECOG E1912)	Phase III (E-RT-switch-ooc)	FCR	Superior OS

Chemotherapy

• Ibrutinib (Imbruvica) 420 mg PO once per day
• Rituximab (Rituxan) as follows:
  • Cycle 2: 50 mg/m² IV once on day 1, then 325 mg/m² IV once on day 2
  • Cycles 3 to 7: 500 mg/m² IV once on day 1

28-day cycles

References

1. ECOG E1912: Shanafelt TD, Wang XV, Kay NE, Hanson CA, O'Brien S, Barrientos J, Jelinek DF, Braggio E, Leis JF, Zhang CC, Coutre SE, Barr PM, Cashen AF, Mato AR, Singh AK, Mullane MP, Little RF, Erba H, Stone RM, Litzow M, Tallman M. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019 Aug 1;381(5):432-443. link to original article contains verified protocol PubMed

Obinutuzumab monotherapy

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

Study	Evidence	Comparator	Comparative Efficacy
Byrd et al. 2015	Randomized Phase II (C)	High-dose obinutuzumab	Might have inferior ORR rate

Chemotherapy

• Obinutuzumab (Gazyva) as follows:
  • Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15
  • Cycle 2 onwards: 1000 mg IV once on day 1

Supportive medications

• Acetaminophen (Tylenol) 650 to 1000 mg PO once per infusion, 30 to 60 minutes prior to Obinutuzumab (Gazyva)
• Antihistamine "such as" Diphenhydramine (Benadryl) 50 to 100 mg PO once per infusion, 30 to 60 minutes prior to Obinutuzumab (Gazyva)
• Prednisolone (Millipred) (or equivalent) 100 mg IV once per infusion, prior to each of the first three doses of Obinutuzumab (Gazyva), afterwards at the discretion of treating physician

21-day cycle up to 8 cycles

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

Study	Evidence	Comparator	Comparative Efficacy
Byrd et al. 2015 (GAGE)	Randomized Phase II (E-esc)	Standard-dose obinutuzumab	Might have superior ORR rate

Chemotherapy

• Obinutuzumab (Gazyva) as follows:
  • Cycle 1: either of the following:
    • 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
    • 100 mg IV once on day 1, then 1900 mg IV once on day 2, then 2000 mg IV once per day on days 8 & 15
  • Cycle 2 onwards: 2000 mg IV once on day 1

Supportive medications

• Acetaminophen (Tylenol) 650 to 1000 mg PO once per infusion, 30 to 60 minutes prior to Obinutuzumab (Gazyva)
• Antihistamine "such as" Diphenhydramine (Benadryl) 50 to 100 mg PO once per infusion, 30 to 60 minutes prior to Obinutuzumab (Gazyva)
• Prednisolone (Millipred) (or equivalent) 100 mg IV once per infusion, prior to each of the first three doses of Obinutuzumab (Gazyva), afterwards at the discretion of treating physician

21-day cycle up to 8 cycles

References

1. GAGE: Byrd JC, Flynn JM, Kipps TJ, Boxer M, Kolibaba KS, Carlile DJ, Fingerle-Rowson G, Tyson N, Hirata J, Sharman JP. Randomized phase 2 study of obinutuzumab monotherapy in symptomatic, previously untreated chronic lymphocytic leukemia. Blood. 2016 Jan 7;127(1):79-86. Epub 2015 Oct 15. link to original article contains verified protocol link to PMC article PubMed

Observation

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Dighiero et al. 1998 (FRE-CLL-85)	Phase III (C)	1. Chlorambucil	Seems to have inferior PFS
		2. Chlorambucil & Prednisone	Inferior PFS
Bergmann et al. 2013 (GCLLSG CLL1)	Phase III (C)	Fludarabine	Inferior PFS
Schweighofer et al. 2013 (GCLLSG CLL7)	Phase III (C)	FCR	Inferior EFS
Langerbeins et al. 2015 (CLL12)	Phase III (C)	Ibrutinib	TBD

No active treatment, also known as "watchful waiting".

References

1. FRE-CLL-85: Dighiero G, Maloum K, Desablens B, Cazin B, Navarro M, Leblay R, Leporrier M, Jaubert J, Lepeu G, Dreyfus B, Binet JL, Travade P. Chlorambucil in indolent chronic lymphocytic leukemia: French Cooperative Group on Chronic Lymphocytic Leukemia. N Engl J Med. 1998 May 21;338(21):1506-14. link to original article contains verified protocol PubMed
2. Abstract: Manuela A. Bergmann, MD, Raymonde Busch, PhD, Barbara Eichhorst, MD, Andreas Buehler, MD, Norbert Fischer, MD, Michael J Eckart, MD, Ursula Vehling-Kaiser, MD, Ulrich Jäger, MD, Georg Hopfinger, MD, Clemens Wendtner, MD, Kirsten Fischer, MD, Bertold Emmerich, MD, Hartmut Döhner, MD, Michael Hallek, M.D. Ph.D. and Stephan Stilgenbauer, MD. Overall Survival In Early Stage Chronic Lymphocytic Leukemia Patients With Treatment Indication Due To Disease Progression: Follow-Up Data Of The CLL1 Trial Of The German CLL Study Group (GCLLSG). Blood 2013 122:4127. link to abstract
3. Abstract: Carmen D Schweighofer, MD, Florence Cymbalista, MD, Carolin Müller, MD, Raymonde Busch, PhD, Raphael Porcher, PhD, Petra Langerbeins, MD, Bruno Cazin, MD, Anna-Maria Fink, MD, Brigitte Dreyfus, MD, Stefan Ibach, Stéphane Leprêtre, MD, Kirsten Fischer, MD, Ursula Vehling-Kaiser, MD, Barbara Eichhorst, MD, Manuela A. Bergmann, MD, Stephan Stilgenbauer, MD, Hartmut Döhner, MD, Veronique Leblond, MD, Michael Hallek, MD, and Vincent Levy, MD, PhD. Early Versus Deferred Treatment With Combined Fludarabine, Cyclophosphamide and Rituximab (FCR) Improves Event-Free Survival In Patients With High-Risk Binet Stage A Chronic Lymphocytic Leukemia – First Results Of a Randomized German-French Cooperative Phase III Trial. 2013 ASH Annual Symposium abstract 524 link to abstract
4. Abstract: Petra Langerbeins, MD, Jasmin Bahlo, Christina Rhein, Paula Cramer, MD, Anna-Maria Fink, MD, Natali Pflug, MD, Julia von Tresckow, MD, Stephan Stilgenbauer, MD, Karl-Anton Kreuzer, Michael J. Eckart, MD, Ursula Vehling-Kaiser, MD, Rudolf Schlag, MD, Christina Balser, MD, Lothar Müller, MD, Clemens-Martin Wendtner, MD, Kirsten Fischer, MD, Barbara Eichhorst, MD and Michael Hallek, MD. Ibrutinib in Early Stage CLL: Preliminary Safety Results of a Placebo-Controlled Phase III Study. ASH Annual Meeting 2015 Abstract 2934. link to abstract

Venetoclax & Obinutuzumab

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VEN+G: VENetoclax & Gazyva (Obinutuzumab)

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Fischer et al. 2019 (GCLLSG CLL14)	NR	Phase III (E-RT-switch-ooc)	Chlorambucil & Obinutuzumab	Superior PFS

Note: Obinutuzumab is only given for the first six cycles.

Chemotherapy

• Venetoclax (Venclexta) as follows:
  • Cycle 1: 20 mg PO once per day on days 22 to 28
  • Cycle 2: 50 mg PO once per day on days 1 to 7, then 100 mg PO once per day on days 8 to 14, then 200 mg PO once per day on days 15 to 21, then 400 mg PO once per day on days 22 to 28
  • Cycles 3 to 12: 400 mg PO once per day
• Obinutuzumab (Gazyva) as follows:
  • Cycle 1: 100 mg IV once on day 1, then 900 mg IV once on day 2, then 1000 mg IV once per day on days 8 & 15
  • Cycles 2 to 6: 1000 mg IV once on day 1

28-day cycle for 12 cycles

References

1. GCLLSG CLL14: Fischer K, Al-Sawaf O, Bahlo J, Fink AM, Tandon M, Dixon M, Robrecht S, Warburton S, Humphrey K, Samoylova O, Liberati AM, Pinilla-Ibarz J, Opat S, Sivcheva L, Le Dû K, Fogliatto LM, Niemann CU, Weinkove R, Robinson S, Kipps TJ, Boettcher S, Tausch E, Humerickhouse R, Eichhorst B, Wendtner CM, Langerak AW, Kreuzer KA, Ritgen M, Goede V, Stilgenbauer S, Mobasher M, Hallek M. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019 Jun 6;380(23):2225-2236. Epub 2019 Jun 4. link to original article contains verified protocol PubMed

First-line therapy, non-randomized or retrospective data

Alemtuzumab & Methylprednisolone

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Regimen

Study	Evidence
Pettitt et al. 2012 (NCRI CLL206)	Phase II

Chemotherapy

• Alemtuzumab (Campath) as follows:
  • Cycle 1: 3 mg IV once, then 10 mg IV once, then 30 mg IV three times per week, increased as tolerated
  • Cycles 2 to 4: 30 mg SC three times per week
• Methylprednisolone (Solumedrol) 1000 mg/m²/day (route not specified) on days 1 to 5

28-day cycle for 4 cycles

References

1. NCRI CLL206: Pettitt AR, Jackson R, Carruthers S, Dodd J, Dodd S, Oates M, Johnson GG, Schuh A, Matutes E, Dearden CE, Catovsky D, Radford JA, Bloor A, Follows GA, Devereux S, Kruger A, Blundell J, Agrawal S, Allsup D, Proctor S, Heartin E, Oscier D, Hamblin TJ, Rawstron A, Hillmen P. Alemtuzumab in combination with methylprednisolone is a highly effective induction regimen for patients with chronic lymphocytic leukemia and deletion of TP53: final results of the National Cancer Research Institute CLL206 trial. J Clin Oncol. 2012 May 10;30(14):1647-55. Epub 2012 Apr 9. link to original article contains verified protocol PubMed

Bendamustine & Obinutuzumab

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G-B: Gazyva (Obinutuzumab), Bendamustine

Regimen

Study	Evidence	Efficacy
Brown et al. 2015 (GALTON)	Phase 1b, 20 pts	ORR: 90%

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
• 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 medications

• Acetaminophen (Tylenol) (dose not specified) once per infusion, prior to Obinutuzumab (Gazyva)
• Antihistamine e.g. Diphenhydramine (Benadryl) once per infusion, prior to Obinutuzumab (Gazyva)
• Highly potent corticosteroid (e.g. Prednisolone (Millipred) 100 mg IV) once, prior to first dose of Obinutuzumab (Gazyva)
• Allopurinol (Zyloprim) or Rasburicase (Elitek) recommended for tumor lysis syndrome prophylaxis
• PCP prophylaxis recommended
• Antiviral prophylaxis recommended

28-day cycle for 6 cycles

References

1. GALTON: Brown JR, O'Brien S, Kingsley CD, Eradat H, Pagel JM, Lymp J, Hirata J, Kipps TJ. Obinutuzumab plus fludarabine/cyclophosphamide or bendamustine in the initial therapy of CLL patients: the phase 1b GALTON trial. Blood. 2015 Apr 30;125(18):2779-85. Epub 2015 Mar 13. link to original article contains verified protocol link to PMC article PubMed

CFAR

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CFAR: Cyclophosphamide, Fludarabine, Alemtuzumab, Rituximab

Regimen

Study	Evidence	Efficacy
Parikh et al. 2011	Phase II	ORR: 92%

Note that 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
• 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 medications

• 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 (Rituxan)/Alemtuzumab (Campath)
• Diphenhydramine (Benadryl) 25 to 50 mg IV or PO once per day on days 1, 2, 3, 5, prior to Rituximab (Rituxan)/Alemtuzumab (Campath)
• Hydrocortisone (Cortef) 100 mg IV once per day on days 1, 2, 3, 5, prior to Rituximab (Rituxan)/Alemtuzumab (Campath)
• Cycle 1: Allopurinol (Zyloprim) 300 mg PO once per day for at least days 1 to 7
• Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg PO once per day during treatment and for at least 3 to 6 months after last course
• Antiviral prophylaxis with ONE of the following:
  • Valacyclovir (Valtrex) 500 mg PO once per day during treatment and for at least 3 to 6 months after last course
  • OR Valganciclovir (Valcyte) 450 mg PO twice per day during treatment and for at least 3 to 6 months after last course

28-day cycle for 6 cycles

References

1. Parikh SA, Keating MJ, O'Brien S, Wang X, Ferrajoli A, Faderl S, Burger J, Koller C, Estrov Z, Badoux X, Lerner S, Wierda WG. Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, alemtuzumab, and rituximab for high-risk chronic lymphocytic leukemia. Blood. 2011 Aug 25;118(8):2062-8. Epub 2011 Jul 12. link to original article link to PMC article contains verified protocol PubMed

G-FC

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

Regimen

Study	Evidence
Brown et al. 2015 (GALTON)	Non-randomized

Chemotherapy

• 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
• 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 medications

• Acetaminophen (Tylenol) (dose not specified) once per infusion, prior to Obinutuzumab (Gazyva)
• Antihistamine e.g. Diphenhydramine (Benadryl) once per infusion, prior to Obinutuzumab (Gazyva)
• Highly potent corticosteroid (e.g. Prednisolone (Millipred) 100 mg IV) once, prior to first dose of Obinutuzumab (Gazyva)
• Allopurinol (Zyloprim) or Rasburicase (Elitek) recommended for tumor lysis syndrome prophylaxis
• PCP prophylaxis recommended
• Antiviral prophylaxis recommended

28-day cycle for 6 cycles

References

1. GALTON: Brown JR, O'Brien S, Kingsley CD, Eradat H, Pagel JM, Lymp J, Hirata J, Kipps TJ. Obinutuzumab plus fludarabine/cyclophosphamide or bendamustine in the initial therapy of CLL patients: the phase 1b GALTON trial. Blood. 2015 Apr 30;125(18):2779-85. Epub 2015 Mar 13. link to original article contains verified protocol link to PMC article PubMed

HDMP-R

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HDMP-R: High Dose, MethylPrednisolone & Rituximab

Regimen

Study	Evidence
Castro et al. 2009	Phase II

Chemotherapy

• Methylprednisolone (Solumedrol) 1000 mg/m² IV over 90 minutes once per day on days 1 to 3
• 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 medications

• Cimetidine (Tagamet) as premedication for Methylprednisolone (Solumedrol)
• Acetaminophen (Tylenol) as premedication for Rituximab (Rituxan)
• Diphenhydramine (Benadryl) as premedication for Rituximab (Rituxan)
• Trimethoprim-Sulfamethoxazole (Bactrim DS) (or equivalent) prophylaxis during therapy and continuing for 2 months after treatment is complete
• Acyclovir (Zovirax) (or equivalent) prophylaxis during therapy and continuing for 2 months after treatment is complete
• Fluconazole (Diflucan) (or equivalent) prophylaxis during therapy and continuing for 2 months after treatment is complete
• Allopurinol (Zyloprim) 300 mg PO once per day, started 3 days before the start of therapy and continued during treatment
• Patients with glucose greater than 200 on days of treatment received regular insulin SC sliding scale on days of treatment

28-day cycle for 3 cycles

References

1. Castro JE, James DF, Sandoval-Sus JD, Jain S, Bole J, Rassenti L, Kipps TJ. Rituximab in combination with high-dose methylprednisolone for the treatment of chronic lymphocytic leukemia. Leukemia. 2009 Oct;23(10):1779-89. Epub 2009 Aug 20. contains protocol link to PMC article PubMed

Ibrutinib & Venetoclax

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Regimen

Study	Evidence
Jain et al. 2019 (MDACC 2015-0860)	Phase II

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.

Chemotherapy

• Ibrutinib (Imbruvica) 420 mg PO once per day
• Venetoclax (Venclexta) as follows:
  • Cycle 4: 20 mg PO once per day on days 1 to 7, then 50 mg PO once per day on days 8 to 14, then 100 mg PO once per day on days 15 to 21, then 200 mg PO once per day on days 22 to 28
  • Cycle 5 onwards: 400 mg PO once per day

28-day cycle for up to 24 cycles

References

1. MDACC 2015-0860: Jain N, Keating M, Thompson P, Ferrajoli A, Burger J, Borthakur G, Takahashi K, Estrov Z, Fowler N, Kadia T, Konopleva M, Alvarado Y, Yilmaz M, DiNardo C, Bose P, Ohanian M, Pemmaraju N, Jabbour E, Sasaki K, Kanagal-Shamanna R, Patel K, Jorgensen J, Garg N, Wang X, Sondermann K, Cruz N, Wei C, Ayala A, Plunkett W, Kantarjian H, Gandhi V, Wierda W. Ibrutinib and venetoclax for first-line treatment of CLL. N Engl J Med. 2019 May 30;380(22):2095-2103. link to original article contains protocol PubMed

Idelalisib & Rituximab

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Regimen

Study	Evidence
O'Brien et al. 2015 (Study 101-08)	Phase II

In a letter dated 3/21/2016, Gilead states that idelalisib should not be used for first line treatment of CLL.

Chemotherapy

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

28-day cycle for 12 cycles

Subsequent treatment

• Patients who had not progressed could continue on an extension study

References

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

Lenalidomide & Rituximab

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Regimen variant #1

Study	Evidence
James et al. 2014 (CRC014)	Phase II

Chemotherapy

• Lenalidomide (Revlimid) with escalation in the absence of grade 2 or higher toxicities as follows:
  • Cycle 1: 2.5 mg PO once per day on days 1 to 7, then 5 mg PO once per day on days 8 to 21
  • Cycle 2: 5 mg PO once per day on days 1 to 21
  • Subsequent cycles: 10 mg PO once per day on days 1 to 21
• Rituximab (Rituxan) as follows:
  • Cycle 1: 375 mg/m² IV once per day on days 31 & 33
  • Cycle 2: 375 mg/m² IV once per day on days 1, 8, 15, 22
  • Subsequent cycles: 375 mg/m² IV once on day 1

Supportive medications

• Allopurinol (Zyloprim) prior to starting lenalidomide and with any dose escalation
• Aspirin 81 mg PO once per day

35-day cycle for 1 cycle, then 28-day cycle for up to 6 cycles

Regimen variant #2

Study	Evidence
Fowler et al. 2014	Phase II

This combination was only studied in SLL (as opposed to CLL). Lenalidomide is dose-escalated to avoid tumor flare.

Chemotherapy

• Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21, with an escalation of 5 mg/month to goal of 20 mg PO once per day
• Rituximab (Rituxan) 375 mg/m² IV once on day 1

28-day cycle for up to 12 cycles

References

1. CRC014: James DF, Werner L, Brown JR, Wierda WG, Barrientos JC, Castro JE, Greaves A, Johnson AJ, Rassenti LZ, Rai KR, Neuberg D, Kipps TJ. Lenalidomide and rituximab for the initial treatment of patients with chronic lymphocytic leukemia: a multicenter clinical-translational study from the Chronic Lymphocytic Leukemia Research Consortium. J Clin Oncol. 2014 Jul 1;32(19):2067-73. Epub 2014 May 27. link to original article contains verified protocol link to PMC article PubMed
2. Fowler NH, Davis RE, Rawal S, Nastoupil L, Hagemeister FB, McLaughlin P, Kwak LW, Romaguera JE, Fanale MA, Fayad LE, Westin JR, Shah J, Orlowski RZ, Wang M, Turturro F, Oki Y, Claret LC, Feng L, Baladandayuthapani V, Muzzafar T, Tsai KY, Samaniego F, Neelapu SS. Safety and activity of lenalidomide and rituximab in untreated indolent lymphoma: an open-label, phase 2 trial. Lancet Oncol. 2014 Nov;15(12):1311-8. Epub 2014 Oct 15. link to original article contains protocol link to PMC article PubMed

O-FC

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O-FC: Ofatumumab, Fludarabine, Cyclophosphamide

Regimen

Study	Evidence
Wierda et al. 2011 (407 Study)	Phase II

Chemotherapy

• 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
• Fludarabine (Fludara) as follows:
  • Cycle 1: 25 mg/m² IV once per day on days 2 to 4
  • Cycles 2 to 6: 25 mg/m² IV once per day on days 1 to 3 (note: there was ambiguity in Wierda et al. 2011 about whether both fludarabine and cyclophosphamide are given three days per cycle, or whether fludarabine is given once per cycle and only cyclophosphamide is given three days per cycle)
• Cyclophosphamide (Cytoxan) as follows:
  • Cycle 1: 250 mg/m² IV once per day on days 2 to 4
  • Cycle 2 to 6: 250 mg/m² IV once per day on days 1 to 3

Supportive medications

• Acetaminophen (Tylenol) 1000 mg PO once on day 1, prior to Ofatumumab (Arzerra)
• Cetirizine (Zyrtec) 10 mg (or equivalent) PO once on day 1, prior to Ofatumumab (Arzerra)
• Prednisolone (Millipred) 100 mg (or equivalent) PO once on day 1, prior to doses 1 & 2 of Ofatumumab (Arzerra), then reduced by physician discretion for later doses
• May be used at physician discretion:
  • Allopurinol (Zyloprim) for tumor lysis syndrome prophylaxis
  • Antiviral prophylaxis
  • PCP (Pneumocystis jiroveci pneumonia) prophylaxis
  • Growth factor support

28-day cycle for 6 cycles

References

1. Wierda WG, Kipps TJ, Dürig J, Griskevicius L, Stilgenbauer S, Mayer J, Smolej L, Hess G, Griniute R, Hernandez-Ilizaliturri FJ, Padmanabhan S, Gorczyca M, Chang CN, Chan G, Gupta I, Nielsen TG, Russell CA; 407 Study Investigators. Chemoimmunotherapy with O-FC in previously untreated patients with chronic lymphocytic leukemia. Blood. 2011 Jun 16;117(24):6450-8. Epub 2011 Apr 15. link to original article contains verified protocol link to PMC article PubMed

PCO

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PCO: Pentostatin, Cyclophosphamide, Ofatumumab

Regimen

Study	Evidence
Shanafelt et al. 2013	Phase II
Tedeschi et al. 2015	Phase II
Strati et al. 2016	Phase II

Chemotherapy

• Pentostatin (Nipent) 2 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1
• 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 medications

• Best described in Shanafelt et al. 2013:
• Methylprednisolone (Solumedrol) 80 mg IV once, prior to Ofatumumab (Arzerra)
• 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

• Strati et al. 2016: Ofatumumab consolidation

References

1. Shanafelt T, Lanasa MC, Call TG, Beaven AW, Leis JF, LaPlant B, Bowen D, Conte M, Jelinek DF, Hanson CA, Kay NE, Zent CS. Ofatumumab-based chemoimmunotherapy is effective and well tolerated in patients with previously untreated chronic lymphocytic leukemia (CLL). Cancer. 2013 Nov 1;119(21):3788-96. Epub 2013 Aug 6. Erratum in: Cancer. 2014 Mar 15;120(6):926. Dosage error in article text. link to original article link to PMC article contains verified protocol PubMed
2. Tedeschi A, Rossi D, Motta M, Quaresmini G, Rossi M, Coscia M, Anastasia A, Rossini F, Cortelezzi A, Nador G, Scarfò L, Cairoli R, Frustaci AM, Dalceggio D, Picardi P, De Paoli L, Orlandi E, Rambaldi A, Massaia M, Gaidano G, Montillo M; Rete Ematologica Lombarda–CLL Workgroup. A phase II multi-center trial of pentostatin plus cyclophosphamide with ofatumumab in older previously untreated chronic lymphocytic leukemia patients. Haematologica. 2015 Dec;100(12):e501-4. Epub 2015 Aug 20. link to original article contains verified protocol link to PMC article PubMed
3. Strati P, Lanasa M, Call TG, Leis JF, Brander DM, LaPlant BR, Pettinger AM, Ding W, Parikh SA, Hanson CA, Chanan-Khan AA, Bowen DA, Conte M, Kay NE, Shanafelt TD. Ofatumumab monotherapy as a consolidation strategy in patients with previously untreated chronic lymphocytic leukaemia: a phase 2 trial. Lancet Haematol. 2016 Sep;3(9):e407-14. Epub 2016 Aug 1. link to original article contains protocol PubMed

PCR

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PCR: Pentostatin, Cyclophosphamide, Rituximab

Regimen variant #1, 2/600/100->375

Study	Evidence
Kay et al. 2007	Phase II
Shanafelt et al. 2007	Phase II

Chemotherapy

• Pentostatin (Nipent) 2 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1
• 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 medications

• 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/uL for 2 straight days
• Cycle 1: Allopurinol (Zyloprim) 300 mg PO once per day on days 1 to 15
• Prophylactic Trimethoprim-Sulfamethoxazole (Bactrim DS) for 1 year
• Prophylactic Acyclovir (Zovirax) for 1 year

28-day cycle for 6 cycles

Regimen variant #2, 4/600/375

Study	Evidence
Samaniego et al. 2015 (MDACC 2004-0818)	Phase II

This regimen was specifically studied in SLL, not CLL.

Chemotherapy

• Pentostatin (Nipent) 4 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1
• Rituximab (Rituxan) 375 mg/m² IV once on day 1

Supportive medications

• Ondansetron (Zofran) 8 mg (route not specified) once on day 1, prior to chemotherapy
• Diphenhydramine (Benadryl) 25 mg (route not specified) once on day 1, prior to chemotherapy
• 500 ml of 5% dextrose/one-half normal saline before and after each Pentostatin (Nipent) dose
• Filgrastim (Neupogen) at the discretion of the treating physician
• Cycle 1: Allopurinol (Zyloprim) 300 mg PO once per day on days 1 to 15
• Trimethoprim-Sulfamethoxazole (Bactrim DS) once per day three days per week during and for 1 month following therapy
• Acyclovir (Zovirax) 400 mg PO twice per day during and for 1 month following therapy

21-day cycle for 6 cycles

References

1. Kay NE, Geyer SM, Call TG, Shanafelt TD, Zent CS, Jelinek DF, Tschumper R, Bone ND, Dewald GW, Lin TS, Heerema NA, Smith L, Grever MR, Byrd JC. Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia. Blood. 2007 Jan 15;109(2):405-11. Epub 2006 Sep 28. link to original article contains protocol link to PMC article PubMed
2. Shanafelt TD, Lin T, Geyer SM, Zent CS, Leung N, Kabat B, Bowen D, Grever MR, Byrd JC, Kay NE. Pentostatin, cyclophosphamide, and rituximab regimen in older patients with chronic lymphocytic leukemia. Cancer. 2007 Jun 1;109(11):2291-8. link to original article PubMed
3. MDACC 2004-0818: Samaniego F, Hagemeister F, Romaguera JE, Fanale MA, Pro B, McLaughlin P, Rodriguez MA, Neelapu SS, Fayad L, Younes A, Feng L, Berkova Z, Khashab T, Sehgal L, Vega-Vasquez F, Kwak LW. Pentostatin, cyclophosphamide and rituximab for previously untreated advanced stage, low-grade B-cell lymphomas. Br J Haematol. 2015 Jun;169(6):814-23. Epub 2015 Mar 31. link to original article contains verified protocol link to PMC article PubMed

RCC

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RCC: Rituximab, Cladribine, Cyclophosphamide

Regimen

Study	Evidence
Robak et al. 2018 (PALG CLL4)	Non-randomized portion of RCT

Chemotherapy

• Rituximab (Rituxan)
• Cladribine (Leustatin)
• Cyclophosphamide (Cytoxan)

28-day cycle for 6 cycles

Subsequent treatment

• Observation versus Rituximab maintenance

References

1. PALG CLL4: Robak T, Błoński J, Skotnicki AB, Piotrowska M, Wróbel T, Rybka J, Kłoczko J, Bołkun Ł, Budziszewska BK, Walczak U, Uss A, Fidecka M, Smolewski P. Rituximab, cladribine, and cyclophosphamide (RCC) induction with rituximab maintenance in chronic lymphocytic leukemia: PALG - CLL4 (ML21283) trial. Eur J Haematol. 2018 May;100(5):465-474. Epub 2018 Mar 22. link to original article PubMed

Rituximab monotherapy

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Regimen

Study	Evidence
Hainsworth et al. 2003	Phase II
Williams et al. 2016 (RESORT substudy)	Non-randomized portion of RCT

Chemotherapy

• Rituximab (Rituxan) 375 mg/m² IV once per day on days 1, 8, 15, 22
  • In Hainsworth et al. 2003, optional alternate initial dosing for patients with WBC count greater than 100 x 10⁹/L: 100 mg IV once on day 1, with remainder of the 375 mg/m² dosage given on day 2

Supportive medications

• Acetaminophen (Tylenol) 650 mg PO once per day on days 1, 8, 15, 22; 30 minutes prior to Rituximab (Rituxan)
• Diphenhydramine (Benadryl) 50 mg PO or IV once per day on days 1, 8, 15, 22; 30 minutes prior to Rituximab (Rituxan)
• In Hainsworth et al. 2003, if WBC count greater than 50 x 10⁹/L or massive lymphadenopathy: Allopurinol (Zyloprim) 300 mg PO once per day, starting 3 days before the first dose of Rituximab (Rituxan)
• In Hainsworth et al. 2003, one of the following:
  • Cimetidine (Tagamet) 300 mg IV once per day on days 1, 8, 15, 22; 30 minutes prior to Rituximab (Rituxan)
  • Ranitidine (Zantac) 50 mg IV once per day on days 1, 8, 15, 22; 30 minutes prior to Rituximab (Rituxan)

4-week course

Subsequent treatment

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

References

1. Hainsworth JD, Litchy S, Barton JH, Houston GA, Hermann RC, Bradof JE, Greco FA; Minnie Pearl Cancer Research Network. Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol. 2003 May 1;21(9):1746-51. link to original article PubMed
2. RESORT substudy: Williams ME, Hong F, Gascoyne RD, Wagner LI, Krauss JC, Habermann TM, Swinnen LJ, Schuster SJ, Peterson CG, Sborov MD, Martin SE, Weiss M, Ehmann WC, Horning SJ, Kahl BS; Eastern Cooperative Oncology Group. Rituximab extended schedule or retreatment trial for low tumour burden non-follicular indolent B-cell non-Hodgkin lymphomas: Eastern Cooperative Oncology Group Protocol E4402. Br J Haematol. 2016 Jun;173(6):867-75. Epub 2016 Mar 11. link to original article contains protocol link to PMC article PubMed

Ruxolitinib monotherapy

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Regimen

Study	Evidence
Jain et al. 2017	Phase II

Note: this was a trial focused on symptom control, not efficacy.

Chemotherapy

• Ruxolitinib (Jakafi) 10 mg PO twice per day

References

1. Jain P, Keating M, Renner S, Cleeland C, Xuelin H, Gonzalez GN, Harris D, Li P, Liu Z, Veletic I, Rozovski U, Jain N, Thompson P, Bose P, DiNardo C, Ferrajoli A, O'Brien S, Burger J, Wierda W, Verstovsek S, Kantarjian H, Estrov Z. Ruxolitinib for symptom control in patients with chronic lymphocytic leukaemia: a single-group, phase 2 trial. Lancet Haematol. 2017 Feb;4(2):e67-e74. Epub 2017 Jan 11. link to original article contains protocol link to PMC article PubMed

Consolidation and/or maintenance after first-line therapy

Alemtuzumab monotherapy

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Regimen variant #1, 6-week course

Study	Evidence
Varghese et al. 2017 (NCRN CLL 207)	Phase II

Preceding treatment

• Chemotherapy (details not specified)

Chemotherapy

• Alemtuzumab (Campath) 30 mg SC 3 times per week

6-week course

Regimen variant #2, 12-week course

Study	Evidence	Comparator	Comparative Efficacy
Wendtner et al. 2004 (GCLLSG CLL4B)	Phase III (E-esc)	Observation	Superior PFS (*)

Note: this study closed early due to high rates of infections in the experimental arm; efficacy is based on the 2009 update.

Preceding treatment

• F x 6 or FC x 6

Chemotherapy

• Alemtuzumab (Campath) as follows:
  • Day 1: 3 mg SC once
  • Day 2, if 3 mg dose is well tolerated: 10 mg SC once
  • Day 3 onwards, if 10 mg dose is well tolerated: 30 mg SC once on day 3, then SC 3 times per week

12-week course

References

1. GCLLSG CLL4B: Wendtner CM, Ritgen M, Schweighofer CD, Fingerle-Rowson G, Campe H, Jäger G, Eichhorst B, Busch R, Diem H, Engert A, Stilgenbauer S, Döhner H, Kneba M, Emmerich B, Hallek M; German CLL Study Group. Consolidation with alemtuzumab in patients with chronic lymphocytic leukemia (CLL) in first remission--experience on safety and efficacy within a randomized multicenter phase III trial of the German CLL Study Group (GCLLSG). Leukemia. 2004 Jun;18(6):1093-101. link to original article contains verified protocol PubMed
   1. Update: Schweighofer CD, Ritgen M, Eichhorst BF, Busch R, Abenhardt W, Kneba M, Hallek M, Wendtner CM. Consolidation with alemtuzumab improves progression-free survival in patients with chronic lymphocytic leukaemia (CLL) in first remission: long-term follow-up of a randomized phase III trial of the German CLL Study Group (GCLLSG). Br J Haematol. 2009 Jan;144(1):95-8. Epub 2008 Oct 30. link to original article PubMed
2. NCRN CLL207: Varghese AM, Howard DR, Pocock C, Rawstron AC, Follows G, McCarthy H, Dearden C, Fegan C, Milligan D, Smith AF, Gregory W, Hillmen P; NCRI CLL Sub-Group. Eradication of minimal residual disease improves overall and progression-free survival in patients with chronic lymphocytic leukaemia, evidence from NCRN CLL207: a phase II trial assessing alemtuzumab consolidation. Br J Haematol. 2017 Feb;176(4):573-582. Epub 2016 Dec 29. link to original article contains protocol PubMed

Lenalidomide monotherapy

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Fink et al. 2017 (GCLLSG CLLM1)	Phase III (E-esc)	Observation	Superior PFS

Note that while the NCT record reports dose increases beyond 15 mg PO once per day, the abstract states that 15 mg PO once per day was the "target dose".

Preceding treatment

• GCLLSG CLLM1: "Chemoimmunotherapy"

Chemotherapy

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

28-day cycles

References

1. GCLLSG CLLM1: Fink AM, Bahlo J, Robrecht S, Al-Sawaf O, Aldaoud A, Hebart H, Jentsch-Ullrich K, Dörfel S, Fischer K, Wendtner CM, Nösslinger T, Ghia P, Bosch F, Kater AP, Döhner H, Kneba M, Kreuzer KA, Tausch E, Stilgenbauer S, Ritgen M, Böttcher S, Eichhorst B, Hallek M. Lenalidomide maintenance after first-line therapy for high-risk chronic lymphocytic leukaemia (CLLM1): final results from a randomised, double-blind, phase 3 study. Lancet Haematol. 2017 Oct;4(10):e475-e486. Epub 2017 Sep 12. link to original article contains protocol PubMed

Observation

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Wendtner et al. 2004 (GCLLSG CLL4B)		Phase III (C)	Alemtuzumab	Inferior PFS (*)
Hochster et al. 2009 (ECOG E1496)		Phase III (C)	Rituximab	Inferior PFS
Michallet et al. 2010		Phase III (C)	1. Cy/TBI, then auto HSCT 2. BEAM, then auto HSCT	Inferior EFS
Sutton et al. 2011 (Auto-LLC 2001)		Phase III (C)	Cy/TBI, then auto HSCT	Inferior EFS
Foà et al. 2014 (ML21445)		Phase III (C)	Rituximab	Might have inferior PFS
Greil et al. 2016 (AGMT CLL-8a)	2010-2013	Phase III (C)	Rituximab	Inferior PFS
Fink et al. 2017 (GCLLSG CLLM1)		Phase III (C)	Lenalidomide	Inferior PFS
Dartigeas et al. 2017 (CLL 2007 SA)		Phase III (C)	Rituximab	Inferior PFS

No further treatment; used as a comparator arm. GCLLSG CLL4B closed early due to high rates of infections in the experimental arm; efficacy is based on the 2009 update.

Preceding treatment

• GCLLSG CLL4B: F x 6 versus FC x 6
• ECOG E1496: CVP
• Auto-LLC 2001: mini-CHOP x 3, then F x 3
• ML21445: Clb-R
• AGMT CLL-8a: Rituximab-containing chemoimmunotherapy
• GCLLSG CLLM1: "Chemoimmunotherapy"
• CLL 2007 SA: FCR x 4

References

1. GCLLSG CLL4B: Wendtner CM, Ritgen M, Schweighofer CD, Fingerle-Rowson G, Campe H, Jäger G, Eichhorst B, Busch R, Diem H, Engert A, Stilgenbauer S, Döhner H, Kneba M, Emmerich B, Hallek M; German CLL Study Group. Consolidation with alemtuzumab in patients with chronic lymphocytic leukemia (CLL) in first remission--experience on safety and efficacy within a randomized multicenter phase III trial of the German CLL Study Group (GCLLSG). Leukemia. 2004 Jun;18(6):1093-101. link to original article PubMed
   1. Update: Schweighofer CD, Ritgen M, Eichhorst BF, Busch R, Abenhardt W, Kneba M, Hallek M, Wendtner CM. Consolidation with alemtuzumab improves progression-free survival in patients with chronic lymphocytic leukaemia (CLL) in first remission: long-term follow-up of a randomized phase III trial of the German CLL Study Group (GCLLSG). Br J Haematol. 2009 Jan;144(1):95-8. Epub 2008 Oct 30. link to original article PubMed
2. ECOG E1496: Hochster H, Weller E, Gascoyne RD, Habermann TM, Gordon LI, Ryan T, Zhang L, Colocci N, Frankel S, Horning SJ. Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG1496 Study. J Clin Oncol. 2009 Apr 1;27(10):1607-14. Epub 2009 Mar 2. link to original article contains verified protocol link to PMC article PubMed
3. Michallet M, Dreger P, Sutton L, Brand R, Richards S, van Os M, Sobh M, Choquet S, Corront B, Dearden C, Gratwohl A, Herr W, Catovsky D, Hallek M, de Witte T, Niederwieser D, Leporrier M, Milligan D; EBMT Chronic Leukemia Working Party. Autologous hematopoietic stem cell transplantation in chronic lymphocytic leukemia: results of European intergroup randomized trial comparing autografting versus observation. Blood. 2011 Feb 3;117(5):1516-21. Epub 2010 Nov 24. link to original article PubMed
4. Auto-LLC 2001: Sutton L, Chevret S, Tournilhac O, Diviné M, Leblond V, Corront B, Leprêtre S, Eghbali H, Van Den Neste E, Michallet M, Maloisel F, Bouabdallah K, Decaudin D, Berthou C, Brice P, Gonzalez H, Chapiro E, Radford-Weiss I, Leporrier N, Maloum K, Nguyen-Khac F, Davi F, Lejeune J, Merle-Béral H, Leporrier M; Société Française de Greffe de Moelle et de Thérapie Cellulaire; Groupe Français d'étude de la Leucémie Lymphoïde Chronique. Autologous stem cell transplantation as a first-line treatment strategy for chronic lymphocytic leukemia: a multicenter, randomized, controlled trial from the SFGM-TC and GFLLC. Blood. 2011 Jun 9;117(23):6109-19. Epub 2011 Mar 15. link to original article PubMed
5. ML21445: Foà R, Del Giudice I, Cuneo A, Del Poeta G, Ciolli S, Di Raimondo F, Lauria F, Cencini E, Rigolin GM, Cortelezzi A, Nobile F, Callea V, Brugiatelli M, Massaia M, Molica S, Trentin L, Rizzi R, Specchia G, Di Serio F, Orsucci L, Ambrosetti A, Montillo M, Zinzani PL, Ferrara F, Morabito F, Mura MA, Soriani S, Peragine N, Tavolaro S, Bonina S, Marinelli M, De Propris MS, Starza ID, Piciocchi A, Alietti A, Runggaldier EJ, Gamba E, Mauro FR, Chiaretti S, Guarini A. Chlorambucil plus rituximab with or without maintenance rituximab as first-line treatment for elderly chronic lymphocytic leukemia patients. Am J Hematol. 2014 May;89(5):480-6. Epub 2014 Feb 18. link to original article contains verified protocol PubMed
6. AGMT CLL-8a: Greil R, Obrtlíková P, Smolej L, Kozák T, Steurer M, Andel J, Burgstaller S, Mikušková E, Gercheva L, Nösslinger T, Papajík T, Ladická M, Girschikofsky M, Hrubiško M, Jäger U, Fridrik M, Pecherstorfer M, Králiková E, Burcoveanu C, Spasov E, Petzer A, Mihaylov G, Raynov J, Oexle H, Zabernigg A, Flochová E, Palášthy S, Stehlíková O, Doubek M, Altenhofer P, Pleyer L, Melchardt T, Klingler A, Mayer J, Egle A. Rituximab maintenance versus observation alone in patients with chronic lymphocytic leukaemia who respond to first-line or second-line rituximab-containing chemoimmunotherapy: final results of the AGMT CLL-8a Mabtenance randomised trial. Lancet Haematol. 2016 Jul;3(7):e317-29. Epub 2016 Jun 16. link to original article contains protocol PubMed NCT01118234
7. GCLLSG CLLM1: Fink AM, Bahlo J, Robrecht S, Al-Sawaf O, Aldaoud A, Hebart H, Jentsch-Ullrich K, Dörfel S, Fischer K, Wendtner CM, Nösslinger T, Ghia P, Bosch F, Kater AP, Döhner H, Kneba M, Kreuzer KA, Tausch E, Stilgenbauer S, Ritgen M, Böttcher S, Eichhorst B, Hallek M. Lenalidomide maintenance after first-line therapy for high-risk chronic lymphocytic leukaemia (CLLM1): final results from a randomised, double-blind, phase 3 study. Lancet Haematol. 2017 Oct;4(10):e475-e486. Epub 2017 Sep 12. link to original article contains protocol PubMed
8. CLL 2007 SA: Dartigeas C, Van Den Neste E, Léger J, Maisonneuve H, Berthou C, Dilhuydy MS, De Guibert S, Leprêtre S, Béné MC, Nguyen-Khac F, Letestu R, Cymbalista F, Rodon P, Aurran-Schleinitz T, Vilque JP, Tournilhac O, Mahé B, Laribi K, Michallet AS, Delmer A, Feugier P, Lévy V, Delépine R, Colombat P, Leblond V; CLL 2007 SA investigators; FILO. Rituximab maintenance versus observation following abbreviated induction with chemoimmunotherapy in elderly patients with previously untreated chronic lymphocytic leukaemia (CLL 2007 SA): an open-label, randomised phase 3 study. Lancet Haematol. 2018 Feb;5(2):e82-e94. Epub 2017 Dec 20. link to original article contains protocol PubMed

Ofatumumab monotherapy

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Regimen

Study	Evidence
Strati et al. 2016	Phase II

Preceding treatment

• PCO x 6

Chemotherapy

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

28-day cycle for 6 cycles

References

1. Strati P, Lanasa M, Call TG, Leis JF, Brander DM, LaPlant BR, Pettinger AM, Ding W, Parikh SA, Hanson CA, Chanan-Khan AA, Bowen DA, Conte M, Kay NE, Shanafelt TD. Ofatumumab monotherapy as a consolidation strategy in patients with previously untreated chronic lymphocytic leukaemia: a phase 2 trial. Lancet Haematol. 2016 Sep;3(9):e407-14. Epub 2016 Aug 1. link to original article contains protocol PubMed

Rituximab monotherapy

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Regimen variant #1, 1 year

Study	Evidence	Comparator	Comparative Efficacy
Foà et al. 2014 (ML21445)	Phase III (E-esc)	Observation	Might have superior PFS
Robak et al. 2018 (PALG CLL4)	Phase IIIb (E-esc)	Observation	Seems to have superior PFS

Note: dosing details for PALG CLL4 were not available in the abstract.

Preceding treatment

• ML21445: Clb-R
• PALG CLL4: RCC x 6

Chemotherapy

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

8-week cycle for 6 cycles

Regimen variant #2, 2 years, given q3mo

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Bosch et al. 2009		Phase II
Greil et al. 2016 (AGMT CLL-8a)	2010-2013	Phase III (E-esc)	Observation	Superior PFS

Preceding treatment

• Bosch et al. 2009: R-FCM
• AGMT CLL-8a: Rituximab-containing chemoimmunotherapy

Chemotherapy

• 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	Evidence	Comparator	Comparative Efficacy
Dartigeas et al. 2017 (CLL 2007 SA)	Phase III (E-esc)	Observation	Superior PFS

Note the higher dose used here.

Preceding treatment

• FCR x 4

Chemotherapy

• 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	Evidence	Comparator	Comparative Efficacy
Hainsworth et al. 2003	Phase II
Hochster et al. 2009 (ECOG E1496)	Phase III (E-esc)	Observation	Superior PFS

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

Preceding treatment

• Hainsworth et al. 2003: Rituximab induction
• ECOG E1496: CVP

Chemotherapy

• Rituximab (Rituxan) 375 mg/m² IV once per day on days 1, 8, 15, 22

Supportive medications

• Acetaminophen (Tylenol) 650 mg PO once per day on days 1, 8, 15, 22; 30 minutes prior to Rituximab (Rituxan)
• Diphenhydramine (Benadryl) 50 mg IV once per day on days 1, 8, 15, 22; 30 minutes prior to Rituximab (Rituxan)
• One of the following:
  • Cimetidine (Tagamet) 300 mg IV once per day on days 1, 8, 15, 22; 30 minutes prior to Rituximab (Rituxan)
  • Ranitidine (Zantac) 50 mg IV once per day on days 1, 8, 15, 22; 30 minutes prior to Rituximab (Rituxan)

6-month cycle for 4 cycles (2 years)

Regimen variant #5, indefinite 375 mg/m² q3mo

Study	Evidence	Comparator	Comparative Efficacy
Williams et al. 2016 (RESORT substudy)	Phase III (C)	Salvage rituximab	Seems to have superior TTTF

Intended for patients with SLL.

Preceding treatment

• Rituximab

Chemotherapy

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

13-week cycles

Regimen variant #6, indefinite 500 mg/m² q3mo

Study	Evidence
Foon et al. 2009	Phase II

Preceding treatment

• FCR-Lite x 6

Chemotherapy

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

3-month cycles

References

1. Hainsworth JD, Litchy S, Barton JH, Houston GA, Hermann RC, Bradof JE, Greco FA; Minnie Pearl Cancer Research Network. Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol. 2003 May 1;21(9):1746-51. link to original article PubMed
2. Foon KA, Boyiadzis M, Land SR, Marks S, Raptis A, Pietragallo L, Meisner D, Laman A, Sulecki M, Butchko A, Schaefer P, Lenzer D, Tarhini A. Chemoimmunotherapy with low-dose fludarabine and cyclophosphamide and high dose rituximab in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009 Feb 1;27(4):498-503. Epub 2008 Dec 15. link to original article contains verified protocol PubMed
   1. Update: Foon KA, Mehta D, Lentzsch S, Kropf P, Marks S, Lenzner D, Pietragallo L, Sulecki M, Tarhini A, Boyiadzis M. Long-term results of chemoimmunotherapy with low-dose fludarabine, cyclophosphamide and high-dose rituximab as initial treatment for patients with chronic lymphocytic leukemia. Blood. 2012 Mar 29;119(13):3184-5. link to original article PubMed
3. ECOG E1496: Hochster H, Weller E, Gascoyne RD, Habermann TM, Gordon LI, Ryan T, Zhang L, Colocci N, Frankel S, Horning SJ. Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG1496 Study. J Clin Oncol. 2009 Apr 1;27(10):1607-14. Epub 2009 Mar 2. link to original article contains verified protocol link to PMC article PubMed
4. Bosch F, Abrisqueta P, Villamor N, Terol MJ, González-Barca E, Ferra C, González Diaz M, Abella E, Delgado J, Carbonell F, García Marco JA, Escoda L, Ferrer S, Monzó E, González Y, Estany C, Jarque I, Salamero O, Muntañola A, Montserrat E. Rituximab, fludarabine, cyclophosphamide, and mitoxantrone: a new, highly active chemoimmunotherapy regimen for chronic lymphocytic leukemia. J Clin Oncol. 2009 Sep 20;27(27):4578-84. Epub 2009 Aug 24. link to original article contains verified protocol PubMed
   1. Update: Abrisqueta P, Villamor N, Terol MJ, González-Barca E, González M, Ferrà C, Abella E, Delgado J, García-Marco JA, González Y, Carbonell F, Ferrer S, Monzó E, Jarque I, Muntañola A, Constants M, Escoda L, Calvo X, Bobillo S, Montoro JB, Montserrat E, Bosch F. Rituximab maintenance after first-line therapy with rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) for chronic lymphocytic leukemia. Blood. 2013 Dec 5;122(24):3951-9. Epub 2013 Oct 11. link to original article contains verified protocol PubMed
5. ML21445: Foà R, Del Giudice I, Cuneo A, Del Poeta G, Ciolli S, Di Raimondo F, Lauria F, Cencini E, Rigolin GM, Cortelezzi A, Nobile F, Callea V, Brugiatelli M, Massaia M, Molica S, Trentin L, Rizzi R, Specchia G, Di Serio F, Orsucci L, Ambrosetti A, Montillo M, Zinzani PL, Ferrara F, Morabito F, Mura MA, Soriani S, Peragine N, Tavolaro S, Bonina S, Marinelli M, De Propris MS, Starza ID, Piciocchi A, Alietti A, Runggaldier EJ, Gamba E, Mauro FR, Chiaretti S, Guarini A. Chlorambucil plus rituximab with or without maintenance rituximab as first-line treatment for elderly chronic lymphocytic leukemia patients. Am J Hematol. 2014 May;89(5):480-6. Epub 2014 Feb 18. link to original article contains verified protocol PubMed
6. RESORT substudy: Williams ME, Hong F, Gascoyne RD, Wagner LI, Krauss JC, Habermann TM, Swinnen LJ, Schuster SJ, Peterson CG, Sborov MD, Martin SE, Weiss M, Ehmann WC, Horning SJ, Kahl BS; Eastern Cooperative Oncology Group. Rituximab extended schedule or retreatment trial for low tumour burden non-follicular indolent B-cell non-Hodgkin lymphomas: Eastern Cooperative Oncology Group Protocol E4402. Br J Haematol. 2016 Jun;173(6):867-75. Epub 2016 Mar 11. link to original article contains protocol link to PMC article PubMed
7. AGMT CLL-8a: Greil R, Obrtlíková P, Smolej L, Kozák T, Steurer M, Andel J, Burgstaller S, Mikušková E, Gercheva L, Nösslinger T, Papajík T, Ladická M, Girschikofsky M, Hrubiško M, Jäger U, Fridrik M, Pecherstorfer M, Králiková E, Burcoveanu C, Spasov E, Petzer A, Mihaylov G, Raynov J, Oexle H, Zabernigg A, Flochová E, Palášthy S, Stehlíková O, Doubek M, Altenhofer P, Pleyer L, Melchardt T, Klingler A, Mayer J, Egle A. Rituximab maintenance versus observation alone in patients with chronic lymphocytic leukaemia who respond to first-line or second-line rituximab-containing chemoimmunotherapy: final results of the AGMT CLL-8a Mabtenance randomised trial. Lancet Haematol. 2016 Jul;3(7):e317-29. Epub 2016 Jun 16. link to original article contains protocol PubMed NCT01118234
8. CLL 2007 SA: Dartigeas C, Van Den Neste E, Léger J, Maisonneuve H, Berthou C, Dilhuydy MS, De Guibert S, Leprêtre S, Béné MC, Nguyen-Khac F, Letestu R, Cymbalista F, Rodon P, Aurran-Schleinitz T, Vilque JP, Tournilhac O, Mahé B, Laribi K, Michallet AS, Delmer A, Feugier P, Lévy V, Delépine R, Colombat P, Leblond V; CLL 2007 SA investigators; FILO. Rituximab maintenance versus observation following abbreviated induction with chemoimmunotherapy in elderly patients with previously untreated chronic lymphocytic leukaemia (CLL 2007 SA): an open-label, randomised phase 3 study. Lancet Haematol. 2018 Feb;5(2):e82-e94. Epub 2017 Dec 20. link to original article contains protocol PubMed
9. PALG CLL4: Robak T, Błoński J, Skotnicki AB, Piotrowska M, Wróbel T, Rybka J, Kłoczko J, Bołkun Ł, Budziszewska BK, Walczak U, Uss A, Fidecka M, Smolewski P. Rituximab, cladribine, and cyclophosphamide (RCC) induction with rituximab maintenance in chronic lymphocytic leukemia: PALG - CLL4 (ML21283) trial. Eur J Haematol. 2018 May;100(5):465-474. Epub 2018 Mar 22. link to original article PubMed

Relapsed or refractory, randomized data

Bendamustine monotherapy

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Regimen variant #1, 70 mg/m²

Study	Evidence	Comparator	Comparative Efficacy
Robak et al. 2016 (TRU-016)	Randomized Phase II (C)	Bendamustine & Otlertuzumab	Seems to have inferior PFS

Chemotherapy

• Bendamustine 70 mg/m² IV over 30 minutes once per day on days 1 & 2

28-day cycle for 6 cycles

Regimen variant #2, 100 mg/m²

Study	Evidence	Comparator	Comparative Efficacy
Niederle et al. 2013 (WiSP RI05)	Phase III (E-switch-ic)	Fludarabine	Seems to have non-inferior PFS

Chemotherapy

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

28-day cycle for up to 8 cycles

Regimen variant #3, 120 mg/m²

Study	Evidence
Friedberg et al. 2008	Phase II
Kahl et al. 2010	Phase II

Chemotherapy

• Bendamustine 120 mg/m² IV once per day on days 1 & 2

21-day cycle for 6 to 8 (Kahl et al. 2010) or up to 12 (Friedberg et al. 2008) cycles

References

1. Friedberg JW, Cohen P, Chen L, Robinson KS, Forero-Torres A, La Casce AS, Fayad LE, Bessudo A, Camacho ES, Williams ME, van der Jagt RH, Oliver JW, Cheson BD. Bendamustine in patients with rituximab-refractory indolent and transformed non-Hodgkin's lymphoma: results from a phase II multicenter, single-agent study. J Clin Oncol. 2008 Jan 10;26(2):204-10. Erratum in: J Clin Oncol. 2008 Apr 10;26(11) 1911. link to original article contains verified protocol PubMed
2. Kahl BS, Bartlett NL, Leonard JP, Chen L, Ganjoo K, Williams ME, Czuczman MS, Robinson KS, Joyce R, van der Jagt RH, Cheson BD. Bendamustine is effective therapy in patients with rituximab-refractory, indolent B-cell non-Hodgkin lymphoma: results from a multicenter study. Cancer. 2010 Jan 1;116(1):106-14. link to original article contains verified protocol link to PMC article PubMed
3. Retrospective: Kolibaba KS, Sterchele JA, Joshi AD, Forsyth M, Alwon E, Beygi H, Kennealey GT. Demographics, treatment patterns, safety, and real-world effectiveness in patients aged 70 years and over with chronic lymphocytic leukemia receiving bendamustine with or without rituximab: a retrospective study. Ther Adv Hematol. 2013 Jun;4(3):157-71. link to PMC article PubMed
4. WiSP RI05: Niederle N, Megdenberg D, Balleisen L, Heit W, Knauf W, Weiß J, Freier W, Hinke A, Ibach S, Eimermacher H. Bendamustine compared to fludarabine as second-line treatment in chronic lymphocytic leukemia. Ann Hematol. 2013 May;92(5):653-60. Epub 2013 Jan 23. link to original article contains verified protocol PubMed
5. TRU-016: Robak T, Hellmann A, Kloczko J, Loscertales J, Lech-Maranda E, Pagel JM, Mato A, Byrd JC, Awan FT, Hebart H, Garcia-Marco JA, Hill BT, Hallek M, Eisenfeld AJ, Stromatt SC, Jaeger U. Randomized phase 2 study of otlertuzumab and bendamustine versus bendamustine in patients with relapsed chronic lymphocytic leukaemia. Br J Haematol. 2017 Feb;176(4):618-628. Epub 2016 Dec 15. link to original article contains verified protocol link to PMC article PubMed

BR

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BR: Bendamustine & Rituximab
R-B: Rituximab & Bendamustine

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Fischer et al. 2011		Phase II
Chanan-Khan et al. 2015 (HELIOS)	2012-2014	Phase III (C)	BR & Ibrutinib	Seems to have inferior OS (*)
Zelenetz et al. 2017 (Tugela)		Phase III (C)	BR & Idelalisib	Inferior PFS
Michallet et al. 2018 (MABLE)		Phase III (E-switch-ic)	R-Clb	Superior CR rate
Seymour et al. 2018 (MURANO)	2014-2015	Phase III (C)	Venetoclax & Rituximab	Inferior OS

Note: Reported efficacy for HELIOS is based on the 2018 update.

Chemotherapy

• Bendamustine 70 mg/m² IV once per day on days 1 & 2
  • HELIOS gave 1st cycle on days 2 & 3
• Rituximab (Rituxan) as follows:
  • Cycle 1: 375 mg/m² IV once on day 0
    • HELIOS gave on day 1
  • Cycles 2 to 6: 500 mg/m² IV once on day 1

28-day cycle for up to 6 cycles

References

1. Fischer K, Cramer P, Busch R, Stilgenbauer S, Bahlo J, Schweighofer CD, Böttcher S, Staib P, Kiehl M, Eckart MJ, Kranz G, Goede V, Elter T, Bühler A, Winkler D, Kneba M, Döhner H, Eichhorst BF, Hallek M, Wendtner CM; GCLLSG. Bendamustine combined with rituximab in patients with relapsed and/or refractory chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. 2011 Sep 10;29(26):3559-66. Epub 2011 Aug 15. link to original article contains protocol PubMed
2. Retrospective: Kolibaba KS, Sterchele JA, Joshi AD, Forsyth M, Alwon E, Beygi H, Kennealey GT. Demographics, treatment patterns, safety, and real-world effectiveness in patients aged 70 years and over with chronic lymphocytic leukemia receiving bendamustine with or without rituximab: a retrospective study. Ther Adv Hematol. 2013 Jun;4(3):157-71. link to PMC article PubMed
3. HELIOS: Chanan-Khan A, Cramer P, Demirkan F, Fraser G, Silva RS, Grosicki S, Pristupa A, Janssens A, Mayer J, Bartlett NL, Dilhuydy MS, Pylypenko H, Loscertales J, Avigdor A, Rule S, Villa D, Samoilova O, Panagiotidis P, Goy A, Mato A, Pavlovsky MA, Karlsson C, Mahler M, Salman M, Sun S, Phelps C, Balasubramanian S, Howes A, Hallek M; HELIOS investigators. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol. 2016 Feb;17(2):200-11. Epub 2015 Dec 5. link to original article contains protocol PubMed
   1. Update: Fraser G, Cramer P, Demirkan F, Silva RS, Grosicki S, Pristupa A, Janssens A, Mayer J, Bartlett NL, Dilhuydy MS, Pylypenko H, Loscertales J, Avigdor A, Rule S, Villa D, Samoilova O, Panagiotidis P, Goy A, Pavlovsky MA, Karlsson C, Hallek M, Mahler M, Salman M, Sun S, Phelps C, Balasubramanian S, Howes A, Chanan-Khan A. Updated results from the phase 3 HELIOS study of ibrutinib, bendamustine, and rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma. Leukemia. 2019 Apr;33(4):969-980. Epub 2018 Oct 12. link to original article link to PMC article PubMed
4. Tugela: Zelenetz AD, Barrientos JC, Brown JR, Coiffier B, Delgado J, Egyed M, Ghia P, Illés Á, Jurczak W, Marlton P, Montillo M, Morschhauser F, Pristupa AS, Robak T, Sharman JP, Simpson D, Smolej L, Tausch E, Adewoye AH, Dreiling LK, Kim Y, Stilgenbauer S, Hillmen P. Idelalisib or placebo in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia: interim results from a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2017 Mar;18(3):297-311. Epub 2017 Jan 28. link to original article link to PMC article contains protocol PubMed
5. MABLE: Michallet AS, Aktan M, Hiddemann W, Ilhan O, Johansson P, Laribi K, Meddeb B, Moreno C, Raposo J, Schuh A, Ünal A, Widenius T, Bernhardt A, Kellershohn K, Messeri D, Osborne S, Leblond V. Rituximab plus bendamustine or chlorambucil for chronic lymphocytic leukemia: primary analysis of the randomized, open-label MABLE study. Haematologica. 2018 Apr;103(4):698-706. Epub 2018 Feb 1. link to original article contains verified protocol link to PMC article PubMed
6. MURANO: Seymour JF, Kipps TJ, Eichhorst B, Hillmen P, D'Rozario J, Assouline S, Owen C, Gerecitano J, Robak T, De la Serna J, Jaeger U, Cartron G, Montillo M, Humerickhouse R, Punnoose EA, Li Y, Boyer M, Humphrey K, Mobasher M, Kater AP. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018 Mar 22;378(12):1107-1120. link to original article contains verified protocol PubMed
   1. Update: Kater AP, Seymour JF, Hillmen P, Eichhorst B, Langerak AW, Owen C, Verdugo M, Wu J, Punnoose EA, Jiang Y, Wang J, Boyer M, Humphrey K, Mobasher M, Kipps TJ. Fixed duration of venetoclax-rituximab in relapsed/refractory chronic lymphocytic leukemia eradicates minimal residual disease and prolongs survival: post-treatment follow-up of the MURANO phase III study. J Clin Oncol. 2019 Feb 1;37(4):269-277. Epub 2018 Dec 3. link to original article PubMed

BR & Ibrutinib

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BR & Ibrutinib: Bendamustine, Rituximab, Ibrutinib
IBR: Ibrutinib, Bendamustine, Rituximab

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Brown et al. 2015 (PCYC-1108)		Phase II
Chanan-Khan et al. 2015 (HELIOS)	2012-2014	Phase III (E-RT-esc)	BR	Seems to have superior OS (*)

Note: PCYC-1108 also evaluated FCR-ibrutinib (non-randomized) but accrual to that arm was extremely low and it was prematurely discontinued. Reported efficacy for HELIOS is based on the 2018 update.

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
• 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

28-day cycles

References

1. PCYC-1108: Brown JR, Barrientos JC, Barr PM, Flinn IW, Burger JA, Tran A, Clow F, James DF, Graef T, Friedberg JW, Rai K, O'Brien S. The Bruton tyrosine kinase inhibitor ibrutinib with chemoimmunotherapy in patients with chronic lymphocytic leukemia. Blood. 2015 May 7;125(19):2915-22. Epub 2015 Mar 9. link to original article contains verified protocol link to PMC article PubMed
2. HELIOS: Chanan-Khan A, Cramer P, Demirkan F, Fraser G, Silva RS, Grosicki S, Pristupa A, Janssens A, Mayer J, Bartlett NL, Dilhuydy MS, Pylypenko H, Loscertales J, Avigdor A, Rule S, Villa D, Samoilova O, Panagiotidis P, Goy A, Mato A, Pavlovsky MA, Karlsson C, Mahler M, Salman M, Sun S, Phelps C, Balasubramanian S, Howes A, Hallek M; HELIOS investigators. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol. 2016 Feb;17(2):200-11. Epub 2015 Dec 5. link to original article contains protocol PubMed
   1. Update: Fraser G, Cramer P, Demirkan F, Silva RS, Grosicki S, Pristupa A, Janssens A, Mayer J, Bartlett NL, Dilhuydy MS, Pylypenko H, Loscertales J, Avigdor A, Rule S, Villa D, Samoilova O, Panagiotidis P, Goy A, Pavlovsky MA, Karlsson C, Hallek M, Mahler M, Salman M, Sun S, Phelps C, Balasubramanian S, Howes A, Chanan-Khan A. Updated results from the phase 3 HELIOS study of ibrutinib, bendamustine, and rituximab in relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma. Leukemia. 2019 Apr;33(4):969-980. Epub 2018 Oct 12. link to original article link to PMC article PubMed

BR & Idelalisib

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BR & Idelalisib: Bendamustine, Rituximab, Idelalisib

Regimen

Study	Evidence	Comparator	Comparative Efficacy
Zelenetz et al. 2017 (Tugela)	Phase III (E-esc)	BR	Superior PFS

Chemotherapy

• Bendamustine as follows:
  • Cycles 1 to 6: 70 mg/m² IV once per day on days 1 & 2
• Rituximab (Rituxan) as follows:
  • Cycle 1: 375 mg/m² IV once on day 0
  • Cycles 2 to 6: 500 mg/m² IV once on day 1
• Idelalisib (Zydelig) 150 mg PO twice per day

28-day cycles

References

1. Tugela: Zelenetz AD, Barrientos JC, Brown JR, Coiffier B, Delgado J, Egyed M, Ghia P, Illés Á, Jurczak W, Marlton P, Montillo M, Morschhauser F, Pristupa AS, Robak T, Sharman JP, Simpson D, Smolej L, Tausch E, Adewoye AH, Dreiling LK, Kim Y, Stilgenbauer S, Hillmen P. Idelalisib or placebo in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia: interim results from a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2017 Mar;18(3):297-311. Epub 2017 Jan 28. link to original article contains protocol link to PMC article PubMed

Duvelisib monotherapy

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Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Flinn et al. 2018 (DUO)	2014-2015	Phase III (E-RT-switch-ooc)	Ofatumumab	Superior PFS

Chemotherapy

• Duvelisib (Copiktra) 25 mg PO twice per day

28-day cycles

References

1. DUO: Flinn IW, Hillmen P, Montillo M, Nagy Z, Illés Á, Etienne G, Delgado J, Kuss BJ, Tam CS, Gasztonyi Z, Offner F, Lunin S, Bosch F, Davids MS, Lamanna N, Jaeger U, Ghia P, Cymbalista F, Portell CA, Skarbnik AP, Cashen AF, Weaver DT, Kelly VM, Turnbull B, Stilgenbauer S. The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL. Blood. 2018 Dec 6;132(23):2446-2455. link to original article contains verified protocol PubMed

FCR

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

Regimen variant #1

Study	Evidence	Comparator	Comparative Efficacy
Awan et al. 2014 (LUCID)	Phase III (C)	Lumiliximab + FCR	Did not meet primary endpoint of CR rate

Chemotherapy

• Fludarabine (Fludara) as follows:
  • Cycle 1: 25 mg/m² IV over at least 10 to 30 minutes once per day on days 2 to 4
  • Cycles 2 to 6: 25 mg/m² IV over at least 10 to 30 minutes once per day on days 1 to 3
• Cyclophosphamide (Cytoxan) as follows:
  • Cycle 1: 250 mg/m² IV over at least 10 to 30 minutes once per day on days 2 to 4
  • Cycles 2 to 6: 250 mg/m² IV over at least 10 to 30 minutes once per day on days 1 to 3
• 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 medications

• Cotrimoxazole or an equivalent
• Acyclovir (Zovirax) 400 mg PO twice per day or an equivalent

28-day cycle for 6 cycles

Regimen variant #2

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Robak et al. 2010 (REACH)	2003-2007	Phase III (E-RT-esc)	FC	Superior PFS

Chemotherapy

• Fludarabine (Fludara) 25 mg/m² IV once per day on days 1 to 3
• Cyclophosphamide (Cytoxan) 250 mg/m² IV once per day on days 1 to 3
• 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 medications

• Note: varied according to reference.
• Diphenhydramine (Benadryl) 25 mg IV once on day 1; 30 minutes prior to Rituximab (Rituxan)
• Acetaminophen (Tylenol) 650 mg PO once on day 1; 30 minutes prior to Rituximab (Rituxan)
• 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	Evidence
Wierda et al. 2005	Phase II

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
• 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 medications

• Diphenhydramine (Benadryl) 25 to 50 mg PO once on day 1, prior to Rituximab (Rituxan)
• Acetaminophen (Tylenol) 650 mg PO once on day 1, prior to Rituximab (Rituxan)
• Ondansetron (Zofran) 24 mg IV once, prior to chemotherapy

28-day cycle for up to 6 cycles

Regimen variant #4

Study	Evidence
Tam et al. 2006	Phase II

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

28-day cycle for up to 6 cycles or "attainment of maximum response"

References

1. Wierda W, O'Brien S, Wen S, Faderl S, Garcia-Manero G, Thomas D, Do KA, Cortes J, Koller C, Beran M, Ferrajoli A, Giles F, Lerner S, Albitar M, Kantarjian H, Keating M. Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. J Clin Oncol. 2005 Jun 20;23(18):4070-8. Epub 2005 Mar 14. link to original article contains verified protocol PubMed
   1. Update: Badoux XC, Keating MJ, Wang X, O'Brien SM, Ferrajoli A, Faderl S, Burger J, Koller C, Lerner S, Kantarjian H, Wierda WG. Fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy is highly effective treatment for relapsed patients with CLL. Blood. 2011 Mar 17;117(11):3016-24. Epub 2011 Jan 18. link to original article link to PMC article PubMed
2. Tam CS, Wolf M, Prince HM, Januszewicz EH, Westerman D, Lin KI, Carney D, Seymour JF. Fludarabine, cyclophosphamide, and rituximab for the treatment of patients with chronic lymphocytic leukemia or indolent non-Hodgkin lymphoma. Cancer. 2006 Jun 1;106(11):2412-20. link to original article contains verified protocol PubMed
3. REACH: Robak T, Dmoszynska A, Solal-Céligny P, Warzocha K, Loscertales J, Catalano J, Afanasiev BV, Larratt L, Geisler CH, Montillo M, Zyuzgin I, Ganly PS, Dartigeas C, Rosta A, Maurer J, Mendila M, Saville MW, Valente N, Wenger MK, Moiseev SI. Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia. J Clin Oncol. 2010 Apr 1;28(10):1756-65. Epub 2010 Mar 1. link to original article contains protocol PubMed content property of HemOnc.org
4. LUCID: Awan FT, Hillmen P, Hellmann A, Robak T, Hughes SG, Trone D, Shannon M, Flinn IW, Byrd JC; LUCID trial investigators. A randomized, open-label, multicentre, phase 2/3 study to evaluate the safety and efficacy of lumiliximab in combination with fludarabine, cyclophosphamide and rituximab versus fludarabine, cyclophosphamide and rituximab alone in subjects with relapsed chronic lymphocytic leukaemia. Br J Haematol. 2014 Nov;167(4):466-77. Epub 2014 Aug 8. link to original article contains verified protocol PubMed

Fludarabine monotherapy

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Johnson et al. 1996	Phase III (E-de-esc)	CAP	Seems to have superior ORR
Niederle et al. 2013 (WiSP RI05)	Phase III (C)	Bendamustine	Seems to have non-inferior PFS

Note: this is an experimental arm that did not meet its primary endpoint; included here because it was eventually used to establish this regimen as a standard comparator.

Chemotherapy

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

28-day cycle for up to 6 to 12 cycles

References

1. Johnson S, Smith AG, Löffler H, Osby E, Juliusson G, Emmerich B, Wyld PJ, Hiddemann W; FRE-CLL. Multicentre prospective randomised trial of fludarabine versus cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of advanced-stage chronic lymphocytic leukaemia. Lancet. 1996 May 25;347(9013):1432-8. link to original article contains protocol PubMed
2. WiSP RI05: Niederle N, Megdenberg D, Balleisen L, Heit W, Knauf W, Weiß J, Freier W, Hinke A, Ibach S, Eimermacher H. Bendamustine compared to fludarabine as second-line treatment in chronic lymphocytic leukemia. Ann Hematol. 2013 May;92(5):653-60. Epub 2013 Jan 23. link to original article contains verified protocol PubMed

Ibrutinib monotherapy

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Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Byrd et al. 2013 (PCYC-1102)	2010-2011	Phase II (RT)
Byrd et al. 2014 (RESONATE)	2012-2013	Phase III (E-RT-switch-ooc)	Ofatumumab	Seems to have superior OS (*)
Farooqui et al. 2014 (NHLBI 12-H-0035)		Phase II, <20 pts
O'Brien et al. 2016 (RESONATE-17)		Phase II
Sharman et al. 2017 (GENUINE)		Phase III (C)	Ibrutinib & Ublituximab	Inferior ORR
Huang et al. 2018 (CR102604)		Phase III (E-switch-ooc)	Rituximab	Seems to have superior OS

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. RESONATE-17 was intended for patients with 17p deletion. Reported efficacy for RESONATE is based on the 2019 update.

Chemotherapy

• Ibrutinib (Imbruvica) 420 mg PO once per day

Continued indefinitely

References

1. PCYC-1102: Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, Grant B, Sharman JP, Coleman M, Wierda WG, Jones JA, Zhao W, Heerema NA, Johnson AJ, Sukbuntherng J, Chang BY, Clow F, Hedrick E, Buggy JJ, James DF, O'Brien S. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013 Jul 4;369(1):32-42. link to original article contains verified protocol link to PMC article PubMed
   1. Update: Byrd JC, Furman RR, Coutre SE, Burger JA, Blum KA, Coleman M, Wierda WG, Jones JA, Zhao W, Heerema NA, Johnson AJ, Shaw Y, Bilotti E, Zhou C, James DF, O'Brien S. Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015 Apr 16;125(16):2497-506. Epub 2015 Feb 19. link to original article link to PMC article PubMed
   2. Update: O'Brien S, Furman RR, Coutre S, Flinn IW, Burger JA, Blum K, Sharman J, Wierda W, Jones J, Zhao W, Heerema NA, Johnson AJ, Luan Y, James DF, Chu AD, Byrd JC. Single-agent ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. Blood. 2018 Apr 26;131(17):1910-1919. Epub 2018 Feb 2. link to original article PubMed
2. RESONATE: Byrd JC, Brown JR, O'Brien S, Barrientos JC, Kay NE, Reddy NM, Coutre S, Tam CS, Mulligan SP, Jaeger U, Devereux S, Barr PM, Furman RR, Kipps TJ, Cymbalista F, Pocock C, Thornton P, Caligaris-Cappio F, Robak T, Delgado J, Schuster SJ, Montillo M, Schuh A, de Vos S, Gill D, Bloor A, Dearden C, Moreno C, Jones JJ, Chu AD, Fardis M, McGreivy J, Clow F, James DF, Hillmen P; the RESONATE Investigators. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014 Jul 17;371(3):213-23. Epub 2014 May 31. link to original article contains verified protocol link to PMC article PubMed
   1. Update: Brown JR, Hillmen P, O'Brien S, Barrientos JC, Reddy NM, Coutre SE, Tam CS, Mulligan SP, Jaeger U, Barr PM, Furman RR, Kipps TJ, Cymbalista F, Thornton P, Caligaris-Cappio F, Delgado J, Montillo M, DeVos 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 PubMed
   2. Update: Byrd JC, Hillmen P, O'Brien S, Barrientos JC, Reddy NM, Coutre S, Tam CS, Mulligan SP, Jaeger U, Barr PM, Furman RR, Kipps TJ, Thornton P, Moreno C, Montillo M, Pagel JM, Burger JA, Woyach JA, Dai S, Vezan R, James DF, Brown JR. Long-term follow-up of the RESONATE phase 3 trial of ibrutinib vs ofatumumab. Blood. 2019 May 9;133(19):2031-2042. Epub 2019 Mar 6. link to original article PubMed
3. NHLBI 12-H-0035: Farooqui MZ, Valdez J, Martyr S, Aue G, Saba N, Niemann CU, Herman SE, Tian X, Marti G, Soto S, Hughes TE, Jones J, Lipsky A, Pittaluga S, Stetler-Stevenson M, Yuan C, Lee YS, Pedersen LB, Geisler CH, Calvo KR, Arthur DC, Maric I, Childs R, Young NS, Wiestner A. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol. 2015 Feb;16(2):169-76. Epub 2014 Dec 31. link to original article contains protocol link to PMC article PubMed
4. RESONATE-17: O'Brien S, Jones JA, Coutre SE, Mato AR, Hillmen P, Tam C, Österborg A, Siddiqi T, Thirman MJ, Furman RR, Ilhan O, Keating MJ, Call TG, Brown JR, Stevens-Brogan M, Li Y, Clow F, James DF, Chu AD, Hallek M, Stilgenbauer S. Ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia with 17p deletion (RESONATE-17): a phase 2, open-label, multicentre study. Lancet Oncol. 2016 Oct;17(10):1409-1418. Epub 2016 Sep 13. link to original article contains protocol PubMed
5. Retrospective: Ryan CE, Sahaf B, Logan AC, O'Brien S, Byrd JC, Hillmen P, Brown JR, Dyer MJ, Mato AR, Keating MJ, Jaglowski S, Clow F, Rezvani AR, Styles L, Coutre SE, Miklos DB. Ibrutinib efficacy and tolerability in patients with relapsed chronic lymphocytic leukemia following allogeneic HCT. Blood. 2016 Dec 22;128(25):2899-2908. link to original article link to PMC article PubMed
6. Abstract: Jeff Porter Sharman, Danielle M. Brander, Anthony R. Mato, Suman Kambhampati, John M. Burke, Frederick Lansigan, Marshall T. Schreeder, Scott D. Lunin, Nilanjan Ghosh, Alexander Zweibach, Mikhail Shtivelband, Patrick M. Travis, Jason Claud Chandler, Kathryn S. Kolibaba, Peter Sportelli, Hari P. Miskin, Michael S. Weiss, and Ian Flinn. Ublituximab and ibrutinib for previously treated genetically high-risk chronic lymphocytic leukemia: Results of the GENUINE phase 3 study. Journal of Clinical Oncology 2017 35:15_suppl, 7504-7504 link to abstract
7. CR102604: Huang X, Qiu L, Jin J, Zhou D, Chen X, Hou M, Hu J, Hu Y, Ke X, Li J, Liang Y, Liu T, Lv Y, Ren H, Sun A, Wang J, Zhao C, Salman M, Sun S, Howes A, Wang J, Wu P, Li J. Ibrutinib versus rituximab in relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma: a randomized, open-label phase 3 study. Cancer Med. 2018 Apr;7(4):1043-1055. Epub 2018 Mar 13. link to original article contains verified protocol link to PMC article PubMed

Idelalisib & Ofatumumab

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Jones et al. 2017 (GS-US-312-0119)	Phase III (E-esc)	Ofatumumab	Superior PFS

Chemotherapy

• Idelalisib (Zydelig) 150 mg PO twice per day
• Ofatumumab (Arzerra) as follows:
  • Cycle 1: 300 mg IV once on day 1, then 1000 mg IV once per day on days 8, 15, 22
  • Cycle 2: 1000 mg IV once per day on days 1, 8, 15, 22
  • Cycles 3 to 6: 1000 mg IV once on day 1

28-day cycle for 6 cycles

References

1. GS-US-312-0119: Jones JA, Robak T, Brown JR, Awan FT, Badoux X, Coutre S, Loscertales J, Taylor K, Vandenberghe E, Wach M, Wagner-Johnston N, Ysebaert L, Dreiling L, Dubowy R, Xing G, Flinn IW, Owen C. Efficacy and safety of idelalisib in combination with ofatumumab for previously treated chronic lymphocytic leukaemia: an open-label, randomised phase 3 trial. Lancet Haematol. 2017 Mar;4(3):e114-e126. link to original article contains protocol PubMed

Idelalisib & Rituximab

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Furman et al. 2014 (GS-US-312-0116)	2012-2013	Phase III (E-RT-esc)	Rituximab	Superior PFS (*)

Note: Reported efficacy is based on the 2019 update.

Chemotherapy

• Idelalisib (Zydelig) 150 mg PO twice per day
• Rituximab (Rituxan) as follows:
  • Week 1: 375 mg/m² IV once
  • Weeks 3, 5, 7, 9, 13, 17, 21: 500 mg/m² IV once

21-day cycle for 1 cycle, then 28-day cycle for up to 17 cycles (18 cycles total)

Subsequent treatment

• Upon progression: Idelalisib can be increased to 300 mg PO twice per day

References

1. GS-US-312-0116: Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, Barrientos JC, Zelenetz AD, Kipps TJ, Flinn I, Ghia P, Eradat H, Ervin T, Lamanna N, Coiffier B, Pettitt AR, Ma S, Stilgenbauer S, Cramer P, Aiello M, Johnson DM, Miller LL, Li D, Jahn TM, Dansey RD, Hallek M, O'Brien SM. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014 Mar 13;370(11):997-1007. Epub 2014 Jan 22. link to original article contains verified protocol link to PMC article PubMed
   1. Update: Sharman JP, Coutre SE, Furman RR, Cheson BD, Pagel JM, Hillmen P, Barrientos JC, Zelenetz AD, Kipps TJ, Flinn IW, Ghia P, Eradat H, Ervin T, Lamanna N, Coiffier B, Pettitt AR, Ma S, Tausch E, Cramer P, Huang J, Mitra S, Hallek M, O'Brien SM, Stilgenbauer S. Final results of a randomized, phase III study of rituximab with or without idelalisib followed by open-label idelalisib in patients with relapsed chronic lymphocytic leukemia. J Clin Oncol. 2019 Jun 1;37(16):1391-1402. Epub 2019 Apr 17. link to original article PubMed

Ofatumumab monotherapy

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Regimen variant #1, 2 cycles

Study	Evidence
Österborg et al. 2015 (GEN416)	Phase II

Patients in this trial were fludarabine refractory and had previously received ofatumumab; this is a re-treatment trial.

Chemotherapy

• 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 medications

• Acetaminophen (Tylenol) 1000 mg PO once per day on days 1, 8, 15, 22, prior to Ofatumumab (Arzerra)
• Cetirizine (Zyrtec) (or equivalent) 10 mg PO once per day on days 1, 8, 15, 22, prior to Ofatumumab (Arzerra)
• 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

• Patients with SD or better could proceed to ofatumumab maintenance

Regimen variant #2, 6 cycles

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Coiffier et al. 2007		Phase I/II
Wierda et al. 2010 (Hx-CD20-406)	2006-NR	Phase II (RT)
Byrd et al. 2014 (RESONATE)	2012-2013	Phase III (C)	Ibrutinib	Seems to have inferior OS (*)
Jones et al. 2017 (GS-US-312-0119)		Phase III (C)	Idelalisib & Ofatumumab	Inferior PFS
Flinn et al. 2018 (DUO)	2014-2015	Phase III (C)	Duvelisib	Inferior PFS

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. Reported efficacy for RESONATE is based on the 2019 update.

Chemotherapy

• 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 medications

• 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	Evidence	Comparator	Comparative Efficacy
Ghia et al. 2017 (P07714)	Phase III (C)	Dinaciclib	Not reported

Note: this trial was terminated early and no statistical tests were performed; note also that cycle 3 is "skipped".

Chemotherapy

• Ofatumumab (Arzerra) as follows:
  • Cycle 1: 300 mg IV once on day 1, then 2000 mg IV once per day on days 8, 15, 22
  • Cycle 2: 2000 mg IV once per day on days 1, 8, 15, 22
  • Cycle 3: no treatment
  • Cycles 4 to 12: 2000 mg IV once on day 1

28-day cycle for 12 cycles

References

1. Coiffier B, Lepretre S, Pedersen LM, Gadeberg O, Fredriksen H, van Oers MH, Wooldridge J, Kloczko J, Holowiecki J, Hellmann A, Walewski J, Flensburg M, Petersen J, Robak T. Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1-2 study. Blood. 2008 Feb 1;111(3):1094-100. Epub 2007 Nov 14. link to original article PubMed
2. Hx-CD20-406: Wierda WG, Kipps TJ, Mayer J, Stilgenbauer S, Williams CD, Hellmann A, Robak T, Furman RR, Hillmen P, Trneny M, Dyer MJ, Padmanabhan S, Piotrowska M, Kozak T, Chan G, Davis R, Losic N, Wilms J, Russell CA, Osterborg A; Hx-CD20-406 Study Investigators. Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol. 2010 Apr 1;28(10):1749-55. Epub 2010 Mar 1. link to original article contains protocol link to PMC article PubMed
   1. Subgroup analysis: Wierda WG, Padmanabhan S, Chan GW, Gupta IV, Lisby S, Osterborg A; Hx-CD20-406 Study Investigators. Ofatumumab is active in patients with fludarabine-refractory CLL irrespective of prior rituximab: results from the phase 2 international study. Blood. 2011 Nov 10;118(19):5126-9. Epub 2011 Aug 19. link to original article link to PMC article PubMed
   2. Update: Österborg A, Jewell RC, Padmanabhan-Iyer S, Kipps TJ, Mayer J, Stilgenbauer S, Williams CD, Hellmann A, Furman RR, Robak T, Hillmen P, Trnêný M, Dyer MJ, Piotrowska M, Kozak T, Gupta IV, Phillips JL, Goldstein N, Struemper H, Losic N, Lisby S, Wierda WG; Hx-CD20-406 Study Investigators. Ofatumumab monotherapy in fludarabine-refractory chronic lymphocytic leukemia: final results from a pivotal study. Haematologica. 2015 Aug;100(8):e311-4. Epub 2015 Mar 13. link to original article link to PMC article PubMed
3. RESONATE: Byrd JC, Brown JR, O'Brien S, Barrientos JC, Kay NE, Reddy NM, Coutre S, Tam CS, Mulligan SP, Jaeger U, Devereux S, Barr PM, Furman RR, Kipps TJ, Cymbalista F, Pocock C, Thornton P, Caligaris-Cappio F, Robak T, Delgado J, Schuster SJ, Montillo M, Schuh A, de Vos S, Gill D, Bloor A, Dearden C, Moreno C, Jones JJ, Chu AD, Fardis M, McGreivy J, Clow F, James DF, Hillmen P; the RESONATE Investigators. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014 Jul 17;371(3):213-23. Epub 2014 May 31. link to original article contains verified protocol link to PMC article PubMed
   1. Update: Brown JR, Hillmen P, O'Brien S, Barrientos JC, Reddy NM, Coutre SE, Tam CS, Mulligan SP, Jaeger U, Barr PM, Furman RR, Kipps TJ, Cymbalista F, Thornton P, Caligaris-Cappio F, Delgado J, Montillo M, DeVos 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 PubMed
   2. Update: Byrd JC, Hillmen P, O'Brien S, Barrientos JC, Reddy NM, Coutre S, Tam CS, Mulligan SP, Jaeger U, Barr PM, Furman RR, Kipps TJ, Thornton P, Moreno C, Montillo M, Pagel JM, Burger JA, Woyach JA, Dai S, Vezan R, James DF, Brown JR. Long-term follow-up of the RESONATE phase 3 trial of ibrutinib vs ofatumumab. Blood. 2019 May 9;133(19):2031-2042. Epub 2019 Mar 6. link to original article PubMed
4. Retrospective: Moreno C, Montillo M, Panayiotidis P, Dimou M, Bloor A, Dupuis J, Schuh A, Norin S, Geisler C, Hillmen P, Doubek M, Trněný M, Obrtlikova P, Laurenti L, Stilgenbauer S, Smolej L, Ghia P, Cymbalista F, Jaeger U, Stamatopoulos K, Stavroyianni N, Carrington P, Zouabi H, Leblond V, Gomez-Garcia JC, Rubio M, Marasca R, Musuraca G, Rigacci L, Farina L, Paolini R, Pospisilova S, Kimby E, Bradley C, Montserrat E. Ofatumumab in poor-prognosis chronic lymphocytic leukemia: a Phase 4, non--interventional, observational study from the European Research Initiative on Chronic Lymphocytic Leukemia. Haematologica. 2015 Apr;100(4):511-6. Epub 2015 Jan 16. link to original article link to PMC article PubMed
5. GEN416: Österborg A, Wierda WG, Mayer J, Hess G, Hillmen P, Schetelig J, Schuh A, Smolej L, Beck C, Dreyfus B, Hellman A, Kozlowski P, Pfreundschuh M, Rizzi R, Spacek M, Phillips JL, Gupta IV, Williams V, Jewell RC, Nebot N, Lisby S, Dyer MJ. Ofatumumab retreatment and maintenance in fludarabine-refractory chronic lymphocytic leukaemia patients. Br J Haematol. 2015 Jul;170(1):40-9. Epub 2015 Mar 30. link to original article contains verified protocol PubMed
6. GS-US-312-0119: Jones JA, Robak T, Brown JR, Awan FT, Badoux X, Coutre S, Loscertales J, Taylor K, Vandenberghe E, Wach M, Wagner-Johnston N, Ysebaert L, Dreiling L, Dubowy R, Xing G, Flinn IW, Owen C. Efficacy and safety of idelalisib in combination with ofatumumab for previously treated chronic lymphocytic leukaemia: an open-label, randomised phase 3 trial. Lancet Haematol. 2017 Mar;4(3):e114-e126. link to original article contains protocol PubMed
7. P07714: Ghia P, Scarfò L, Perez S, Pathiraja K, Derosier M, Small K, McCrary Sisk C, Patton N. Efficacy and safety of dinaciclib vs ofatumumab in patients with relapsed/refractory chronic lymphocytic leukemia. Blood. 2017 Mar 30;129(13):1876-1878. Epub 2017 Jan 26. link to original article PubMed
8. DUO: Flinn IW, Hillmen P, Montillo M, Nagy Z, Illés Á, Etienne G, Delgado J, Kuss BJ, Tam CS, Gasztonyi Z, Offner F, Lunin S, Bosch F, Davids MS, Lamanna N, Jaeger U, Ghia P, Cymbalista F, Portell CA, Skarbnik AP, Cashen AF, Weaver DT, Kelly VM, Turnbull B, Stilgenbauer S. The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL. Blood. 2018 Dec 6;132(23):2446-2455. link to original article contains verified protocol PubMed

O-FC

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O-FC: Ofatumumab, Fludarabine, Cyclophosphamide

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Robak et al. 2016 (COMPLEMENT 2)	2008-NR	Phase III (E-RT-esc)	FC	Superior PFS

Chemotherapy

• 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
• Fludarabine (Fludara) 25 mg/m² IV once per day on days 1 to 3
• Cyclophosphamide (Cytoxan) 250 mg/m² IV once per day on days 1 to 3

Supportive medications

• Acetaminophen (Tylenol) 1000 mg PO once on day 1, prior to Ofatumumab (Arzerra)
• Cetirizine (Zyrtec) 10 mg (or equivalent) PO once on day 1, prior to Ofatumumab (Arzerra)
• Prednisolone (Millipred) 100 mg (or equivalent) PO once on day 1, prior to doses 1 & 2 of Ofatumumab (Arzerra), then reduced by physician discretion for later doses
• May be used at physician discretion:
  • Allopurinol (Zyloprim) for tumor lysis syndrome prophylaxis
  • prophylaxis
  • prophylaxis
  • Growth factor support

28-day cycle for 6 cycles

References

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

Rituximab monotherapy

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Regimen variant #1, 4-week course

Study	Evidence	Comparator	Comparative Efficacy
McLaughlin et al. 1998	Phase II
Williams et al. 2016 (RESORT substudy)	Phase III (E-de-esc)	Maintenance rituximab	Seems to have inferior TTTF

Preceding treatment

• RESORT substudy: Rituximab, with progression

Chemotherapy

• Rituximab (Rituxan) 375 mg/m² IV once per day on days 1, 8, 15, 22

4-week course

Regimen variant #2, 8 doses

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Furman et al. 2014 (GS-US-312-0116)	2012-2013	Phase III (C)	Idelalisib & Rituximab	Inferior PFS

Note: Reported efficacy is based on the 2019 update.

Chemotherapy

• Rituximab (Rituxan) as follows:
  • Cycle 1: 375 mg/m² IV once on day 1
  • Cycles 2 to 8: 500 mg/m² IV once on day 1

14-day cycle for 4 cycles, then 21-day cycle for 4 cycles

Regimen variant #3, 8 doses alternate schedule

Study	Evidence	Comparator	Comparative Efficacy
Huang et al. 2018 (CR102604)	Phase III (C)	Ibrutinib	Seems to have inferior OS

Chemotherapy

• Rituximab (Rituxan) as follows:
  • Cycle 1: 375 mg/m² IV once on day 1, then 500 mg/m² IV once on day 15
  • Cycle 2: 500 mg/m² IV once per day on days 1 & 15
  • Cycles 3 to 6: 500 mg/m² IV once on day 1

28-day cycle for 6 cycles

References

1. McLaughlin P, Grillo-López AJ, Link BK, Levy R, Czuczman MS, Williams ME, Heyman MR, Bence-Bruckler I, White CA, Cabanillas F, Jain V, Ho AD, Lister J, Wey K, Shen D, Dallaire BK. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998 Aug;16(8):2825-33. link to original article contains verified protocol PubMed
2. GS-US-312-0116: Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, Barrientos JC, Zelenetz AD, Kipps TJ, Flinn I, Ghia P, Eradat H, Ervin T, Lamanna N, Coiffier B, Pettitt AR, Ma S, Stilgenbauer S, Cramer P, Aiello M, Johnson DM, Miller LL, Li D, Jahn TM, Dansey RD, Hallek M, O'Brien SM. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014 Mar 13;370(11):997-1007. Epub 2014 Jan 22. link to original article contains verified protocol link to PMC article PubMed
   1. Update: Sharman JP, Coutre SE, Furman RR, Cheson BD, Pagel JM, Hillmen P, Barrientos JC, Zelenetz AD, Kipps TJ, Flinn IW, Ghia P, Eradat H, Ervin T, Lamanna N, Coiffier B, Pettitt AR, Ma S, Tausch E, Cramer P, Huang J, Mitra S, Hallek M, O'Brien SM, Stilgenbauer S. Final results of a randomized, phase III study of rituximab with or without idelalisib followed by open-label idelalisib in patients with relapsed chronic lymphocytic leukemia. J Clin Oncol. 2019 Jun 1;37(16):1391-1402. Epub 2019 Apr 17. link to original article PubMed
3. RESORT substudy: Williams ME, Hong F, Gascoyne RD, Wagner LI, Krauss JC, Habermann TM, Swinnen LJ, Schuster SJ, Peterson CG, Sborov MD, Martin SE, Weiss M, Ehmann WC, Horning SJ, Kahl BS; Eastern Cooperative Oncology Group. Rituximab extended schedule or retreatment trial for low tumour burden non-follicular indolent B-cell non-Hodgkin lymphomas: Eastern Cooperative Oncology Group Protocol E4402. Br J Haematol. 2016 Jun;173(6):867-75. Epub 2016 Mar 11. link to original article contains protocol link to PMC article PubMed
4. CR102604: Huang X, Qiu L, Jin J, Zhou D, Chen X, Hou M, Hu J, Hu Y, Ke X, Li J, Liang Y, Liu T, Lv Y, Ren H, Sun A, Wang J, Zhao C, Salman M, Sun S, Howes A, Wang J, Wu P, Li J. Ibrutinib versus rituximab in relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma: a randomized, open-label phase 3 study. Cancer Med. 2018 Apr;7(4):1043-1055. Epub 2018 Mar 13. link to original article contains verified protocol link to PMC article PubMed

Venetoclax & Rituximab

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VEN+R: VENetoclax & Rituximab

Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Seymour et al. 2018 (MURANO)	2014-2015	Phase III (E-RT-switch-ooc)	BR	Superior OS

Chemotherapy

• Venetoclax (Venclexta) as follows:
  • Week 1: 20 mg PO once per day
  • Week 2: 50 mg PO once per day
  • Week 3: 100 mg PO once per day
  • Week 4: 200 mg PO once per day
  • Week 5 onwards: 400 mg PO once per day
• Rituximab (Rituxan) as follows:
  • Week 6: 375 mg/m² IV once on day 1
  • Weeks 10, 14, 18, 22, 26: 500 mg/m² IV once on day 1

Up to 2-year course

References

1. MURANO: Seymour JF, Kipps TJ, Eichhorst B, Hillmen P, D'Rozario J, Assouline S, Owen C, Gerecitano J, Robak T, De la Serna J, Jaeger U, Cartron G, Montillo M, Humerickhouse R, Punnoose EA, Li Y, Boyer M, Humphrey K, Mobasher M, Kater AP. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018 Mar 22;378(12):1107-1120. link to original article contains verified protocol PubMed
   1. Update: Kater AP, Seymour JF, Hillmen P, Eichhorst B, Langerak AW, Owen C, Verdugo M, Wu J, Punnoose EA, Jiang Y, Wang J, Boyer M, Humphrey K, Mobasher M, Kipps TJ. Fixed duration of venetoclax-rituximab in relapsed/refractory chronic lymphocytic leukemia eradicates minimal residual disease and prolongs survival: post-treatment follow-up of the MURANO phase III study. J Clin Oncol. 2019 Feb 1;37(4):269-277. Epub 2018 Dec 3. link to original article PubMed

Relapsed or refractory, non-randomized or retrospective data

Acalabrutinib monotherapy

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Regimen

FDA-recommended dose

Study	Evidence	Efficacy
Byrd et al. 2015 (ACE-CL-001)	Phase I/II	ORR: 95%

Note: this is the dose used in the expansion cohort. It is also the FDA-recommended dose that was used in the ASCEND trial, which has yet to be published.

Chemotherapy

• Acalabrutinib (Calquence) 100 mg PO twice per day

Continued indefinitely

References

1. ACE-CL-001: Byrd JC, Harrington B, O'Brien S, Jones JA, Schuh A, Devereux S, Chaves J, Wierda WG, Awan FT, Brown JR, Hillmen P, Stephens DM, Ghia P, Barrientos JC, Pagel JM, Woyach J, Johnson D, Huang J, Wang X, Kaptein A, Lannutti BJ, Covey T, Fardis M, McGreivy J, Hamdy A, Rothbaum W, Izumi R, Diacovo TG, Johnson AJ, Furman RR. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016 Jan 28;374(4):323-32. Epub 2015 Dec 7. link to original article link to PMC article contains verified protocol PubMed

Alemtuzumab monotherapy

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Regimen variant #1

Study	Years of enrollment	Evidence
Keating et al. 2002	1998	Phase II (RT)
Rai et al. 2002	NR-1994	Phase II (RT)

Note: total course varies depending on reference.

Chemotherapy

• Alemtuzumab (Campath) as follows:
  • 3 mg IV once per day, then increased as tolerated in terms of infusion reactions to 10 mg IV once per day, and then to 30 mg IV once per day
  • Once 30 mg dose is tolerated: 30 mg IV over 2 hours, 3 times per week

Supportive medications

• Note: see references for details, as they differ by paper.
• Diphenhydramine (Benadryl) 50 mg PO once per infusion; 30 minutes prior to Alemtuzumab (Campath)
• Acetaminophen (Tylenol) 650 mg PO once per infusion; 30 minutes prior to Alemtuzumab (Campath)
• 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	Years of enrollment	Evidence
Lozanski et al. 2004	NR	Phase II (RT)

Chemotherapy

• 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 medications

• G-CSF or GM-CSF per institutional protocol
• Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg PO 3 times per week during therapy and continued for 6 months after treatment is complete
• Acyclovir (Zovirax) 800 mg PO three times per day during therapy and continued for 6 months after treatment is complete; similar medication can be used if intolerant of acyclovir

12-week course

References

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

Alemtuzumab & Rituximab

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Regimen

Study	Evidence
Faderl et al. 2003	Phase II

Chemotherapy

• Alemtuzumab (Campath) 3 mg IV once on day 1, 10 mg IV once on day 2, 30 mg IV once on day 3 of week 1, then 30 mg IV once per day on days 10, 12, 17, 19, 24, 26 (i.e. days 3 and 5 of weeks 2 to 4)
• Rituximab (Rituxan) 375 mg/m² IV once per day on days 1, 8, 15, 22
  • For patients with WBC count greater than 50 x 10⁹/L, the first dose of Rituximab (Rituxan) was split into 100 mg/m² IV once on day 1 and 275 mg/m² IV once on day 2

Supportive medications

• Prophylactic Trimethoprim-Sulfamethoxazole (Bactrim DS), given during therapy and continuing at a minimum until 2 months after treatment is complete
• Prophylactic Valacyclovir (Valtrex) (or equivalent), given during therapy and continuing at a minimum until 2 months after treatment is complete

28-day cycle for 1 to 2 cycles depending on response and toxicity

References

1. Faderl S, Thomas DA, O'Brien S, Garcia-Manero G, Kantarjian HM, Giles FJ, Koller C, Ferrajoli A, Verstovsek S, Pro B, Andreeff M, Beran M, Cortes J, Wierda W, Tran N, Keating MJ. Experience with alemtuzumab plus rituximab in patients with relapsed and refractory lymphoid malignancies. Blood. 2003 May 1;101(9):3413-5. Epub 2003 Jan 9. link to original article contains protocol Pubmed

Bendamustine & Ofatumumab

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BendOfa: Bendamustine & Ofatumumab

Regimen

Study	Evidence	Efficacy
Cortelezzi et al. 2013 (GIMEMA CLL0809)	Phase II	ORR: 72% (95% CI, 57–84%)

Chemotherapy

• Bendamustine 70 mg/m² IV once per day on days 1 & 2
• Ofatumumab (Arzerra) as follows:
  • Cycle 1: 300 mg IV once on day 1, then 1000 mg IV once on day 7
  • Cycle 2 onwards: 1000 mg IV once on day 1

Supportive medications

• Acetaminophen (Tylenol) 1000 mg PO once per infusion, prior to Ofatumumab (Arzerra)
• Diphenhydramine (Benadryl) 50 mg PO once per infusion, prior to Ofatumumab (Arzerra)
• Methylprednisolone (Solumedrol) 40 mg IV once per infusion, prior to Ofatumumab (Arzerra)
• Allopurinol (Zyloprim) or Rasburicase (Elitek) required for prophylaxis against TLS; dose not specified
• Trimethoprim-Sulfamethoxazole (Bactrim DS) required; dose not specified
• Acyclovir (Zovirax) required; dose not specified

28-day cycle up to 6 cycles

References

1. GIMEMA CLL0809: Cortelezzi A, Sciumè M, Liberati AM, Vincenti D, Cuneo A, Reda G, Laurenti L, Zaja F, Marasca R, Chiarenza A, Gritti G, Orsucci L, Storti S, Angelucci E, Cascavilla N, Gobbi M, Mauro FR, Morabito F, Fabris S, Piciocchi A, Vignetti M, Neri A, Rossi D, Giannarelli D, Guarini A, Foà R. Bendamustine in combination with ofatumumab in relapsed or refractory chronic lymphocytic leukemia: a GIMEMA multicenter phase II trial. Leukemia. 2014 Mar;28(3):642-8. Epub 2013 Nov 13. link to original article contains verified protocol PubMed

CFAR

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CFAR: Cyclophosphamide, Fludarabine, Alemtuzumab, Rituximab

Regimen

Study	Evidence	Efficacy
Badoux et al. 2011	Phase II	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
• 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 medications

• 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 (Rituxan)/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 (Rituxan)/Alemtuzumab (Campath)
  • Hydrocortisone (Cortef) 100 mg IV once per day on days 1, 2, 3, 5; 30 minutes prior to Alemtuzumab (Campath)

28-day cycle for 6 cycles

References

1. Badoux XC, Keating MJ, Wang X, O'Brien SM, Ferrajoli A, Faderl S, Burger J, Koller C, Lerner S, Kantarjian H, Wierda WG. Cyclophosphamide, fludarabine, alemtuzumab, and rituximab as salvage therapy for heavily pretreated patients with chronic lymphocytic leukemia. Blood. 2011 Aug 25;118(8):2085-93. Epub 2011 Jun 13. link to original article contains protocol link to PMC article PubMed

FluCam

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FluCam: Fludarabine, Campath

Regimen

Study	Evidence
Elter et al. 2005	Phase II

Chemotherapy

• Fludarabine (Fludara) 30 mg/m² IV once per day on days 1 to 3
• 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 medications

• 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 (Campath), then with subsequent doses if clinically indicated
• Clemastine (Tavist) 2 mg IV once on day 1, prior to first dose of Alemtuzumab (Campath), then with subsequent doses if clinically indicated
• Prednisone (Sterapred) 100 mg IV once on day 1, prior to first dose of Alemtuzumab (Campath), then with subsequent doses if clinically indicated
• For patients with WBC count greater than 50 x 10⁹/L, bulky disease, or history of hyperuricemia: Allopurinol (Zyloprim) 300 mg PO once on day 1, prior to first dose of Alemtuzumab (Campath), and used later if clinically indicated

28-day cycle for 6 cycles

References

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

Fludarabine & Prednisone

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Regimen

Study	Evidence
O'Brien et al. 1993	Phase II

Chemotherapy

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

28-day cycles

References

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

HDMP-R

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HDMP-R: High Dose, MethylPrednisolone, Rituximab

Regimen variant #1, 3 cycles

Study	Evidence
Castro et al. 2008	Phase II

Chemotherapy

• Methylprednisolone (Solumedrol) 1000 mg/m² IV over 90 minutes once per day on days 1 to 5
• Rituximab (Rituxan) as follows:
  • Cycle 1: 375 mg/m² IV once per day on days 1, 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	Evidence
Pileckyte et al. 2011	Phase II

Chemotherapy

• Methylprednisolone (Solumedrol) 1000 mg/m² IV over 4 hours once per day on days 1 to 5
• 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 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 medications

• Trimethoprim/sulfamethoxazole "or an equivalent antibiotic throughout the treatment period and up to 6 months after the completion of therapy"

21-day cycle for 6 cycles

References

1. Castro JE, Sandoval-Sus JD, Bole J, Rassenti L, Kipps TJ. Rituximab in combination with high-dose methylprednisolone for the treatment of fludarabine refractory high-risk chronic lymphocytic leukemia. Leukemia. 2008 Nov;22(11):2048-53. Epub 2008 Aug 28. link to original article link to PMC article contains verified protocol PubMed
2. Pileckyte R, Jurgutis M, Valceckiene V, Stoskus M, Gineikiene E, Sejoniene J, Degulys A, Zvirblis T, Griskevicius L. Dose-dense high-dose methylprednisolone and rituximab in the treatment of relapsed or refractory high-risk chronic lymphocytic leukemia. Leuk Lymphoma. 2011 Jun;52(6):1055-65. link to original article contains protocol PubMed

Ibrutinib & Ofatumumab

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Regimen variant #1, concurrent ibrutinib and ofatumumab

Study	Evidence
Jaglowski et al. 2015	Phase II

This study to patients who had failed two or more prior therapies, or had Richter's transformation.

Chemotherapy

• Ibrutinib (Imbruvica) 420 mg PO once per day
• Ofatumumab (Arzerra) as follows:
  • Cycle 1: 300 mg IV once on day 1, then 2000 mg IV once per day on days 8, 15, 22
  • Cycle 2: 2000 mg IV once per day on days 1, 8, 15, 22
  • Cycles 3 to 6: 2000 mg IV once on day 1

28-day cycles

Regimen variant #2, ibrutinib lead-in

Study	Evidence
Jaglowski et al. 2015	Phase II

This study to patients who had failed two or more prior therapies, or had Richter's transformation.

Chemotherapy

• Ibrutinib (Imbruvica) 420 mg PO once per day
• Ofatumumab (Arzerra) as follows:
  • Cycle 2: 300 mg IV once on day 1, then 2000 mg IV once per day on days 8, 15, 22
  • Cycle 3: 2000 mg IV once per day on days 1, 8, 15, 22
  • Cycles 4 to 7: 2000 mg IV once on day 1

28-day cycles

Regimen variant #3, ofatumumab lead-in

Study	Evidence
Jaglowski et al. 2015	Phase II

This study to patients who had failed two or more prior therapies, or had Richter's transformation.

Chemotherapy

• Ibrutinib (Imbruvica) as follows:
  • Cycle 3 onwards: 420 mg PO once per day
• Ofatumumab (Arzerra) as follows:
  • Cycle 1: 300 mg IV once on day 1, then 2000 mg IV once per day on days 8, 15, 22
  • Cycle 2: 2000 mg IV once per day on days 1, 8, 15, 22
  • Cycles 3 to 6: 2000 mg IV once on day 1

28-day cycles

References

1. Jaglowski SM, Jones JA, Nagar V, Flynn JM, Andritsos LA, Maddocks KJ, Woyach JA, Blum KA, Grever MR, Smucker K, Ruppert AS, Heerema NA, Lozanski G, Stefanos M, Munneke B, West JS, Neuenburg JK, James DF, Hall N, Johnson AJ, Byrd JC. Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab in chronic lymphocytic leukemia: a phase 1b/2 study. Blood. 2015 Aug 13;126(7):842-50. Epub 2015 Jun 26. link to original article contains verified protocol link to PMC article PubMed

Ibrutinib & Rituximab

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Regimen

Study	Evidence
Burger et al. 2014	Phase II

This study was open to patients with high-risk CLL (del17p or TP53 mutation, PFS less than 36 months from initial therapy, or relapsed CLL with del11q). Only 4 patients in the published study were untreated.

Chemotherapy

• Ibrutinib (Imbruvica) 420 mg PO once per day
• Rituximab (Rituxan) as follows:
  • Cycle 1: 375 mg/m² IV once per day on days 1, 8, 15, 22
  • Cycles 2 to 6: 375 mg/m² IV once on day 1

28-day cycles

References

1. Burger JA, Keating MJ, Wierda WG, Hartmann E, Hoellenriegel J, Rosin NY, de Weerdt I, Jeyakumar G, Ferrajoli A, Cardenas-Turanzas M, Lerner S, Jorgensen JL, Nogueras-González GM, Zacharian G, Huang X, Kantarjian H, Garg N, Rosenwald A, O'Brien S. Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study. Lancet Oncol. 2014 Sep;15(10):1090-9. Epub 2014 Aug 20. link to original article contains verified protocol link to PMC article PubMed
   1. Update: Jain P, Keating MJ, Wierda WG, Sivina M, Thompson PA, Ferrajoli A, Estrov Z, Kantarjian H, O'Brien S, Burger JA. Long-term follow-up of treatment with ibrutinib and rituximab in patients with high-risk chronic lymphocytic leukemia. Clin Cancer Res. 2017 May 1;23(9):2154-2158. Epub 2016 Oct 19. link to original article link to PMC article PubMed

Idelalisib monotherapy

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Regimen

Study	Years of enrollment	Evidence
Brown et al. 2014 (Gilead 101-02)	2008-2011	Phase I, >20 pts
Gopal et al. 2014 (DELTA)	2011-2012	Phase II (RT)

Chemotherapy

• Idelalisib (Zydelig) 150 mg PO twice per day

Continued indefinitely

References

1. DELTA: Gopal AK, Kahl BS, de Vos S, Wagner-Johnston ND, Schuster SJ, Jurczak WJ, Flinn IW, Flowers CR, Martin P, Viardot A, Blum KA, Goy AH, Davies AJ, Zinzani PL, Dreyling M, Johnson D, Miller LL, Holes L, Li D, Dansey RD, Godfrey WR, Salles GA. PI3Kd inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014 Mar 13;370(11):1008-18. Epub 2014 Jan 22. link to original article contains verified protocol link to PMC article PubMed
   1. Update: Abstract: Ajay K. Gopal, MD, Brad S. Kahl, MD, Sven de Vos, MD, PhD, Nina D. Wagner-Johnston, MD, Stephen J. Schuster, MD, Wojciech Jurczak, MD, PhD, Ian W. Flinn, MD, PhD, Christopher R. Flowers, MD, Peter Martin, MD, Andreas Viardot, MD, Kristie A. Blum, MD, Andre Goy, MD, Andrew Davies, BM PhD, Pier Luigi Zinzani, MD, Martin H. Dreyling, MD, PhD, Leanne M. Holes, Bess Sorensen, PhD, Wayne R. Godfrey, MD and Gilles Andre Salles, MD, PhD. Mature Follow up from a Phase 2 Study of PI3K-Delta Inhibitor Idelalisib in Patients with Double (Rituximab and Alkylating agent)-Refractory Indolent B-Cell Non-Hodgkin Lymphoma (iNHL). ASH Annual Meeting 2014, Abstract 1708 link to abstract
2. Phase 1: Brown JR, Byrd JC, Coutre SE, Benson DM, Flinn IW, Wagner-Johnston ND, Spurgeon SE, Kahl BS, Bello C, Webb HK, Johnson DM, Peterman S, Li D, Jahn TM, Lannutti BJ, Ulrich RG, Yu AS, Miller LL, Furman RR. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110d, for relapsed/refractory chronic lymphocytic leukemia. Blood. 2014 May 29;123(22):3390-7. Epub 2014 Mar 10. link to original article link to PMC article PubMed

Lenalidomide monotherapy

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Regimen variant #1

Study	Evidence
Chanan-Khan et al. 2006	Phase II

Chemotherapy

• 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 medications

• Allopurinol (Zyloprim) 300 mg PO once per day, starting 2 to 3 days prior to Lenalidomide (Revlimid), and continued up to a total of 14 days

28-day cycles

Regimen variant #2

Study	Evidence
Ferrajoli et al. 2008	Phase II

Chemotherapy

• Lenalidomide (Revlimid) as follows:
  • Cycle 1: 10 mg PO once per day
  • Cycle 2: 15 mg PO once per day
  • Cycle 3: 20 mg PO once per day
  • Cycle 4 onwards: 25 mg PO once per day

28-day cycles

Regimen variant #3

Study	Evidence
Witzig et al. 2009 (NHL-001)	Phase II, <20 patients in this subgroup

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

Chemotherapy

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

28-day cycles

References

1. Chanan-Khan A, Miller KC, Musial L, Lawrence D, Padmanabhan S, Takeshita K, Porter CW, Goodrich DW, Bernstein ZP, Wallace P, Spaner D, Mohr A, Byrne C, Hernandez-Ilizaliturri F, Chrystal C, Starostik P, Czuczman MS. Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study. J Clin Oncol. 2006 Dec 1;24(34):5343-9. Epub 2006 Nov 6. link to original article contains protocol PubMed
2. Ferrajoli A, Lee BN, Schlette EJ, O'Brien SM, Gao H, Wen S, Wierda WG, Estrov Z, Faderl S, Cohen EN, Li C, Reuben JM, Keating MJ. Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood. 2008 Jun 1;111(11):5291-7. Epub 2008 Mar 11. link to original article link to PMC article PubMed
3. Witzig TE, Wiernik PH, Moore T, Reeder C, Cole C, Justice G, Kaplan H, Voralia M, Pietronigro D, Takeshita K, Ervin-Haynes A, Zeldis JB, Vose JM. Lenalidomide oral monotherapy produces durable responses in relapsed or refractory indolent non-Hodgkin's Lymphoma. J Clin Oncol. 2009 Nov 10;27(32):5404-9. Epub 2009 Oct 5. link to original article contains verified protocol PubMed

Lenalidomide & Ofatumumab

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Regimen variant #1

Study	Evidence
Vitale et al. 2016	Phase II

Chemotherapy

• Lenalidomide (Revlimid) as follows:
  • Cycle 1: 10 mg PO once per day on days 9 to 28
  • Cycle 2 to 24: 10 mg PO once per day
• Ofatumumab (Arzerra) as follows:
  • Cycle 1: 300 mg IV once on day 1, then 1000 mg IV once per day on days 8, 15, 22
  • Cycles 3 to 6, 8, 10, 12, 14, 16, 18, 20, 22, 24: 1000 mg IV once on day 1

Supportive medications

• 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

• Patients with a sustained PR or CR were allowed to continue treatment with lenalidomide monotherapy indefinitely

References

1. Vitale C, Falchi L, Ten Hacken E, Gao H, Shaim H, Van Roosbroeck K, Calin G, O'Brien S, Faderl S, Wang X, Wierda WG, Rezvani K, Reuben JM, Burger JA, Keating MJ, Ferrajoli A. Ofatumumab and Lenalidomide for Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia: Correlation between Responses and Immune Characteristics. Clin Cancer Res. 2016 May 15;22(10):2359-67. Epub 2016 Jan 5. link to original article contains verified protocol link to PMC article PubMed

Lenalidomide & Rituximab

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Regimen variant #1

Study	Evidence
Chanan-Khan et al. 2006	Phase II

Chemotherapy

• 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
  • Subsequent Cycles: 375 mg/m² IV once per day on days 1 & 15

Supportive medications

• 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	Evidence
Badoux et al. 2013	Phase II

Chemotherapy

• Lenalidomide (Revlimid) as follows:
  • Cycle 1: 10 mg PO once per day on days 9 to 28
  • Subsequent Cycles: 10 mg PO once per day on days 1 to 28
• Rituximab (Rituxan) as follows:
  • Cycle 1: 375 mg/m² IV once per day on days 1, 8, 15, 22
  • Cycle 2: no rituximab given
  • Cycles 3 to 12: 375 mg/m² IV once on day 1

Supportive medications

• 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

Lenalidomide could continue indefinitely in responders.

References

1. Chanan-Khan A, Miller KC, Musial L, Lawrence D, Padmanabhan S, Takeshita K, Porter CW, Goodrich DW, Bernstein ZP, Wallace P, Spaner D, Mohr A, Byrne C, Hernandez-Ilizaliturri F, Chrystal C, Starostik P, Czuczman MS. Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study. J Clin Oncol. 2006 Dec 1;24(34):5343-9. Epub 2006 Nov 6. link to original article contains protocol PubMed
2. Badoux XC, Keating MJ, Wen S, Wierda WG, O'Brien SM, Faderl S, Sargent R, Burger JA, Ferrajoli A. Phase II Study of Lenalidomide and Rituximab As Salvage Therapy for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia. J Clin Oncol. 2013 Feb 10;31(5):584-91. Epub 2012 Dec 26. link to original article contains verified protocol link to PMC article PubMed

Obinutuzumab monotherapy

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Regimen

Study	Evidence
Salles et al. 2012 (GAUGUIN)	Phase I/II

Note: Dose here is the phase II dose reported in the Cartron et al. 2014 update.

Chemotherapy

• 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 medications

• Acetaminophen (Tylenol) 650 to 1000 mg PO once on cycle 1 day 1; 30 minutes prior to Obinutuzumab (Gazyva), 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 (Gazyva), 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 (Rituxan) reactions: Corticosteroids (no drug/dose/route specified) once on cycle 1 day 1, prior to Obinutuzumab (Gazyva)

21-day cycle for up to 8 cycles

References

1. GAUGUIN: Salles G, Morschhauser F, Lamy T, Milpied N, Thieblemont C, Tilly H, Bieska G, Asikanius E, Carlile D, Birkett J, Pisa P, Cartron G. Phase 1 study results of the type II glycoengineered humanized anti-CD20 monoclonal antibody obinutuzumab (GA101) in B-cell lymphoma patients. Blood. 2012 May 31;119(22):5126-32. Epub 2012 Mar 19. link to original article PubMed
   1. Subgroup analysis: Morschhauser FA, Cartron G, Thieblemont C, Solal-Céligny P, Haioun C, Bouabdallah R, Feugier P, Bouabdallah K, Asikanius E, Lei G, Wenger M, Wassner-Fritsch E, Salles GA. Obinutuzumab (GA101) monotherapy in relapsed/refractory diffuse large B-cell lymphoma or mantle-cell lymphoma: results from the phase II GAUGUIN study. J Clin Oncol. 2013 Aug 10;31(23):2912-9. Epub 2013 Jul 8. link to original article contains verified protocol PubMed
   2. Subgroup analysis: Salles GA, Morschhauser F, Solal-Céligny P, Thieblemont C, Lamy T, Tilly H, Gyan E, Lei G, Wenger M, Wassner-Fritsch E, Cartron G. Obinutuzumab (GA101) in patients with relapsed/refractory indolent non-Hodgkin lymphoma: results from the phase II GAUGUIN study. J Clin Oncol. 2013 Aug 10;31(23):2920-6. Epub 2013 Jul 8. link to original article contains verified protocol PubMed
   3. Subgroup analysis: Cartron G, de Guibert S, Dilhuydy MS, Morschhauser F, Leblond V, Dupuis J, Mahe B, Bouabdallah R, Lei G, Wenger M, Wassner-Fritsch E, Hallek M. Obinutuzumab (GA101) in relapsed/refractory chronic lymphocytic leukemia: final data from the phase 1/2 GAUGUIN study. Blood. 2014 Oct 2;124(14):2196-202. Epub 2014 Aug 20. link to original article contains verified protocol PubMed

OFAR

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

Regimen

Study	Evidence
Tsimberidou et al. 2008	Phase II

Chemotherapy

• Oxaliplatin (Eloxatin) 25 mg/m² IV over 2 hours once per day on days 1 to 4
• Fludarabine (Fludara) 30 mg/m² IV once per day on days 2 & 3, administered within 30 minutes of completion of oxaliplatin
• Cytarabine (Ara-C) 1000 mg/m² IV over 2 hours once per day on days 2 & 3, 4 hours after fludarabine started
• Rituximab (Rituxan) as follows:
  • Cycle 1: 375 mg/m² IV over 4 to 6 hours once on day 3
  • Cycles 2 to 6: 375 mg/m² IV over 4 to 6 hours once on day 1

Supportive medications

• Pegfilgrastim (Neulasta) 6 mg SC once on day 6
• Herpes zoster and PCP (Pneumocystis jiroveci pneumonia) prophylaxis used

28-day cycle for up to 6 cycles

References

1. Tsimberidou AM, Wierda WG, Plunkett W, Kurzrock R, O'Brien S, Wen S, Ferrajoli A, Ravandi-Kashani F, Garcia-Manero G, Estrov Z, Kipps TJ, Brown JR, Fiorentino A, Lerner S, Kantarjian HM, Keating MJ. Phase I-II study of oxaliplatin, fludarabine, cytarabine, and rituximab combination therapy in patients with Richter's syndrome or fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol. 2008 Jan 10;26(2):196-203. link to original article contains protocol PubMed

PCR

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PCR: Pentostatin, Cyclophosphamide, Rituximab

Regimen

Study	Evidence
Lamanna et al. 2006	Phase II

Chemotherapy

• Pentostatin (Nipent) 4 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1
• Rituximab (Rituxan) as follows:
  • Cycle 1: no dose
  • Cycles 2 to 6: 375 mg/m² IV once on day 1

Supportive medications

• Note: paper says they were "administered prophylactically," without additional details.
• Filgrastim (Neupogen)
• Trimethoprim-Sulfamethoxazole (Bactrim DS)
• Acyclovir (Zovirax)

21-day cycle for 6 cycles

References

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

R-BAC

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

Regimen

Study	Evidence
Visco et al. 2013	Pilot, <20 patients reported

Chemotherapy

• Rituximab (Rituxan) as follows:
  • Cycle 1: 375 mg/m² IV once on day 1
  • Subsequent cycles: 500 mg/m² IV once on day 1
• 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 medications

• Primary prophylaxis with granulocyte colony-stimulating factor was routinely used starting from Day 5 after chemotherapy completion, and lasting for 3 to 6 days or until neutrophil count recovery.

28-day cycle for up to 4 cycles

References

1. Visco C, Finotto S, Pomponi F, Sartori R, Laveder F, Trentin L, Paolini R, Di Bona E, Ruggeri M, Rodeghiero F. The combination of rituximab, bendamustine, and cytarabine for heavily pretreated relapsed/refractory cytogenetically high-risk patients with chronic lymphocytic leukemia. Am J Hematol. 2013 Apr;88(4):289-93. Epub 2013 Feb 28. link to original article contains verified protocol PubMed

Ruxolitinib monotherapy

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Regimen

Study	Evidence
Jain et al. 2017	Phase II, <20 pts in this subgroup

Note: this was a trial focused on symptom control, not efficacy.

Chemotherapy

• Ruxolitinib (Jakafi) 10 mg PO twice per day

References

1. Jain P, Keating M, Renner S, Cleeland C, Xuelin H, Gonzalez GN, Harris D, Li P, Liu Z, Veletic I, Rozovski U, Jain N, Thompson P, Bose P, DiNardo C, Ferrajoli A, O'Brien S, Burger J, Wierda W, Verstovsek S, Kantarjian H, Estrov Z. Ruxolitinib for symptom control in patients with chronic lymphocytic leukaemia: a single-group, phase 2 trial. Lancet Haematol. 2017 Feb;4(2):e67-e74. Epub 2017 Jan 11. link to original article contains protocol link to PMC article PubMed

Venetoclax monotherapy

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Regimen variant #1, standard lead-in

FDA-recommended dose

Study	Years of enrollment	Evidence	Efficacy
Roberts et al. 2015 (M12-175)	2011-2014	Phase I/II (RT)	ORR: 79%
Stilgenbauer et al. 2016 (M13-982)	2013-2014	Phase II (RT)	ORR: 79% (95% CI, 70.5-87)
Coutre et al. 2018 (M14-032)	NR	Phase II (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.

Chemotherapy

• Venetoclax (Venclexta) as follows:
  • Week 1: 20 mg PO once per day
  • Week 2: 50 mg PO once per day
  • Week 3: 100 mg PO once per day
  • Week 4: 200 mg PO once per day
  • Week 5 onwards: 400 mg PO once per day

Continued indefinitely

Regimen variant #2, modified lead-in

Study	Evidence	Efficacy
Coutre et al. 2018 (M14-032)	Phase II	ORR: 67%

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.

Chemotherapy

• Venetoclax (Venclexta) as follows:
  • Day 1: 20 mg PO once per day
  • Days 2 & 3: 50 mg PO once per day
  • Days 4 to 7: 100 mg PO once per day
  • Week 2: 200 mg PO once per day
  • Week 3 onwards: 400 mg PO once per day

Continued indefinitely

References

1. M12-175: Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF, Kipps TJ, Anderson MA, Brown JR, Gressick L, Wong S, Dunbar M, Zhu M, Desai MB, Cerri E, Heitner Enschede S, Humerickhouse RA, Wierda WG, Seymour JF. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016 Jan 28;374(4):311-22. Epub 2015 Dec 6. link to original article contains verified protocol PubMed
2. M13-982: Stilgenbauer S, Eichhorst B, Schetelig J, Coutre S, Seymour JF, Munir T, Puvvada SD, Wendtner CM, Roberts AW, Jurczak W, Mulligan SP, Böttcher S, Mobasher M, Zhu M, Desai M, Chyla B, Verdugo M, Heitner Enschede S, Cerri E, Humerickhouse R, Gordon G, Hallek M, Wierda WG. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 2016 Jun;17(6):768-78. Epub 2016 May 10. link to original article contains protocol PubMed
   1. Update: Stilgenbauer S, Eichhorst B, Schetelig J, Hillmen P, Seymour JF, Coutre S, Jurczak W, Mulligan SP, Schuh A, Assouline S, Wendtner CM, Roberts AW, Davids MS, Bloehdorn J, Munir T, Böttcher S, Zhou L, Salem AH, Desai M, Chyla B, Arzt J, Kim SY, Verdugo M, Gordon G, Hallek M, Wierda WG. Venetoclax for patients with chronic lymphocytic leukemia with 17p deletion: results from the full population of a phase II pivotal trial. J Clin Oncol. 2018 Jul 1;36(19):1973-1980. Epub 2018 May 1. PubMed
3. M14-032: Coutre S, Choi M, Furman RR, Eradat H, Heffner L, Jones JA, Chyla B, Zhou L, Agarwal S, Waskiewicz T, Verdugo M, Humerickhouse RA, Potluri J, Wierda WG, Davids MS. Venetoclax for patients with chronic lymphocytic leukemia who progressed during or after idelalisib therapy. Blood. 2018 Apr 12;131(15):1704-1711. Epub 2018 Jan 5. link to original article contains verified protocol in supplement PubMed

Consolidation and/or maintenance after subsequent lines of therapy

FC, then allo HSCT

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FC: Fludarabine & Cyclophosphamide

Regimen

Study	Evidence
Dreger et al. 2010 (GCLLSG CLL3X)	Phase II

Chemotherapy

• Fludarabine (Fludara) 30 mg/m² IV once per day on days -6 to -2
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once per day on days -6 to -2

Immunotherapy

• Allogeneic stem cells

Stem cells transfused on day 0

References

1. GCLLSG CLL3X: Dreger P, Döhner H, Ritgen M, Böttcher S, Busch R, Dietrich S, Bunjes D, Cohen S, Schubert J, Hegenbart U, Beelen D, Zeis M, Stadler M, Hasenkamp J, Uharek L, Scheid C, Humpe A, Zenz T, Winkler D, Hallek M, Kneba M, Schmitz N, Stilgenbauer S; German CLL Study Group. Allogeneic stem cell transplantation provides durable disease control in poor-risk chronic lymphocytic leukemia: long-term clinical and MRD results of the German CLL Study Group CLL3X trial. Blood. 2010 Oct 7;116(14):2438-47. Epub 2010 Jul 1. link to original article contains verified protocol PubMed
   1. Update: Dreger P, Schnaiter A, Zenz T, Böttcher S, Rossi M, Paschka P, Bühler A, Dietrich S, Busch R, Ritgen M, Bunjes D, Zeis M, Stadler M, Uharek L, Scheid C, Hegenbart U, Hallek M, Kneba M, Schmitz N, Döhner H, Stilgenbauer S. TP53, SF3B1, and NOTCH1 mutations and outcome of allotransplantation for chronic lymphocytic leukemia: six-year follow-up of the GCLLSG CLL3X trial. Blood. 2013 Apr 18;121(16):3284-8. Epub 2013 Feb 22. link to original article PubMed
   2. Update: Krämer I, Stilgenbauer S, Dietrich S, Böttcher S, Zeis M, Stadler M, Bittenbring J, Uharek L, Scheid C, Hegenbart U, Ho A, Hallek M, Kneba M, Schmitz N, Döhner H, Dreger P. Allogeneic hematopoietic cell transplantation for high-risk CLL: 10-year follow-up of the GCLLSG CLL3X trial. Blood. 2017 Sep 21;130(12):1477-1480. Epub 2017 Jul 17. link to original article PubMed

Fludarabine & TBI, then allo HSCT

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Regimen

Study	Evidence
Sorror et al. 2005	Phase II

Chemotherapy

• Fludarabine (Fludara) 30 mg/m² IV once per day on days -4 to -2

Radiotherapy

• Total body irradiation (TBI) 2 Gy at a rate of 0.07 Gy/min on day 0

GVHD prophylaxis

• Cyclosporine A (type not specified) 6.25 mg/kg PO twice per day starting 4 to 6 hours after transplant, tapered at day 100 over 80 days (if no GVHD)
• Mycophenolate mofetil (CellCept) 15 mg/kg PO twice per day starting 4 to 6 hours after transplant, tapered at day 40 over 56 days (if no GVHD)

Immunotherapy

• Allogeneic stem cells

Stem cells transfused on day 0

References

1. Sorror ML, Maris MB, Sandmaier BM, Storer BE, Stuart MJ, Hegenbart U, Agura E, Chauncey TR, Leis J, Pulsipher M, McSweeney P, Radich JP, Bredeson C, Bruno B, Langston A, Loken MR, Al-Ali H, Blume KG, Storb R, Maloney DG. Hematopoietic cell transplantation after nonmyeloablative conditioning for advanced chronic lymphocytic leukemia. J Clin Oncol. 2005 Jun 1;23(16):3819-29. Epub 2005 Apr 4. link to original article PubMed
   1. Update: Sorror ML, Storer BE, Sandmaier BM, Maris M, Shizuru J, Maziarz R, Agura E, Chauncey TR, Pulsipher MA, McSweeney PA, Wade JC, Bruno B, Langston A, Radich J, Niederwieser D, Blume KG, Storb R, Maloney DG. Five-year follow-up of patients with advanced chronic lymphocytic leukemia treated with allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. J Clin Oncol. 2008 Oct 20;26(30):4912-20. Epub 2008 Sep 15. link to original article link to PMC article PubMed

Fludarabine, Busulfan, ATG, then allo HSCT

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Regimen

Study	Evidence
Slavin et al. 1998	Phase II
Schetelig et al. 2003	Phase II

Chemotherapy

• Fludarabine (Fludara) 30 mg/m² IV once per day on days -10 to -5 (6 consecutive days)
• Busulfan (Myleran) 4 mg/kg/day PO on days -6 to -5 (2 consecutive days)

Immunosuppressive therapy

• ATG-Fresenius 10 mg/kg/day IV once per day on days -4 to -1 (4 consecutive days)

Immunotherapy

• Allogeneic stem cells

Stem cells transfused on day 0

References

1. Slavin S, Nagler A, Naparstek E, Kapelushnik Y, Aker M, Cividalli G, Varadi G, Kirschbaum M, Ackerstein A, Samuel S, Amar A, Brautbar C, Ben-Tal O, Eldor A, Or R. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood. 1998 Feb 1;91(3):756-63. link to original article contains verified protocol PubMed
2. Schetelig J, Thiede C, Bornhauser M, Schwerdtfeger R, Kiehl M, Beyer J, Sayer HG, Kroger N, Hensel M, Scheffold C, Held TK, Hoffken K, Ho AD, Kienast J, Neubauer A, Zander AR, Fauser AA, Ehninger G, Siegert W; Cooperative German Transplant Study Group. Evidence of a graft-versus-leukemia effect in chronic lymphocytic leukemia after reduced-intensity conditioning and allogeneic stem-cell transplantation: the Cooperative German Transplant Study Group. J Clin Oncol. 2003 Jul 15;21(14):2747-53. link to original article contains reference to protocol PubMed

Fludarabine, Cyclophosphamide, ATG, then allo HSCT

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Regimen

Study	Evidence
Dreger et al. 2010 (GCLLSG CLL3X)	Phase II

Chemotherapy

• Fludarabine (Fludara) 30 mg/m² IV once per day on days -6 to -2 (5 consecutive days)
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once per day on days -6 to -2 (5 consecutive days)

Immunosuppressive therapy

• ATG-Fresenius 10 mg/kg/day IV on days -4 to -1 (4 consecutive days)

Immunotherapy

• Allogeneic stem cells

Stem cells transfused on day 0

References

1. GCLLSG CLL3X: Dreger P, Döhner H, Ritgen M, Böttcher S, Busch R, Dietrich S, Bunjes D, Cohen S, Schubert J, Hegenbart U, Beelen D, Zeis M, Stadler M, Hasenkamp J, Uharek L, Scheid C, Humpe A, Zenz T, Winkler D, Hallek M, Kneba M, Schmitz N, Stilgenbauer S; German CLL Study Group. Allogeneic stem cell transplantation provides durable disease control in poor-risk chronic lymphocytic leukemia: long-term clinical and MRD results of the German CLL Study Group CLL3X trial. Blood. 2010 Oct 7;116(14):2438-47. Epub 2010 Jul 1. link to original article contains verified protocol PubMed
   1. Update: Dreger P, Schnaiter A, Zenz T, Böttcher S, Rossi M, Paschka P, Bühler A, Dietrich S, Busch R, Ritgen M, Bunjes D, Zeis M, Stadler M, Uharek L, Scheid C, Hegenbart U, Hallek M, Kneba M, Schmitz N, Döhner H, Stilgenbauer S. TP53, SF3B1, and NOTCH1 mutations and outcome of allotransplantation for chronic lymphocytic leukemia: six-year follow-up of the GCLLSG CLL3X trial. Blood. 2013 Apr 18;121(16):3284-8. Epub 2013 Feb 22. link to original article PubMed
   2. Update: Krämer I, Stilgenbauer S, Dietrich S, Böttcher S, Zeis M, Stadler M, Bittenbring J, Uharek L, Scheid C, Hegenbart U, Ho A, Hallek M, Kneba M, Schmitz N, Döhner H, Dreger P. Allogeneic hematopoietic cell transplantation for high-risk CLL: 10-year follow-up of the GCLLSG CLL3X trial. Blood. 2017 Sep 21;130(12):1477-1480. Epub 2017 Jul 17. link to original article PubMed

Observation

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Greil et al. 2016 (AGMT CLL-8a)	2010-2013	Phase III (C)	Rituximab	Inferior PFS
van Oers et al. 2015 (PROLONG)	2010-2014	Phase III (C)	Ofatumumab	Inferior PFS

No further treatment offered to patients in their second or third CR or PR; prior treatment was not specified in PROLONG.

Preceding treatment

• AGMT CLL-8a: Rituximab-containing chemoimmunotherapy

References

1. PROLONG: van Oers MH, Kuliczkowski K, Smolej L, Petrini M, Offner F, Grosicki S, Levin MD, Gupta I, Phillips J, Williams V, Manson S, Lisby S, Geisler C; PROLONG study investigators. Ofatumumab maintenance versus observation in relapsed chronic lymphocytic leukaemia (PROLONG): an open-label, multicentre, randomised phase 3 study. Lancet Oncol. 2015 Oct;16(13):1370-9. Epub 2015 Sep 13. link to original article contains verified protocol PubMed
   1. Update: van Oers M, Smolej L, Petrini M, Offner F, Grosicki S, Levin MD, Davis J, Banerjee H, Stefanelli T, Hoever P, Geisler C. Ofatumumab maintenance prolongs progression-free survival in relapsed chronic lymphocytic leukemia: final analysis of the PROLONG study. Blood Cancer J. 2019 Dec 4;9(12):98. link to original article link to PMC article PubMed.
2. AGMT CLL-8a: Greil R, Obrtlíková P, Smolej L, Kozák T, Steurer M, Andel J, Burgstaller S, Mikušková E, Gercheva L, Nösslinger T, Papajík T, Ladická M, Girschikofsky M, Hrubiško M, Jäger U, Fridrik M, Pecherstorfer M, Králiková E, Burcoveanu C, Spasov E, Petzer A, Mihaylov G, Raynov J, Oexle H, Zabernigg A, Flochová E, Palášthy S, Stehlíková O, Doubek M, Altenhofer P, Pleyer L, Melchardt T, Klingler A, Mayer J, Egle A. Rituximab maintenance versus observation alone in patients with chronic lymphocytic leukaemia who respond to first-line or second-line rituximab-containing chemoimmunotherapy: final results of the AGMT CLL-8a Mabtenance randomised trial. Lancet Haematol. 2016 Jul;3(7):e317-29. Epub 2016 Jun 16. link to original article contains protocol PubMed NCT01118234

Ofatumumab monotherapy

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Regimen variant #1

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
van Oers et al. 2015 (PROLONG)	2010-2014	Phase III (E-RT-esc)	Observation	Superior PFS

Treatment offered to patients in their second or third CR or PR; prior treatment was not specified.

Chemotherapy

• 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 medications

• Acetaminophen (Tylenol) 1000 mg PO once per infusion, 30 to 120 minutes prior to Ofatumumab (Arzerra)
• Diphenhydramine (Benadryl) (or equivalent antihistamine) 50 mg IV or PO once per infusion, 30 to 120 minutes prior to Ofatumumab (Arzerra)
• Prednisolone (Millipred) (or equivalent glucocorticoid) 50 mg IV once per infusion, 30 to 120 minutes prior to Ofatumumab (Arzerra)

8-week cycle for up to 13 cycles (2 years)

Regimen variant #2

Study	Evidence
Österborg et al. 2015 (GEN416)	Phase II

Preceding treatment

• Ofatumumab x 8

Chemotherapy

• Ofatumumab (Arzerra) 2000 mg IV once on day 1

Supportive medications

• Acetaminophen (Tylenol) 1000 mg PO once on day 1, prior to Ofatumumab (Arzerra)
• Cetirizine (Zyrtec) (or equivalent antihistamine) 10 mg PO once on day 1, prior to Ofatumumab (Arzerra)

Monthly cycle for up to 24 cycles (2 years)

References

1. GEN416: Österborg A, Wierda WG, Mayer J, Hess G, Hillmen P, Schetelig J, Schuh A, Smolej L, Beck C, Dreyfus B, Hellman A, Kozlowski P, Pfreundschuh M, Rizzi R, Spacek M, Phillips JL, Gupta IV, Williams V, Jewell RC, Nebot N, Lisby S, Dyer MJ. Ofatumumab retreatment and maintenance in fludarabine-refractory chronic lymphocytic leukaemia patients. Br J Haematol. 2015 Jul;170(1):40-9. Epub 2015 Mar 30. link to original article contains verified protocol PubMed
2. PROLONG: van Oers MH, Kuliczkowski K, Smolej L, Petrini M, Offner F, Grosicki S, Levin MD, Gupta I, Phillips J, Williams V, Manson S, Lisby S, Geisler C; PROLONG study investigators. Ofatumumab maintenance versus observation in relapsed chronic lymphocytic leukaemia (PROLONG): an open-label, multicentre, randomised phase 3 study. Lancet Oncol. 2015 Oct;16(13):1370-9. Epub 2015 Sep 13. link to original article contains verified protocol PubMed

Placebo

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Regimen

Study	Evidence	Comparator	Comparative Efficacy
Chanan-Khan et al. 2017 (CONTINUUM)	Phase III (C)	Lenalidomide	Did not meet primary endpoint of OS

No active antineoplastic treatment offered to patients with at least partial response to second-line therapy.

References

1. CONTINUUM: Chanan-Khan AA, Zaritskey A, Egyed M, Vokurka S, Semochkin S, Schuh A, Kassis J, Simpson D, Zhang J, Purse B, Foà R. Lenalidomide maintenance therapy in previously treated chronic lymphocytic leukaemia (CONTINUUM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Haematol. 2017 Nov;4(11):e534-e543. Epub 2017 Sep 25. link to original article PubMed

Rituximab monotherapy

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Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Greil et al. 2016 (AGMT CLL-8a)	2010-2013	Phase III (E-esc)	Observation	Superior PFS

Preceding treatment

• "Rituximab-containing chemoimmunotherapy"

Chemotherapy

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

3-month cycle for 8 cycles (2 years)

References

1. AGMT CLL-8a: Greil R, Obrtlíková P, Smolej L, Kozák T, Steurer M, Andel J, Burgstaller S, Mikušková E, Gercheva L, Nösslinger T, Papajík T, Ladická M, Girschikofsky M, Hrubiško M, Jäger U, Fridrik M, Pecherstorfer M, Králiková E, Burcoveanu C, Spasov E, Petzer A, Mihaylov G, Raynov J, Oexle H, Zabernigg A, Flochová E, Palášthy S, Stehlíková O, Doubek M, Altenhofer P, Pleyer L, Melchardt T, Klingler A, Mayer J, Egle A. Rituximab maintenance versus observation alone in patients with chronic lymphocytic leukaemia who respond to first-line or second-line rituximab-containing chemoimmunotherapy: final results of the AGMT CLL-8a Mabtenance randomised trial. Lancet Haematol. 2016 Jul;3(7):e317-29. Epub 2016 Jun 16. link to original article contains protocol PubMed NCT01118234

Prognosis

These are various staging and risk prediction systems that are in approximate chronological order.

Original Rai staging (1975)

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• Stage 0: bone marrow and blood lymphocytosis only
• Stage I: lymphocytosis with enlarged nodes
• Stage II: lymphocytosis with enlarged spleen or liver or both
• Stage III: lymphocytosis with anemia
• Stage IV: lymphocytosis with thrombocytopenia

1. Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. Clinical staging of chronic lymphocytic leukemia. Blood. 1975 Aug;46(2):219-34. link to original article PubMed

Binet staging (1981)

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• Group A: no anemia, no thrombocytopenia, less than three involved areas
• Group B: no anemia, no thrombocytopenia, three or more involved areas (counting as one each of the following: axillary, cervical, inguinal, lymph nodes, whether unilateral or bilateral, spleen and liver)
• Group C: anemia (hemoglobin less than 10 g/dL) and/or thrombocytopenia (platelets less than 100 x 10⁹/L)

1. Binet JL, Auquier A, Dighiero G, Chastang C, Piguet H, Goasguen J, Vaugier G, Potron G, Colona P, Oberling F, Thomas M, Tchernia G, Jacquillat C, Boivin P, Lesty C, Duault MT, Monconduit M, Belabbes S, Gremy F. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer. 1981 Jul 1;48(1):198-206. link to original article PubMed

Risk by cytogenetics

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• Classic NEJM paper establishing abnormal karyotype as an adverse prognostic marker

1. Han T, Ozer H, Sadamori N, Emrich L, Gomez GA, Henderson ES, Bloom ML, Sandberg AA. Prognostic importance of cytogenetic abnormalities in patients with chronic lymphocytic leukemia. N Engl J Med. 1984 Feb 2;310(5):288-92. to original article PubMed

• Large retrospective series looking at cytogenetic complexity

1. Baliakas P, Jeromin S, Iskas M, Puiggros A, Plevova K, Nguyen-Khac F, Davis Z, Rigolin GM, Visentin A, Xochelli A, Delgado J, Baran-Marszak F, Stalika E, Abrisqueta P, Durechova K, Papaioannou G, Eclache V, Dimou M, Iliakis T, Collado R, Doubek M, Calasanz MJ, Ruiz-Xiville N, Moreno C, Jarosova M, Leeksma AC, Panayiotidis P, Podgornik H, Cymbalista F, Anagnostopoulos A, Trentin L, Stavroyianni N, Davi F, Ghia P, Kater AP, Cuneo A, Pospisilova S, Espinet B, Athanasiadou A, Oscier D, Haferlach C, Stamatopoulos K; ERIC, the European Research Initiative on CLL. Cytogenetic complexity in chronic lymphocytic leukemia: definitions, associations, and clinical impact. Blood. 2019 Mar 14;133(11):1205-1216. Epub 2019 Jan 2. link to original article PubMed

Risk by lymphocyte doubling time

1. Montserrat E, Sanchez-Bisono J, Viñolas N, Rozman C. Lymphocyte doubling time in chronic lymphocytic leukaemia: analysis of its prognostic significance. Br J Haematol. 1986 Mar;62(3):567-75. link to original article PubMed
2. Molica S, Alberti A. Prognostic value of the lymphocyte doubling time in chronic lymphocytic leukemia. Cancer. 1987 Dec 1;60(11):2712-6. link to original article PubMed

Risk by FISH

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• Classic 2000 NEJM paper establishing that 17p deletion has the worst prognosis:

1. Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L, Döhner K, Bentz M, Lichter P. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000 Dec 28;343(26):1910-6. link to original article PubMed

• This article and abstract explore the significance of 13q deletions in more detail:

1. Van Dyke DL, Shanafelt TD, Call TG, Zent CS, Smoley SA, Rabe KG, Schwager SM, Sonbert JC, Slager SL, Kay NE. A comprehensive evaluation of the prognostic significance of 13q deletions in patients with B-chronic lymphocytic leukaemia. Br J Haematol. 2010 Feb;148(4):544-50. Epub 2009 Nov 6. link to original article link to PMC article PubMed
2. Abstract: Claudia Haferlach, Melanie Zenger, Vera Grossmann, Frank Dicker, Sabine Jeromin, Alexander Kohlmann, Susanne Schnittger, Wolfgang Kern, Torsten Haferlach. The Impact of Homozygosity and Size of the 13q Deletion in Patients with CLL. Blood 2012 120:3892 abstract 3892 link to abstract

Risk by TP53 mutation

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1. Zenz T, Eichhorst B, Busch R, Denzel T, Häbe S, Winkler D, Bühler A, Edelmann J, Bergmann M, Hopfinger G, Hensel M, Hallek M, Döhner H, Stilgenbauer S. TP53 mutation and survival in chronic lymphocytic leukemia. J Clin Oncol. 2010 Oct 10;28(29):4473-9. Epub 2010 Aug 9. link to original article PubMed

Risk by CD38 expression

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1. Damle RN, Wasil T, Fais F, Ghiotto F, Valetto A, Allen SL, Buchbinder A, Budman D, Dittmar K, Kolitz J, Lichtman SM, Schulman P, Vinciguerra VP, Rai KR, Ferrarini M, Chiorazzi N. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood. 1999 Sep 15;94(6):1840-7. link to original article PubMed
2. Review: Malavasi F, Deaglio S, Damle R, Cutrona G, Ferrarini M, Chiorazzi N. CD38 and chronic lymphocytic leukemia: a decade later. Blood. 2011 Sep 29;118(13):3470-8. link to original article link to PMC article PubMed

Risk by ZAP-70 expression (2003)

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1. Crespo M, Bosch F, Villamor N, Bellosillo B, Colomer D, Rozman M, Marcé S, López-Guillermo A, Campo E, Montserrat E. ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med. 2003 May 1;348(18):1764-75. link to original article PubMed

Prognostic scoring system using molecular and cytogenetic features (2012)

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1. Rossi D, Rasi S, Spina V, Bruscaggin A, Monti S, Ciardullo C, Deambrogi C, Khiabanian H, Serra R, Bertoni F, Forconi F, Laurenti L, Marasca R, Dal-Bo M, Rossi FM, Bulian P, Nomdedeu J, Del Poeta G, Gattei V, Pasqualucci L, Rabadan R, Foà R, Dalla-Favera R, Gaidano G. Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia. Blood. 2013 Feb 21;121(8):1403-12. Epub 2012 Dec 13. link to original article link to PMC article PubMed

CLL-IPI (2016)

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• QxMD calculator

1. International CLL-IPI working group. An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncol. 2016 Jun;17(6):779-90. Epub 2016 May 13. link to original article PubMed

Investigational agents

• Otlertuzumab (TRU-016)