Indolent lymphoma

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Section editor
Sanjai Sharma, MD
Sequoia Regional Cancer Center
Visalia, CA, USA
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Are you looking for a regimen but can't find it here? It is possible that we've moved it to the historical regimens page. For placebo or observational studies in this condition, other than watchful waiting, please visit this page. If you still can't find it, please let us know so we can add it!
The purpose of this page is to gather regimens that have been studied generically in the indolent lymphomas, as opposed to a specific subtype (e.g., follicular lymphoma). For subtype-specific regimens, please visit:

Last updated on 2024-12-02:
51 regimens on this page
72 variants on this page


Guidelines

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

NCCN


Early disease, definitive therapy

Ibritumomab tiuxetan protocol

Regimen

Study Dates of enrollment Evidence
Samaniego et al. 2014 (MDACC 2005-0512) 2006-2009 Phase 2

Targeted therapy

Radioconjugate therapy

  • Ibritumomab tiuxetan & Yttrium-90 (Zevalin) given second, by the following laboratory-based criteria:
    • Platelet count more than 150 x 109/L: 14.8 MBq/kg (maximum dose of 1184 MBq) IV once on day 8
    • Platelet count 100 to 149 x 109/L: 11.1 MBq/kg (maximum dose of 1184 MBq) IV once on day 8

One course

References

  1. MDACC 2005-0512: Samaniego F, Berkova Z, Romaguera JE, Fowler N, Fanale MA, Pro B, Shah JJ, McLaughlin P, Sehgal L, Selvaraj V, Braun FK, Mathur R, Feng L, Neelapu SS, Kwak LW. 90Y-ibritumomab tiuxetan radiotherapy as first-line therapy for early stage low-grade B-cell lymphomas, including bulky disease. Br J Haematol. 2014 Oct;167(2):207-13. Epub 2014 Jul 8. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00493467


Radiation therapy

RT: Radiation Therapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kelsey et al. 1994 1974-1981 Non-randomized part of RCT
Yahalom et al. 1993 1980-1988 Non-randomized part of RCT
Lowry et al. 2011 1997-2005 Phase 3 (E-de-esc) RT x 4000 to 4500 cGy Did not meet primary endpoint of ORR
Hoskin et al. 2014 (FORT) 2006-2011 Phase 3 (C) RT x 400 cGy Superior TTP

This is the current "standard dose" radiotherapy - dose varies per protocol and location radiated.

Radiotherapy

Subsequent treatment

References

  1. Yahalom J, Varsos G, Fuks Z, Myers J, Clarkson BD, Straus DJ. Adjuvant cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy after radiation therapy in stage I low-grade and intermediate-grade non-Hodgkin lymphoma: results of a prospective randomized study. Cancer. 1993 Apr 1;71(7):2342-50. link to original article PubMed
  2. Kelsey SM, Newland AC, Hudson GV, Jelliffe AM. A British National Lymphoma Investigation randomised trial of single agent chlorambucil plus radiotherapy versus radiotherapy alone in low grade, localised non-Hodgkins lymphoma. Med Oncol. 1994;11(1):19-25. link to original article PubMed
  3. Lowry L, Smith P, Qian W, Falk S, Benstead K, Illidge T, Linch D, Robinson M, Jack A, Hoskin P. Reduced dose radiotherapy for local control in non-Hodgkin lymphoma: a randomised phase III trial. Radiother Oncol. 2011 Jul;100(1):86-92. Epub 2011 Jun 12. link to original article PubMed
  4. FORT: Hoskin PJ, Kirkwood AA, Popova B, Smith P, Robinson M, Gallop-Evans E, Coltart S, Illidge T, Madhavan K, Brammer C, Diez P, Jack A, Syndikus I. 4 Gy versus 24 Gy radiotherapy for patients with indolent lymphoma (FORT): a randomised phase 3 non-inferiority trial. Lancet Oncol. 2014 Apr;15(4):457-63. Epub 2014 Feb 24. link to original article PubMed NCT00310167


Advanced disease, first-line therapy

Bendamustine & Ofatumumab

Regimen

Study Dates of enrollment Evidence
Czuczman et al. 2015 (C18083-2048) 2010-05 to 2011-10 Phase 2

Chemotherapy

Targeted therapy

  • Ofatumumab (Arzerra) as follows:
    • Cycle 1: 300 mg IV once on day 1, then 1000 mg IV once on day 8
    • Cycles 2 to 6: 1000 mg IV once on day 1

28-day cycle for 6 cycles

References

  1. C18083-2048: Czuczman MS, Kahanic S, Forero A, Davis G, Munteanu M, Van Den Neste E, Offner F, Bron D, Quick D, Fowler N. Results of a phase II study of bendamustine and ofatumumab in untreated indolent B cell non-Hodgkin's lymphoma. Ann Hematol. 2015 Apr;94(4):633-41. Epub 2015 Jan 30. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT01108341


Bendamustine & Rituximab (BR)

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

Regimen variant #1, 6 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rummel et al. 2013 (StiL NHL1) 2003-2008 Phase 3 (E-de-esc) R-CHOP Superior PFS (primary endpoint)
Median PFS: 69.5 vs 31.2 mo
(HR 0.58, 95% CI 0.44-0.74)

Chemotherapy

Targeted therapy

Supportive therapy

  • Antiemetics, antipyretics, and antibiotics according to local standard of care
  • Prophylactic use of G-CSF allowed according ASCO guidelines (2006)

28-day cycle for up to 6 cycles


Regimen variant #2, 6 cycles with rituximab extension

Study Evidence
Awaiting publication (MAINTAIN) Non-randomized part of phase 3 RCT

Chemotherapy

  • Bendamustine as follows:
    • Cycles 1 to 6: 90 mg/m2 IV once per day on days 1 & 2

Targeted therapy

28-day cycle for 8 cycles

Subsequent treatment


Regimen variant #3, 8 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Flinn et al. 2014 (BRIGHT) 2009-2012 Phase 3 (E-de-esc) 1a. R-CHOP
1b. R-CVP 		Superior PFS1 (secondary endpoint)
Median PFS: NYR vs NYR
(HR 0.61, 95% CI 0.45-0.85)

1Reported efficacy in BRIGHT is based on the 2019 update.
Patients in BRIGHT were required to be treatment-naive with a need for treatment per any of the following: B symptoms, large tumor mass (lymphomas with a diameter greater than 3 cm in 3 or more regions or diameter greater than 7 cm in 1 region), presence of lymphoma-related complications, or hyperviscosity syndrome attributed to monoclonal gammopathy.

Chemotherapy

Targeted therapy

Supportive therapy

  • Antiemetics, antipyretics, and antibiotics according to local standard of care
  • Prophylactic use of G-CSF allowed according ASCO guidelines (2006)

28-day cycle for up to 8 cycles

References

  1. StiL NHL1: Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grünhagen U, Losem C, Kofahl-Krause D, Heil G, Welslau M, Balser C, Kaiser U, Weidmann E, Dürk H, Ballo H, Stauch M, Roller F, Barth J, Hoelzer D, Hinke A, Brugger W; StiL. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013 Apr 6;381(9873):1203-10. Epub 2013 Feb 20. Erratum in: Lancet. 2013 Apr 6;381(9873):1184. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00991211
    1. Update: Abstract: Mathias J. Rummel, MD, Georg Maschmeyer, MD, Arnold Ganser, Andrea Heider, PhD, Ulrich von Grünhagen, MD, PhD5, Christoph Losem, Gerhard Heil, MD, Manfred Welslau, Christina Balser, MD, Ulrich Kaiser, MD, Eckhart Weidmann, Heinz Dürk, MD, Hans Peter Böck, Martina Beate Stauch, MD, Jürgen Barth, Wolfgang Blau, MD, Alexander Burchardt, MD, Frank Kauff, PhD, Axel Hinke, PhD and Wolfram Brugger, MD. Bendamustine Plus Rituximab (B-R) Versus CHOP Plus Rituximab (CHOP-R) As First-Line Treatment in Patients with Indolent and Mantle Cell Lymphomas (MCL) – 7 Year Updated Results from the StiL NHL1 Study. Blood 2014 124:4407. link to abstract
    2. Update: Abstract: Mathias J. Rummel, Georg Maschmeyer, Arnold Ganser, Andrea Heider, Ulrich von Gruenhagen, Christoph Losem, Gerhard Heil, Manfred Welslau, Christina Balser, Ulrich Kaiser, Eckhart Weidmann, Heinz Albert Dürk, Harald Ballo, Martina Stauch, Wolfgang Blau, Alexander Burchardt, Juergen Barth, Frank Kauff, and Wolfram Brugger. Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent lymphomas: Nine-year updated results from the StiL NHL1 study. Journal of Clinical Oncology 2017 35:15_suppl, 7501-7501 link to abstract
  2. BRIGHT: Flinn IW, van der Jagt R, Kahl BS, Wood P, Hawkins TE, Macdonald D, Hertzberg M, Kwan YL, Simpson D, Craig M, Kolibaba K, Issa S, Clementi R, Hallman DM, Munteanu M, Chen L, Burke JM. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood. 2014 May 8;123(19):2944-52. Epub 2014 Mar 3. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00877006
    1. Update: Flinn IW, van der Jagt R, Kahl B, Wood P, Hawkins T, MacDonald D, Simpson D, Kolibaba K, Issa S, Chang J, Trotman J, Hallman D, Chen L, Burke JM. First-line treatment of patients with indolent non-Hodgkin lymphoma or mantle-cell lymphoma with bendamustine plus rituximab versus R-CHOP or R-CVP: results of the BRIGHT 5-year follow-up study. J Clin Oncol. 2019 Apr 20;37(12):984-991. Epub 2019 Feb 27. link to original article link to PMC article PubMed
  3. MAINTAIN: link to abstract NCT00877214


Bortezomib & Rituximab (VR)

VR: Velcade (Bortezomib) & Rituximab

Regimen

Study Dates of enrollment Evidence
Evens et al. 2014 (NU 06H1) Not reported Phase 2

Targeted therapy

  • Bortezomib (Velcade) 1.6 mg/m2 IV once per day on days 1, 8, 15, 22
  • Rituximab (Rituxan) as follows:
    • Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15, 22
    • Cycles 2 & 3: 375 mg/m2 IV once on day 1

35-day cycle for 3 cycles

Subsequent treatment

  • VR consolidation

References

  1. NU 06H1: Evens AM, Smith MR, Lossos IS, Helenowski I, Millenson M, Winter JN, Rosen ST, Gordon LI. Frontline bortezomib and rituximab for the treatment of newly diagnosed high tumour burden indolent non-hodgkin lymphoma: a multicentre phase II study. Br J Haematol. 2014 Aug;166(4):514-20. Epub 2014 Apr 25. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00369707


Chlorambucil monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ardeshna et al. 2003 1981-1990 Phase 3 (C) Watchful waiting Did not meet primary endpoint of OS

Note: This is the comparator arm to the "watch and wait" strategy, and is not commonly used.

Chemotherapy

Continued indefinitely

References

  1. Ardeshna KM, Smith P, Norton A, Hancock BW, Hoskin PJ, MacLennan KA, Marcus RE, Jelliffe A, Vaughan G, Hudson GV, Linch DC; British National Lymphoma Investigation. Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial. Lancet. 2003 Aug 16;362(9383):516-22. link to original article dosing details in manuscript have been reviewed by our editors PubMed


Fludarabine & Rituximab (FR)

FR: Fludarabine & Rituximab

Regimen

Study Dates of enrollment Evidence Efficacy
Czuczman et al. 2005 1998-05 to 2000-11 Phase 2 ORR: 90%

Chemotherapy

Targeted therapy

  • Rituximab (Rituxan) as follows:
    • Weeks 1 & 26: 375 mg/m2 IV once per day on days 1 & 4
    • Weeks 6, 14, 22: 375 mg/m2 IV once 72 hours before day 1

26-week course

References

  1. Czuczman MS, Koryzna A, Mohr A, Stewart C, Donohue K, Blumenson L, Bernstein ZP, McCarthy P, Alam A, Hernandez-Ilizaliturri F, Skipper M, Brown K, Chanan-Khan A, Klippenstein D, Loud P, Rock MK, Benyunes M, Grillo-Lopez A, Bernstein SH. Rituximab in combination with fludarabine chemotherapy in low-grade or follicular lymphoma. J Clin Oncol. 2005 Feb 1;23(4):694-704. link to original article dosing details in manuscript have been reviewed by our editors PubMed


Lenalidomide & Rituximab (R2)

Regimen

Study Dates of enrollment Evidence
Fowler et al. 2014 (MDACC 2008-0042) 2008-06 to 2011-08 Phase 2

Targeted therapy

28-day cycle for up to 8 to 12 cycles

References

  1. MDACC 2008-0042: Fowler NH, Davis RE, Rawal S, Nastoupil L, Hagemeister FB, McLaughlin P, Kwak LW, Romaguera JE, Fanale MA, Fayad LE, Westin JR, Shah J, Orlowski RZ, Wang M, Turturro F, Oki Y, Claret LC, Feng L, Baladandayuthapani V, Muzzafar T, Tsai KY, Samaniego F, Neelapu SS. Safety and activity of lenalidomide and rituximab in untreated indolent lymphoma: an open-label, phase 2 trial. Lancet Oncol. 2014 Nov;15(12):1311-8. Epub 2014 Oct 15. link to original article dosing details in abstract have been reviewed by our editors link to PMC article PubMed NCT00695786


PCR

PCR: Pentostatin, Cyclophosphamide, Rituximab

Regimen

Study Dates of enrollment Evidence
Samaniego et al. 2015 (MDACC 2004-0818) Not reported Phase 2

Chemotherapy

Targeted therapy

Supportive therapy

21-day cycle for 6 cycles

References

  1. MDACC 2004-0818: Samaniego F, Hagemeister F, Romaguera JE, Fanale MA, Pro B, McLaughlin P, Rodriguez MA, Neelapu SS, Fayad L, Younes A, Feng L, Berkova Z, Khashab T, Sehgal L, Vega-Vasquez F, Kwak LW. Pentostatin, cyclophosphamide and rituximab for previously untreated advanced stage, low-grade B-cell lymphomas. Br J Haematol. 2015 Jun;169(6):814-23. Epub 2015 Mar 31. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00496873
    1. Update: Khashab T, Hagemeister F, Romaguera JE, Fanale MA, Pro B, McLaughlin P, Rodriguez MA, Neelapu SS, Fayad L, Younes A, Feng L, Vega F, Kwak LW, Samaniego F. Long-term overall- and progression-free survival after pentostatin, cyclophosphamide and rituximab therapy for indolent non-Hodgkin lymphoma. Br J Haematol. 2019 May;185(4):670-678. Epub 2019 Feb 28. link to original article PubMed


Rituximab monotherapy

Regimen variant #1, 4 doses

Study Dates of enrollment Evidence
Hainsworth et al. 2000 1998-1999 Phase 2
Hainsworth et al. 2002 1998-1999 Phase 2
Williams et al. 2016 (RESORT substudy) 2003-2008 Non-randomized part of phase 3 RCT

Targeted therapy

Supportive therapy

4-week course

Subsequent treatment

  • Hainsworth et al. 2002, SD or better: Rituximab maintenance
  • RESORT substudy, patients with PR/CR: Rituximab maintenance versus salvage rituximab at time of progression

Regimen variant #2, 8 doses

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kimby et al. 2015 (NLG ML16865) 2002-2008 Phase 3 (C) Rituximab & IFN-α2a Did not meet primary endpoint of TTF
Median TTF: 28 vs 21.5 mo

Note: only patients achieving some degree of measurable response in NLG ML16865 proceeded to the 2nd course of rituximab.

Targeted therapy

12-week cycle for 2 cycles

References

  1. Hainsworth JD, Burris HA 3rd, Morrissey LH, Litchy S, Scullin DC Jr, Bearden JD 3rd, Richards P, Greco FA. Rituximab monoclonal antibody as initial systemic therapy for patients with low-grade non-Hodgkin lymphoma. Blood. 2000 May 15;95(10):3052-6. link to original article PubMed
  2. Hainsworth JD, Litchy S, Burris HA 3rd, Scullin DC Jr, Corso SW, Yardley DA, Morrissey L, Greco FA. Rituximab as first-line and maintenance therapy for patients with indolent non-hodgkin's lymphoma. J Clin Oncol. 2002 Oct 15;20(20):4261-7. link to original article dosing details in manuscript have been reviewed by our editors PubMed
  3. NLG ML16865: Kimby E, Östenstad B, Brown P, Hagberg H, Erlanson M, Holte H, Linden O, Johansson AS, Ahlgren T, Wader K, Wahlin BE, Delabie J, Sundström C; Nordic Lymphoma Group. Two courses of four weekly infusions of rituximab with or without interferon-α2a: final results from a randomized phase III study in symptomatic indolent B-cell lymphomas. Leuk Lymphoma. 2015;56(9):2598-607. Epub 2015 Mar 11. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01609010
    1. Pooled update: Lockmer S, Østenstad B, Hagberg H, Holte H, Johansson AS, Wahlin BE, Wader KF, Steen CB, Meyer P, Maisenhølder M, Smedby KE, Brown P, Kimby E. Chemotherapy-free initial treatment of advanced indolent lymphoma has durable effect with low toxicity: results from two Nordic Lymphoma Group trials with more than 10 years of follow-up. J Clin Oncol. 2018 Nov 20;36(33):3315-23. Epub 2018 Oct 4. link to original article PubMed
  4. RESORT substudy: Williams ME, Hong F, Gascoyne RD, Wagner LI, Krauss JC, Habermann TM, Swinnen LJ, Schuster SJ, Peterson CG, Sborov MD, Martin SE, Weiss M, Ehmann WC, Horning SJ, Kahl BS; Eastern Cooperative Oncology Group. Rituximab extended schedule or retreatment trial for low tumour burden non-follicular indolent B-cell non-Hodgkin lymphomas: Eastern Cooperative Oncology Group Protocol E4402. Br J Haematol. 2016 Jun;173(6):867-75. Epub 2016 Mar 11. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01406782


R-CHOP

R-CHOP: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone

Regimen variant #1, prednisone 100 mg, 6 to 8 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Flinn et al. 2014 (BRIGHT) 2009-2012 Phase 3 (C) BR Seems to have non-inferior CR rate

Note: Patients in BRIGHT were required to be treatment-naive with a need for treatment per any of the following: B symptoms, large tumor mass (lymphomas with a diameter greater than 3 cm in 3 or more regions or diameter greater than 7 cm in 1 region), presence of lymphoma-related complications, or hyperviscosity syndrome attributed to monoclonal gammopathy.

Targeted therapy

Chemotherapy

Glucocorticoid therapy

Supportive therapy

21-day cycle for 6 to 8 cycles


Regimen variant #2, variant rituximab schedule

Study Dates of enrollment Evidence
Czuczman et al. 1999 Not reported Phase 2

Targeted therapy

  • Rituximab (Rituxan) as follows:
    • Cycle 1: 375 mg/m2 IV once per day on days -7 & -2
    • Cycles 3 & 5: 375 mg/m2 IV once on day -2
    • Cycle 6*: 375 mg/m2 IV once per day 8 days and 15 days after completion of cycle 6 (i.e., what would be cycle 7 days 8 & 15)

Chemotherapy

Glucocorticoid therapy

21-day cycle for 6 cycles


Regimen variant #3, 4 doses of rituximab

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Watanabe et al. 2011 (JCOG 0203) 2002-2007 Phase 3 (C) R-CHOP-14 Did not meet primary endpoint of PFS
Median PFS: 3.7 vs 4.7 y
(HR 1.08, 95% CI 0.80-1.47)

This regimen was intended for patients with previously untreated stage III to IV indolent B-cell NHL, including FL grade 3B.

Targeted therapy

Chemotherapy

Glucocorticoid therapy

Supportive therapy

21-day cycle for 6 cycles

References

  1. Czuczman MS, Grillo-López AJ, White CA, Saleh M, Gordon L, LoBuglio AF, Jonas C, Klippenstein D, Dallaire B, Varns C. Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol. 1999 Jan;17(1):268-76. link to original article dosing details in manuscript have been reviewed by our editors PubMed
    1. Update: Czuczman MS, Weaver R, Alkuzweny B, Berlfein J, Grillo-López AJ. Prolonged clinical and molecular remission in patients with low-grade or follicular non-Hodgkin's lymphoma treated with rituximab plus CHOP chemotherapy: 9-year follow-up. J Clin Oncol. 2004 Dec 1;22(23):4711 to 6. Epub 2004 Oct 13. link to original article PubMed
  2. JCOG 0203: Watanabe T, Tobinai K, Shibata T, Tsukasaki K, Morishima Y, Maseki N, Kinoshita T, Suzuki T, Yamaguchi M, Ando K, Ogura M, Taniwaki M, Uike N, Takeuchi K, Nawano S, Terauchi T, Hotta T. Phase II/III study of R-CHOP-21 versus R-CHOP-14 for untreated indolent B-cell non-Hodgkin's lymphoma: JCOG 0203 trial. J Clin Oncol. 2011 Oct 20;29(30):3990-8. Epub 2011 Sep 19. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00147121
    1. Subgroup analysis: Watanabe T, Tobinai K, Wakabayashi M, Morishima Y, Kobayashi H, Kinoshita T, Suzuki T, Yamaguchi M, Ando K, Ogura M, Taniwaki M, Uike N, Yoshino T, Nawano S, Terauchi T, Hotta T, Nagai H, Tsukasaki K; JCOG0203 Collaborators. Outcomes after R-CHOP in patients with newly diagnosed advanced follicular lymphoma: a 10-year follow-up analysis of the JCOG0203 trial. Lancet Haematol. 2018 Nov;5(11):e520-e531. link to original article PubMed
  3. StiL NHL1: Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grünhagen U, Losem C, Kofahl-Krause D, Heil G, Welslau M, Balser C, Kaiser U, Weidmann E, Dürk H, Ballo H, Stauch M, Roller F, Barth J, Hoelzer D, Hinke A, Brugger W; StiL. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013 Apr 6;381(9873):1203-10. Epub 2013 Feb 20. Erratum in: Lancet. 2013 Apr 6;381(9873):1184. link to original article PubMed NCT00991211
    1. Update: Abstract: Mathias J. Rummel, MD, Georg Maschmeyer, MD, Arnold Ganser, Andrea Heider, PhD, Ulrich von Grünhagen, MD, PhD5, Christoph Losem, Gerhard Heil, MD, Manfred Welslau, Christina Balser, MD, Ulrich Kaiser, MD, Eckhart Weidmann, Heinz Dürk, MD, Hans Peter Böck, Martina Beate Stauch, MD, Jürgen Barth, Wolfgang Blau, MD, Alexander Burchardt, MD, Frank Kauff, PhD, Axel Hinke, PhD and Wolfram Brugger, MD. Bendamustine Plus Rituximab (B-R) Versus CHOP Plus Rituximab (CHOP-R) As First-Line Treatment in Patients with Indolent and Mantle Cell Lymphomas (MCL) – 7 Year Updated Results from the StiL NHL1 Study. Blood 2014 124:4407. link to abstract
    2. Update: Abstract: Mathias J. Rummel, Georg Maschmeyer, Arnold Ganser, Andrea Heider, Ulrich von Gruenhagen, Christoph Losem, Gerhard Heil, Manfred Welslau, Christina Balser, Ulrich Kaiser, Eckhart Weidmann, Heinz Albert Dürk, Harald Ballo, Martina Stauch, Wolfgang Blau, Alexander Burchardt, Juergen Barth, Frank Kauff, and Wolfram Brugger. Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent lymphomas: Nine-year updated results from the StiL NHL1 study. Journal of Clinical Oncology 2017 35:15_suppl, 7501-7501 link to abstract
  4. BRIGHT: Flinn IW, van der Jagt R, Kahl BS, Wood P, Hawkins TE, Macdonald D, Hertzberg M, Kwan YL, Simpson D, Craig M, Kolibaba K, Issa S, Clementi R, Hallman DM, Munteanu M, Chen L, Burke JM. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood. 2014 May 8;123(19):2944-52. Epub 2014 Mar 3. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00877006
    1. Update: Flinn IW, van der Jagt R, Kahl B, Wood P, Hawkins T, MacDonald D, Simpson D, Kolibaba K, Issa S, Chang J, Trotman J, Hallman D, Chen L, Burke JM. First-line treatment of patients with indolent non-Hodgkin lymphoma or mantle-cell lymphoma with bendamustine plus rituximab versus R-CHOP or R-CVP: results of the BRIGHT 5-year follow-up study. J Clin Oncol. 2019 Apr 20;37(12):984-991. Epub 2019 Feb 27. link to original article link to PMC article PubMed


R-CMD

R-CMD: Rituximab, Cladribine, Mitoxantrone, Dexamethasone

Regimen

Study Dates of enrollment Evidence
Sakai et al. 2015 2008-2011 Phase 2

Note: the dose of dexamethasone in the manuscript text as well as the accompanying table was listed as 8 mg/body. It is unclear to us what this means.

Targeted therapy

Chemotherapy

Glucocorticoid therapy

21-day cycle for 4 cycles

Subsequent treatment

References

  1. Sakai T, Masaki Y, Otsuki N, Sakamaki I, Kishi S, Miyazono T, Urasaki Y, Murakami J, Satoh T, Nakamura T, Iwao H, Nakajima A, Kawanami T, Miki M, Fujita Y, Tanaka M, Fukushima T, Okazaki T, Ueda T; Hokuriku Hematology Oncology Study Group. Prospective clinical study of R-CMD therapy for indolent B cell lymphoma and mantle cell lymphoma from the Hokuriku Hematology Oncology Study Group. Med Oncol. 2015 Sep;32(9):232. Epub 2015 Aug 15. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed


R-CVP

R-CVP: Rituximab, Cyclophosphamide, Vincristine, Prednisone

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Walewski et al. 2019 (PLRG4) 2007-2011 Phase 3 (C) R-CHOP Did not meet primary endpoint of EFS
Flinn et al. 2014 (BRIGHT) 2009-2012 Phase 3, <20 in this arm (C) BR Seems to have non-inferior CR rate

Note: Patients in BRIGHT were required to be treatment-naive with a need for treatment per any of the following: B symptoms, large tumor mass (lymphomas with a diameter greater than 3 cm in 3 or more regions or diameter greater than 7 cm in 1 region), presence of lymphoma-related complications, or hyperviscosity syndrome attributed to monoclonal gammopathy.

Targeted therapy

Chemotherapy

Glucocorticoid therapy

Supportive therapy

21-day cycle for up to 8 cycles

Subsequent treatment

References

  1. BRIGHT: Flinn IW, van der Jagt R, Kahl BS, Wood P, Hawkins TE, Macdonald D, Hertzberg M, Kwan YL, Simpson D, Craig M, Kolibaba K, Issa S, Clementi R, Hallman DM, Munteanu M, Chen L, Burke JM. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood. 2014 May 8;123(19):2944-52. Epub 2014 Mar 3. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00877006
  2. PLRG4: Walewski J, Paszkiewicz-Kozik E, Michalski W, Rymkiewicz G, Szpila T, Butrym A, Giza A, Zaucha JM, Kalinka-Warzocha E, Wieczorkiewicz A, Zimowska-Curyło D, Knopińska-Posłuszny W, Tyczyńska A, Romejko-Jarosińska J, Dąbrowska-Iwanicka A, Gruszecka B, Jamrozek-Jedlińska M, Borawska A, Hołda W, Porowska A, Romanowicz A, Hellmann A, Stella-Hołowiecka B, Deptała A, Jurczak W. First-line R-CVP versus R-CHOP induction immunochemotherapy for indolent lymphoma with rituximab maintenance: a multicentre, phase III randomized study by the Polish Lymphoma Research Group PLRG4. Br J Haematol. 2020 Mar;188(6):898-906. Epub 2019 Dec 2. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00801281


VR-CHOP

VR-CHOP: Velcade (Bortezomib) Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Predniso(lo)ne

Regimen

Study Dates of enrollment Evidence
Cohen et al. 2015 (X05215) Not reported Phase 2

The largest group of patients studied in this trial had follicular lymphoma. Note the decreased cap on vincristine.

Targeted therapy

Chemotherapy

Glucocorticoid therapy

21-day cycle for 6 to 8 cycles

Subsequent treatment

  • X05215, patients with CR: Rituximab maintenance
  • X05215, patients with SD/PR: VR maintenance

References

  1. X05215: Cohen JB, Switchenko JM, Koff JL, Sinha R, Kaufman JL, Khoury HJ, Bumpers N, Colbert A, Hutchison-Rzepka A, Nastoupil LJ, Heffner LT, Langston AA, Lechowicz MJ, Lonial S, Flowers CR. A phase II study of bortezomib added to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone in patients with previously untreated indolent non-Hodgkin's lymphoma. Br J Haematol. 2015 Nov;171(4):539-46. Epub 2015 Aug 7. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00634179


Watchful waiting

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Horning & Rosenberg 1984 1963-1984 Non-randomized
Young et al. 1988 Not reported in abstract Phase 3 (E-de-esc) ProMACE-MOPP, then TNI Not reported
Ardeshna et al. 2003 1981-1990 Phase 3 (E-de-esc) Chlorambucil Did not meet primary endpoint of OS

No treatment other than observation.

References

  1. Horning SJ, Rosenberg SA. The natural history of initially untreated low-grade non-Hodgkin's lymphomas. N Engl J Med. 1984 Dec 6;311(23):1471-5. link to original article PubMed
  2. Young RC, Longo DL, Glatstein E, Ihde DC, Jaffe ES, DeVita VT Jr. The treatment of indolent lymphomas: watchful waiting v aggressive combined modality treatment. Semin Hematol. 1988 Apr;25(2 Suppl 2):11-6. PubMed
  3. Ardeshna KM, Smith P, Norton A, Hancock BW, Hoskin PJ, MacLennan KA, Marcus RE, Jelliffe A, Vaughan G, Hudson GV, Linch DC; British National Lymphoma Investigation. Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial. Lancet. 2003 Aug 16;362(9383):516-22. link to original article PubMed


Consolidation after first-line therapy

Note: consolidation here is defined as any regimen with an intended length of treatment of 12 months or less.

Bortezomib & Rituximab (VR)

VR: Velcade (Bortezomib) & Rituximab

Regimen

Study Dates of enrollment Evidence
Evens et al. 2014 (NU 06H1) Not reported Phase 2

Preceding treatment

  • First-line VR

Targeted therapy

2-month cycle for 4 cycles

References

  1. NU 06H1: Evens AM, Smith MR, Lossos IS, Helenowski I, Millenson M, Winter JN, Rosen ST, Gordon LI. Frontline bortezomib and rituximab for the treatment of newly diagnosed high tumour burden indolent non-hodgkin lymphoma: a multicentre phase II study. Br J Haematol. 2014 Aug;166(4):514-20. Epub 2014 Apr 25. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00369707


Rituximab monotherapy, abbreviated course

Consolidation or maintenance regimens of less than one year duration or less than 12 total doses.

Regimen variant #1, 4 doses in 4 weeks

Study Dates of enrollment Evidence
Hainsworth et al. 2002 1998-1999 Phase 2

Preceding treatment

Targeted therapy

Supportive therapy

7-day cycle for 4 cycles


Regimen variant #2, 4 doses in 4 months

Study Dates of enrollment Evidence
Sakai et al. 2015 2008-2011 Phase 2

Preceding treatment

Targeted therapy

28-day cycle for 4 cycles

References

  1. Hainsworth JD, Litchy S, Burris HA 3rd, Scullin DC Jr, Corso SW, Yardley DA, Morrissey L, Greco FA. Rituximab as first-line and maintenance therapy for patients with indolent non-hodgkin's lymphoma. J Clin Oncol. 2002 Oct 15;20(20):4261-7. link to original article dosing details in abstract have been reviewed by our editors PubMed
  2. Sakai T, Masaki Y, Otsuki N, Sakamaki I, Kishi S, Miyazono T, Urasaki Y, Murakami J, Satoh T, Nakamura T, Iwao H, Nakajima A, Kawanami T, Miki M, Fujita Y, Tanaka M, Fukushima T, Okazaki T, Ueda T; Hokuriku Hematology Oncology Study Group. Prospective clinical study of R-CMD therapy for indolent B cell lymphoma and mantle cell lymphoma from the Hokuriku Hematology Oncology Study Group. Med Oncol. 2015 Sep;32(9):232. Epub 2015 Aug 15. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed


Maintenance after first-line therapy

Bortezomib & Rituximab (VR)

VR: Velcade (Bortezomib) & Rituximab

Regimen

Study Dates of enrollment Evidence
Cohen et al. 2015 (X05215) Not reported Phase 2

Preceding treatment

Targeted therapy

6-month cycle for up to 4 cycles (2 years)

References

  1. X05215: Cohen JB, Switchenko JM, Koff JL, Sinha R, Kaufman JL, Khoury HJ, Bumpers N, Colbert A, Hutchison-Rzepka A, Nastoupil LJ, Heffner LT, Langston AA, Lechowicz MJ, Lonial S, Flowers CR. A phase II study of bortezomib added to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone in patients with previously untreated indolent non-Hodgkin's lymphoma. Br J Haematol. 2015 Nov;171(4):539-46. Epub 2015 Aug 7. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00634179


Rituximab monotherapy, extended course

Maintenance regimens of one to two years duration or 12 to 16 total doses.

Regimen variant #1, q6mo cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hochster et al. 2009 (ECOG E1496) Not reported Phase 3 (E-RT-esc) Observation Superior PFS (primary endpoint)
Median PFS: 4.3 vs 1.3 y
(HR 0.40, 95% CI 0.30-0.60)

Preceding treatment

  • First-line CVP x 6 to 8 cycles

Targeted therapy

6-month cycle for 4 cycles (2 years)


Regimen variant #2, 12 doses in 2 years

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Awaiting publication (MAINTAIN) 2009-2012 Phase 3 (C) Rituximab x 4 y TBD if different primary endpoint of PFS

Preceding treatment

  • MAINTAIN: First-line BR x 6 + 2 doses of rituximab

Targeted therapy

2-month cycle for 12 cycles (2 years)

References

  1. ECOG E1496: Hochster H, Weller E, Gascoyne RD, Habermann TM, Gordon LI, Ryan T, Zhang L, Colocci N, Frankel S, Horning SJ. Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG1496 Study. J Clin Oncol. 2009 Apr 1;27(10):1607-14. Epub 2009 Mar 2. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00003204
    1. Update: Barta SK, Li H, Hochster HS, Hong F, Weller E, Gascoyne RD, Habermann TM, Gordon LI, Colocci N, Bengtson EM, Horning SJ, Kahl BS. Randomized phase 3 study in low-grade lymphoma comparing maintenance anti-CD20 antibody with observation after induction therapy: A trial of the ECOG-ACRIN Cancer Research Group (E1496). Cancer. 2016 Oct;122(19):2996-3004. Epub 2016 Jun 28. link to original article link to PMC article PubMed
  2. MAINTAIN: link to abstract NCT00877214


Rituximab monotherapy, very extended course

Maintenance regimens of more than two years duration, including indefinitely.

Regimen variant #1, 4 years

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Awaiting publication (MAINTAIN) 2009-2012 Phase 3 (E-esc) Rituximab x 2 y TBD if different primary endpoint of PFS

Preceding treatment

  • First-line BR x 6 + 2 doses of rituximab

Targeted therapy

2-month cycle for 24 cycles (4 years)


Regimen variant #2, indefinite

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Williams et al. 2016 (RESORT substudy) 2003-2008 Phase 3 (E-esc) Rituximab salvage Seems to have superior TTTF (primary endpoint)
Median TTTF: 4.8 vs 1.4 y

Preceding treatment

Targeted therapy

13-week cycles

References

  1. RESORT substudy: Williams ME, Hong F, Gascoyne RD, Wagner LI, Krauss JC, Habermann TM, Swinnen LJ, Schuster SJ, Peterson CG, Sborov MD, Martin SE, Weiss M, Ehmann WC, Horning SJ, Kahl BS; Eastern Cooperative Oncology Group. Rituximab extended schedule or retreatment trial for low tumour burden non-follicular indolent B-cell non-Hodgkin lymphomas: Eastern Cooperative Oncology Group Protocol E4402. Br J Haematol. 2016 Jun;173(6):867-75. Epub 2016 Mar 11. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01406782
  2. MAINTAIN: link to abstract NCT00877214


Relapsed or refractory

Axicabtagene ciloleucel monotherapy

Regimen

Study Dates of enrollment Evidence
Jacobson et al. 2021 (ZUMA-5) 2017-2020 Phase 2 (RT)

Preceding treatment

  • Lymphodepletion with FC

Immunotherapy

One course

References

  1. ZUMA-5: Jacobson CA, Chavez JC, Sehgal AR, William BM, Munoz J, Salles G, Munshi PN, Casulo C, Maloney DG, de Vos S, Reshef R, Leslie LA, Yakoub-Agha I, Oluwole OO, Fung HCH, Rosenblatt J, Rossi JM, Goyal L, Plaks V, Yang Y, Vezan R, Avanzi MP, Neelapu SS. Axicabtagene ciloleucel in relapsed or refractory indolent non-Hodgkin lymphoma (ZUMA-5): a single-arm, multicentre, phase 2 trial. Lancet Oncol. 2022 Jan;23(1):91-103. Epub 2021 Dec 8. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT03105336
    1. Update: Neelapu SS, Chavez JC, Sehgal AR, Epperla N, Ulrickson M, Bachy E, Munshi PN, Casulo C, Maloney DG, de Vos S, Reshef R, Leslie LA, Oluwole OO, Yakoub-Agha I, Khanal R, Rosenblatt J, Korn R, Peng W, Lui C, Wulff J, Shen R, Poddar S, Jung AS, Miao H, Beygi S, Jacobson CA. Three-year follow-up analysis of axicabtagene ciloleucel in relapsed/refractory indolent non-Hodgkin lymphoma (ZUMA-5). Blood. 2024 Feb 8;143(6):496-506. link to original article link to PMC article PubMed


Bendamustine monotherapy

Regimen

Study Dates of enrollment Evidence
Friedberg et al. 2008 2003-09 to 2005-02 Phase 2
Kahl et al. 2010 (SDX-105-01 part 2) 2005-10 to 2007-07 Phase 3b (RT)

Chemotherapy

21-day cycle for varying durations: 6 to 8 cycles (SDX-105-01 part 2); 12 cycles (Friedberg et al. 2008)

References

  1. Friedberg JW, Cohen P, Chen L, Robinson KS, Forero-Torres A, La Casce AS, Fayad LE, Bessudo A, Camacho ES, Williams ME, van der Jagt RH, Oliver JW, Cheson BD. Bendamustine in patients with rituximab-refractory indolent and transformed non-Hodgkin's lymphoma: results from a phase II multicenter, single-agent study. J Clin Oncol. 2008 Jan 10;26(2):204-10. Erratum in: J Clin Oncol. 2008 Apr 10;26(11) 1911. link to original article dosing details in manuscript have been reviewed by our editors PubMed
  2. SDX-105-01 part 2: Kahl BS, Bartlett NL, Leonard JP, Chen L, Ganjoo K, Williams ME, Czuczman MS, Robinson KS, Joyce R, van der Jagt RH, Cheson BD. Bendamustine is effective therapy in patients with rituximab-refractory, indolent B-cell non-Hodgkin lymphoma: results from a multicenter study. Cancer. 2010 Jan 1;116(1):106-14. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00069758


Bendamustine & Rituximab (BR)

BR: Bendamustine, Rituximab

Regimen variant #1, 4 cycles

Study Dates of enrollment Evidence
Matsumoto et al. 2015 (BRB) 2011-04 to 2013-03 Phase 2

Note: rituximab could be given on day 0, 1, 2, or 3 "according to the clinical convenience of each institution."

Chemotherapy

Targeted therapy

28-day cycle for 4 cycles


Regimen variant #2, 4 cycles with rituximab lead-in

Study Dates of enrollment Evidence
Rummel et al. 2005 2000-07 to 2003-07 Phase 2
Robinson et al. 2008 (SDX-105-01 part 1) 2004-2005 Phase 2

Note: Robinson et al. 2008 said that patients "could receive up to six cycles if disease regression was evident between the second and fourth cycles".

Chemotherapy

Targeted therapy

  • Rituximab (Rituxan) as follows:
    • One week prior to start of cycle 1: 375 mg/m2 IV once
    • Cycles 1 to 4: 375 mg/m2 IV once on day 1
    • 4 weeks after cycle 4: 375 mg/m2 IV once

28-day cycle for 4 cycles (see note)


Regimen variant #3, 6 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rummel et al. 2015 (StiL NHL 2-2003) 2003-2010 Phase 3 (E-switch-ic) FR Superior PFS (primary endpoint)
Median PFS: 34.2 vs 11.7 mo
(HR 0.54, 95% CI 0.38-0.72)
Zinzani et al. 2024 (CHRONOS-4) Not reported Phase 3 (C) BR & Copanlisib Did not meet primary endpoint of PFS
Median PFS: 33.3 vs 32.9 mo
(HR 0.88, 95% CI 0.69-1.14)

Chemotherapy

Targeted therapy

28-day cycle for up to 6 cycles

References

  1. Rummel MJ, Al-Batran SE, Kim SZ, Welslau M, Hecker R, Kofahl-Krause D, Josten KM, Dürk H, Rost A, Neise M, von Grünhagen U, Chow KU, Hansmann ML, Hoelzer D, Mitrou PS. Bendamustine plus rituximab is effective and has a favorable toxicity profile in the treatment of mantle cell and low-grade non-Hodgkin's lymphoma. J Clin Oncol. 2005 May 20;23(15):3383-9. link to original article dosing details in manuscript have been reviewed by our editors PubMed
  2. SDX-105-01 part 1: Robinson KS, Williams ME, van der Jagt RH, Cohen P, Herst JA, Tulpule A, Schwartzberg LS, Lemieux B, Cheson BD. Phase II multicenter study of bendamustine plus rituximab in patients with relapsed indolent B-cell and mantle cell non-Hodgkin's lymphoma. J Clin Oncol. 2008 Sep 20;26(27):4473-9. Epub 2008 Jul 14. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00069758
  3. BRB: Matsumoto K, Takayama N, Aisa Y, Ueno H, Hagihara M, Watanabe K, Nakaya A, Chen K, Shimizu T, Tsukada Y, Yamada Y, Nakazato T, Ishida A, Miyakawa Y, Yokoyama K, Nakajima H, Masuda Y, Yano T, Okamoto S; Keio BRB Study Group. A phase II study of bendamustine plus rituximab in Japanese patients with relapsed or refractory indolent B-cell non-Hodgkin lymphoma and mantle cell lymphoma previously treated with rituximab: BRB study. Int J Hematol. 2015 Jun;101(6):554-62. Epub 2015 Mar 19. link to original article dosing details in manuscript have been reviewed by our editors PubMed
  4. StiL NHL 2-2003: Rummel M, Kaiser U, Balser C, Stauch M, Brugger W, Welslau M, Niederle N, Losem C, Boeck HP, Weidmann E, von Gruenhagen U, Mueller L, Sandherr M, Hahn L, Vereshchagina J, Kauff F, Blau W, Hinke A, Barth J; StiL. Bendamustine plus rituximab versus fludarabine plus rituximab for patients with relapsed indolent and mantle-cell lymphomas: a multicentre, randomised, open-label, non-inferiority phase 3 trial. Lancet Oncol. 2016 Jan;17(1):57-66. Epub 2015 Dec 5. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT01456351
  5. CHRONOS-4: Zinzani PL, Wang H, Feng J, Kim TM, Tao R, Zhang H, Fogliatto L, Maluquer Artigal C, Özcan M, Yanez E, Kim WS, Kirtbaya D, Kriachok I, Maciel F, Xue H, Bouabdallah K, Phelps C, Chaturvedi S, Weispfenning A, Morcos PN, Odongo F, Buvaylo V, Childs BH, Dreyling M, Matasar M, Ghione P. CHRONOS-4: phase 3 study of copanlisib plus rituximab-based immunochemotherapy in relapsed indolent B-cell lymphoma. Blood Adv. 2024 Sep 24;8(18):4866-4876. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT02626455


Bortezomib monotherapy

Regimen

Study Dates of enrollment Evidence
O'Connor et al. 2005 2001-2003 Phase 2, fewer than 20 pts reported

Targeted therapy

Supportive therapy

  • "Use of antiemetics, erythropoietin, and Filgrastim (Neupogen) was allowed if deemed necessary by the treating physician."

21-day cycles

References

  1. O'Connor OA, Wright J, Moskowitz C, Muzzy J, MacGregor-Cortelli B, Stubblefield M, Straus D, Portlock C, Hamlin P, Choi E, Dumetrescu O, Esseltine D, Trehu E, Adams J, Schenkein D, Zelenetz AD. Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin's lymphoma and mantle cell lymphoma. J Clin Oncol. 2005 Feb 1;23(4):676-84. Epub 2004 Dec 21. link to original article dosing details in manuscript have been reviewed by our editors PubMed


BVR

BVR: Bendamustine, Velcade (Bortezomib), Rituximab
VBR: Velcade (Bortezomib), Bendamustine, Rituximab

Regimen

Study Dates of enrollment Evidence
Friedberg et al. 2011 (ULYM07054) 2007-2009 Phase 2, less than 20 patients in this subgroup

Chemotherapy

  • Bendamustine 90 mg/m2 IV once per day on days 1 & 4, given third

Targeted therapy

Supportive therapy

  • Premedications, antiemetic therapy, and growth factor support per institutional guidelines
  • No routine antibiotic or antiviral prophylaxis was given

28-day cycle for 6 cycles

References

  1. ULYM07054: Friedberg JW, Vose JM, Kelly JL, Young F, Bernstein SH, Peterson D, Rich L, Blumel S, Proia NK, Liesveld J, Fisher RI, Armitage JO, Grant S, Leonard JP. The combination of bendamustine, bortezomib, and rituximab for patients with relapsed/refractory indolent and mantle cell non-Hodgkin lymphoma. Blood. 2011 Mar 10;117(10):2807-12. Epub 2011 Jan 14. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00547534


Duvelisib monotherapy

Regimen

Study Dates of enrollment Evidence
Flinn et al. 2019 (DYNAMO) 2013-2015 Phase 2 (RT)

Targeted therapy

28-day cycles

References

  1. DYNAMO: Flinn IW, Miller CB, Ardeshna KM, Tetreault S, Assouline SE, Mayer J, Merli M, Lunin SD, Pettitt AR, Nagy Z, Tournilhac O, Abou-Nassar KE, Crump M, Jacobsen ED, de Vos S, Kelly VM, Shi W, Steelman L, Le N, Weaver DT, Lustgarten S, Wagner-Johnston ND, Zinzani PL. DYNAMO: A Phase II Study of Duvelisib (IPI-145) in Patients With Refractory Indolent Non-Hodgkin Lymphoma. J Clin Oncol. 2019 Apr 10;37(11):912-922. Epub 2019 Feb 11. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01882803


Ibritumomab tiuxetan protocol

Regimen variant #1, 0.3 mCi/kg

Study Dates of enrollment Evidence
Wiseman et al. 2002 1998-1999 Phase 2 (RT)

Note: this dosing was intended for patients with mild thrombocytopenia.

Targeted therapy

Radioconjugate therapy

8-day course


Regimen variant #2, 0.4 mCi/kg

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Witzig et al. 1999 Not reported Phase 1/2
Witzig et al. 2002a Not reported Phase 3 (E-RT-switch-ic) Rituximab Superior ORR (primary endpoint)

Targeted therapy

Radioconjugate therapy

8-day course

References

  1. Witzig TE, White CA, Wiseman GA, Gordon LI, Emmanouilides C, Raubitschek A, Janakiraman N, Gutheil J, Schilder RJ, Spies S, Silverman DH, Parker E, Grillo-López AJ. Phase I/II trial of IDEC-Y2B8 radioimmunotherapy for treatment of relapsed or refractory CD20(+) B-cell non-Hodgkin's lymphoma. J Clin Oncol. 1999 Dec;17(12):3793-803. link to original article dosing details in manuscript have been reviewed by our editors PubMed
  2. Witzig TE, Gordon LI, Cabanillas F, Czuczman MS, Emmanouilides C, Joyce R, Pohlman BL, Bartlett NL, Wiseman GA, Padre N, Grillo-López AJ, Multani P, White CA. Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma. J Clin Oncol. 2002 May 15;20(10):2453-63. link to original article dosing details in manuscript have been reviewed by our editors PubMed
  3. Wiseman GA, Gordon LI, Multani PS, Witzig TE, Spies S, Bartlett NL, Schilder RJ, Murray JL, Saleh M, Allen RS, Grillo-López AJ, White CA. Ibritumomab tiuxetan radioimmunotherapy for patients with relapsed or refractory non-Hodgkin lymphoma and mild thrombocytopenia: a phase II multicenter trial. Blood. 2002 Jun 15;99(12):4336-42. link to original article PubMed


Idelalisib monotherapy

Regimen

Study Dates of enrollment Evidence
Gopal et al. 2014 (DELTA) 2011-2012 Phase 2 (RT)

Targeted therapy

Continued indefinitely

References

  1. DELTA: Gopal AK, Kahl BS, de Vos S, Wagner-Johnston ND, Schuster SJ, Jurczak WJ, Flinn IW, Flowers CR, Martin P, Viardot A, Blum KA, Goy AH, Davies AJ, Zinzani PL, Dreyling M, Johnson D, Miller LL, Holes L, Li D, Dansey RD, Godfrey WR, Salles GA. PI3Kd inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014 Mar 13;370(11):1008-18. Epub 2014 Jan 22. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01282424
    1. Update: Abstract: Ajay K. Gopal, MD, Brad S. Kahl, MD, Sven de Vos, MD, PhD, Nina D. Wagner-Johnston, MD, Stephen J. Schuster, MD, Wojciech Jurczak, MD, PhD, Ian W. Flinn, MD, PhD, Christopher R. Flowers, MD, Peter Martin, MD, Andreas Viardot, MD, Kristie A. Blum, MD, Andre Goy, MD, Andrew Davies, BM PhD, Pier Luigi Zinzani, MD, Martin H. Dreyling, MD, PhD, Leanne M. Holes, Bess Sorensen, PhD, Wayne R. Godfrey, MD and Gilles Andre Salles, MD, PhD. Mature Follow up from a Phase 2 Study of PI3K-Delta Inhibitor Idelalisib in Patients with Double (Rituximab and Alkylating agent)-Refractory Indolent B-Cell Non-Hodgkin Lymphoma (iNHL). ASH Annual Meeting 2014, Abstract 1708


Inotuzumab ozogamicin monotherapy

Regimen

Study Dates of enrollment Evidence
Goy et al. 2016 (B1931007) Not reported Phase 2

Antibody-drug conjugate therapy

28-day cycle for 4 to 8 cycles

References

  1. B1931007: Goy A, Forero A, Wagner-Johnston N, Christopher Ehmann W, Tsai M, Hatake K, Ananthakrishnan R, Volkert A, Vandendries E, Ogura M. A phase 2 study of inotuzumab ozogamicin in patients with indolent B-cell non-Hodgkin lymphoma refractory to rituximab alone, rituximab and chemotherapy, or radioimmunotherapy. Br J Haematol. 2016 Aug;174(4):571-81. Epub 2016 Apr 22. link to original article PubMed NCT00868608


Lenalidomide monotherapy

Regimen

Study Dates of enrollment Evidence
Witzig et al. 2009 (CC-5013-NHL-001) 2005-2006 Phase 2

Targeted therapy

28-day cycles

References

  1. CC-5013-NHL-001: Witzig TE, Wiernik PH, Moore T, Reeder C, Cole C, Justice G, Kaplan H, Voralia M, Pietronigro D, Takeshita K, Ervin-Haynes A, Zeldis JB, Vose JM. Lenalidomide oral monotherapy produces durable responses in relapsed or refractory indolent non-Hodgkin's Lymphoma. J Clin Oncol. 2009 Nov 10;27(32):5404-9. Epub 2009 Oct 5. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00179673


Lenalidomide & Rituximab (R2)

Regimen variant #1, len 10

Study Dates of enrollment Evidence
Chong et al. 2015 (UPCC 02408 R2) 2008-2012 Phase 2

Targeted therapy

28-day cycles


Regimen variant #2, len 20 x 2

Study Dates of enrollment Evidence
Tuscano et al. 2014 (RV-PI-NHL-0488) 2010 to not reported Phase 2

Targeted therapy

Supportive therapy

28-day cycle for 2 cycles

Subsequent treatment

  • RV-PI-NHL-0488, responders: Lenalidomide maintenance
  • RV-PI-NHL-0488, patients with less than a CR after induction: more rituximab could be given at the discretion of the treating physician. Dosing details not provided in the reference

Regimen variant #3, len 20 x 12

FDA-recommended dose
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Leonard et al. 2019 (AUGMENT) 2014-2017 Phase 3 (E-RT-esc) Rituximab Superior PFS (primary endpoint)
Median PFS: 39.4 vs 14.1 mo
(HR 0.46, 95% CI 0.34-0.62)
Awaiting publication (InMIND) 2021-ongoing Phase 3 (C) R2 & Tafasitamb TBD if different primary endpoint of PFS

Prior treatment criteria

  • AUGMENT: At least 1 prior chemotherapy, immunotherapy, or chemoimmunotherapy and 2 or more previous doses of rituximab
  • InMIND: At least 1 prior systemic anti-CD20 therapy

Targeted therapy

28-day cycle for 12 cycles

Dose and schedule modifications

  • AUGMENT, CrCl 30 to 59 mL/min: Lenalidomide reduced to 10 mg PO once per day on days 1 to 21

Regimen variant #4, len 20 x 12, staggered rituximab

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Awaiting publication (MAGNIFY) 2014 to not reported Phase 3b (C-RT) R2, then Lenalidomide TBD if different primary endpoint of PFS

Note: this trial has not been published to our knowledge, but is cited in the package insert. Dosing information is from CT.gov.

Targeted therapy

28-day cycle for 12 cycles

Subsequent treatment

References

  1. RV-PI-NHL-0488: Tuscano JM, Dutia M, Chee K, Brunson A, Reed-Pease C, Abedi M, Welborn J, O'Donnell RT. Lenalidomide plus rituximab can produce durable clinical responses in patients with relapsed or refractory, indolent non-Hodgkin lymphoma. Br J Haematol. 2014 May;165(3):375-81. Epub 2014 Mar 7. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01316523
  2. UPCC 02408 2: Chong EA, Ahmadi T, Aqui NA, Svoboda J, Nasta SD, Mato AR, Walsh KM, Schuster SJ. Combination of lenalidomide and rituximab overcomes rituximab resistance in patients with indolent B-cell and mantle cell lymphomas. Clin Cancer Res. 2015 Apr 15;21(8):1835-42. Epub 2015 Jan 28. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00783367
  3. AUGMENT: Leonard JP, Trneny M, Izutsu K, Fowler NH, Hong X, Zhu J, Zhang H, Offner F, Scheliga A, Nowakowski GS, Pinto A, Re F, Fogliatto LM, Scheinberg P, Flinn IW, Moreira C, Cabeçadas J, Liu D, Kalambakas S, Fustier P, Wu C, Gribben JG; AUGMENT Trial Investigators. AUGMENT: a phase III study of lenalidomide plus rituximab versus placebo plus rituximab in relapsed or refractory indolent lymphoma. J Clin Oncol. 2019 May 10;37(14):1188-1199. Epub 2019 Mar 21. link to original article link to PMC article PubMed NCT01938001
  4. EZH-302: NCT04224493
  5. InMIND: NCT04680052
  6. MAGNIFY: NCT01996865


Lenalidomide, Dexamethasone, Rituximab

Regimen

Study Dates of enrollment Evidence
Ahmadi et al. 2013 (UPCC 02408) 2008-2010 Phase 2, less than 20 pts in subgroup

Targeted therapy

Glucocorticoid therapy

28-day cycles

References

  1. UPCC 02408: Ahmadi T, Chong EA, Gordon A, Aqui NA, Nasta SD, Svoboda J, Mato AR, Schuster SJ. Combined lenalidomide, low-dose dexamethasone, and rituximab achieves durable responses in rituximab-resistant indolent and mantle cell lymphomas. Cancer. 2014 Jan 15;120(2):222-8. Epub 2013 Oct 7. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00783367


Obinutuzumab monotherapy

Regimen variant #1, 4 doses

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Sehn et al. 2015 (GAUSS) 2009-2010 Randomized Phase 2 (E-switch-ic) Rituximab Might have superior ORR (primary endpoint)

Targeted therapy

7-day cycle for 4 cycles

Subsequent treatment

  • GAUSS, patients with SD or better: Optional obinutuzumab maintenance

Regimen variant #2, 9 doses

Study Dates of enrollment Evidence
Salles et al. 2012 (GAUGUIN) 2008-2009 Phase 1/2

Note: Dose here is that recommended by Salles et al. 2013 as having "encouraging activity with an acceptable safety profile"

Targeted therapy

  • Obinutuzumab (Gazyva) as follows:
    • Cycle 1: 1600 mg (diluted to 10 mg/mL) IV once per day on days 1 & 8
    • Cycles 2 to 8: 800 mg IV once on day 1
    • Initial infusion rate is 50 mg/hour. In the absence of infusion-related reactions (IRRs), the rate is then increased by 50 mg/hour every 30 minutes, up to a maximum of 400 mg/hour.

Supportive therapy

  • Acetaminophen (Tylenol) (no dose specified) PO once per infusion, given 30 minutes prior to obinutuzumab
  • Antihistamine (no drug or dose specified) PO once per infusion, given 30 minutes prior to obinutuzumab
  • Corticosteroids prior to obinutuzumab for patients at "high risk" of infusion reaction

21-day cycle for 8 cycles

References

  1. GAUGUIN: Salles G, Morschhauser F, Lamy T, Milpied N, Thieblemont C, Tilly H, Bieska G, Asikanius E, Carlile D, Birkett J, Pisa P, Cartron G. Phase 1 study results of the type II glycoengineered humanized anti-CD20 monoclonal antibody obinutuzumab (GA101) in B-cell lymphoma patients. Blood. 2012 May 31;119(22):5126-32. Epub 2012 Mar 19. link to original article PubMed NCT00517530
    1. Subgroup analysis: Morschhauser FA, Cartron G, Thieblemont C, Solal-Céligny P, Haioun C, Bouabdallah R, Feugier P, Bouabdallah K, Asikanius E, Lei G, Wenger M, Wassner-Fritsch E, Salles GA. Obinutuzumab (GA101) monotherapy in relapsed/refractory diffuse large B-cell lymphoma or mantle-cell lymphoma: results from the phase II GAUGUIN study. J Clin Oncol. 2013 Aug 10;31(23):2912-9. Epub 2013 Jul 8. link to original article dosing details in manuscript have been reviewed by our editors PubMed
    2. Subgroup analysis: Salles GA, Morschhauser F, Solal-Céligny P, Thieblemont C, Lamy T, Tilly H, Gyan E, Lei G, Wenger M, Wassner-Fritsch E, Cartron G. Obinutuzumab (GA101) in patients with relapsed/refractory indolent non-Hodgkin lymphoma: results from the phase II GAUGUIN study. J Clin Oncol. 2013 Aug 10;31(23):2920-6. Epub 2013 Jul 8. link to original article dosing details in manuscript have been reviewed by our editors PubMed
    3. Subgroup analysis: Cartron G, de Guibert S, Dilhuydy MS, Morschhauser F, Leblond V, Dupuis J, Mahe B, Bouabdallah R, Lei G, Wenger M, Wassner-Fritsch E, Hallek M. Obinutuzumab (GA101) in relapsed/refractory chronic lymphocytic leukemia: final data from the phase 1/2 GAUGUIN study. Blood. 2014 Oct 2;124(14):2196-202. Epub 2014 Aug 20. link to original article dosing details in manuscript have been reviewed by our editors PubMed
  2. GAUSS: Sehn LH, Goy A, Offner FC, Martinelli G, Caballero MD, Gadeberg O, Baetz T, Zelenetz AD, Gaidano G, Fayad LE, Buckstein R, Friedberg JW, Crump M, Jaksic B, Zinzani PL, Padmanabhan Iyer S, Sahin D, Chai A, Fingerle-Rowson G, Press OW. Randomized phase II trial comparing obinutuzumab (GA101) with rituximab in patients with relapsed CD20+ indolent B-cell non-Hodgkin lymphoma: final analysis of the GAUSS study. J Clin Oncol. 2015 Oct 20;33(30):3467-74. Epub 2015 Aug 17. link to original article] dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00576758


PEP-C

PEP-C: Prednisone, Etoposide, Procarbazine, Cyclophosphamide

Regimen

Study Dates of enrollment Evidence
Coleman et al. 2008 Not reported Retrospective

Note: the dosing below is for the induction phase. Once WBC count is at goal, the same medications and doses are used as in the induction phase, but the number of days per week they are used is titrated to maintain a WBC count of at least 3; for example, 5 out of 7 days, every other day, once per week, etc.

Glucocorticoid therapy

Chemotherapy

Supportive therapy

Continue until WBC count less than 3 x 109/L, hold until WBC count recovery, then titrate in maintenance phase per paper (see publication for details)

References

  1. Retrospective: Coleman M, Martin P, Ruan J, Furman R, Niesvizky R, Elstrom R, George P, Kaufman TP, Leonard JP. Prednisone, etoposide, procarbazine, and cyclophosphamide (PEP-C) oral combination chemotherapy regimen for recurring/refractory lymphoma: low-dose metronomic, multidrug therapy. Cancer. 2008 May 15;112(10):2228-32. link to original article dosing details in manuscript have been reviewed by our editors PubMed


Rituximab monotherapy

Regimen variant #1, 4 doses in 4 weeks

Study Dates of enrollment Evidence Comparator Comparative Efficacy
McLaughlin et al. 1998 1995-1996 Phase 2 (RT)
Hainsworth et al. 2005b 1998-2002 Non-randomized part of phase 2 RCT
Williams et al. 2016 (RESORT substudy) 2003-2008 Phase 3 (E-de-esc) Rituximab maintenance Seems to have inferior TTTF
Sehn et al. 2015 (GAUSS) 2009-2010 Randomized Phase 2 (C) Obinutuzumab Might have inferior ORR

Preceding treatment

  • RESORT substudy: First-line Rituximab, with progression

Targeted therapy

Supportive therapy

7-day cycle for 4 cycles

Subsequent treatment

  • Hainsworth et al. 2005b, patients with SD or better: Rituximab maintenance versus re-treatment with rituximab at time of progression
  • GAUSS, SD or better: Optional rituximab maintenance

Regimen variant #2, 8 doses in 20 weeks

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Leonard et al. 2019 (AUGMENT) 2014-2017 Phase 3 (C) Lenalidomide & Rituximab Inferior PFS

Targeted therapy

  • Rituximab (Rituxan) as follows:
    • Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15, 22
    • Cycles 2 to 5: 375 mg/m2 IV once on day 1

28-day cycle for 5 cycles


Regimen variant #3, 8 doses in 36 weeks

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Matasar et al. 2021 (CHRONOS-3) 2015-2019 Phase 3 (C) Copanlisib & Rituximab Inferior PFS

Targeted therapy

  • Rituximab (Rituxan) as follows:
    • Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15, 22
    • Cycles 3, 5, 7, 9: 375 mg/m2 IV once on day 1

28-day cycle for 9 cycles


Regimen variant #4, 8 doses in 40 weeks

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Maloney et al. 2020 (HOMER) 2010-2016 Phase 3 (C) Ofatumumab Did not meet primary endpoint of PFS
Median PFS: 21.29 vs 16.33 mo
(HR 0.87, 95% CI 0.67-1.12)

Targeted therapy

  • Rituximab (Rituxan) as follows:
    • Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15, 22
    • Cycles 4, 6, 8, 10: 375 mg/m2 IV once on day 1

28-day cycle for 10 cycles

References

  1. McLaughlin P, Grillo-López AJ, Link BK, Levy R, Czuczman MS, Williams ME, Heyman MR, Bence-Bruckler I, White CA, Cabanillas F, Jain V, Ho AD, Lister J, Wey K, Shen D, Dallaire BK. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998 Aug;16(8):2825-33. link to original article dosing details in manuscript have been reviewed by our editors PubMed
  2. Hainsworth JD, Litchy S, Shaffer DW, Lackey VL, Grimaldi M, Greco FA. Maximizing therapeutic benefit of rituximab: maintenance therapy versus re-treatment at progression in patients with indolent non-Hodgkin's lymphoma--a randomized phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol. 2005 Feb 20;23(6):1088-95. Epub 2005 Jan 18. link to original article dosing details in abstract have been reviewed by our editors PubMed
  3. GAUSS: Sehn LH, Goy A, Offner FC, Martinelli G, Caballero MD, Gadeberg O, Baetz T, Zelenetz AD, Gaidano G, Fayad LE, Buckstein R, Friedberg JW, Crump M, Jaksic B, Zinzani PL, Padmanabhan Iyer S, Sahin D, Chai A, Fingerle-Rowson G, Press OW. Randomized phase II trial comparing obinutuzumab (GA101) with rituximab in patients with relapsed CD20+ indolent B-cell non-Hodgkin lymphoma: final analysis of the GAUSS study. J Clin Oncol. 2015 Oct 20;33(30):3467-74. Epub 2015 Aug 17. link to original article] dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00576758
  4. RESORT substudy: Williams ME, Hong F, Gascoyne RD, Wagner LI, Krauss JC, Habermann TM, Swinnen LJ, Schuster SJ, Peterson CG, Sborov MD, Martin SE, Weiss M, Ehmann WC, Horning SJ, Kahl BS; Eastern Cooperative Oncology Group. Rituximab extended schedule or retreatment trial for low tumour burden non-follicular indolent B-cell non-Hodgkin lymphomas: Eastern Cooperative Oncology Group Protocol E4402. Br J Haematol. 2016 Jun;173(6):867-75. Epub 2016 Mar 11. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01406782
  5. AUGMENT: Leonard JP, Trneny M, Izutsu K, Fowler NH, Hong X, Zhu J, Zhang H, Offner F, Scheliga A, Nowakowski GS, Pinto A, Re F, Fogliatto LM, Scheinberg P, Flinn IW, Moreira C, Cabeçadas J, Liu D, Kalambakas S, Fustier P, Wu C, Gribben JG; AUGMENT Trial Investigators. AUGMENT: a phase III study of lenalidomide plus rituximab versus placebo plus rituximab in relapsed or refractory indolent lymphoma. J Clin Oncol. 2019 May 10;37(14):1188-1199. Epub 2019 Mar 21. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01938001
  6. HOMER: Maloney DG, Ogura M, Fukuhara N, Davis J, Lasher J, Izquierdo M, Banerjee H, Tobinai K. A phase 3 randomized study (HOMER) of ofatumumab vs rituximab in iNHL relapsed after rituximab-containing therapy. Blood Adv. 2020 Aug 25;4(16):3886-3893. link to original article link to PMC article PubMed NCT01200589
  7. CHRONOS-3: Matasar MJ, Capra M, Özcan M, Lv F, Li W, Yañez E, Sapunarova K, Lin T, Jin J, Jurczak W, Hamed A, Wang MC, Baker R, Bondarenko I, Zhang Q, Feng J, Geissler K, Lazaroiu M, Saydam G, Szomor Á, Bouabdallah K, Galiulin R, Uchida T, Mongay Soler L, Cao A, Hiemeyer F, Mehra A, Childs BH, Shi Y, Zinzani PL. Copanlisib plus rituximab versus placebo plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma (CHRONOS-3): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2021 May;22(5):678-689. Epub 2021 Apr 10. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT02367040


R-CHOP

R-CHOP: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone

Regimen

Study Dates of enrollment Evidence
Czuczman et al. 1999 Not reported Phase 2

Targeted therapy

  • Rituximab (Rituxan) as follows:
    • Cycle 1: 375 mg/m2 IV once per day on days -6 & -1 (7 and 2 days before cycle 1 day 1)
    • Cycles 3 & 5: 375 mg/m2 IV once on day -2
    • Cycle 6*: 375 mg/m2 IV once per day on days 29 & 36 (i.e., what would be cycle 7 days 8 & 15)

Chemotherapy

Glucocorticoid therapy

21-day cycle for 6 cycles

References

  1. Czuczman MS, Grillo-López AJ, White CA, Saleh M, Gordon L, LoBuglio AF, Jonas C, Klippenstein D, Dallaire B, Varns C. Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol. 1999 Jan;17(1):268-76. link to original article dosing details in manuscript have been reviewed by our editors PubMed
    1. Update: Czuczman MS, Weaver R, Alkuzweny B, Berlfein J, Grillo-López AJ. Prolonged clinical and molecular remission in patients with low-grade or follicular non-Hodgkin's lymphoma treated with rituximab plus CHOP chemotherapy: 9-year follow-up. J Clin Oncol. 2004 Dec 1;22(23):4711 to 6. Epub 2004 Oct 13. link to original article PubMed


R-DexaBEAM

R-DexaBEAM: Rituximab, Dexamethasone, BiCNU (Carmustine), Etoposide, Ara-C (Cytarabine), Melphalan

Regimen

Study Dates of enrollment Evidence
Kirschey et al. 2014 (Mz-135) 2002-2006 Phase 2

Note: the dosing in the manuscript was different than what is reported below. The below are the correct doses as verified by the authors.

Targeted therapy

Glucocorticoid therapy

Chemotherapy

3- to 4-week cycle for 2 cycles

Subsequent treatment

References

  1. Mz-135: Kirschey S, Flohr T, Wolf HH, Frickhofen N, Gramatzki M, Link H, Basara N, Peter N, Meyer RG, Schmitz N, Weidmann E, Banat A, Schulz A, Kolbe K, Derigs G, Theobald M, Hess G. Rituximab combined with DexaBEAM followed by high dose therapy as salvage therapy in patients with relapsed or refractory B-cell lymphoma: mature results of a phase II multicentre study. Br J Haematol. 2015 Mar;168(6):824-34. Epub 2014 Dec 28. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT02099292


R-FND

R-FND: Rituximab, Fludarabine, Novantrone (Mitoxantrone), Dexamethasone

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Nastoupil et al. 2017 (DM97-261) 1997-2002 Randomized (E-switch-ic) FND, then R Did not meet primary endpoint of CR rate

Note: although this was the experimental arm of a negative study, the concurrent approach is the standard approach now.

Targeted therapy

  • Rituximab (Rituxan) as follows:
    • Cycle 1: 375 mg/m2 IV once per day on days 1 & 8
    • Cycles 2 to 5: 375 mg/m2 IV once on day 1

Chemotherapy

Glucocorticoid therapy

28-day cycle for up to 8 cycles

Subsequent treatment

References

  1. Review: Hagemeister F, Cabanillas F, Coleman M, Gregory SA, Zinzani PL. The role of mitoxantrone in the treatment of indolent lymphomas. Oncologist. 2005 Feb;10(2):150-9. link to original article PubMed content property of HemOnc.org
  2. Retrospective: Liu Q, Fayad L, Cabanillas F, Hagemeister FB, Ayers GD, Hess M, Romaguera J, Rodriguez MA, Tsimberidou AM, Verstovsek S, Younes A, Pro B, Lee MS, Ayala A, McLaughlin P. Improvement of overall and failure-free survival in stage IV follicular lymphoma: 25 years of treatment experience at The University of Texas M.D. Anderson Cancer Center. J Clin Oncol. 2006 Apr 1;24(10):1582-9. link to original article PubMed
  3. DM97-261: Nastoupil LJ, McLaughlin P, Feng L, Neelapu SS, Samaniego F, Hagemeister FB, Ayala A, Romaguera JE, Goy AH, Neal E, Wang M, Fayad L, Fanale MA, Oki Y, Westin JR, Rodriguez MA, Cabanillas F, Fowler NH. High ten-year remission rates following rituximab, fludarabine, mitoxantrone and dexamethasone (R-FND) with interferon maintenance in indolent lymphoma: results of a randomized study. Br J Haematol. 2017 Apr;177(2):263-270. Epub 2017 Mar 24. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00577993


R-INO

R-INO: Rituximab, INOtuzumab ozogamicin

Regimen

Study Dates of enrollment Evidence Efficacy
Fayad et al. 2013 (B1931004) 2006 to not reported Phase 1/2 ORR: 87%

Targeted therapy

Antibody-drug conjugate therapy

28-day cycle for up to 8 cycles

References

  1. B1931004: Fayad L, Offner F, Smith MR, Verhoef G, Johnson P, Kaufman JL, Rohatiner A, Advani A, Foran J, Hess G, Coiffier B, Czuczman M, Giné E, Durrant S, Kneissl M, Luu KT, Hua SY, Boni J, Vandendries E, Dang NH. Safety and clinical activity of a combination therapy comprising two antibody-based targeting agents for the treatment of non-Hodgkin lymphoma: results of a phase I/II study evaluating the immunoconjugate inotuzumab ozogamicin with rituximab. J Clin Oncol. 2013 Feb 10;31(5):573-83. Epub 2013 Jan 7. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00299494


Temsirolimus monotherapy

Regimen

Study Dates of enrollment Evidence
Smith et al. 2010 (NCI-6199) Not reported Phase 2

Targeted therapy

7-day cycle for at least 8 cycles

References

  1. NCI-6199: Smith SM, van Besien K, Karrison T, Dancey J, McLaughlin P, Younes A, Smith S, Stiff P, Lester E, Modi S, Doyle LA, Vokes EE, Pro B. Temsirolimus has activity in non-mantle cell non-Hodgkin's lymphoma subtypes: The University of Chicago phase II consortium. J Clin Oncol. 2010 Nov 1;28(31):4740-6. Epub 2010 Sep 13. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00290472


Vorinostat monotherapy

Regimen

Study Dates of enrollment Evidence
Kirschbaum et al. 2011 (PHII-63) 2005-2008 Phase 2, fewer than 20 pts in subgroup
Ogura et al. 2014 (MK-0683-103) 2009-2010 Phase 2

Targeted therapy

21-day cycles

References

  1. PHII-63: Kirschbaum M, Frankel P, Popplewell L, Zain J, Delioukina M, Pullarkat V, Matsuoka D, Pulone B, Rotter AJ, Espinoza-Delgado I, Nademanee A, Forman SJ, Gandara D, Newman E. Phase II study of vorinostat for treatment of relapsed or refractory indolent non-Hodgkin's lymphoma and mantle cell lymphoma. J Clin Oncol. 2011 Mar 20;29(9):1198-203. Epub 2011 Feb 7. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00253630
  2. MK-0683-103: Ogura M, Ando K, Suzuki T, Ishizawa K, Oh SY, Itoh K, Yamamoto K, Au WY, Tien HF, Matsuno Y, Terauchi T, Yamamoto K, Mori M, Tanaka Y, Shimamoto T, Tobinai K, Kim WS. A multicentre phase II study of vorinostat in patients with relapsed or refractory indolent B-cell non-Hodgkin lymphoma and mantle cell lymphoma. Br J Haematol. 2014 Jun;165(6):768-776. Epub 2014 Mar 12. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00875056


Vorinostat & Rituximab

Regimen

Study Dates of enrollment Evidence
Chen et al. 2015 (CoH 07195) 2008-07 to 2013-01 Phase 2, less than 20 patients in this subgroup

Targeted therapy

21-day cycles until progression or two cycles past documented CR

References

  1. CoH 07195: Chen R, Frankel P, Popplewell L, Siddiqi T, Ruel N, Rotter A, Thomas SH, Mott M, Nathwani N, Htut M, Nademanee A, Forman SJ, Kirschbaum M. A phase II study of vorinostat and rituximab for treatment of newly diagnosed and relapsed/refractory indolent non-Hodgkin lymphoma. Haematologica. 2015 Mar;100(3):357-62. Epub 2015 Jan 16. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00720876


Rituximab-refractory

Bendamustine monotherapy

Regimen variant #1, q3wk x 6-8

Study Dates of enrollment Evidence
Kahl et al. 2010 (SDX-105-01 part 2) 2005-10 to 2007-07 Phase 3b (RT)

Chemotherapy

21-day cycle for 6 to 8 cycles


Regimen variant #2, q3wk x up to 8

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rummel et al. 2021 (COMPLEMENT A plus B) 2010-2016 Phase 3 (C) Bendamustine & Ofatumumab Did not meet primary endpoint of PFS
Median PFS: 13.8 vs 16.7 mo
(HR 1.22, 95% CI 0.93-1.61)

Chemotherapy

21-day cycle for up to 8 cycles


Regimen variant #3, q4wk x 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Sehn et al. 2016 (GADOLIN) 2010-2014 Phase 3 (C) Bendamustine & Obinutuzumab Inferior OS1

1Reported efficacy in GADOLIN is for the FL subgroup based on the 2018 update.

Chemotherapy

28-day cycle for 6 cycles


Regimen variant #4, q3wk x 12

Study Dates of enrollment Evidence
Friedberg et al. 2008 2003-09 to 2005-02 Phase 2

Chemotherapy

21-day cycle for up to 12 cycles

References

  1. Friedberg JW, Cohen P, Chen L, Robinson KS, Forero-Torres A, La Casce AS, Fayad LE, Bessudo A, Camacho ES, Williams ME, van der Jagt RH, Oliver JW, Cheson BD. Bendamustine in patients with rituximab-refractory indolent and transformed non-Hodgkin's lymphoma: results from a phase II multicenter, single-agent study. J Clin Oncol. 2008 Jan 10;26(2):204-10. Erratum in: J Clin Oncol. 2008 Apr 10;26(11) 1911. link to original article dosing details in manuscript have been reviewed by our editors PubMed
  2. SDX-105-01 part 2: Kahl BS, Bartlett NL, Leonard JP, Chen L, Ganjoo K, Williams ME, Czuczman MS, Robinson KS, Joyce R, van der Jagt RH, Cheson BD. Bendamustine is effective therapy in patients with rituximab-refractory, indolent B-cell non-Hodgkin lymphoma: results from a multicenter study. Cancer. 2010 Jan 1;116(1):106-14. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00069758
  3. GADOLIN: Sehn LH, Chua N, Mayer J, Dueck G, Trněný M, Bouabdallah K, Fowler N, Delwail V, Press O, Salles G, Gribben J, Lennard A, Lugtenburg PJ, Dimier N, Wassner-Fritsch E, Fingerle-Rowson G, Cheson BD. Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol. 2016 Aug;17(8):1081-93. Epub 2016 Jun 23. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01059630
    1. Update: Cheson BD, Chua N, Mayer J, Dueck G, Trněný M, Bouabdallah K, Fowler N, Delwail V, Press O, Salles G, Gribben JG, Lennard A, Lugtenburg PJ, Fingerle-Rowson G, Mattiello F, Knapp A, Sehn LH. Overall survival benefit in patients with rituximab-refractory indolent non-Hodgkin lymphoma who received obinutuzumab plus bendamustine induction and obinutuzumab maintenance in the GADOLIN study. J Clin Oncol. 2018 Aug 1;36(22):2259-2266. Epub 2018 Mar 27. link to original article PubMed
  4. COMPLEMENT A plus B: Rummel MJ, Janssens A, MacDonald D, Keating MM, Zaucha JM, Davis J, Lasher J, Babanrao Pisal C, Izquierdo M, Friedberg JW. A phase 3, randomized study of ofatumumab combined with bendamustine in rituximab-refractory iNHL (COMPLEMENT A + B study). Br J Haematol. 2021 Jun;193(6):1123-1133. Epub 2021 May 10. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01077518


Bendamustine & Obinutuzumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Sehn et al. 2016 (GADOLIN) 2010-2014 Phase 3 (E-RT-esc) Bendamustine Superior OS1 (secondary endpoint)
Median OS: NYR vs 53.9 mo
(HR 0.58, 95% CI 0.39-0.86)

Superior PFS (primary endpoint)
Median PFS: NYR vs 14.9 mo
(HR 0.55, 95% CI 0.40-0.74)

1Reported efficacy is for the FL subgroup based on the 2018 update.

Chemotherapy

Targeted therapy

  • Obinutuzumab (Gazyva) as follows:
    • Cycle 1: 1000 mg IV once per day on days 1, 8, 15
    • Cycles 2 to 6: 1000 mg IV once on day 1

28-day cycle for 6 cycles

Subsequent treatment

References

  1. GADOLIN: Sehn LH, Chua N, Mayer J, Dueck G, Trněný M, Bouabdallah K, Fowler N, Delwail V, Press O, Salles G, Gribben J, Lennard A, Lugtenburg PJ, Dimier N, Wassner-Fritsch E, Fingerle-Rowson G, Cheson BD. Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol. 2016 Aug;17(8):1081-93. Epub 2016 Jun 23. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01059630
    1. Update: Cheson BD, Chua N, Mayer J, Dueck G, Trněný M, Bouabdallah K, Fowler N, Delwail V, Press O, Salles G, Gribben JG, Lennard A, Lugtenburg PJ, Fingerle-Rowson G, Mattiello F, Knapp A, Sehn LH. Overall survival benefit in patients with rituximab-refractory indolent non-Hodgkin lymphoma who received obinutuzumab plus bendamustine induction and obinutuzumab maintenance in the GADOLIN study. J Clin Oncol. 2018 Aug 1;36(22):2259-2266. Epub 2018 Mar 27. link to original article PubMed


Obinutuzumab monotherapy

Regimen

Study Dates of enrollment Evidence
Sehn et al. 2016 (GADOLIN) 2010-2014 Non-randomized part of phase 3 RCT

Preceding treatment

Targeted therapy

2-month cycle for 12 cycles

References

  1. GADOLIN: Sehn LH, Chua N, Mayer J, Dueck G, Trněný M, Bouabdallah K, Fowler N, Delwail V, Press O, Salles G, Gribben J, Lennard A, Lugtenburg PJ, Dimier N, Wassner-Fritsch E, Fingerle-Rowson G, Cheson BD. Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol. 2016 Aug;17(8):1081-93. Epub 2016 Jun 23. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01059630
    1. Update: Cheson BD, Chua N, Mayer J, Dueck G, Trněný M, Bouabdallah K, Fowler N, Delwail V, Press O, Salles G, Gribben JG, Lennard A, Lugtenburg PJ, Fingerle-Rowson G, Mattiello F, Knapp A, Sehn LH. Overall survival benefit in patients with rituximab-refractory indolent non-Hodgkin lymphoma who received obinutuzumab plus bendamustine induction and obinutuzumab maintenance in the GADOLIN study. J Clin Oncol. 2018 Aug 1;36(22):2259-2266. Epub 2018 Mar 27. link to original article PubMed


Consolidation after subsequent lines of therapy

Bortezomib & Rituximab (VR)

VR: Velcade (Bortezomib) & Rituximab

Regimen

Study Dates of enrollment Evidence
Evens et al. 2014 (NU 06H1) Not reported Phase 2

Preceding treatment

  • VR salvage

Targeted therapy

2-month cycle for 4 cycles

References

  1. NU 06H1: Evens AM, Smith MR, Lossos IS, Helenowski I, Millenson M, Winter JN, Rosen ST, Gordon LI. Frontline bortezomib and rituximab for the treatment of newly diagnosed high tumour burden indolent non-hodgkin lymphoma: a multicentre phase II study. Br J Haematol. 2014 Aug;166(4):514-20. Epub 2014 Apr 25. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00369707


R-BEAM, then auto HSCT

R-BEAM: Rituximab, BiCNU (Carmustine), Etoposide, Ara-C (Cytarabine), Melphalan

Regimen

Study Dates of enrollment Evidence
Kirschey et al. 2014 (Mz-135) 2002-2006 Phase 2

A minimum number of 2 x 106/kg bw CD34-positive cells were required to proceed.

Preceding treatment

Targeted therapy

Chemotherapy

Supportive therapy

One course

References

  1. Mz-135: Kirschey S, Flohr T, Wolf HH, Frickhofen N, Gramatzki M, Link H, Basara N, Peter N, Meyer RG, Schmitz N, Weidmann E, Banat A, Schulz A, Kolbe K, Derigs G, Theobald M, Hess G. Rituximab combined with DexaBEAM followed by high dose therapy as salvage therapy in patients with relapsed or refractory B-cell lymphoma: mature results of a phase II multicentre study. Br J Haematol. 2015 Mar;168(6):824-34. Epub 2014 Dec 28. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT02099292


R-TBI/Cy, then auto HSCT

R-TBI/Cy: Rituximab, Total, Body, Irradiation, Cyclophosphamide

Regimen

Study Dates of enrollment Evidence
Kirschey et al. 2014 (Mz-135) 2002-2006 Phase 2

Preceding treatment

Targeted therapy

Chemotherapy

Radiotherapy

Supportive therapy

One course

References

  1. Mz-135: Kirschey S, Flohr T, Wolf HH, Frickhofen N, Gramatzki M, Link H, Basara N, Peter N, Meyer RG, Schmitz N, Weidmann E, Banat A, Schulz A, Kolbe K, Derigs G, Theobald M, Hess G. Rituximab combined with DexaBEAM followed by high dose therapy as salvage therapy in patients with relapsed or refractory B-cell lymphoma: mature results of a phase II multicentre study. Br J Haematol. 2015 Mar;168(6):824-34. Epub 2014 Dec 28. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT02099292


Maintenance after subsequent lines of therapy

Lenalidomide monotherapy

Regimen

Study Dates of enrollment Evidence
Tuscano et al. 2014 (RV-PI-NHL-0488) Not reported Phase 2

Preceding treatment

Targeted therapy

Supportive therapy

28-day cycles

References

  1. RV-PI-NHL-0488: Tuscano JM, Dutia M, Chee K, Brunson A, Reed-Pease C, Abedi M, Welborn J, O'Donnell RT. Lenalidomide plus rituximab can produce durable clinical responses in patients with relapsed or refractory, indolent non-Hodgkin lymphoma. Br J Haematol. 2014 May;165(3):375-81. Epub 2014 Mar 7. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01316523


Obinutuzumab monotherapy

Regimen

Study Dates of enrollment Evidence
Sehn et al. 2015 (GAUSS) 2009-2010 Non-randomized part of phase 2 RCT

Preceding treatment

Targeted therapy

2-month cycle for 12 cycles

References

  1. GAUSS: Sehn LH, Goy A, Offner FC, Martinelli G, Caballero MD, Gadeberg O, Baetz T, Zelenetz AD, Gaidano G, Fayad LE, Buckstein R, Friedberg JW, Crump M, Jaksic B, Zinzani PL, Padmanabhan Iyer S, Sahin D, Chai A, Fingerle-Rowson G, Press OW. Randomized phase II trial comparing obinutuzumab (GA101) with rituximab in patients with relapsed CD20+ indolent B-cell non-Hodgkin lymphoma: final analysis of the GAUSS study. J Clin Oncol. 2015 Oct 20;33(30):3467-74. Epub 2015 Aug 17. link to original article] dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00576758


Rituximab monotherapy, extended course

Maintenance regimens of one to two years duration or 12 to 16 total doses.

Regimen

Study Dates of enrollment Evidence
Sehn et al. 2015 (GAUSS) 2009-2010 Non-randomized part of phase 2 RCT

Preceding treatment

Targeted therapy

2-month cycle for up to 12 cycles (2 years)

References

  1. GAUSS: Sehn LH, Goy A, Offner FC, Martinelli G, Caballero MD, Gadeberg O, Baetz T, Zelenetz AD, Gaidano G, Fayad LE, Buckstein R, Friedberg JW, Crump M, Jaksic B, Zinzani PL, Padmanabhan Iyer S, Sahin D, Chai A, Fingerle-Rowson G, Press OW. Randomized phase II trial comparing obinutuzumab (GA101) with rituximab in patients with relapsed CD20+ indolent B-cell non-Hodgkin lymphoma: final analysis of the GAUSS study. J Clin Oncol. 2015 Oct 20;33(30):3467-74. Epub 2015 Aug 17. link to original article] dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00576758


Response criteria

NCI Sponsored International Working Group Criteria (1999)

  1. Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM, Lister TA, Vose J, Grillo-López A, Hagenbeek A, Cabanillas F, Klippensten D, Hiddemann W, Castellino R, Harris NL, Armitage JO, Carter W, Hoppe R, Canellos GP. Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group. J Clin Oncol. 1999 Apr;17(4):1244. Review. Erratum in: J Clin Oncol 2000 Jun;18(11):2351. link to original article PubMed


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