Indolent lymphoma

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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:
*Regimens for follicular lymphoma (FL) are here.
*Regimens for lymphoplasmacytic lymphoma (LPL) are here.
*Regimens for marginal zone lymphoma (MZL) are here.
*Regimens for small lymphocytic lymphoma (SLL) are here.
*Regimens for Waldenström macroglobulinemia (WM) are here.
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==
*NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - B-cell Lymphomas.
=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====
*Rituximab (Rituxan) 250 mg/m2 IV once per day on days 1 & 8, given first on day 8
====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===
#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 EuroPMC 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 	Longer TTP
This is the current "standard dose" radiotherapy - dose varies per protocol and location radiated.
====Radiotherapy====
*External beam radiotherapy 2400 to 3600 cGy
====Subsequent treatment====
*Yahalom et al. 1993: Adjuvant CHOP versus no further treatment
*Kelsey et al. 1994: Adjuvant Chlorambucil versus no further treatment
===References===
#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 EuroPMC
#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 EuroPMC
#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 EuroPMC
#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 EuroPMC 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====
*Bendamustine 90 mg/m2 IV once per day on days 1 & 2
====Targeted therapy====
*Ofatumumab (Arzerra) as follows:
**Cycle 1: 300 mg IV once on day 1, then 1000 mg IV once on day 8
**Cycles 2 to 6: 1000 mg IV once on day 1
28-day cycle for 6 cycles
===References===
#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 EuroPMC 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 	Longer PFS (primary endpoint)Median PFS: 69.5 vs 31.2 mo(HR 0.58, 95% CI 0.44-0.74)
====Chemotherapy====
*Bendamustine 90 mg/m2 IV once per day on days 1 & 2
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====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====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
28-day cycle for 8 cycles
====Subsequent treatment====
*Rituximab maintenance x 2 y versus rituximab maintenance x 4 y
===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-CHOP1b. R-CVP	Longer 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====
*Bendamustine 90 mg/m2 IV once per day on days 1 & 2
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====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===
#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 EuroPMC NCT00991211
##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
##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
#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 EuroPMC NCT00877006
##HRQoL analysis: Burke JM, van der Jagt RH, Kahl BS, Wood P, Hawkins TE, MacDonald D, Hertzberg M, Simpson D, Craig M, Kolibaba K, Issa S, Munteanu M, Victor TW, Flinn IW. Differences in Quality of Life Between Bendamustine-Rituximab and R-CHOP/R-CVP in Patients With Previously Untreated Advanced Indolent Non-Hodgkin Lymphoma or Mantle Cell Lymphoma. Clin Lymphoma Myeloma Leuk. 2016 Apr;16(4):182-190.e1. Epub 2016 Jan 15. link to original article EuroPMC
##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 EuroPMC
#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===
#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 EuroPMC 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====
*Chlorambucil (Leukeran) 10 mg PO once per day
Continued indefinitely
===References===
#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 EuroPMC
==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====
*Fludarabine (Fludara) as follows:
**Weeks 2, 6, 10, 14, 18, 22: 25 mg/m2 IV once per day on days 1 to 5
====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===
#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 EuroPMC
==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====
*Lenalidomide (Revlimid) 20 mg PO once per day on days 1 to 21
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
28-day cycle for up to 8 to 12 cycles
===References===
# 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 EuroPMC NCT00695786
==PCR==
PCR: Pentostatin, Cyclophosphamide, Rituximab
===Regimen===
Study 	Dates of enrollment	Evidence
Samaniego et al. 2015 (MDACC 2004-0818)	Not reported 	Phase 2
====Chemotherapy====
*Pentostatin (Nipent) 4 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Supportive therapy====
*Ondansetron (Zofran) 8 mg (route not specified) prior to chemo
*Diphenhydramine (Benadryl) 25 mg (route not specified) prior to chemo
*500 ml of 5% dextrose/one-half normal saline before and after each pentostatin dose
*Filgrastim (Neupogen) at the discretion of the treating physician
*Cycle 1: Allopurinol (Zyloprim) 300 mg PO once per day on days 1 to 15
*Trimethoprim-Sulfamethoxazole (Bactrim DS) once per day three days per week during and for 1 month following therapy
*Acyclovir (Zovirax) 400 mg PO twice per day during and for 1 month following therapy
21-day cycle for 6 cycles
===References===
#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 EuroPMC NCT00496873
##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 EuroPMC
==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====
*Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1, 8, 15, 22
====Supportive therapy====
*Acetaminophen (Tylenol) 650 mg PO once per day on days 1, 8, 15, 22, given 30 minutes prior to rituximab
*Diphenhydramine (Benadryl) 50 mg PO once per day on days 1, 8, 15, 22, given 30 minutes prior to rituximab
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 TTFMedian 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====
*Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1, 8, 15, 22
12-week cycle for 2 cycles
===References===
#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 EuroPMC
#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 EuroPMC
#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 EuroPMC NCT01609010
##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 EuroPMC
# 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 EuroPMC 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====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5
====Supportive therapy====
*Antiemetics, antipyretics, and antibiotics per local standard of care
*G-CSF according to the American Society of Clinical Oncology guidelines
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====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 100 mg/m2 PO once per day on days 1 to 5
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 PFSMedian 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====
*Rituximab (Rituxan) as follows:
**Cycles 1, 2, 4, 6: 375 mg/m2 IV once on day -2
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5
====Supportive therapy====
*G-CSF "according to the [2000] American Society of Clinical Oncology guidelines," i.e., generally no routine use except for patients at high risk (more than 40%) for febrile neutropenia due to special circumstances
21-day cycle for 6 cycles
===References===
#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 EuroPMC
##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 EuroPMC
#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 EuroPMC NCT00147121
##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 EuroPMC
#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 EuroPMC NCT00991211
##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
##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
#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 EuroPMC NCT00877006
##HRQoL analysis: Burke JM, van der Jagt RH, Kahl BS, Wood P, Hawkins TE, MacDonald D, Hertzberg M, Simpson D, Craig M, Kolibaba K, Issa S, Munteanu M, Victor TW, Flinn IW. Differences in Quality of Life Between Bendamustine-Rituximab and R-CHOP/R-CVP in Patients With Previously Untreated Advanced Indolent Non-Hodgkin Lymphoma or Mantle Cell Lymphoma. Clin Lymphoma Myeloma Leuk. 2016 Apr;16(4):182-190.e1. Epub 2016 Jan 15. link to original article EuroPMC
##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 EuroPMC
==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====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cladribine (Leustatin) 0.10 mg/kg IV once per day on days 1 to 3
*Mitoxantrone (Novantrone) 8 mg/m2 IV once on day 1
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 8 mg/body (route not specified) on days 1 to 3
21-day cycle for 4 cycles
====Subsequent treatment====
*Rituximab consolidation
===References===
#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 EuroPMC
==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====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 or 1000 mg/m2 IV once on day 1
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5
====Supportive therapy====
*Antiemetics, antipyretics, and antibiotics per local standard of care
*G-CSF "according to the American Society of Clinical Oncology guidelines"
21-day cycle for up to 8 cycles
====Subsequent treatment====
*PLRG4: Rituximab maintenance
===References===
# 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 EuroPMC NCT00877006
##HRQoL analysis: Burke JM, van der Jagt RH, Kahl BS, Wood P, Hawkins TE, MacDonald D, Hertzberg M, Simpson D, Craig M, Kolibaba K, Issa S, Munteanu M, Victor TW, Flinn IW. Differences in Quality of Life Between Bendamustine-Rituximab and R-CHOP/R-CVP in Patients With Previously Untreated Advanced Indolent Non-Hodgkin Lymphoma or Mantle Cell Lymphoma. Clin Lymphoma Myeloma Leuk. 2016 Apr;16(4):182-190.e1. Epub 2016 Jan 15. link to original article EuroPMC
##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 EuroPMC
#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 EuroPMC 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====
*Bortezomib (Velcade) 1.6 mg/m2 IV once per day on days 1 & 8
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 1.5 mg) IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5
21-day cycle for 6 to 8 cycles
====Subsequent treatment====
*X05215, patients with CR: Rituximab maintenance
*X05215, patients with SD/PR: VR maintenance
===References===
#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 EuroPMC 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
Note: The full manuscript for Young et al. 1988 was not available for review.
No treatment other than observation.
===References===
#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 EuroPMC
#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. EuroPMC
#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 EuroPMC
=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====
*Bortezomib (Velcade) 1.6 mg/m2 IV once on day 1
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
2-month cycle for 4 cycles
===References===
#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 EuroPMC 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====
*Hainsworth et al. 2002: First-line Rituximab
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Supportive therapy====
*Acetaminophen (Tylenol) 650 mg PO once on day 1, given 30 minutes prior to rituximab
*Diphenhydramine (Benadryl) 50 mg PO once on day 1, given 30 minutes prior to rituximab
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====
*First-line R-CMD x 4
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
28-day cycle for 4 cycles
===References===
#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 EuroPMC
#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 EuroPMC
=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====
*First-line VR-CHOP x 6 to 8
====Targeted therapy====
*Bortezomib (Velcade) 1.6 mg/m2 IV once per day on days 1, 8, 15, 22
*Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1, 8, 15, 22
6-month cycle for up to 4 cycles (2 years)
===References===
#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 EuroPMC 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	Longer 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====
*Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1, 8, 15, 22
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====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
2-month cycle for 12 cycles (2 years)
===References===
#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 EuroPMC NCT00003204
##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 EuroPMC
#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====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
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 longer TTTF (primary endpoint)Median TTTF: 4.8 vs 1.4 y
====Preceding treatment====
*First-line Rituximab
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
13-week cycles
===References===
# 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 EuroPMC NCT01406782
#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====
*Axicabtagene ciloleucel (Yescarta) 2 x 106 CAR T cells/kg IV once on day 0
One course
===References===
#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 EuroPMC NCT03105336
##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 EuroPMC
==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====
*Bendamustine 120 mg/m2 IV once per day on days 1 & 2
21-day cycle for varying durations: 6 to 8 cycles (SDX-105-01 part 2); 12 cycles (Friedberg et al. 2008)
===References===
# Friedberg JW, Cohen P, Chen L, Robinson KS, Forero-Torres A, La Casce AS, Fayad LE, Bessudo A, Camacho ES, Williams ME, van der Jagt RH, Oliver JW, Cheson BD. Bendamustine in patients with rituximab-refractory indolent and transformed non-Hodgkin's lymphoma: results from a phase II multicenter, single-agent study. J Clin Oncol. 2008 Jan 10;26(2):204-10. Erratum in: J Clin Oncol. 2008 Apr 10;26(11) 1911. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 
# 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 EuroPMC 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====
*Bendamustine 90 mg/m2 IV once per day on days 1 & 2
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
28-day cycle for 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====
*Bendamustine 90 mg/m2 IV once per day on days 2 & 3
====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 	Longer 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 PFSMedian PFS: 33.3 vs 32.9 mo(HR 0.88, 95% CI 0.69-1.14)
====Chemotherapy====
*Bendamustine 90 mg/m2 IV once per day on days 1 & 2
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
28-day cycle for up to 6 cycles
===References===
#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 EuroPMC
#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 EuroPMC NCT00069758
#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 EuroPMC
#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 EuroPMC NCT01456351
#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 EuroPMC 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====
*Bortezomib (Velcade) 1.5 mg/m2 IV once per day on days 1, 4, 8, 11
====Supportive therapy====
*"Use of antiemetics, erythropoietin, and Filgrastim (Neupogen) was allowed if deemed necessary by the treating physician."
21-day cycles 
===References===
#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 EuroPMC
==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====
*Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11, given first
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1, given second
====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===
#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 EuroPMC NCT00547534
==Duvelisib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Flinn et al. 2019 (DYNAMO)	2013-2015 	Phase 2 (RT)
====Targeted therapy====
*Duvelisib (Copiktra) 25 mg PO twice per day on days 1 to 28
28-day cycles
===References===
#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 EuroPMC 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====
*Rituximab (Rituxan) 250 mg/m2 IV once per day on days 1 & 8
====Radioconjugate therapy====
*Ibritumomab tiuxetan 1.6 mg & Indium-111 5 mCi IV over 10 minutes once on day 1
*Ibritumomab tiuxetan & Yttrium-90 (Zevalin) 0.3 mCi/kg (11 MBq/kg) (maximum dose of 32 mCi/1.2 GBq) IV over 10 minutes once on day 8, given immediately following rituximab
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 	Higher ORR (primary endpoint)
====Targeted therapy====
*Rituximab (Rituxan) 250 mg/m2 IV once per day on days 1 & 8
====Radioconjugate therapy====
*Ibritumomab tiuxetan 1.6 mg & Indium-111 5 mCi IV over 10 minutes once on day 1
*Ibritumomab tiuxetan & Yttrium-90 (Zevalin) 0.4 mCi/kg (15 MBq/kg) (maximum dose of 32 mCi/1.2 GBq) IV over 10 minutes once on day 8, given immediately following rituximab
8-day course
===References===
#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 EuroPMC
#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 EuroPMC
#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 EuroPMC
==Idelalisib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Gopal et al. 2014 (DELTA)	2011-2012 	Phase 2 (RT)
====Targeted therapy====
*Idelalisib (Zydelig) 150 mg PO twice per day
Continued indefinitely
===References===
# DELTA: Gopal AK, Kahl BS, de Vos S, Wagner-Johnston ND, Schuster SJ, Jurczak WJ, Flinn IW, Flowers CR, Martin P, Viardot A, Blum KA, Goy AH, Davies AJ, Zinzani PL, Dreyling M, Johnson D, Miller LL, Holes L, Li D, Dansey RD, Godfrey WR, Salles GA. PI3Kd inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014 Mar 13;370(11):1008-18. Epub 2014 Jan 22. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01282424
## 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====
*Inotuzumab ozogamicin (Besponsa) 1.8 mg/m2 IV once on day 1
28-day cycle for 4 to 8 cycles
===References===
#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 EuroPMC NCT00868608
==Lenalidomide monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Witzig et al. 2009 (CC-5013-NHL-001)	2005-2006 	Phase 2
====Targeted therapy====
*Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
28-day cycles
===References===
#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 EuroPMC 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====
*Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 28
*Rituximab (Rituxan) as follows:
**Cycle 3: 375 mg/m2 IV once per day on days 1, 8, 15, 22
28-day cycles
===Regimen variant #2, len 20 x 2===
Study 	Dates of enrollment	Evidence
Tuscano et al. 2014 (RV-PI-NHL-0488)	Not reported 	Phase 2
====Targeted therapy====
*Lenalidomide (Revlimid) 20 mg PO once per day on days 1 to 21
*Rituximab (Rituxan) as follows:
**Cycle 1: 375 mg/m2 IV once on day 15
**Cycle 2: 375 mg/m2 IV once per day on days 1, 8, 15, 22
====Supportive therapy====
*Allopurinol (Zyloprim) as follows:
**Cycle 1: 300 mg PO once per day
*Aspirin 81 mg PO once per day
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 	Longer 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====
*Lenalidomide (Revlimid) 20 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, 22
**Cycles 2 to 5: 375 mg/m2 IV once on day 1
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====
*Lenalidomide (Revlimid) 20 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, 22
**Cycles 3, 5, 7, 9, 11: 375 mg/m2 IV once on day 1
28-day cycle for 12 cycles
====Subsequent treatment====
*Rituximab maintenance
===References===
#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 EuroPMC NCT01316523
#UPCC 02408 R2: 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 EuroPMC NCT00783367
#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 EuroPMC NCT01938001
#EZH-302: NCT04224493
#InMIND: NCT04680052
#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====
*Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 28
*Rituximab (Rituxan) as follows:
**Cycle 3: 375 mg/m2 IV once per day on days 1, 8, 15, 22
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 8 mg (route not specified) once per day on days 1, 8, 15, 22
28-day cycles
===References===
#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 EuroPMC 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 higher ORR (primary endpoint)
====Targeted therapy====
*Obinutuzumab (Gazyva) 1000 mg IV once on day 1
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===
#GAUGUIN: Salles G, Morschhauser F, Lamy T, Milpied N, Thieblemont C, Tilly H, Bieska G, Asikanius E, Carlile D, Birkett J, Pisa P, Cartron G. Phase 1 study results of the type II glycoengineered humanized anti-CD20 monoclonal antibody obinutuzumab (GA101) in B-cell lymphoma patients. Blood. 2012 May 31;119(22):5126-32. Epub 2012 Mar 19. link to original article EuroPMC NCT00517530
##Subgroup analysis: Morschhauser FA, Cartron G, Thieblemont C, Solal-Céligny P, Haioun C, Bouabdallah R, Feugier P, Bouabdallah K, Asikanius E, Lei G, Wenger M, Wassner-Fritsch E, Salles GA. Obinutuzumab (GA101) monotherapy in relapsed/refractory diffuse large B-cell lymphoma or mantle-cell lymphoma: results from the phase II GAUGUIN study. J Clin Oncol. 2013 Aug 10;31(23):2912-9. Epub 2013 Jul 8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Subgroup analysis: Salles GA, Morschhauser F, Solal-Céligny P, Thieblemont C, Lamy T, Tilly H, Gyan E, Lei G, Wenger M, Wassner-Fritsch E, Cartron G. Obinutuzumab (GA101) in patients with relapsed/refractory indolent non-Hodgkin lymphoma: results from the phase II GAUGUIN study. J Clin Oncol. 2013 Aug 10;31(23):2920-6. Epub 2013 Jul 8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Subgroup analysis: Cartron G, de Guibert S, Dilhuydy MS, Morschhauser F, Leblond V, Dupuis J, Mahe B, Bouabdallah R, Lei G, Wenger M, Wassner-Fritsch E, Hallek M. Obinutuzumab (GA101) in relapsed/refractory chronic lymphocytic leukemia: final data from the phase 1/2 GAUGUIN study. Blood. 2014 Oct 2;124(14):2196-202. Epub 2014 Aug 20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#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 EuroPMC 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====
*Prednisone (Sterapred) 20 mg PO once per day, taken after breakfast
====Chemotherapy====
*Etoposide (Vepesid) 50 mg PO once per day, taken after dinner
*Procarbazine (Matulane) 50 mg PO once per day, taken at bedtime
*Cyclophosphamide (Cytoxan) 50 mg PO once per day, taken after lunch
====Supportive therapy====
*Ondansetron (Zofran) (dose not specified) with each procarbazine dose
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===
#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 EuroPMC
==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 shorter TTTF
Sehn et al. 2015 (GAUSS) 	2009-2010 	Randomized Phase 2 (C) 	Obinutuzumab 	Might have lower ORR
====Preceding treatment====
*RESORT substudy: First-line Rituximab, with progression
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Supportive therapy====
*(not explicitly mentioned in all references)
*Acetaminophen (Tylenol) 650 mg PO once on day 1, given 30 minutes prior to rituximab
*Diphenhydramine (Benadryl) 50 mg PO once on day 1, given 30 minutes prior to rituximab
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	Shorter PFSMedian PFS: 14.1 vs 39.4 mo(HR 2.17, 95% CI 1.61-2.94)
====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	Shorter PFSMedian PFS: 13.8 vs 21.5 mo(HR 1.92, 95% CI 1.45-2.56)
====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 PFSMedian 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===
#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 EuroPMC
#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 EuroPMC
#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 EuroPMC NCT00576758
# 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 EuroPMC NCT01406782
# 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 EuroPMC NCT01938001
#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 EuroPMC NCT01200589
#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 EuroPMC 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====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 100 mg/m2 PO once per day on days 1 to 5
21-day cycle for 6 cycles
===References===
#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 EuroPMC
##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 EuroPMC
==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====
*Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1 & 8
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 8 mg PO three times per day on days 1 to 10
====Chemotherapy====
*Carmustine (BCNU) 60 mg/m2 IV once on day 3
*Etoposide (Vepesid) 75 mg/m2 IV once per day on days 4 to 7
*Cytarabine (Ara-C) 100 mg/m2 IV twice per day on days 4 to 7
*Melphalan (Alkeran) 20 mg/m2 IV once on day 2
3- to 4-week cycle for 2 cycles
====Subsequent treatment====
*R-BEAM with autologous hematopoietic stem cell transplant or R-TBI/Cy with autologous hematopoietic stem cell transplant
===References===
#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 EuroPMC 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====
*Fludarabine (Fludara) 25 mg/m2 IV once per day on days 2 to 4
*Mitoxantrone (Novantrone) 10 mg/m2 IV once on day 2
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 20 mg IV or PO once per day on days 1 to 5
28-day cycle for up to 8 cycles
====Subsequent treatment====
*Interferon alfa maintenance
===References===
#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 EuroPMC content property of HemOnc.org
#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 EuroPMC
#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 EuroPMC 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====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Antibody-drug conjugate therapy====
*Inotuzumab ozogamicin (Besponsa) 1.8 mg/m2 IV once on day 2
28-day cycle for up to 8 cycles
===References===
#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 EuroPMC NCT00299494
==Temsirolimus monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Smith et al. 2010 (NCI-6199)	Not reported 	Phase 2
====Targeted therapy====
*Temsirolimus (Torisel) 25 mg IV over 30 minutes once on day 1
7-day cycle for at least 8 cycles
===References===
#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 EuroPMC 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====
*Vorinostat (Zolinza) 200 mg PO twice per day on days 1 to 14
21-day cycles
===References===
# 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 EuroPMC NCT00253630
#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 EuroPMC 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====
*Vorinostat (Zolinza) 200 mg PO twice per day on days 1 to 14
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
21-day cycles until progression or two cycles past documented CR
===References===
#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 EuroPMC 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====
*Bendamustine 120 mg/m2 IV once per day on days 1 & 2
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 PFSMedian PFS: 13.8 vs 16.7 mo(HR 1.22, 95% CI 0.93-1.61)
====Chemotherapy====
*Bendamustine 120 mg/m2 IV once per day on days 1 & 2
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	Shorter OS1
1Reported efficacy in GADOLIN is for the FL subgroup based on the 2018 update.
====Chemotherapy====
*Bendamustine 120 mg/m2 IV once per day on days 1 & 2
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====
*Bendamustine 120 mg/m2 IV once per day on days 1 & 2
21-day cycle for up to 12 cycles
===References===
#Friedberg JW, Cohen P, Chen L, Robinson KS, Forero-Torres A, La Casce AS, Fayad LE, Bessudo A, Camacho ES, Williams ME, van der Jagt RH, Oliver JW, Cheson BD. Bendamustine in patients with rituximab-refractory indolent and transformed non-Hodgkin's lymphoma: results from a phase II multicenter, single-agent study. J Clin Oncol. 2008 Jan 10;26(2):204-10. Erratum in: J Clin Oncol. 2008 Apr 10;26(11) 1911. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#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 EuroPMC NCT00069758
#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 EuroPMC NCT01059630
##HRQoL analysis: Cheson BD, Trask PC, Gribben JG, Dimier N, Kimby E, Lugtenburg PJ, Thieblemont C, Wassner-Fritsch E, Launonen A, Sehn LH. Health-related quality of life and symptoms in patients with rituximab-refractory indolent non-Hodgkin lymphoma treated in the phase III GADOLIN study with obinutuzumab plus bendamustine versus bendamustine alone. Ann Hematol. 2017 Feb;96(2):253-259. link to original article link to EuroPMC
##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 EuroPMC
#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 EuroPMC 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	Longer OS1 (secondary endpoint)Median OS: NYR vs 53.9 mo(HR 0.58, 95% CI 0.39-0.86)Longer 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====
*Bendamustine 90 mg/m2 IV once per day on days 1 & 2
====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====
*Obinutuzumab maintenance
===References===
#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 EuroPMC NCT01059630
##HRQoL analysis: Cheson BD, Trask PC, Gribben JG, Dimier N, Kimby E, Lugtenburg PJ, Thieblemont C, Wassner-Fritsch E, Launonen A, Sehn LH. Health-related quality of life and symptoms in patients with rituximab-refractory indolent non-Hodgkin lymphoma treated in the phase III GADOLIN study with obinutuzumab plus bendamustine versus bendamustine alone. Ann Hematol. 2017 Feb;96(2):253-259. link to original article link to EuroPMC
##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 EuroPMC
==Obinutuzumab monotherapy==
===Regimen=== 
Study 	Dates of enrollment	Evidence
Sehn et al. 2016 (GADOLIN)	2010-2014 	Non-randomized part of phase 3 RCT
====Preceding treatment====
*Salvage Bendamustine & Obinutuzumab x 6
====Targeted therapy====
*Obinutuzumab (Gazyva) 1000 mg IV once on day 1
2-month cycle for 12 cycles
===References===
#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 EuroPMC NCT01059630
##HRQoL analysis: Cheson BD, Trask PC, Gribben JG, Dimier N, Kimby E, Lugtenburg PJ, Thieblemont C, Wassner-Fritsch E, Launonen A, Sehn LH. Health-related quality of life and symptoms in patients with rituximab-refractory indolent non-Hodgkin lymphoma treated in the phase III GADOLIN study with obinutuzumab plus bendamustine versus bendamustine alone. Ann Hematol. 2017 Feb;96(2):253-259. link to original article link to EuroPMC
##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 EuroPMC
=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====
*Bortezomib (Velcade) 1.6 mg/m2 IV once on day 1
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
2-month cycle for 4 cycles
===References===
#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 EuroPMC 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====
*Salvage R-DexaBEAM x 2
===References===
#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 EuroPMC 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====
*Salvage R-DexaBEAM x 2
===References===
#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 EuroPMC 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====
*Salvage Lenalidomide & Rituximab
====Targeted therapy====
*Lenalidomide (Revlimid) 20 mg PO once per day on days 1 to 21
====Supportive therapy====
*Aspirin 81 mg PO once per day
28-day cycles
===References===
#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 EuroPMC 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====
*Salvage Obinutuzumab
====Targeted therapy====
*Obinutuzumab (Gazyva) 1000 mg IV once on day 1
2-month cycle for 12 cycles
===References===
#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 EuroPMC 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====
*Salvage Rituximab
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
2-month cycle for up to 12 cycles (2 years)
===References===
#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 EuroPMC NCT00576758
=Response criteria=
==NCI Sponsored International Working Group Criteria (1999)==
#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 EuroPMC
Category:Indolent lymphoma regimens
Category:Disease-specific pages
Category:Indolent lymphomas
Category:B-cell lymphomas