Follicular lymphoma

Back to Top
Are you looking for a regimen but can't find it here? It is possible that we've moved it to the historical regimens page. For placebo or observational studies in this condition, other than watchful waiting, please visit this page. If you still can't find it, please let us know so we can add it!
Note: this page has regimens which are specific to follicular lymphoma. Please see the indolent lymphoma page for other regimens that have been tested in the broader population.
*We have moved How I Treat articles to a dedicated page.
Last updated on 2024-12-02:57 regimens on this page
90 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.
==BSH==
*2020: McNamara et al. The investigation and management of follicular lymphoma EuroPMC
**2012: McNamara et al. Guidelines on the investigation and management of follicular lymphoma EuroPMC
==ESMO==
*2020: Dreyling et al. Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2016: Dreyling et al. Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2014: Dreyling et al. Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2011: Dreyling et al. Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2010: Dreyling. Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2009: Dreyling. Newly diagnosed and relapsed follicular lymphoma: ESMO clinical recommendations for diagnosis, treatment and follow-up EuroPMC
**2008: Dreyling. Newly diagnosed and relapsed follicular lymphoma: ESMO clinical recommendations for diagnosis, treatment and follow-up EuroPMC
**2003: Hiddemann. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of newly diagnosed follicular lymphoma EuroPMC
*2013: Ghielmini et al. ESMO Guidelines consensus conference on malignant lymphoma 2011 part 1: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL) EuroPMC
==NCCN==
*NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - B-cell Lymphomas.
=Early disease, definitive therapy=
==Radiation therapy==
RT: Radiation Therapy
===Regimen===
Study 	Dates of enrollment	Evidence
MacManus et al. 2018 (TROG 99.03)	2000-2012 	Non-randomized part of phase 3 RCT
This is the current "standard dose" radiotherapy - dose varies per protocol and location radiated.
====Radiotherapy====
*External beam radiotherapy 2400 to 3600 cGy
====Subsequent treatment====
*Adjuvant CVP or R-CVP versus no further treatment
===References===
#TROG 99.03: MacManus M, Fisher R, Roos D, O'Brien P, Macann A, Davis S, Tsang R, Christie D, McClure B, Joseph D, Jayamohan J, Seymour JF. Randomized trial of systemic therapy after involved-field radiotherapy in patients with early-stage follicular lymphoma: TROG 99.03. J Clin Oncol. 2018 Oct 10;36(29):2918-2925. Epub 2018 Jul 5. link to original article EuroPMC NCT00115700
##Update: MacManus MP, Seymour JF, Tsang H, Fisher R, Keane C, Sabdia MB, Law SC, Gunawardana J, Nath K, Kazakoff SH, Marques-Piubelli ML, Duenas DE, Green MR, Roos D, O'Brien P, McCann A, Tsang R, Davis S, Christie D, Cheah C, Amanuel B, Cochrane T, Butler J, Johnston A, Shanavas M, Li L, Vajdic C, Kridel R, Shelton V, Hershenfield S, Baetz T, Lebrun D, Johnson N, Brodtkorb M, Ludvigsen M, d'Amore F, Thompson ER, Blombery P, Gandhi MK, Tobin JWD. Adjuvant rituximab and elevated intratumoural CD8 expression are associated with sustained disease control after radiotherapy in a randomised trial of systemic therapy in early-stage follicular lymphoma. EBioMedicine. 2024 Dec;110:105468. Epub 2024 Dec 3. link to original article EuroPMC
=Advanced disease, first-line therapy, randomized data=
==Bendamustine & Obinutuzumab==
G-B: Gazyva (Obinutuzumab) & Bendamustine
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy	Comparative Toxicity
Marcus et al. 2017 (GALLIUM)	2011-2014 	Phase 3 (E-RT-switch-ic)	See link 	See link 	See link
====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===
#GALLIUM: Marcus R, Davies A, Ando K, Klapper W, Opat S, Owen C, Phillips E, Sangha R, Schlag R, Seymour JF, Townsend W, Trněný M, Wenger M, Fingerle-Rowson G, Rufibach K, Moore T, Herold M, Hiddemann W. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med. 2017 Oct 5;377(14):1331-1344. link to original article link to appendix dosing details in supplement have been reviewed by our editors EuroPMC NCT01332968
##Update: Hiddemann W, Barbui AM, Canales MA, Cannell PK, Collins GP, Dürig J, Forstpointner R, Herold M, Hertzberg M, Klanova M, Radford J, Seymour JF, Tobinai K, Trotman J, Burciu A, Fingerle-Rowson G, Wolbers M, Nielsen T, Marcus RE. Immunochemotherapy with obinutuzumab or rituximab for previously untreated follicular lymphoma in the GALLIUM study: influence of chemotherapy on efficacy and safety. J Clin Oncol. 2018 Aug 10;36(23):2395-2404. Epub 2018 Jun 1. link to original article EuroPMC
##HRQoL analysis: Davies A, Trask P, Demeter J, Florschütz A, Hänel M, Kinoshita T, Pettengell R, Quach H, Robinson S, Sadullah S, Sancho JM, Udvardy M, Witzens-Harig M, Knapp A, Liu W. Health-related quality of life in the phase III GALLIUM study of obinutuzumab- or rituximab-based chemotherapy in patients with previously untreated advanced follicular lymphoma. Ann Hematol. 2020 Dec;99(12):2837-2846. link to original article link to EuroPMC
==Bendamustine & Rituximab (BR)==
BR: Bendamustine & Rituximab
R-B: Rituximab & Bendamustine
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Marcus et al. 2017 (GALLIUM) 	2011-2014 	Phase 3 (C)	See link 	See link 	See link
Morschhauser et al. 2018 (RELEVANCE)	2011-2014 	Phase 3 (C)	Lenalidomide & Rituximab	Did not meet co-primary endpoints of CR rate/PFS	Different toxicity
Paikaray et al. 2023 	2016-01 to 2019-07 	Phase 3 (C)	Lenalidomide & Rituximab	Did not meet primary endpoint of CR rate 	
====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
====Subsequent treatment====
*GALLIUM & RELEVANCE: Rituximab maintenance
===References===
#GALLIUM: Marcus R, Davies A, Ando K, Klapper W, Opat S, Owen C, Phillips E, Sangha R, Schlag R, Seymour JF, Townsend W, Trněný M, Wenger M, Fingerle-Rowson G, Rufibach K, Moore T, Herold M, Hiddemann W. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med. 2017 Oct 5;377(14):1331-1344. link to original article link to appendix dosing details in supplement have been reviewed by our editors EuroPMC NCT01332968
##Update: Hiddemann W, Barbui AM, Canales MA, Cannell PK, Collins GP, Dürig J, Forstpointner R, Herold M, Hertzberg M, Klanova M, Radford J, Seymour JF, Tobinai K, Trotman J, Burciu A, Fingerle-Rowson G, Wolbers M, Nielsen T, Marcus RE. Immunochemotherapy with obinutuzumab or rituximab for previously untreated follicular lymphoma in the GALLIUM study: influence of chemotherapy on efficacy and safety. J Clin Oncol. 2018 Aug 10;36(23):2395-2404. Epub 2018 Jun 1. link to original article EuroPMC
##HRQoL analysis: Davies A, Trask P, Demeter J, Florschütz A, Hänel M, Kinoshita T, Pettengell R, Quach H, Robinson S, Sadullah S, Sancho JM, Udvardy M, Witzens-Harig M, Knapp A, Liu W. Health-related quality of life in the phase III GALLIUM study of obinutuzumab- or rituximab-based chemotherapy in patients with previously untreated advanced follicular lymphoma. Ann Hematol. 2020 Dec;99(12):2837-2846. link to original article link to EuroPMC
#RELEVANCE: Morschhauser F, Fowler NH, Feugier P, Bouabdallah R, Tilly H, Palomba ML, Fruchart C, Libby EN, Casasnovas RO, Flinn IW, Haioun C, Maisonneuve H, Ysebaert L, Bartlett NL, Bouabdallah K, Brice P, Ribrag V, Daguindau N, Le Gouill S, Pica GM, Martin Garcia-Sancho A, López-Guillermo A, Larouche JF, Ando K, Gomes da Silva M, André M, Zachée P, Sehn LH, Tobinai K, Cartron G, Liu D, Wang J, Xerri L, Salles GA; RELEVANCE Trial Investigators. Rituximab plus lenalidomide in advanced untreated follicular lymphoma. N Engl J Med. 2018 Sep 6;379(10):934-947. link to original article dosing details in supplement have been reviewed by our editors link to PMC article EuroPMC NCT01650701
##Update: Morschhauser F, Nastoupil L, Feugier P, Schiano de Colella JM, Tilly H, Palomba ML, Bachy E, Fruchart C, Libby EN, Casasnovas RO, Flinn IW, Haioun C, Maisonneuve H, Ysebaert L, Bartlett NL, Bouabdallah K, Brice P, Ribrag V, Le Gouill S, Daguindau N, Guidez S, Pica GM, García-Sancho AM, López-Guillermo A, Larouche JF, Ando K, Gomes da Silva M, André M, Kalung W, Sehn LH, Izutsu K, Cartron G, Gkasiamis A, Crowe R, Xerri L, Fowler NH, Salles G. Six-Year Results From RELEVANCE: Lenalidomide Plus Rituximab (R2) Versus Rituximab-Chemotherapy Followed by Rituximab Maintenance in Untreated Advanced Follicular Lymphoma. J Clin Oncol. 2022 Oct 1;40(28):3239-3245. Epub 2022 Aug 10. link to original article link to PMC article EuroPMC
#Paikaray SK, Gogia A, Kumar L, Sharma A, Biswas AA, Vishnubhatla S, Mallick S. A Phase III open-label randomized study to compare the efficacy of lenalidomide-rituximab with bendamustine-rituximab in treatment-naïve follicular lymphoma. Indian J Cancer. 2023 Oct 1;60(4):501-504. Epub 2024 Jan 4. link to original article dosing details in abstract have been reviewed by our editors EuroPMC CTRI/2016/05/006904
==Cyclophosphamide monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Peterson et al. 2003 (CALGB 7951)	1980-1985 	Phase 3 (E-de-esc)	CHOP-B 	Did not meet primary endpoint of OS
Smith et al. 2009 (CALGB 8691) 	1986-1991 	Phase 3 (C) 	Cyclophosphamide & IFN alfa-2a	Did not meet primary endpoint of EFS
Note: This was an experimental arm that did not meet its primary endpoint; included here because it was eventually used to establish this regimen as a standard comparator.
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day
Treatment continued in responders for 2 years beyond maximal response
====Dose and schedule modifications====
*Dose modifications according to WBC and platelet count as listed in Table 1 of Peterson et al. 2003
===References===
#CALGB 7951: Peterson BA, Petroni GR, Frizzera G, Barcos M, Bloomfield CD, Nissen NI, Hurd DD, Henderson ES, Sartiano GP, Johnson JL, Holland JF, Gottlieb AJ. Prolonged single-agent versus combination chemotherapy in indolent follicular lymphomas: a study of the Cancer and Leukemia Group B. J Clin Oncol. 2003 Jan 1;21(1):5-15. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#CALGB 8691: Smith SM, Johnson J, Cheson BD, Canellos G, Petroni G, Oken M, Duggan D, Hurd D, Gockerman JP, Parker B, Prchal J, Peterson BA; CALGB; ECOG. Recombinant interferon-alpha2b added to oral cyclophosphamide either as induction or maintenance in treatment-naive follicular lymphoma: final analysis of CALGB 8691. Leuk Lymphoma. 2009 Oct;50(10):1606-17. link to original article link to PMC article EuroPMC
==G-CVP==
G-CVP: Gazyva (Obinutuzumab), Cyclophosphamide, Vincristine, Prednisone
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy	Comparative Toxicity
Marcus et al. 2017 (GALLIUM)	2011-2014 	Phase 3 (E-RT-switch-ic)	See link 	See link 	See link
Note: Patients received obinutuzumab only in cycles 7 & 8.
====Targeted therapy====
*Obinutuzumab (Gazyva) as follows:
**Cycle 1: 1000 mg IV once per day on days 1, 8, 15
**Cycles 2 to 8: 1000 mg IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 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
21-day cycle for 8 cycles
====Subsequent treatment====
*Obinutuzumab maintenance
===References===
#GALLIUM: Marcus R, Davies A, Ando K, Klapper W, Opat S, Owen C, Phillips E, Sangha R, Schlag R, Seymour JF, Townsend W, Trněný M, Wenger M, Fingerle-Rowson G, Rufibach K, Moore T, Herold M, Hiddemann W. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med. 2017 Oct 5;377(14):1331-1344. link to original article link to appendix dosing details in supplement have been reviewed by our editors EuroPMC NCT01332968
##Update: Hiddemann W, Barbui AM, Canales MA, Cannell PK, Collins GP, Dürig J, Forstpointner R, Herold M, Hertzberg M, Klanova M, Radford J, Seymour JF, Tobinai K, Trotman J, Burciu A, Fingerle-Rowson G, Wolbers M, Nielsen T, Marcus RE. Immunochemotherapy with obinutuzumab or rituximab for previously untreated follicular lymphoma in the GALLIUM study: influence of chemotherapy on efficacy and safety. J Clin Oncol. 2018 Aug 10;36(23):2395-2404. Epub 2018 Jun 1. link to original article EuroPMC
##HRQoL analysis: Davies A, Trask P, Demeter J, Florschütz A, Hänel M, Kinoshita T, Pettengell R, Quach H, Robinson S, Sadullah S, Sancho JM, Udvardy M, Witzens-Harig M, Knapp A, Liu W. Health-related quality of life in the phase III GALLIUM study of obinutuzumab- or rituximab-based chemotherapy in patients with previously untreated advanced follicular lymphoma. Ann Hematol. 2020 Dec;99(12):2837-2846. link to original article link to EuroPMC
==G-CHOP==
G-CHOP: Gazyva (Obinutuzumab), Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Predniso(lo)ne
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy	Comparative Toxicity
Marcus et al. 2017 (GALLIUM)	2011-2014 	Phase 3 (E-RT-switch-ic)	See link 	See link 	See link
Note: Patients received obinutuzumab only in cycles 7 & 8.
====Targeted therapy====
*Obinutuzumab (Gazyva) as follows:
**Cycle 1: 1000 mg IV once per day on days 1, 8, 15
**Cycles 2 to 8: 1000 mg 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
21-day cycle for 8 cycles
====Subsequent treatment====
*Obinutuzumab maintenance
===References===
#GALLIUM: Marcus R, Davies A, Ando K, Klapper W, Opat S, Owen C, Phillips E, Sangha R, Schlag R, Seymour JF, Townsend W, Trněný M, Wenger M, Fingerle-Rowson G, Rufibach K, Moore T, Herold M, Hiddemann W. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med. 2017 Oct 5;377(14):1331-1344. link to original article link to appendix dosing details in supplement have been reviewed by our editors EuroPMC NCT01332968
##Update: Hiddemann W, Barbui AM, Canales MA, Cannell PK, Collins GP, Dürig J, Forstpointner R, Herold M, Hertzberg M, Klanova M, Radford J, Seymour JF, Tobinai K, Trotman J, Burciu A, Fingerle-Rowson G, Wolbers M, Nielsen T, Marcus RE. Immunochemotherapy with obinutuzumab or rituximab for previously untreated follicular lymphoma in the GALLIUM study: influence of chemotherapy on efficacy and safety. J Clin Oncol. 2018 Aug 10;36(23):2395-2404. Epub 2018 Jun 1. link to original article EuroPMC
##HRQoL analysis: Davies A, Trask P, Demeter J, Florschütz A, Hänel M, Kinoshita T, Pettengell R, Quach H, Robinson S, Sadullah S, Sancho JM, Udvardy M, Witzens-Harig M, Knapp A, Liu W. Health-related quality of life in the phase III GALLIUM study of obinutuzumab- or rituximab-based chemotherapy in patients with previously untreated advanced follicular lymphoma. Ann Hematol. 2020 Dec;99(12):2837-2846. link to original article link to EuroPMC
==Lenalidomide & Rituximab (R2)==
R2: Rituximab & Revlimid (Lenalidomide)
===Regimen variant #1===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Zucca et al. 2019 (SAKK 35/10)	2011-2013 	Randomized Phase 2 (E-esc)	Rituximab 	Might have higher CR/CRu rate at 6 months (composite primary endpoint)
====Targeted therapy====
*Lenalidomide (Revlimid) 15 mg PO once per day, starting 14 days prior to first rituximab infusion and continuing until 14 days past last rituximab infusion
*Rituximab (Rituxan) as follows:
**Cycles 1 & 3: 375 mg/m2 IV once per day on days 1, 8, 15, 22
28-day cycle for 4 cycles
===Regimen variant #3===
Study 	Dates of enrollment	Evidence
Martin et al. 2017 (CALGB 50803)	2010-10 to 2011-09 	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 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 12 cycles
===Regimen variant #3===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Morschhauser et al. 2018 (RELEVANCE)	2011-2014 	Phase 3 (E-switch-ooc)	1a. R-B1b. R-CHOP1c. R-CVP	Did not meet co-primary endpoints of CR rate/PFS	Different toxicity
====Targeted therapy====
*Lenalidomide (Revlimid) 20 mg PO once per day on days 2 to 22
*Rituximab (Rituxan) as follows:
**Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15, 22
**Cycles 2 to 6: 375 mg/m2 IV once on day 1
28-day cycle for 6 cycles
====Subsequent treatment====
*RELEVANCE, responders: Lenalidomide & Rituximab maintenance
===References===
#SAKK 35/10: Zucca E, Rondeau S, Vanazzi A, Østenstad B, Mey UJM, Rauch D, Wahlin BE, Hitz F, Hernberg M, Johansson AS, de Nully Brown P, Hagberg H, Ferreri AJM, Lohri A, Novak U, Zander T, Bersvendsen H, Bargetzi M, Mingrone W, Krasniqi F, Dirnhofer S, Hayoz S, Hawle H, Vilei SB, Ghielmini M, Kimby E; Swiss Group for Clinical Cancer Research; Nordic Lymphoma Group. Short regimen of rituximab plus lenalidomide in follicular lymphoma patients in need of first-line therapy. Blood. 2019 Jul 25;134(4):353-362. Epub 2019 May 17. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01307605
#CALGB 50803: Martin P, Jung SH, Pitcher B, Bartlett NL, Blum KA, Shea T, Hsi ED, Ruan J, Smith SE, Leonard JP, Cheson BD. A phase II trial of lenalidomide plus rituximab in previously untreated follicular non-Hodgkin's lymphoma (NHL): CALGB 50803 (Alliance). Ann Oncol. 2017 Nov 1;28(11):2806-2812. link to original article dosing details in abstract have been reviewed by our editors link to PMC article EuroPMC NCT01145495
#RELEVANCE: Morschhauser F, Fowler NH, Feugier P, Bouabdallah R, Tilly H, Palomba ML, Fruchart C, Libby EN, Casasnovas RO, Flinn IW, Haioun C, Maisonneuve H, Ysebaert L, Bartlett NL, Bouabdallah K, Brice P, Ribrag V, Daguindau N, Le Gouill S, Pica GM, Martin Garcia-Sancho A, López-Guillermo A, Larouche JF, Ando K, Gomes da Silva M, André M, Zachée P, Sehn LH, Tobinai K, Cartron G, Liu D, Wang J, Xerri L, Salles GA; RELEVANCE Trial Investigators. Rituximab plus lenalidomide in advanced untreated follicular lymphoma. N Engl J Med. 2018 Sep 6;379(10):934-947. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01650701
##Update: Morschhauser F, Nastoupil L, Feugier P, Schiano de Colella JM, Tilly H, Palomba ML, Bachy E, Fruchart C, Libby EN, Casasnovas RO, Flinn IW, Haioun C, Maisonneuve H, Ysebaert L, Bartlett NL, Bouabdallah K, Brice P, Ribrag V, Le Gouill S, Daguindau N, Guidez S, Pica GM, García-Sancho AM, López-Guillermo A, Larouche JF, Ando K, Gomes da Silva M, André M, Kalung W, Sehn LH, Izutsu K, Cartron G, Gkasiamis A, Crowe R, Xerri L, Fowler NH, Salles G. Six-Year Results From RELEVANCE: Lenalidomide Plus Rituximab (R2) Versus Rituximab-Chemotherapy Followed by Rituximab Maintenance in Untreated Advanced Follicular Lymphoma. J Clin Oncol. 2022 Oct 1;40(28):3239-3245. Epub 2022 Aug 10. link to original article link to PMC article EuroPMC
==R-CHOP==
R-CHOP: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone
===Regimen variant #1, 3 cycles with prednisone 100 mg===
Study 	Dates of enrollment	Evidence
Hainsworth et al. 2005a	2000-2001 	Phase 2
Hainsworth et al. 2009 	2002-04 to 2004-03 	Phase 2
Note: this was a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
====Targeted therapy====
*Rituximab (Rituxan) as follows:
**Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15, 22
**Cycles 2 to 4: 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) as follows:
**Cycles 2 to 4: 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) as follows:
**Cycles 2 to 4: 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) as follows:
**Cycles 2 to 4: 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) as follows:
**Cycles 2 to 4: 100 mg PO once per day on days 1 to 5
28-day course, then 21-day cycle for 3 cycles
====Subsequent treatment====
*Hainsworth et al. 2005a: Rituximab consolidation
*Hainsworth et al. 2009: Ibritumumab tiuxetan consolidation, in 4 weeks
===Regimen variant #2, 3 cycles with prednisone 100 mg/m2===
Study 	Dates of enrollment	Evidence
Jacobs et al. 2008 (UPCI 03-005)	2004-03 to 2007-02 	Phase 2
Note: this was a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. R-CHOP given as per standard ECOG dosing, except that rituximab is given on day 1 of each cycle:
====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/m2 PO once per day on days 1 to 5
====Supportive therapy====
*Filgrastim (Neupogen) "recommended according to guidelines"
21-day cycle for 3 cycles
====Subsequent treatment====
*Ibritumumab tiuxetan consolidation
===Regimen variant #3, prednisone 100 mg, 6+2===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Salles et al. 2010 (PRIMAFL) 	2004-2007 	Non-randomized part of phase 3 RCT	 	 	
Marcus et al. 2017 (GALLIUM) 	2011-2014 	Phase 3 (C) 	See link 	See link 	See link
Morschhauser et al. 2018 (RELEVANCE)	2011-2014 	Phase 3 (C) 	Lenalidomide & Rituximab	Did not meet co-primary endpoints of CR rate/PFS	Different toxicity
Note: In PRIMA, initial therapy was investigator's choice.
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) as follows:
**Cycles 1 to 6: 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) as follows:
**Cycles 1 to 6: 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) as follows:
**Cycles 1 to 6: 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) as follows:
**Cycles 1 to 6: 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 8 cycles
====Subsequent treatment====
*PRIMAFL, responders (PR or CR): Rituximab maintenance versus no further treatment
*GALLIUM & RELEVANCE: Rituximab maintenance
===Regimen variant #4, prednisone 100 mg/m2===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy 	Comparative Toxicity
Hiddemann et al. 2005 (GLSG '00)	2000-2003 	Phase 3 (E-esc)	CHOP 	Seems to have longer OS (secondary endpoint) 	Increased toxicity
Federico et al. 2013 (FOLL05) 	2006-2010 	Phase 3 (E-esc)	1. R-CVP 	Seems to have longer PFS (secondary endpoint)	
Federico et al. 2013 (FOLL05) 	2006-2010 	Phase 3 (E-esc)	2. R-FM 	Did not meet primary endpoint of TTF 	
In FOLL05, PFS was longer than R-CVP but equivalent to R-FM; risk/benefit ratio was better than R-FM. Patients in FOLL05 received a total of 8 doses of rituximab, regardless of the number of CHOP cycles.
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on either day 1 or 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/m2 PO once per day on days 1 to 5
21-day cycle for 6 to 8 cycles
===Regimen variant #5, variant rituximab schedule===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Czuczman et al. 1999 	Not reported 	Phase 2 	 	
Press et al. 2012 (SWOG S0016)	2001-2008 	Phase 3 (C)	CHOP, then 131Iodine-Tositumomab	Shorter PFS1
1Reported efficacy for SWOG S0016 is based on the 2018 update.
In SWOG S0016, this regimen was intended for patients greater than 18 years with untreated bulky stage II or stage III-IV FL (all grades) expressing CD20.
====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 #7, 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
#Hainsworth JD, Litchy S, Morrissey LH, Andrews MB, Grimaldi M, McCarty M, Greco FA. Rituximab plus short-duration chemotherapy as first-line treatment for follicular non-Hodgkin's lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol. 2005 Mar 1;23(7):1500-6. Epub 2005 Jan 4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#GLSG '00: Hiddemann W, Kneba M, Dreyling M, Schmitz N, Lengfelder E, Schmits R, Reiser M, Metzner B, Harder H, Hegewisch-Becker S, Fischer T, Kropff M, Reis HE, Freund M, Wörmann B, Fuchs R, Planker M, Schimke J, Eimermacher H, Trümper L, Aldaoud A, Parwaresch R, Unterhalt M. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2005 Dec 1;106(12):3725-32. Epub 2005 Aug 25. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#UPCI 03-005: Jacobs SA, Swerdlow SH, Kant J, Foon KA, Jankowitz R, Land SR, DeMonaco N, Joyce J, Osborn JL, Evans TL, Schaefer PM, Luong TM. Phase II trial of short-course CHOP-R followed by 90Y-ibritumomab tiuxetan and extended rituximab in previously untreated follicular lymphoma. Clin Cancer Res. 2008 Nov 1;14(21):7088-94. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00177554
#Hainsworth JD, Spigel DR, Markus TM, Shipley D, Thompson D, Rotman R, Dannaher C, Greco FA. Rituximab plus short-duration chemotherapy followed by yttrium-90 ibritumomab tiuxetan as first-line treatment for patients with follicular non-Hodgkin lymphoma: a phase II trial of the Sarah Cannon Oncology Research Consortium. Clin Lymphoma Myeloma. 2009 Jun;9(3):223-8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#PRIMAFL: Salles G, Seymour JF, Offner F, López-Guillermo A, Belada D, Xerri L, Feugier P, Bouabdallah R, Catalano JV, Brice P, Caballero D, Haioun C, Pedersen LM, Delmer A, Simpson D, Leppa S, Soubeyran P, Hagenbeek A, Casasnovas O, Intragumtornchai T, Fermé C, da Silva MG, Sebban C, Lister A, Estell JA, Milone G, Sonet A, Mendila M, Coiffier B, Tilly H. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet. 2011 Jan 1;377(9759):42-51. Epub 2010 Dec 20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00140582
##HRQoL analysis: Zhou X, Wang J, Zhang J, Copley-Merriman C, Torigoe Y, Reyes C, Seymour JF, Offner FC, Trneny M, Salles GA. Symptoms and toxicity of rituximab maintenance relative to observation following immunochemotherapy in patients with follicular lymphoma. Hematology. 2015 Apr;20(3):129-36. Epub 2014 Jul 16. link to original article EuroPMC
##Update: Bachy E, Seymour JF, Feugier P, Offner F, López-Guillermo A, Belada D, Xerri L, Catalano JV, Brice P, Lemonnier F, Martin A, Casasnovas O, Pedersen LM, Dorvaux V, Simpson D, Leppa S, Gabarre J, da Silva MG, Glaisner S, Ysebaert L, Vekhoff A, Intragumtornchai T, Le Gouill S, Lister A, Estell JA, Milone G, Sonet A, Farhi J, Zeuner H, Tilly H, Salles G. Sustained Progression-Free Survival Benefit of Rituximab Maintenance in Patients With Follicular Lymphoma: Long-Term Results of the PRIMA Study. J Clin Oncol. 2019 Nov 1;37(31):2815-2824. Epub 2019 Jul 24. link to original article link to PMC 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
##Update: 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
#SWOG S0016: Press OW, Unger JM, Rimsza LM, Friedberg JW, LeBlanc M, Czuczman MS, Kaminski M, Braziel RM, Spier C, Gopal AK, Maloney DG, Cheson BD, Dakhil SR, Miller TP, Fisher RI. Phase III randomized intergroup trial of CHOP plus rituximab compared with CHOP chemotherapy plus 131Iodine-tositumomab for previously untreated follicular non-Hodgkin lymphoma: SWOG S0016. J Clin Oncol. 2013 Jan 20;31(3):314-20. Epub 2012 Dec 10. link to original article link to PMC article EuroPMC NCT00006721
##Update: Shadman M, Li H, Rimsza L, Leonard JP, Kaminski MS, Braziel RM, Spier CM, Gopal AK, Maloney DG, Cheson BD, Dakhil S, LeBlanc M, Smith SM, Fisher RI, Friedberg JW, Press OW. Continued excellent outcomes in previously untreated patients with follicular lymphoma after treatment with CHOP plus rituximab or CHOP plus (131)I-tositumomab: long-term follow-up of phase III randomized study SWOG-S0016. J Clin Oncol. 2018 Mar 1;36(7):697-703. Epub 2018 Jan 22. link to original article link to PMC article EuroPMC
#FOLL05: Federico M, Luminari S, Dondi A, Tucci A, Vitolo U, Rigacci L, Di Raimondo F, Carella AM, Pulsoni A, Merli F, Arcaini L, Angrilli F, Stelitano C, Gaidano G, Dell'olio M, Marcheselli L, Franco V, Galimberti S, Sacchi S, Brugiatelli M. R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage follicular lymphoma: results of the FOLL05 trial conducted by the Fondazione Italiana Linfomi. J Clin Oncol. 2013 Apr 20;31(12):1506-13. Epub 2013 Mar 25. Erratum in: J Clin Oncol. 2014 Apr 1;32(10):1095. Dosage error in article text. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00774826
##Update: Luminari S, Ferrari A, Manni M, Dondi A, Chiarenza A, Merli F, Rusconi C, Tarantino V, Tucci A, Vitolo U, Kovalchuk S, Angelucci E, Pulsoni A, Arcaini L, Angrilli F, Gaidano G, Stelitano C, Bertoldero G, Cascavilla N, Salvi F, Ferreri AJM, Vallisa D, Marcheselli L, Federico M. Long-term results of the FOLL05 trial comparing R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage symptomatic follicular lymphoma. J Clin Oncol. 2018 Mar 1;36(7):689-696. Epub 2017 Nov 2. link to original article EuroPMC
#Abstract: Armando Lopez-Guillermo, MD, PhD, Miguel A. Canales, MD, PhD, Ivan Dlouhy, Javier Briones, MD, Dolores Caballero, MD, PhD, Juan Manuel Sancho Sr., MD, Santiago Mercadal Vilchez, MD, Jose María Moraleda, MD, María José Terol, MD, PhD, Antonio Salar, MD, Luis Palomera, MD, Santiago Gardella, MD, Isidro Jarque, MD, Secundino Ferrer, Joan Bargay, MD, Andres Lopez, Carlos Panizo, Anna Muntanola, MD, Carlos Montalban, Eulogio Conde, MD, PhD, Miguel Hernandez, MD, Alfons Soler, Julian Marin, MD, Jose García Marco, Guillermo Deben and José Francisco Tomas, MD, PhD. A Randomized Phase II Study Comparing Consolidation With a Single Dose Of 90y Ibritumomab Tiuxetan (Zevalin®) (Z) Vs. Maintenance With Rituximab (R) For Two Years In Patients With Newly Diagnosed Follicular Lymphoma (FL) Responding To R-CHOP. Preliminary Results At 36 Months From Randomization. Blood 2013 122:369. link to abstract
#GALLIUM: Marcus R, Davies A, Ando K, Klapper W, Opat S, Owen C, Phillips E, Sangha R, Schlag R, Seymour JF, Townsend W, Trněný M, Wenger M, Fingerle-Rowson G, Rufibach K, Moore T, Herold M, Hiddemann W. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med. 2017 Oct 5;377(14):1331-1344. link to original article link to appendix dosing details in supplement have been reviewed by our editors EuroPMC NCT01332968
##Update: Hiddemann W, Barbui AM, Canales MA, Cannell PK, Collins GP, Dürig J, Forstpointner R, Herold M, Hertzberg M, Klanova M, Radford J, Seymour JF, Tobinai K, Trotman J, Burciu A, Fingerle-Rowson G, Wolbers M, Nielsen T, Marcus RE. Immunochemotherapy with obinutuzumab or rituximab for previously untreated follicular lymphoma in the GALLIUM study: influence of chemotherapy on efficacy and safety. J Clin Oncol. 2018 Aug 10;36(23):2395-2404. Epub 2018 Jun 1. link to original article EuroPMC
##HRQoL analysis: Davies A, Trask P, Demeter J, Florschütz A, Hänel M, Kinoshita T, Pettengell R, Quach H, Robinson S, Sadullah S, Sancho JM, Udvardy M, Witzens-Harig M, Knapp A, Liu W. Health-related quality of life in the phase III GALLIUM study of obinutuzumab- or rituximab-based chemotherapy in patients with previously untreated advanced follicular lymphoma. Ann Hematol. 2020 Dec;99(12):2837-2846. link to original article link to EuroPMC
#RELEVANCE: Morschhauser F, Fowler NH, Feugier P, Bouabdallah R, Tilly H, Palomba ML, Fruchart C, Libby EN, Casasnovas RO, Flinn IW, Haioun C, Maisonneuve H, Ysebaert L, Bartlett NL, Bouabdallah K, Brice P, Ribrag V, Daguindau N, Le Gouill S, Pica GM, Martin Garcia-Sancho A, López-Guillermo A, Larouche JF, Ando K, Gomes da Silva M, André M, Zachée P, Sehn LH, Tobinai K, Cartron G, Liu D, Wang J, Xerri L, Salles GA; RELEVANCE Trial Investigators. Rituximab plus lenalidomide in advanced untreated follicular lymphoma. N Engl J Med. 2018 Sep 6;379(10):934-947. link to original article dosing details in supplement have been reviewed by our editors link to PMC article EuroPMC NCT01650701
##Update: Morschhauser F, Nastoupil L, Feugier P, Schiano de Colella JM, Tilly H, Palomba ML, Bachy E, Fruchart C, Libby EN, Casasnovas RO, Flinn IW, Haioun C, Maisonneuve H, Ysebaert L, Bartlett NL, Bouabdallah K, Brice P, Ribrag V, Le Gouill S, Daguindau N, Guidez S, Pica GM, García-Sancho AM, López-Guillermo A, Larouche JF, Ando K, Gomes da Silva M, André M, Kalung W, Sehn LH, Izutsu K, Cartron G, Gkasiamis A, Crowe R, Xerri L, Fowler NH, Salles G. Six-Year Results From RELEVANCE: Lenalidomide Plus Rituximab (R2) Versus Rituximab-Chemotherapy Followed by Rituximab Maintenance in Untreated Advanced Follicular Lymphoma. J Clin Oncol. 2022 Oct 1;40(28):3239-3245. Epub 2022 Aug 10. link to original article link to PMC article EuroPMC
==R-CHVP+I==
R-CHVP+I: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), VP-16 (Etoposide), Prednisolone, Interferon-a2a
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Salles et al. 2008 (FL2000)	2000-2002 	Phase 3 (E-esc)	CHVP+I 	Longer EFS (primary endpoint)Median EFS: NYR vs 2.9 y(aHR 0.59, 95% CI 0.44-0.78)
====Targeted therapy====
*Rituximab (Rituxan) as follows:
**Cycles 3 & 4: 375 mg/m2 IV once per day on days 1 and 8
**Cycles 5 & 6: 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 25 mg/m2 IV once on day 1
*Etoposide (Vepesid) 100 mg/m2 IV once on day 1
====Glucocorticoid therapy====
*Prednisolone (Millipred) 40 mg/m2 PO once per day on days 1 to 5
28-day cycle for 6 cycles
====Subsequent treatment====
*Interferon alfa-2a maintenance
===References===
#FL2000: Salles G, Mounier N, de Guibert S, Morschhauser F, Doyen C, Rossi JF, Haioun C, Brice P, Mahé B, Bouabdallah R, Audhuy B, Ferme C, Dartigeas C, Feugier P, Sebban C, Xerri L, Foussard C. Rituximab combined with chemotherapy and interferon in follicular lymphoma patients: results of the GELA-GOELAMS FL2000 study. Blood. 2008 Dec 15;112(13):4824-31. Epub 2008 Sep 17. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00136552
##Update: Bachy E, Houot R, Morschhauser F, Sonet A, Brice P, Belhadj K, Cartron G, Audhuy B, Fermé C, Feugier P, Sebban C, Delwail V, Maisonneuve H, Le Gouill S, Lefort S, Brousse N, Foussard C, Salles G; Groupe d'Etude des Lymphomes de l'Adulte. Long-term follow up of the FL2000 study comparing CHVP-interferon to CHVP-interferon plus rituximab in follicular lymphoma. Haematologica. 2013 Jul;98(7):1107-14. Epub 2013 May 3. link to original article link to PMC article EuroPMC
==R-CVP==
R-CVP: Rituximab, Cyclophosphamide, Vincristine, Prednisone
===Regimen variant #1, prednisone 40 mg/m2===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Marcus et al. 2004 (M39021) 	2000-2002 	Phase 3 (E-RT-esc) 	CVP 	Longer TTP (secondary endpoint)Longer TTF (primary endpoint)Median TTF: 27 vs 7 mo	Similar toxicity
Salles et al. 2010 (PRIMAFL) 	2004-2007 	Non-randomized part of phase 3 RCT	 	 	
Federico et al. 2013 (FOLL05) 	2006-2010 	Phase 3 (E-de-esc) 	1. R-CHOP 	Seems to have shorter PFS (secondary endpoint) 	See paper
Federico et al. 2013 (FOLL05) 	2006-2010 	Phase 3 (E-de-esc) 	2. R-FM 	Shorter PFS1 	See paper
Morschhauser et al. 2018 (RELEVANCE)	2011-2014 	Phase 3 (C) 	Lenalidomide & Rituximab	Did not meet co-primary endpoints of CR rate/PFS 	Different toxicity
Kim et al. 2017 (CT-P10 3.3) 	2014-07-28 to 2015-12-29	Phase 3 (C) 	R-CVP (rituximab-abbs) 	Non-inferior ORR (primary endpoint)ORR: 92.6% vs 97% 	
1Reported efficacy for this arm of FOLL05 is based on the 2017 update.
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 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) 40 mg/m2 PO once per day on days 1 to 5
21-day cycle for up to 8 cycles
====Subsequent treatment====
*PRIMAFL, responders (PR or CR): Rituximab maintenance versus no further treatment
*RELEVANCE: Rituximab maintenance
===Regimen variant #2, prednisone 100 mg/day===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy 	Comparative Toxicity
Marcus et al. 2017 (GALLIUM) 	2011-2014 	Phase 3 (C)	See link 	See link 	See link
Jurczak et al. 2017 (ASSIST-FL)	2011-12-01 to 2015-01-15	Phase 3 (C)	GP2013-CVP	Equivalent ORRORR: 88% vs 87%	
Patients in GALLIUM received rituximab only in cycles 7 & 8.
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 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====
*ASSIST-FL & GALLIUM: Rituximab maintenance
===Regimen variant #3, 3 cycles===
Study 	Dates of enrollment	Evidence
Hainsworth et al. 2005a	2000-2001 	Phase 2
====Preceding treatment====
*Rituximab pre-phase x 4
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 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
21-day cycle for 3 cycles
====Subsequent treatment====
*Rituximab consolidation
===References===
#Hainsworth JD, Litchy S, Morrissey LH, Andrews MB, Grimaldi M, McCarty M, Greco FA. Rituximab plus short-duration chemotherapy as first-line treatment for follicular non-Hodgkin's lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol. 2005 Mar 1;23(7):1500-6. Epub 2005 Jan 4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#M39021: Marcus R, Imrie K, Belch A, Cunningham D, Flores E, Catalano J, Solal-Celigny P, Offner F, Walewski J, Raposo J, Jack A, Smith P. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood. 2005 Feb 15;105(4):1417-23. Epub 2004 Oct 19. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Update: Marcus R, Imrie K, Solal-Celigny P, Catalano JV, Dmoszynska A, Raposo JC, Offner FC, Gomez-Codina J, Belch A, Cunningham D, Wassner-Fritsch E, Stein G. Phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisone alone in patients with previously untreated advanced follicular lymphoma. J Clin Oncol. 2008 Oct 1;26(28):4579-86. Epub 2008 Jul 28. link to original article EuroPMC
#PRIMAFL: Salles G, Seymour JF, Offner F, López-Guillermo A, Belada D, Xerri L, Feugier P, Bouabdallah R, Catalano JV, Brice P, Caballero D, Haioun C, Pedersen LM, Delmer A, Simpson D, Leppa S, Soubeyran P, Hagenbeek A, Casasnovas O, Intragumtornchai T, Fermé C, da Silva MG, Sebban C, Lister A, Estell JA, Milone G, Sonet A, Mendila M, Coiffier B, Tilly H. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet. 2011 Jan 1;377(9759):42-51. Epub 2010 Dec 20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00140582
##HRQoL analysis: Zhou X, Wang J, Zhang J, Copley-Merriman C, Torigoe Y, Reyes C, Seymour JF, Offner FC, Trneny M, Salles GA. Symptoms and toxicity of rituximab maintenance relative to observation following immunochemotherapy in patients with follicular lymphoma. Hematology. 2015 Apr;20(3):129-36. Epub 2014 Jul 16. link to original article EuroPMC
##Update: Bachy E, Seymour JF, Feugier P, Offner F, López-Guillermo A, Belada D, Xerri L, Catalano JV, Brice P, Lemonnier F, Martin A, Casasnovas O, Pedersen LM, Dorvaux V, Simpson D, Leppa S, Gabarre J, da Silva MG, Glaisner S, Ysebaert L, Vekhoff A, Intragumtornchai T, Le Gouill S, Lister A, Estell JA, Milone G, Sonet A, Farhi J, Zeuner H, Tilly H, Salles G. Sustained Progression-Free Survival Benefit of Rituximab Maintenance in Patients With Follicular Lymphoma: Long-Term Results of the PRIMA Study. J Clin Oncol. 2019 Nov 1;37(31):2815-2824. Epub 2019 Jul 24. link to original article link to PMC article EuroPMC
#FOLL05: Federico M, Luminari S, Dondi A, Tucci A, Vitolo U, Rigacci L, Di Raimondo F, Carella AM, Pulsoni A, Merli F, Arcaini L, Angrilli F, Stelitano C, Gaidano G, Dell'olio M, Marcheselli L, Franco V, Galimberti S, Sacchi S, Brugiatelli M. R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage follicular lymphoma: results of the FOLL05 trial conducted by the Fondazione Italiana Linfomi. J Clin Oncol. 2013 Apr 20;31(12):1506-13. Epub 2013 Mar 25. Erratum in: J Clin Oncol. 2014 Apr 1;32(10):1095. Dosage error in article text. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00774826
##Update: Luminari S, Ferrari A, Manni M, Dondi A, Chiarenza A, Merli F, Rusconi C, Tarantino V, Tucci A, Vitolo U, Kovalchuk S, Angelucci E, Pulsoni A, Arcaini L, Angrilli F, Gaidano G, Stelitano C, Bertoldero G, Cascavilla N, Salvi F, Ferreri AJM, Vallisa D, Marcheselli L, Federico M. Long-term results of the FOLL05 trial comparing R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage symptomatic follicular lymphoma. J Clin Oncol. 2018 Mar 1;36(7):689-696. Epub 2017 Nov 2. link to original article EuroPMC
#ASSIST-FL: Jurczak W, Moreira I, Kanakasetty GB, Munhoz E, Echeveste MA, Giri P, Castro N, Pereira J, Akria L, Alexeev S, Osmanov E, Zhu P, Alexandrova S, Zubel A, Harlin O, Amersdorffer J. Rituximab biosimilar and reference rituximab in patients with previously untreated advanced follicular lymphoma (ASSIST-FL): primary results from a confirmatory phase 3, double-blind, randomised, controlled study. Lancet Haematol. 2017 Aug;4(8):e350-e361. Epub 2017 Jul 14. link to original article EuroPMC NCT01419665
#CT-P10 3.3: Kim WS, Buske C, Ogura M, Jurczak W, Sancho JM, Zhavrid E, Kim JS, Hernández-Rivas JÁ, Prokharau A, Vasilica M, Nagarkar R, Osmanov D, Kwak LW, Lee SJ, Lee SY, Bae YJ, Coiffier B. Efficacy, pharmacokinetics, and safety of the biosimilar CT-P10 compared with rituximab in patients with previously untreated advanced-stage follicular lymphoma: a randomised, double-blind, parallel-group, non-inferiority phase 3 trial. Lancet Haematol. 2017 Aug;4(8):e362-e373. Epub 2017 Jul 14. link to original article EuroPMC NCT02162771
##Update: Buske C, Jurczak W, Sancho JM, Zhavrid E, Kim JS, Hernández-Rivas JÁ, Prokharau A, Vasilica M, Nagarkar R, Kwak L, Kim WS, Lee S, Kim S, Ahn K, Ogura M. Long-term efficacy and safety of CT-P10 or rituximab in untreated advanced follicular lymphoma: a randomized phase 3 study. Blood Adv. 2021 Sep 14;5(17):3354-3361. link to original article link to PMC article EuroPMC
#GALLIUM: Marcus R, Davies A, Ando K, Klapper W, Opat S, Owen C, Phillips E, Sangha R, Schlag R, Seymour JF, Townsend W, Trněný M, Wenger M, Fingerle-Rowson G, Rufibach K, Moore T, Herold M, Hiddemann W. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med. 2017 Oct 5;377(14):1331-1344. link to original article link to appendix dosing details in supplement have been reviewed by our editors EuroPMC NCT01332968
##Update: Hiddemann W, Barbui AM, Canales MA, Cannell PK, Collins GP, Dürig J, Forstpointner R, Herold M, Hertzberg M, Klanova M, Radford J, Seymour JF, Tobinai K, Trotman J, Burciu A, Fingerle-Rowson G, Wolbers M, Nielsen T, Marcus RE. Immunochemotherapy with obinutuzumab or rituximab for previously untreated follicular lymphoma in the GALLIUM study: influence of chemotherapy on efficacy and safety. J Clin Oncol. 2018 Aug 10;36(23):2395-2404. Epub 2018 Jun 1. link to original article EuroPMC
##HRQoL analysis: Davies A, Trask P, Demeter J, Florschütz A, Hänel M, Kinoshita T, Pettengell R, Quach H, Robinson S, Sadullah S, Sancho JM, Udvardy M, Witzens-Harig M, Knapp A, Liu W. Health-related quality of life in the phase III GALLIUM study of obinutuzumab- or rituximab-based chemotherapy in patients with previously untreated advanced follicular lymphoma. Ann Hematol. 2020 Dec;99(12):2837-2846. link to original article link to EuroPMC
#RELEVANCE: Morschhauser F, Fowler NH, Feugier P, Bouabdallah R, Tilly H, Palomba ML, Fruchart C, Libby EN, Casasnovas RO, Flinn IW, Haioun C, Maisonneuve H, Ysebaert L, Bartlett NL, Bouabdallah K, Brice P, Ribrag V, Daguindau N, Le Gouill S, Pica GM, Martin Garcia-Sancho A, López-Guillermo A, Larouche JF, Ando K, Gomes da Silva M, André M, Zachée P, Sehn LH, Tobinai K, Cartron G, Liu D, Wang J, Xerri L, Salles GA; RELEVANCE Trial Investigators. Rituximab plus lenalidomide in advanced untreated follicular lymphoma. N Engl J Med. 2018 Sep 6;379(10):934-947. link to original article dosing details in supplement have been reviewed by our editors link to PMC article EuroPMC NCT01650701
##Update: Morschhauser F, Nastoupil L, Feugier P, Schiano de Colella JM, Tilly H, Palomba ML, Bachy E, Fruchart C, Libby EN, Casasnovas RO, Flinn IW, Haioun C, Maisonneuve H, Ysebaert L, Bartlett NL, Bouabdallah K, Brice P, Ribrag V, Le Gouill S, Daguindau N, Guidez S, Pica GM, García-Sancho AM, López-Guillermo A, Larouche JF, Ando K, Gomes da Silva M, André M, Kalung W, Sehn LH, Izutsu K, Cartron G, Gkasiamis A, Crowe R, Xerri L, Fowler NH, Salles G. Six-Year Results From RELEVANCE: Lenalidomide Plus Rituximab (R2) Versus Rituximab-Chemotherapy Followed by Rituximab Maintenance in Untreated Advanced Follicular Lymphoma. J Clin Oncol. 2022 Oct 1;40(28):3239-3245. Epub 2022 Aug 10. link to original article link to PMC article EuroPMC
==R-FM==
R-FM: Rituximab, Fludarabine, Mitoxantrone
FMR: Fludarabine, Mitoxantrone, Rituximab
===Regimen variant #1, 4 cycles===
Study 	Dates of enrollment	Evidence
Zinzani et al. 2011	2006-12 to 2008-11 	Phase 2
====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
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
28-day cycle for 4 cycles
====Subsequent treatment====
*Patients were restaged 2 to 3 weeks after finishing cycle 4. 
*Zinzani et al. 2011, at least a partial response (PR), ANC greater than 1500/μL, platelet count greater than 100 x 109/L, and less than 25% bone marrow involvement were eligible for: consolidation therapy with ibritumomab tiuxetan, given within 12 weeks (paper does not specify "within 12 weeks" of what)
====Dose and schedule modifications====
*G-CSF could be used for later cycles at physician discretion if grade 3 or 4 neutropenia or delayed neutropenic fever occurred.
===Regimen variant #2, 8 cycles===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Federico et al. 2013 (FOLL05)	2006-2010 	Phase 3 (E-switch-ic)	1. R-CHOP 	Did not meet primary endpoint of TTF
Federico et al. 2013 (FOLL05)	2006-2010 	Phase 3 (E-switch-ic)	2. R-CVP 	Longer PFS1 (secondary endpoint)
1Reported efficacy for this arm of FOLL05 is based on the 2017 update.
Note: risk/benefit ratio was worse than R-CHOP.
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Fludarabine (Fludara) as follows:
**Cycles 1 to 6: 25 mg/m2 IV once per day on days 1 to 3
*Mitoxantrone (Novantrone) as follows:
**Cycles 1 to 6: 10 mg/m2 IV once on day 1
21-day cycle for 8 cycles
===References===
#Zinzani PL, Tani M, Pulsoni A, De Renzo A, Stefoni V, Broccoli A, Montini GC, Fina M, Pellegrini C, Gandolfi L, Cavalieri E, Torelli F, Scopinaro F, Argnani L, Quirini F, Derenzini E, Rossi M, Pileri S, Fanti S, Baccarani M. A phase II trial of short course fludarabine, mitoxantrone, rituximab followed by 90Y-ibritumomab tiuxetan in untreated intermediate/high-risk follicular lymphoma. Ann Oncol. 2012 Feb;23(2):415-20. Epub 2011 May 2. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#FOLL05: Federico M, Luminari S, Dondi A, Tucci A, Vitolo U, Rigacci L, Di Raimondo F, Carella AM, Pulsoni A, Merli F, Arcaini L, Angrilli F, Stelitano C, Gaidano G, Dell'olio M, Marcheselli L, Franco V, Galimberti S, Sacchi S, Brugiatelli M. R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage follicular lymphoma: results of the FOLL05 trial conducted by the Fondazione Italiana Linfomi. J Clin Oncol. 2013 Apr 20;31(12):1506-13. Epub 2013 Mar 25. Erratum in: J Clin Oncol. 2014 Apr 1;32(10):1095. Dosage error in article text. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00774826
##Update: Luminari S, Ferrari A, Manni M, Dondi A, Chiarenza A, Merli F, Rusconi C, Tarantino V, Tucci A, Vitolo U, Kovalchuk S, Angelucci E, Pulsoni A, Arcaini L, Angrilli F, Gaidano G, Stelitano C, Bertoldero G, Cascavilla N, Salvi F, Ferreri AJM, Vallisa D, Marcheselli L, Federico M. Long-term results of the FOLL05 trial comparing R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage symptomatic follicular lymphoma. J Clin Oncol. 2018 Mar 1;36(7):689-696. Epub 2017 Nov 2. link to original article EuroPMC
==R-FND==
R-FND: Rituximab, Fludarabine, Novantrone (mitoxantrone), Dexamethasone
===Regimen===
Study 	Dates of enrollment	Evidence
Vitolo et al. 2013 (ML17638)	2004-2007 	Non-randomized part of phase 3 RCT
====Targeted therapy====
*Rituximab (Rituxan) 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) 10 mg (route not specified) once per day on days 2 to 4
1-month cycle for 4 cycles
====Subsequent treatment====
*ML17638, non-progressors: Rituximab consolidation
*ML17638, responders: Rituximab maintenance versus observation
===References===
#ML17638: Vitolo U, Ladetto M, Boccomini C, Baldini L, De Angelis F, Tucci A, Botto B, Chiappella A, Chiarenza A, Pinto A, De Renzo A, Zaja F, Castellino C, Bari A, Alvarez De Celis I, Evangelista A, Parvis G, Gamba E, Lobetti-Bodoni C, Ciccone G, Rossi G. Rituximab maintenance compared with observation after brief first-line R-FND chemoimmunotherapy with rituximab consolidation in patients age older than 60 years with advanced follicular lymphoma: a phase III randomized study by the Fondazione Italiana Linfomi. J Clin Oncol. 2013 Sep 20;31(27):3351-9. Epub 2013 Aug 19. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01144364
==R-MCP==
R-MCP: Rituximab, Mitoxantrone, Chlorambucil, Prednisolone
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Herold et al. 2007 (OSHO-39)	1998-2003 	Phase 3 (E-esc)	MCP 	Longer OS (secondary endpoint)OS48: 87% vs 74%Higher ORR (primary endpoint)
Note: the chlorambucil dose was written in the reference as "3 x 3 mg/m2"; total dose per day is 9 mg/m2.
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Mitoxantrone (Novantrone) 8 mg/m2 IV once per day on days 3 & 4
*Chlorambucil (Leukeran) 3 mg/m2 PO three times per day on days 3 to 7
====Glucocorticoid therapy====
*Prednisolone (Millipred) 25 mg/m2 PO once per day on days 3 to 7
28-day cycle for up to 8 cycles
====Subsequent treatment====
*OSHO-39, patients who achieved a PR or CR: Interferon alfa-2a maintenance within 4 to 8 weeks of completion of chemotherapy
===References===
#OSHO-39: Herold M, Haas A, Srock S, Neser S, Al-Ali KH, Neubauer A, Dölken G, Naumann R, Knauf W, Freund M, Rohrberg R, Höffken K, Franke A, Ittel T, Kettner E, Haak U, Mey U, Klinkenstein C, Assmann M, von Grünhagen U; East German Study Group Hematology and Oncology. Rituximab added to first-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: an East German Study Group Hematology and Oncology Study. J Clin Oncol. 2007 May 20;25(15):1986-92. Epub 2007 Apr 9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00269113
##Update: Herold M, Scholz CW, Rothmann F, Hirt C, Lakner V, Naumann R. Long-term follow-up of rituximab plus first-line mitoxantrone, chlorambucil, prednisolone and interferon-alpha as maintenance therapy in follicular lymphoma. J Cancer Res Clin Oncol. 2015 Sep;141(9):1689-95. Epub 2015 Mar 25. link to original article EuroPMC
==Rituximab monotherapy==
===Regimen variant #1, 4 doses===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Colombat et al. 2001 	1997-1998 	Phase 2 	 	
Ghielmini et al. 2004 (SAKK 35/98FL) 	1998-2002 	Non-randomized part of phase 3 RCT	 	
Kahl et al. 2014 (RESORT) 	2003-2008 	Non-randomized part of phase 3 RCT	 	
Taverna et al. 2015 (SAKK 35/03) 	2004-2007 	Non-randomized part of phase 3 RCT	 	
Ardeshna et al. 2014 (CRUK-2004-001621-16)	2004-2009 	Phase 3 (E-esc) 	1. Watchful waiting 	Longer TTNT (primary endpoint)
Ardeshna et al. 2014 (CRUK-2004-001621-16)	2004-2009 	Phase 3 (E-esc) 	2. Rituximab induction, then Rituximab maintenance	Did not meet primary endpoint of TTNT
Ogura et al. 2018 (CT-P10 3.4) 	2015-2018 	Phase 3 (C) 	Rituximab-abbs 	Equivalent ORR (primary endpoint)ORR7m: 81% vs 83%
Sharman et al. 2020 (REFLECTIONS B328-06) 	Not reported 	Phase 3 (C) 	Rituximab-pvvr x 4 	Equivalent ORR (primary endpoint)ORR24w: 70.7% vs 75.5%
Niederwieser et al. 2020 (JASMINE) 	Not reported 	Phase 3 (C) 	Rituximab-arrx 	Equivalent ORR (primary endpoint)
====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
====Subsequent treatment====
*CT-P10 3.4, SD or better: Rituximab maintenance
*SAKK 35/98FL, SD or better: Rituximab maintenance versus no further treatment
*RESORT, PR or CR: Indefinite rituximab maintenance versus salvage rituximab at time of progression
*SAKK 35/03, PR or CR: Rituximab maintenance x 9 mo versus Rituximab maintenance x 5 y
*JASMINE: Rituximab consolidation x 2
===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
Zucca et al. 2019 (SAKK 35/10) 	2011-2013 	Randomized Phase 2 (C)	Lenalidomide & Rituximab	Might have lower composite CR/CRu rate
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===
#Colombat P, Salles G, Brousse N, Eftekhari P, Soubeyran P, Delwail V, Deconinck E, Haïoun C, Foussard C, Sebban C, Stamatoullas A, Milpied N, Boué F, Taillan B, Lederlin P, Najman A, Thièblemont C, Montestruc F, Mathieu-Boué A, Benzohra A, Solal-Céligny P. Rituximab (anti-CD20 monoclonal antibody) as single first-line therapy for patients with follicular lymphoma with a low tumor burden: clinical and molecular evaluation. Blood. 2001 Jan 1;97(1):101-6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Update: Colombat P, Brousse N, Salles G, Morschhauser F, Brice P, Soubeyran P, Delwail V, Deconinck E, Haioun C, Foussard C, Sebban C, Tilly H, Thieblemont C, Bergougnoux L, Lazreg F, Solal-Celigny P. Rituximab induction immunotherapy for first-line low-tumor-burden follicular lymphoma: survival analyses with 7-year follow-up. Ann Oncol. 2012 Sep;23(9):2380-5. Epub 2012 Jul 10. link to original article EuroPMC
#SAKK 35/98FL: Ghielmini M, Schmitz SF, Cogliatti SB, Pichert G, Hummerjohann J, Waltzer U, Fey MF, Betticher DC, Martinelli G, Peccatori F, Hess U, Zucca E, Stupp R, Kovacsovics T, Helg C, Lohri A, Bargetzi M, Vorobiof D, Cerny T. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood. 2004 Jun 15;103(12):4416-23. Epub 2004 Feb 19. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00003280
##Update: Martinelli G, Schmitz SF, Utiger U, Cerny T, Hess U, Bassi S, Okkinga E, Stupp R, Stahel R, Heizmann M, Vorobiof D, Lohri A, Dietrich PY, Zucca E, Ghielmini M. Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98. J Clin Oncol. 2010 Oct 10;28(29):4480-4. Epub 2010 Aug 9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Meta-analysis: Vidal L, Gafter-Gvili A, Leibovici L, Dreyling M, Ghielmini M, Hsu Schmitz SF, Cohen A, Shpilberg O. Rituximab maintenance for the treatment of patients with follicular lymphoma: systematic review and meta-analysis of randomized trials. J Natl Cancer Inst. 2009 Feb 18;101(4):248-55. Epub 2009 Feb 10. EuroPMC
#CRUK-2004-001621-16: Ardeshna KM, Qian W, Smith P, Braganca N, Lowry L, Patrick P, Warden J, Stevens L, Pocock CF, Miall F, Cunningham D, Davies J, Jack A, Stephens R, Walewski J, Ferhanoglu B, Bradstock K, Linch DC. Rituximab versus a watch-and-wait approach in patients with advanced-stage, asymptomatic, non-bulky follicular lymphoma: an open-label randomised phase 3 trial. Lancet Oncol. 2014 Apr;15(4):424-35. Epub 2014 Mar 4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00112931
##HRQoL analysis: Marzolini MAV, Qian W, Clifton-Hadley L, Patrick P, Warden J, Stevens L, Pocock CFE, Miall F, Cunningham D, Stephens R, Walewski J, Johnston A, Seymour JF, Linch DC, Ardeshna KM. Quality of life in advanced-stage, asymptomatic, non-bulky follicular lymphoma treated with rituximab shows significant improvement compared with watchful-waiting. Br J Haematol. 2024 Nov 27. Epub ahead of print. link to original article EuroPMC
#RESORT: Kahl BS, Hong F, Williams ME, Gascoyne RD, Wagner LI, Krauss JC, Habermann TM, Swinnen LJ, Schuster SJ, Peterson CG, Sborov MD, Martin SE, Weiss M, Ehmann WC, Horning SJ. Rituximab extended schedule or re-treatment trial for low-tumor burden follicular lymphoma: Eastern Cooperative Oncology Group protocol E4402. J Clin Oncol. 2014 Oct 1;32(28):3096-102. Epub 2014 Aug 25. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00075946
##Update: Kahl BS, Jegede OA, Peterson C, Swinnen LJ, Habermann TM, Schuster SJ, Weiss M, Fishkin PA, Fenske TS, Williams ME. Long-Term Follow-Up of the RESORT Study (E4402): A Randomized Phase III Comparison of Two Different Rituximab Dosing Strategies for Low-Tumor Burden Follicular Lymphoma. J Clin Oncol. 2024 Mar 1;42(7):774-778. Epub 2024 Jan 9. link to original article link to PMC article EuroPMC
#SAKK 35/10: Zucca E, Rondeau S, Vanazzi A, Østenstad B, Mey UJM, Rauch D, Wahlin BE, Hitz F, Hernberg M, Johansson AS, de Nully Brown P, Hagberg H, Ferreri AJM, Lohri A, Novak U, Zander T, Bersvendsen H, Bargetzi M, Mingrone W, Krasniqi F, Dirnhofer S, Hayoz S, Hawle H, Vilei SB, Ghielmini M, Kimby E; Swiss Group for Clinical Cancer Research; Nordic Lymphoma Group. Short regimen of rituximab plus lenalidomide in follicular lymphoma patients in need of first-line therapy. Blood. 2019 Jul 25;134(4):353-362. Epub 2019 May 17. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01307605
#SAKK 35/03: Taverna C, Martinelli G, Hitz F, Mingrone W, Pabst T, Cevreska L, Del Giglio A, Vanazzi A, Laszlo D, Raats J, Rauch D, Vorobiof DA, Lohri A, Biaggi Rudolf C, Rondeau S, Rusterholz C, Heijnen IA, Zucca E, Ghielmini M. Rituximab maintenance for a maximum of 5 years after single-agent rituximab induction in follicular lymphoma: results of the randomized controlled phase III trial SAKK 35/03. J Clin Oncol. 2016 Feb 10;34(5):495-500. Epub 2015 Dec 28. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00227695
## Update: Moccia AA, Taverna C, Schär S, Vanazzi A, Rondeau S, Hitz F, Mingrone W, Pabst T, Cevreska L, Del Giglio A, Raats J, Rauch D, Vorobiof DA, Lohri A, Ruegsegger C, Biaggi Rudolf C, Rusterholz C, Hayoz S, Ghielmini M, Zucca E. Prolonged rituximab maintenance in follicular lymphoma patients: long-term results of the SAKK 35/03 randomized trial. Blood Adv. 2020 Dec 8;4(23):5951-5957. link to original article link to PMC article EuroPMC
#CT-P10 3.4: Ogura M, Sancho JM, Cho SG, Nakazawa H, Suzumiya J, Tumyan G, Kim JS, Lennard A, Mariz J, Ilyin N, Jurczak W, Lopez Martinez A, Samoilova O, Zhavrid E, Yañez Ruiz E, Trneny M, Popplewell L, Coiffier B, Buske C, Kim WS, Lee SJ, Lee SY, Bae YJ, Kwak LW. Efficacy, pharmacokinetics, and safety of the biosimilar CT-P10 in comparison with rituximab in patients with previously untreated low-tumour-burden follicular lymphoma: a randomised, double-blind, parallel-group, phase 3 trial. Lancet Haematol. 2018 Nov;5(11):e543-e553. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT02260804
#REFLECTIONS B328-06: Sharman JP, Liberati AM, Ishizawa K, Khan T, Robbins J, Alcasid A, Rosenberg JA, Aurer I. A Randomized, Double-Blind, Efficacy and Safety Study of PF-05280586 (a Rituximab Biosimilar) Compared with Rituximab Reference Product (MabThera®) in Subjects with Previously Untreated CD20-Positive, Low-Tumor-Burden Follicular Lymphoma (LTB-FL). BioDrugs. 2020 Apr;34(2):171-181. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02213263
#JASMINE: Niederwieser D, Hamm C, Cobb P, Mo M, Forsyth C, Tucci A, Hanes V, Delwail V, Hajek R, Chien D. Efficacy and Safety of ABP 798: Results from the JASMINE Trial in Patients with Follicular Lymphoma in Comparison with Rituximab Reference Product. Target Oncol. 2020 Oct;15(5):599-611. Erratum in: Target Oncol. 2020 Dec;15(6):807. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02747043
==Rituximab and hyaluronidase monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Cartron et al. 2023 (FLIRT)	2015-02 to 2018-06 	Phase 3 (E-switch-ic)	IV Rituximab	Longer PFS (primary endpoint)PFS48: 58.1% vs 41.2%(HR 0.585, 95% CI 0.39-0.87)
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
*Rituximab and hyaluronidase human (Rituxan Hycela) 1400 mg SC once per day on days 8, 15, 22
4-week course
====Subsequent treatment====
*SC rituximab maintenance
===References===
#FLIRT: Cartron G, Bachy E, Tilly H, Daguindau N, Pica GM, Bijou F, Mounier C, Clavert A, Damaj GL, Slama B, Casasnovas O, Houot R, Bouabdallah K, Sibon D, Fitoussi O, Morineau N, Herbaux C, Gastinne T, Fornecker LM, Haioun C, Launay V, Araujo C, Benbrahim O, Sanhes L, Gressin R, Gonzalez H, Morschhauser F, Ternant D, Xerri L, Tarte K, Pranger D. Randomized Phase III Trial Evaluating Subcutaneous Rituximab for the First-Line Treatment of Low-Tumor Burden Follicular Lymphoma: Results of a LYSA Study. J Clin Oncol. 2023 Jul 1;41(19):3523-3533. Epub 2023 Apr 18. Erratum in: J Clin Oncol. 2023 Sep 1;41(25):4187. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02303119
==Watchful waiting==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Brice et al. 1997 	1986-1995 	Phase 3 (E-de-esc)	1. Interferon alfa2. Prednimustine 	Did not meet primary endpoint of OS
Ardeshna et al. 2014 (CRUK-2004-001621-16)	2004-2009 	Phase 3 (C) 	1. Rituximab induction 	Shorter TTNT
Ardeshna et al. 2014 (CRUK-2004-001621-16)	2004-2009 	Phase 3 (C) 	2. Rituximab induction, then Rituximab maintenance	Shorter TTNT
===References===
#Brice P, Bastion Y, Lepage E, Brousse N, Haïoun C, Moreau P, Straetmans N, Tilly H, Tabah I, Solal-Céligny P; Groupe d'Etude des Lymphomes de l'Adulte. Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: a randomized study from the Groupe d'Etude des Lymphomes Folliculaires. J Clin Oncol. 1997 Mar;15(3):1110-7. link to original article EuroPMC
#CRUK-2004-001621-16: Ardeshna KM, Qian W, Smith P, Braganca N, Lowry L, Patrick P, Warden J, Stevens L, Pocock CF, Miall F, Cunningham D, Davies J, Jack A, Stephens R, Walewski J, Ferhanoglu B, Bradstock K, Linch DC. Rituximab versus a watch-and-wait approach in patients with advanced-stage, asymptomatic, non-bulky follicular lymphoma: an open-label randomised phase 3 trial. Lancet Oncol. 2014 Apr;15(4):424-35. Epub 2014 Mar 4. link to original article EuroPMC NCT00112931
##HRQoL analysis: Marzolini MAV, Qian W, Clifton-Hadley L, Patrick P, Warden J, Stevens L, Pocock CFE, Miall F, Cunningham D, Stephens R, Walewski J, Johnston A, Seymour JF, Linch DC, Ardeshna KM. Quality of life in advanced-stage, asymptomatic, non-bulky follicular lymphoma treated with rituximab shows significant improvement compared with watchful-waiting. Br J Haematol. 2024 Nov 27. Epub ahead of print. link to original article EuroPMC
</div>
=Advanced disease, first-line therapy, non-randomized or retrospective data=
==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
==Ibritumomab tiuxetan protocol==
===Regimen variant #1===
Study 	Dates of enrollment	Evidence
Ibatici et al. 2013	2007-01 to 2010-12 	Phase 2
Scholz et al. 2013 	2007-06 to 2010-06 	Phase 2
Recruitment in Scholz et al. was limited to patients at least 50 years old due to radiation safety concerns; Ibatici et al. was open to all adult patients greater than 18 years old. Treatment regimen is identical.
====Targeted therapy====
*Rituximab (Rituxan) 250 mg/m2 IV once per day on days 1 & either day 8 or 9, given first on day 8 or 9
====Radioconjugate therapy====
*Ibritumomab tiuxetan & Yttrium-90 (Zevalin) 15 MBq/kg (maximum dose of 1200 MBq) IV once on day 8 or 9, given second
One course
===Regimen variant #2, fractionated===
Study 	Dates of enrollment	Evidence
Illidge et al. 2013 (FIZZ)	2007-06 to 2010-06 	Phase 2
This regimen was for patients with less than or equal to 20% bone marrow involvement; others received induction rituximab, first. See paper for details.
====Targeted therapy====
*Rituximab (Rituxan) 250 mg/m2 IV once per day on days 1 & 8 or 9, given first on day 8 or 9
====Radioconjugate therapy====
*Ibritumomab tiuxetan & Yttrium-90 (Zevalin) 11.1 MBq/kg (maximum dose of 888 MBq) IV once on either day 8 or 9, given second
8- to 12-week cycle for 2 cycles
===References===
#Scholz CW, Pinto A, Linkesch W, Lindén O, Viardot A, Keller U, Hess G, Lastoria S, Lerch K, Frigeri F, Arcamone M, Stroux A, Frericks B, Pott C, Pezzutto A. 90Yttrium-ibritumomab-tiuxetan as first-line treatment for follicular lymphoma: 30 months of follow-up data from an international multicenter phase II clinical trial. J Clin Oncol. 2013 Jan 20;31(3):308-13. Epub 2012 Dec 10. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00772655
##Update: Rieger K, De Filippi R, Lindén O, Viardot A, Hess G, Lerch K, Neumeister P, Stroux A, Peuker CA, Pezzutto A, Pinto A, Keller U, Scholz CW. 90-yttrium-ibritumomab tiuxetan as first-line treatment for follicular lymphoma: updated efficacy and safety results at an extended median follow-up of 9.6 years. Ann Hematol. 2022 Apr;101(4):781-788. Epub 2022 Feb 12. link to original article link to PMC article EuroPMC
#FIZZ: Illidge TM, Mayes S, Pettengell R, Bates AT, Bayne M, Radford JA, Ryder WD, Le Gouill S, Jardin F, Tipping J, Zivanovic M, Kraeber-Bodere F, Bardies M, Bodet-Milin C, Malek E, Huglo D, Morschhauser F. Fractionated 90Y-ibritumomab tiuxetan radioimmunotherapy as an initial therapy of follicular lymphoma: an international phase II study in patients requiring treatment according to GELF/BNLI criteria. J Clin Oncol. 2014 Jan 20;32(3):212-8. Epub 2013 Dec 2. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01493479
#Ibatici A, Pica GM, Nati S, Vitolo U, Botto B, Ciochetto C, Petrini M, Galimberti S, Ciabatti E, Orciuolo E, Zinzani PL, Cascavilla N, Guolo F, Fraternali Orcioni G, Carella AM. Safety and efficacy of (90) Yttrium-ibritumomab-tiuxetan for untreated follicular lymphoma patients: an Italian cooperative study. Br J Haematol. 2014 Mar;164(5):710-6. Epub 2013 Dec 17. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==O-CHOP==
O-CHOP: Ofatumumab, Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone
===Regimen=== 
Study 	Dates of enrollment	Evidence
Czuczman et al. 2012 (MUNIN)	2007-10 to 2009-04 	Phase 2
Note: both 500 mg and 1000 mg doses of ofatumumab were tested, but since there was no increase in toxicity in patients receiving the 1000 mg dose, the 1000 mg dose was chosen for future ofatumumab trials "to avoid underdosing patients"
====Targeted therapy====
*Ofatumumab (Arzerra) as follows:
**Cycle 1: 300 mg IV once on day 1
**Cycles 2 to 6: 1000 mg IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 3
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 3
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 3
====Glucocorticoid therapy====
*Prednisone (Sterapred) 100 mg PO once per day on days 3 to 7
====Supportive therapy====
*Acetaminophen (Tylenol) 1000 mg (no route specified) before each dose of ofatumumab
*Cetirizine (Zyrtec) 10 mg (or equivalent) PO before each dose of ofatumumab
*Prednisolone (Millipred) (or equivalent) 100 mg before dose 1 and 2 of ofatumumab
21-day cycle for 6 cycles
===References===
#MUNIN: Czuczman MS, Hess G, Gadeberg OV, Pedersen LM, Goldstein N, Gupta I, Jewell RC, Lin TS, Lisby S, Strange C, Windfeld K, Viardot A; 409 Study Investigators. Chemoimmunotherapy with ofatumumab in combination with CHOP in previously untreated follicular lymphoma. Br J Haematol. 2012 May;157(4):438-45. Epub 2012 Mar 13. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00494780
==R-FCM==
R-FCM: Rituximab, Fludarabine, Cyclophosphamide, Mitoxantrone
===Regimen===
Study 	Dates of enrollment	Evidence
Salles et al. 2010 (PRIMAFL)	2004-2007 	Non-randomized part of phase 3 RCT
====Targeted therapy====
*Rituximab (Rituxan) as follows:
**Cycles 1, 3, 5, 6: 375 mg/m2 IV once on day 1
**Cycles 2 & 4: 375 mg/m2 IV once per day on days 1 & 15
====Chemotherapy====
*Fludarabine (Fludara) 25 mg/m2 IV once per day on days 1 to 3
*Cyclophosphamide (Cytoxan) 200 mg/m2 PO once per day on days 1 to 3
*Mitoxantrone (Novantrone) 6 mg/m2 IV once on day 1
28-day cycle for 6 cycles
====Subsequent treatment====
*PRIMAFL, responders (PR or CR): Rituximab maintenance versus no further treatment
===References===
#PRIMAFL: Salles G, Seymour JF, Offner F, López-Guillermo A, Belada D, Xerri L, Feugier P, Bouabdallah R, Catalano JV, Brice P, Caballero D, Haioun C, Pedersen LM, Delmer A, Simpson D, Leppa S, Soubeyran P, Hagenbeek A, Casasnovas O, Intragumtornchai T, Fermé C, da Silva MG, Sebban C, Lister A, Estell JA, Milone G, Sonet A, Mendila M, Coiffier B, Tilly H. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet. 2011 Jan 1;377(9759):42-51. Epub 2010 Dec 20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00140582
##HRQoL analysis: Zhou X, Wang J, Zhang J, Copley-Merriman C, Torigoe Y, Reyes C, Seymour JF, Offner FC, Trneny M, Salles GA. Symptoms and toxicity of rituximab maintenance relative to observation following immunochemotherapy in patients with follicular lymphoma. Hematology. 2015 Apr;20(3):129-36. Epub 2014 Jul 16. link to original article EuroPMC
##Update: Bachy E, Seymour JF, Feugier P, Offner F, López-Guillermo A, Belada D, Xerri L, Catalano JV, Brice P, Lemonnier F, Martin A, Casasnovas O, Pedersen LM, Dorvaux V, Simpson D, Leppa S, Gabarre J, da Silva MG, Glaisner S, Ysebaert L, Vekhoff A, Intragumtornchai T, Le Gouill S, Lister A, Estell JA, Milone G, Sonet A, Farhi J, Zeuner H, Tilly H, Salles G. Sustained Progression-Free Survival Benefit of Rituximab Maintenance in Patients With Follicular Lymphoma: Long-Term Results of the PRIMA Study. J Clin Oncol. 2019 Nov 1;37(31):2815-2824. Epub 2019 Jul 24. link to original article link to PMC 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.
==Ibritumomab tiuxetan protocol==
An abstract presented at ASH 2013 from the ZAR2007 trial has preliminary results that R-CHOP followed by Zevalin is inferior to R-CHOP followed by rituximab maintenance; detailed results are not yet available and therefore only the reference is provided, here.
===Regimen variant #1===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Morschhauser et al. 2008 (FIT)	2001-2005 	Phase 3 (E-RT-esc)	Observation	Longer PFS (primary endpoint)Median PFS: 36.5 vs 13.3 mo(HR 0.465, 95% CI 0.36-0.605)
====Preceding treatment====
*First-line therapy (most received CHOP or CVP; some received "CHOP-like", "rituximab combination", "fludarabine combination", or chlorambucil), with PR/CR
====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) 14.8 MBq/kg (maximum dose of 1184 MBq) IV over 10 minutes once on day 8, given second
8-day course
===Regimen variant #2===
Study 	Dates of enrollment	Evidence	Efficacy
Zinzani et al. 2011	2006-12 to 2008-11 	Phase 2 	ORR: 89%
====Preceding treatment====
*First-line FMR
====Targeted therapy====
*Rituximab (Rituxan) 250 mg/m2 IV once per day on days 1 & 8 +/- 1 day (total dose: 500 mg/m2)
====Radioconjugate therapy====
*Ibritumomab tiuxetan & Yttrium-90 (Zevalin) by the following laboratory-based criteria:
**Platelet count more than 150 x 109/L: 14.8 MBq/kg (maximum dose of 1184 MBq) IV over 10 minutes once on day 8, given immediately following second dose of rituximab
**Platelet count 100 to 149 x 109/L: 11.1 MBq/kg (maximum dose of 1184 MBq) IV over 10 minutes once on day 8, given immediately following second dose of rituximab
 
8-day course
===Regimen variant #3===
Study 	Dates of enrollment	Evidence
Hainsworth et al. 2009	2002-04 to 2004-03 	Phase 2
See text for further information about Zevalin eligbility criteria. If patient did not meet criteria within 7 weeks after final R-CHOP, Zevalin was omitted.
====Preceding treatment====
*First-line R-CHOP x 3
====Targeted therapy====
*Rituximab (Rituxan) details not specified
====Radioconjugate therapy====
*Ibritumomab tiuxetan & Yttrium-90 (Zevalin) by the following laboratory-based criteria:
**Platelet count 150 x 109/L or more: 0.4 mCi/kg IV once
**Platelet count 100 to 149 x 109/L: 0.3 mCi/kg IV once
8-day course
===Regimen variant #4===
Study 	Dates of enrollment 	Evidence	Efficacy
Zinzani et al. 2008 (FLUMIZ)	2004-06-01 to 2006-04-15	Phase 2 	ORR: 98%
====Preceding treatment====
*First-line FM x 6
====Targeted therapy====
*Rituximab (Rituxan) 250 mg/m2 IV once per day on days 1 & 8 +/- 1 day (total dose: 500 mg/m2)
====Radioconjugate therapy====
*Ibritumomab tiuxetan & Yttrium-90 (Zevalin) by the following laboratory-based criteria:
**Platelet count more than 150 x 109/L: 14.8 MBq/kg (maximum dose of 1184 MBq) IV over 10 minutes once on day 8, given immediately following second dose of rituximab
**Platelet count 100 to 149 x 109/L: 11.1 MBq/kg (maximum dose of 1184 MBq) IV over 10 minutes once on day 8, given immediately following second dose of rituximab
8-day course
===Regimen variant #5===
Study 	Dates of enrollment	Evidence	Efficacy
Jacobs et al. 2008 (UPCI 03-005)	2004-03 to 2007-02 	Phase 2 	ORR: 89%
====Preceding treatment====
*First-line R-CHOP x 3
====Targeted therapy====
*Rituximab (Rituxan) 250 mg/m2 IV once per day on days 1 & 8
====Radioconjugate therapy====
*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, followed in 1 to 2 weeks by:
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
7-day cycle for 4 cycles
===Regimen variant #6===
Study 	Dates of enrollment	Evidence	Efficacy
Provencio et al. 2013 (GOTEL-FL1LC)	2008-04 to 2010-04 	Phase 2 	ORR: 93%
====Preceding treatment====
*First-line R-CHOP x 4, then CHOP de-intensification x 2
====Targeted therapy====
*Rituximab (Rituxan) 250 mg/m2 IV once per day on days 1 & 8
====Radioconjugate therapy====
*Ibritumomab tiuxetan & Yttrium-90 (Zevalin) by the following laboratory-based criteria:
**Platelet count more than 150 x 109/L, Granulocyte count more than 1500/uL, and bone marrow with no more than 25% lymphom involvement: 0.4 mCi/kg (maximum dose of 32 mCi) IV once on day 8, given no more than four hours after rituximab
**Platelet count 100 to 149 x 109/L: 0.3 mCi/kg (maximum dose of 32 mCi) IV once on day 8, given no more than four hours after rituximab
One course
===References===
#FLUMIZ: Zinzani PL, Tani M, Pulsoni A, Gobbi M, Perotti A, De Luca S, Fabbri A, Zaccaria A, Voso MT, Fattori P, Guardigni L, Ronconi S, Cabras MG, Rigacci L, De Renzo A, Marchi E, Stefoni V, Fina M, Pellegrini C, Musuraca G, Derenzini E, Pileri S, Fanti S, Piccaluga PP, Baccarani M. Fludarabine and mitoxantrone followed by yttrium-90 ibritumomab tiuxetan in previously untreated patients with follicular non-Hodgkin lymphoma trial: a phase II non-randomised trial (FLUMIZ). Lancet Oncol. 2008 Apr;9(4):352-8. Epub 2008 Mar 14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC EudraCT 2004-002211-92
#FIT: Morschhauser F, Radford J, Van Hoof A, Vitolo U, Soubeyran P, Tilly H, Huijgens PC, Kolstad A, d'Amore F, Gonzalez Diaz M, Petrini M, Sebban C, Zinzani PL, van Oers MH, van Putten W, Bischof-Delaloye A, Rohatiner A, Salles G, Kuhlmann J, Hagenbeek A. Phase III trial of consolidation therapy with yttrium-90-ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma. J Clin Oncol. 2008 Nov 10;26(32):5156-64. Epub 2008 Oct 14. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00185393
##Update: Morschhauser F, Radford J, Van Hoof A, Botto B, Rohatiner AZ, Salles G, Soubeyran P, Tilly H, Bischof-Delaloye A, van Putten WL, Kylstra JW, Hagenbeek A. 90Yttrium-ibritumomab tiuxetan consolidation of first remission in advanced-stage follicular non-Hodgkin lymphoma: updated results after a median follow-up of 7.3 years from the international, randomized, phase III First-Line Indolent Trial. J Clin Oncol. 2013 Jun 1;31(16):1977-83. Epub 2013 Apr 1. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
#UPCI 03-005: Jacobs SA, Swerdlow SH, Kant J, Foon KA, Jankowitz R, Land SR, DeMonaco N, Joyce J, Osborn JL, Evans TL, Schaefer PM, Luong TM. Phase II trial of short-course CHOP-R followed by 90Y-ibritumomab tiuxetan and extended rituximab in previously untreated follicular lymphoma. Clin Cancer Res. 2008 Nov 1;14(21):7088-94. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00177554
#Hainsworth JD, Spigel DR, Markus TM, Shipley D, Thompson D, Rotman R, Dannaher C, Greco FA. Rituximab plus short-duration chemotherapy followed by yttrium-90 ibritumomab tiuxetan as first-line treatment for patients with follicular non-Hodgkin lymphoma: a phase II trial of the Sarah Cannon Oncology Research Consortium. Clin Lymphoma Myeloma. 2009 Jun;9(3):223-8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Zinzani PL, Tani M, Pulsoni A, De Renzo A, Stefoni V, Broccoli A, Montini GC, Fina M, Pellegrini C, Gandolfi L, Cavalieri E, Torelli F, Scopinaro F, Argnani L, Quirini F, Derenzini E, Rossi M, Pileri S, Fanti S, Baccarani M. A phase II trial of short course fludarabine, mitoxantrone, rituximab followed by 90Y-ibritumomab tiuxetan in untreated intermediate/high-risk follicular lymphoma. Ann Oncol. 2012 Feb;23(2):415-20. Epub 2011 May 2. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#GOTEL-FL1LC: Provencio M, Cruz Mora MÁ, Gómez-Codina J, Quero Blanco C, Llanos M, García-Arroyo FR, de la Cruz L, Gumá Padró J, Delgado Pérez JR, Sánchez A, Alvarez Cabellos R, Rueda A; GOTEL. Consolidation treatment with Yttrium-90 ibritumomab tiuxetan after new induction regimen in patients with intermediate- and high-risk follicular lymphoma according to the follicular lymphoma international prognostic index: a multicenter, prospective phase II trial of the Spanish Lymphoma Oncology Group. Leuk Lymphoma. 2014 Jan;55(1):51-5. Epub 2013 Jun 12. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00722930
#ZAR2007: Armando Lopez-Guillermo, MD, PhD, Miguel A. Canales, MD, PhD, Ivan Dlouhy, Javier Briones, MD, Dolores Caballero, MD, PhD, Juan Manuel Sancho Sr., MD, Santiago Mercadal Vilchez, MD, Jose María Moraleda, MD, María José Terol, MD, PhD, Antonio Salar, MD, Luis Palomera, MD, Santiago Gardella, MD, Isidro Jarque, MD, Secundino Ferrer, Joan Bargay, MD, Andres Lopez, Carlos Panizo, Anna Muntanola, MD, Carlos Montalban, Eulogio Conde, MD, PhD, Miguel Hernandez, MD, Alfons Soler, Julian Marin, MD, Jose García Marco, Guillermo Deben and José Francisco Tomas, MD, PhD. A Randomized Phase II Study Comparing Consolidation With a Single Dose Of 90y Ibritumomab Tiuxetan (Zevalin®) (Z) Vs. Maintenance With Rituximab (R) For Two Years In Patients With Newly Diagnosed Follicular Lymphoma (FL) Responding To R-CHOP. Preliminary Results At 36 Months From Randomization. Blood 2013 122:369. link to abstract NCT00662948
==Rituximab monotherapy, abbreviated course==
Consolidation or maintenance regimens of less than one year duration or less than 12 total doses.
===Regimen variant #1, 2 doses in 2 weeks===
Study 	Dates of enrollment	Evidence
Hainsworth et al. 2005a	2000-2001 	Phase 2
Counting from the beginning, this is given in weeks 14 & 15.
====Preceding treatment====
*Rituximab pre-phase x 4, then first-line R-CHOP x 3
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1 & 8
14-day course
===Regimen variant #2, 4 doses in 4 weeks===
Study 	Dates of enrollment	Evidence
Rambaldi et al. 2002 	Not reported 	Phase 2
Ladetto et al. 2008 (GITMO 3320)	2000-2005 	Non-randomized part of phase 3 RCT
====Preceding treatment====
*Rambaldi et al. 2002 & GITMO 3320: First-line CHOP x 6
*Zinzani et al. 2004: First-line CHOP x 6 versus FM x 6
====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 #3, 8 doses in 8 months===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Vitolo et al. 2013 (ML17638)	2004-2007 	Phase 3 (E-esc)	Observation	Did not meet primary endpoint of PFS
====Preceding treatment====
*First-line R-FND x 4
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
2-month cycle for 4 cycles
===Regimen variant #4, 8 doses in 9 months===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Ghielmini et al. 2004 (SAKK 35/98FL)	1998-2002 	Phase 3 (E-esc)	Observation 	Longer EFS (primary endpoint)Median EFS: 23 vs 12 mo(aHR 0.40, 95% CI 0.26-0.64)
Taverna et al. 2015 (SAKK 35/03) 	2004-2007 	Phase 3 (C) 	Rituximab x 5 y	Did not meet primary endpoint of EFS
Note: maintenance treatment began in week 12.
====Preceding treatment====
*First-line Rituximab
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
2-month cycle for 4 cycles
===References===
#Rambaldi A, Lazzari M, Manzoni C, Carlotti E, Arcaini L, Baccarani M, Barbui T, Bernasconi C, Dastoli G, Fuga G, Gamba E, Gargantini L, Gattei V, Lauria F, Lazzarino M, Mandelli F, Morra E, Pulsoni A, Ribersani M, Rossi-Ferrini PL, Rupolo M, Tura S, Zagonel V, Zaja F, Zinzani P, Reato G, Foa R. Monitoring of minimal residual disease after CHOP and rituximab in previously untreated patients with follicular lymphoma. Blood. 2002 Feb 1;99(3):856-62. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#SAKK 35/98FL: Ghielmini M, Schmitz SF, Cogliatti SB, Pichert G, Hummerjohann J, Waltzer U, Fey MF, Betticher DC, Martinelli G, Peccatori F, Hess U, Zucca E, Stupp R, Kovacsovics T, Helg C, Lohri A, Bargetzi M, Vorobiof D, Cerny T. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood. 2004 Jun 15;103(12):4416-23. Epub 2004 Feb 19. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00003280
##Update: Martinelli G, Schmitz SF, Utiger U, Cerny T, Hess U, Bassi S, Okkinga E, Stupp R, Stahel R, Heizmann M, Vorobiof D, Lohri A, Dietrich PY, Zucca E, Ghielmini M. Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98. J Clin Oncol. 2010 Oct 10;28(29):4480-4. Epub 2010 Aug 9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Hainsworth JD, Litchy S, Morrissey LH, Andrews MB, Grimaldi M, McCarty M, Greco FA. Rituximab plus short-duration chemotherapy as first-line treatment for follicular non-Hodgkin's lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol. 2005 Mar 1;23(7):1500-6. Epub 2005 Jan 4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#GITMO 3320: Ladetto M, De Marco F, Benedetti F, Vitolo U, Patti C, Rambaldi A, Pulsoni A, Musso M, Liberati AM, Olivieri A, Gallamini A, Pogliani E, Rota Scalabrini D, Callea V, Di Raimondo F, Pavone V, Tucci A, Cortelazzo S, Levis A, Boccadoro M, Majolino I, Pileri A, Gianni AM, Passera R, Corradini P, Tarella C; GITMO; Intergruppo Italiano Linfomi. Prospective, multicenter randomized GITMO/IIL trial comparing intensive (R-HDS) versus conventional (CHOP-R) chemoimmunotherapy in high-risk follicular lymphoma at diagnosis: the superior disease control of R-HDS does not translate into an overall survival advantage. Blood. 2008 Apr 15;111(8):4004-13. Epub 2008 Jan 31. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00435955
#ML17638: Vitolo U, Ladetto M, Boccomini C, Baldini L, De Angelis F, Tucci A, Botto B, Chiappella A, Chiarenza A, Pinto A, De Renzo A, Zaja F, Castellino C, Bari A, Alvarez De Celis I, Evangelista A, Parvis G, Gamba E, Lobetti-Bodoni C, Ciccone G, Rossi G. Rituximab maintenance compared with observation after brief first-line R-FND chemoimmunotherapy with rituximab consolidation in patients age older than 60 years with advanced follicular lymphoma: a phase III randomized study by the Fondazione Italiana Linfomi. J Clin Oncol. 2013 Sep 20;31(27):3351-9. Epub 2013 Aug 19. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01144364
#SAKK 35/03: Taverna C, Martinelli G, Hitz F, Mingrone W, Pabst T, Cevreska L, Del Giglio A, Vanazzi A, Laszlo D, Raats J, Rauch D, Vorobiof DA, Lohri A, Biaggi Rudolf C, Rondeau S, Rusterholz C, Heijnen IA, Zucca E, Ghielmini M. Rituximab maintenance for a maximum of 5 years after single-agent rituximab induction in follicular lymphoma: results of the randomized controlled phase III trial SAKK 35/03. J Clin Oncol. 2016 Feb 10;34(5):495-500. Epub 2015 Dec 28. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00227695
## Update: Moccia AA, Taverna C, Schär S, Vanazzi A, Rondeau S, Hitz F, Mingrone W, Pabst T, Cevreska L, Del Giglio A, Raats J, Rauch D, Vorobiof DA, Lohri A, Ruegsegger C, Biaggi Rudolf C, Rusterholz C, Hayoz S, Ghielmini M, Zucca E. Prolonged rituximab maintenance in follicular lymphoma patients: long-term results of the SAKK 35/03 randomized trial. Blood Adv. 2020 Dec 8;4(23):5951-5957. link to original article link to PMC article EuroPMC
=Maintenance after first-line therapy=
==Lenalidomide & Rituximab (R2)==
R2: Rituximab & Revlimid (Lenalidomide)
===Regimen===
Study 	Dates of enrollment	Evidence
Morschhauser et al. 2018 (RELEVANCE)	2011-2014 	Non-randomized part of phase 3 RCT
====Preceding treatment====
*First-line Lenalidomide & Rituximab
====Targeted therapy====
*Lenalidomide (Revlimid) 10 mg PO once per day
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
8-week cycle for 12 cycles
===References===
#RELEVANCE: Morschhauser F, Fowler NH, Feugier P, Bouabdallah R, Tilly H, Palomba ML, Fruchart C, Libby EN, Casasnovas RO, Flinn IW, Haioun C, Maisonneuve H, Ysebaert L, Bartlett NL, Bouabdallah K, Brice P, Ribrag V, Daguindau N, Le Gouill S, Pica GM, Martin Garcia-Sancho A, López-Guillermo A, Larouche JF, Ando K, Gomes da Silva M, André M, Zachée P, Sehn LH, Tobinai K, Cartron G, Liu D, Wang J, Xerri L, Salles GA; RELEVANCE Trial Investigators. Rituximab plus lenalidomide in advanced untreated follicular lymphoma. N Engl J Med. 2018 Sep 6;379(10):934-947. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01650701
##Update: Morschhauser F, Nastoupil L, Feugier P, Schiano de Colella JM, Tilly H, Palomba ML, Bachy E, Fruchart C, Libby EN, Casasnovas RO, Flinn IW, Haioun C, Maisonneuve H, Ysebaert L, Bartlett NL, Bouabdallah K, Brice P, Ribrag V, Le Gouill S, Daguindau N, Guidez S, Pica GM, García-Sancho AM, López-Guillermo A, Larouche JF, Ando K, Gomes da Silva M, André M, Kalung W, Sehn LH, Izutsu K, Cartron G, Gkasiamis A, Crowe R, Xerri L, Fowler NH, Salles G. Six-Year Results From RELEVANCE: Lenalidomide Plus Rituximab (R2) Versus Rituximab-Chemotherapy Followed by Rituximab Maintenance in Untreated Advanced Follicular Lymphoma. J Clin Oncol. 2022 Oct 1;40(28):3239-3245. Epub 2022 Aug 10. link to original article link to PMC article EuroPMC
==Obinutuzumab monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy	Comparative Toxicity
Marcus et al. 2017 (GALLIUM)	2011-2014 	Phase 3 (E-RT-switch-ic)	See link 	See link 	See link
====Preceding treatment====
*First-line G-B x 6 or G-CHOP x 6 or G-CVP x 6
====Targeted therapy====
*Obinutuzumab (Gazyva) 1000 mg IV once on day 1
2-month cycle for 12 cycles
===References===
#GALLIUM: Marcus R, Davies A, Ando K, Klapper W, Opat S, Owen C, Phillips E, Sangha R, Schlag R, Seymour JF, Townsend W, Trněný M, Wenger M, Fingerle-Rowson G, Rufibach K, Moore T, Herold M, Hiddemann W. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med. 2017 Oct 5;377(14):1331-1344. link to original article link to appendix dosing details in supplement have been reviewed by our editors EuroPMC NCT01332968
##Update: Hiddemann W, Barbui AM, Canales MA, Cannell PK, Collins GP, Dürig J, Forstpointner R, Herold M, Hertzberg M, Klanova M, Radford J, Seymour JF, Tobinai K, Trotman J, Burciu A, Fingerle-Rowson G, Wolbers M, Nielsen T, Marcus RE. Immunochemotherapy with obinutuzumab or rituximab for previously untreated follicular lymphoma in the GALLIUM study: influence of chemotherapy on efficacy and safety. J Clin Oncol. 2018 Aug 10;36(23):2395-2404. Epub 2018 Jun 1. link to original article EuroPMC
##HRQoL analysis: Davies A, Trask P, Demeter J, Florschütz A, Hänel M, Kinoshita T, Pettengell R, Quach H, Robinson S, Sadullah S, Sancho JM, Udvardy M, Witzens-Harig M, Knapp A, Liu W. Health-related quality of life in the phase III GALLIUM study of obinutuzumab- or rituximab-based chemotherapy in patients with previously untreated advanced follicular lymphoma. Ann Hematol. 2020 Dec;99(12):2837-2846. link to original article link to EuroPMC
==Rituximab monotherapy, extended course==
Maintenance regimens of one to two years duration or 12 to 16 total doses.
===Regimen variant #1, q8wk cycles===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Salles et al. 2010 (PRIMAFL) 	2004-2007 	Phase 3 (E-RT-esc)	Observation 	Longer PFS1 (primary endpoint)Median PFS: 10.5 vs 4.1 y(HR 0.61, 95% CI 0.52-0.73)
Davies et al. 2017 (SABRINA) 	2011-2013 	Phase 3 (C) 	SC Rituximab 	Similar efficacy
Luminari et al. 2021 (FOLL12)	2012-2018 	Phase 3 (C) 	Response-adapted strategy	Longer PFSPFS36: 86% vs 72%
1Reported efficacy is based on the 2019 update.
Starts 8 weeks after the last induction treatment.
====Preceding treatment====
*PRIMAFL: First-line R-CHOP or R-CVP or R-FCM
*SABRINA: First-line R-CHOP x 6 to 8 or R-CVP x 8
*FOLL12: First-line R-CHOP x 6 + 2 or BR x 6 + 2
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
8-week cycle for 12 cycles (2 years)
===Regimen variant #2, 16 doses in 2 years===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Ardeshna et al. 2014 (CRUK-2004-001621-16)	2004-2009 	Phase 3 (E-esc)	1. Observation 	Longer TTNT (primary endpoint)
Ardeshna et al. 2014 (CRUK-2004-001621-16)	2004-2009 	Phase 3 (E-esc)	2. Rituximab induction, no maintenance	Did not meet primary endpoint of TTNT
====Preceding treatment====
*First-line Rituximab
====Targeted therapy====
*Rituximab (Rituxan) as follows:
**Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15, 22
**Cycles 2 to 13: 375 mg/m2 IV once on day 1
28-day course, then 2-month cycle for 12 cycles
===Regimen variant #3, 12 doses in 2 years===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy	Comparative Toxicity
Witzens-Harig et al. 2014 (MAXIMA)	2006 to not reported	Non-randomized	 	 	
Marcus et al. 2017 (GALLIUM) 	2011-2014 	Phase 3 (C) 	See link 	See link 	See link
====Preceding treatment====
*MAXIMA: First-line Rituximab monotherapy or rituximab and chemotherapy (Most patients, 62%, received an anthracycline-based regimen)
*GALLIUM: First-line BR x 6 or R-CHOP x 8 or R-CVP x 8
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
2-month cycle for 12 cycles (2 years)
===References===
#Meta-analysis: Vidal L, Gafter-Gvili A, Leibovici L, Dreyling M, Ghielmini M, Hsu Schmitz SF, Cohen A, Shpilberg O. Rituximab maintenance for the treatment of patients with follicular lymphoma: systematic review and meta-analysis of randomized trials. J Natl Cancer Inst. 2009 Feb 18;101(4):248-55. Epub 2009 Feb 10. EuroPMC
#PRIMAFL: Salles G, Seymour JF, Offner F, López-Guillermo A, Belada D, Xerri L, Feugier P, Bouabdallah R, Catalano JV, Brice P, Caballero D, Haioun C, Pedersen LM, Delmer A, Simpson D, Leppa S, Soubeyran P, Hagenbeek A, Casasnovas O, Intragumtornchai T, Fermé C, da Silva MG, Sebban C, Lister A, Estell JA, Milone G, Sonet A, Mendila M, Coiffier B, Tilly H. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet. 2011 Jan 1;377(9759):42-51. Epub 2010 Dec 20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00140582
##HRQoL analysis: Zhou X, Wang J, Zhang J, Copley-Merriman C, Torigoe Y, Reyes C, Seymour JF, Offner FC, Trneny M, Salles GA. Symptoms and toxicity of rituximab maintenance relative to observation following immunochemotherapy in patients with follicular lymphoma. Hematology. 2015 Apr;20(3):129-36. Epub 2014 Jul 16. link to original article EuroPMC
##Update: Bachy E, Seymour JF, Feugier P, Offner F, López-Guillermo A, Belada D, Xerri L, Catalano JV, Brice P, Lemonnier F, Martin A, Casasnovas O, Pedersen LM, Dorvaux V, Simpson D, Leppa S, Gabarre J, da Silva MG, Glaisner S, Ysebaert L, Vekhoff A, Intragumtornchai T, Le Gouill S, Lister A, Estell JA, Milone G, Sonet A, Farhi J, Zeuner H, Tilly H, Salles G. Sustained Progression-Free Survival Benefit of Rituximab Maintenance in Patients With Follicular Lymphoma: Long-Term Results of the PRIMA Study. J Clin Oncol. 2019 Nov 1;37(31):2815-2824. Epub 2019 Jul 24. link to original article link to PMC article EuroPMC
#CRUK-2004-001621-16: Ardeshna KM, Qian W, Smith P, Braganca N, Lowry L, Patrick P, Warden J, Stevens L, Pocock CF, Miall F, Cunningham D, Davies J, Jack A, Stephens R, Walewski J, Ferhanoglu B, Bradstock K, Linch DC. Rituximab versus a watch-and-wait approach in patients with advanced-stage, asymptomatic, non-bulky follicular lymphoma: an open-label randomised phase 3 trial. Lancet Oncol. 2014 Apr;15(4):424-35. Epub 2014 Mar 4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00112931
##HRQoL analysis: Marzolini MAV, Qian W, Clifton-Hadley L, Patrick P, Warden J, Stevens L, Pocock CFE, Miall F, Cunningham D, Stephens R, Walewski J, Johnston A, Seymour JF, Linch DC, Ardeshna KM. Quality of life in advanced-stage, asymptomatic, non-bulky follicular lymphoma treated with rituximab shows significant improvement compared with watchful-waiting. Br J Haematol. 2024 Nov 27. Epub ahead of print. link to original article EuroPMC
#MAXIMA: Witzens-Harig M, Foá R, Di Rocco A, van Hazel G, Chamone DF, Rowe JM, Arcaini L, Poddubnaya I, Ho AD, Ivanova V, Vranovsky A, Thurley D, Oertel S. Maintenance with rituximab is safe and not associated with severe or uncommon infections in patients with follicular lymphoma: results from the phase IIIb MAXIMA study. Ann Hematol. 2014 Oct;93(10):1717-24. Epub 2014 May 14. Erratum in: Ann Hematol. 2014 Oct;93(10):1807. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00430352
#SABRINA: Davies A, Merli F, Mihaljević B, Mercadal S, Siritanaratkul N, Solal-Céligny P, Boehnke A, Berge C, Genevray M, Zharkov A, Dixon M, Brewster M, Barrett M, MacDonald D. Efficacy and safety of subcutaneous rituximab versus intravenous rituximab for first-line treatment of follicular lymphoma (SABRINA): a randomised, open-label, phase 3 trial. Lancet Haematol. 2017 Jun;4(6):e272-e282. Epub 2017 May 2. link to original article does not contain dosing details EuroPMC NCT01200758
#GALLIUM: Marcus R, Davies A, Ando K, Klapper W, Opat S, Owen C, Phillips E, Sangha R, Schlag R, Seymour JF, Townsend W, Trněný M, Wenger M, Fingerle-Rowson G, Rufibach K, Moore T, Herold M, Hiddemann W. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med. 2017 Oct 5;377(14):1331-1344. link to original article link to appendix dosing details in supplement have been reviewed by our editors EuroPMC NCT01332968
##Update: Hiddemann W, Barbui AM, Canales MA, Cannell PK, Collins GP, Dürig J, Forstpointner R, Herold M, Hertzberg M, Klanova M, Radford J, Seymour JF, Tobinai K, Trotman J, Burciu A, Fingerle-Rowson G, Wolbers M, Nielsen T, Marcus RE. Immunochemotherapy with obinutuzumab or rituximab for previously untreated follicular lymphoma in the GALLIUM study: influence of chemotherapy on efficacy and safety. J Clin Oncol. 2018 Aug 10;36(23):2395-2404. Epub 2018 Jun 1. link to original article EuroPMC
##HRQoL analysis: Davies A, Trask P, Demeter J, Florschütz A, Hänel M, Kinoshita T, Pettengell R, Quach H, Robinson S, Sadullah S, Sancho JM, Udvardy M, Witzens-Harig M, Knapp A, Liu W. Health-related quality of life in the phase III GALLIUM study of obinutuzumab- or rituximab-based chemotherapy in patients with previously untreated advanced follicular lymphoma. Ann Hematol. 2020 Dec;99(12):2837-2846. link to original article link to EuroPMC
#FOLL12: Luminari S, Manni M, Galimberti S, Versari A, Tucci A, Boccomini C, Farina L, Olivieri J, Marcheselli L, Guerra L, Ferrero S, Arcaini L, Cavallo F, Kovalchuk S, Skrypets T, Del Giudice I, Chauvie S, Patti C, Stelitano C, Ricci F, Pinto A, Margiotta Casaluci G, Zilioli VR, Merli A, Ladetto M, Bolis S, Pavone V, Chiarenza A, Arcari A, Anastasia A, Dondi A, Mannina D, Federico M; Fondazione Italiana Linfomi. Response-Adapted Postinduction Strategy in Patients With Advanced-Stage Follicular Lymphoma: The FOLL12 Study. J Clin Oncol. 2022 Mar 1;40(7):729-739. Epub 2021 Oct 28. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02063685
==Rituximab monotherapy, very extended course==
Maintenance regimens of more than two years duration.
===Regimen variant #1, 5 years===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Taverna et al. 2015 (SAKK 35/03)	2004-2007 	Phase 3 (E-esc)	Rituximab x 9 mo	Did not meet primary endpoint of EFS
====Preceding treatment====
*First-line Rituximab
====Targeted therapy====
*Rituximab (Rituxan) as follows:
**Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15, 22
**Cycles 2 to 30: 375 mg/m2 IV once on day 1
2-month cycle for up to 30 cycles (5 years)
===Regimen variant #2, indefinite===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Kahl et al. 2014 (RESORT)	2003-2008 	Phase 3 (E-esc)	Rituximab; salvage	Did not meet primary endpoint of TTF
====Preceding treatment====
*First-line Rituximab
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
13-week cycles
===References===
#RESORT: Kahl BS, Hong F, Williams ME, Gascoyne RD, Wagner LI, Krauss JC, Habermann TM, Swinnen LJ, Schuster SJ, Peterson CG, Sborov MD, Martin SE, Weiss M, Ehmann WC, Horning SJ. Rituximab extended schedule or re-treatment trial for low-tumor burden follicular lymphoma: Eastern Cooperative Oncology Group protocol E4402. J Clin Oncol. 2014 Oct 1;32(28):3096-102. Epub 2014 Aug 25. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00075946
##Update: Kahl BS, Jegede OA, Peterson C, Swinnen LJ, Habermann TM, Schuster SJ, Weiss M, Fishkin PA, Fenske TS, Williams ME. Long-Term Follow-Up of the RESORT Study (E4402): A Randomized Phase III Comparison of Two Different Rituximab Dosing Strategies for Low-Tumor Burden Follicular Lymphoma. J Clin Oncol. 2024 Mar 1;42(7):774-778. Epub 2024 Jan 9. link to original article link to PMC article EuroPMC
#SAKK 35/03: Taverna C, Martinelli G, Hitz F, Mingrone W, Pabst T, Cevreska L, Del Giglio A, Vanazzi A, Laszlo D, Raats J, Rauch D, Vorobiof DA, Lohri A, Biaggi Rudolf C, Rondeau S, Rusterholz C, Heijnen IA, Zucca E, Ghielmini M. Rituximab maintenance for a maximum of 5 years after single-agent rituximab induction in follicular lymphoma: results of the randomized controlled phase III trial SAKK 35/03. J Clin Oncol. 2016 Feb 10;34(5):495-500. Epub 2015 Dec 28. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00227695
## Update: Moccia AA, Taverna C, Schär S, Vanazzi A, Rondeau S, Hitz F, Mingrone W, Pabst T, Cevreska L, Del Giglio A, Raats J, Rauch D, Vorobiof DA, Lohri A, Ruegsegger C, Biaggi Rudolf C, Rusterholz C, Hayoz S, Ghielmini M, Zucca E. Prolonged rituximab maintenance in follicular lymphoma patients: long-term results of the SAKK 35/03 randomized trial. Blood Adv. 2020 Dec 8;4(23):5951-5957. link to original article link to PMC article EuroPMC
==Rituximab and hyaluronidase monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Davies et al. 2017 (SABRINA)	2011-2013 	Phase 3 (E-RT-switch-ic)	IV Rituximab	Similar ORR (primary endpoint)
Starts 8 weeks after the last induction treatment.
====Preceding treatment====
*First-line R-CHOP x 6 to 8 or R-CVP x 8
====Targeted therapy====
*Rituximab and hyaluronidase human (Rituxan Hycela) 1400 mg SC once on day 1
8-week cycle for 12 cycles
===References===
#SABRINA: Davies A, Merli F, Mihaljević B, Mercadal S, Siritanaratkul N, Solal-Céligny P, Boehnke A, Berge C, Genevray M, Zharkov A, Dixon M, Brewster M, Barrett M, MacDonald D. Efficacy and safety of subcutaneous rituximab versus intravenous rituximab for first-line treatment of follicular lymphoma (SABRINA): a randomised, open-label, phase 3 trial. Lancet Haematol. 2017 Jun;4(6):e272-e282. Epub 2017 May 2. link to original article does not contain dosing details EuroPMC NCT01200758
#FLIRT: Cartron G, Bachy E, Tilly H, Daguindau N, Pica GM, Bijou F, Mounier C, Clavert A, Damaj GL, Slama B, Casasnovas O, Houot R, Bouabdallah K, Sibon D, Fitoussi O, Morineau N, Herbaux C, Gastinne T, Fornecker LM, Haioun C, Launay V, Araujo C, Benbrahim O, Sanhes L, Gressin R, Gonzalez H, Morschhauser F, Ternant D, Xerri L, Tarte K, Pranger D. Randomized Phase III Trial Evaluating Subcutaneous Rituximab for the First-Line Treatment of Low-Tumor Burden Follicular Lymphoma: Results of a LYSA Study. J Clin Oncol. 2023 Jul 1;41(19):3523-3533. Epub 2023 Apr 18. Erratum in: J Clin Oncol. 2023 Sep 1;41(25):4187. link to original article EuroPMC NCT02303119
=Relapsed or refractory, randomized data=
==Bendamustine & Rituximab (BR)==
BR: Bendamustine, Rituximab
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Nastoupil et al. 2023 (SELENE)	2014-03-28 to 2015-11-05	Phase 3 (C)	1a. BR & Ibrutinib1b. R-CHOP & Ibrutinib	Might have shorter PFS (primary endpoint)Median PFS: 23.8 vs 40.5 mo(HR 1.24, 95% CI 0.96-1.60)
====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===
#SELENE: Nastoupil LJ, Hess G, Pavlovsky MA, Danielewicz I, Freeman J, García-Sancho AM, Glazunova V, Grigg A, Hou JZ, Janssens A, Kim SJ, Masliak Z, McKay P, Merli F, Munakata W, Nagai H, Özcan M, Preis M, Wang T, Rowe M, Tamegnon M, Qin R, Henninger T, Curtis M, Caces DB, Thieblemont C, Salles G. Phase 3 SELENE study: ibrutinib plus BR/R-CHOP in previously treated patients with follicular or marginal zone lymphoma. Blood Adv. 2023 Nov 28;7(22):7141-7150. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01974440
==Bevacizumab & Rituximab==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Hainsworth et al. 2014	2005-2012 	Randomized Phase 2 (E-esc)	Rituximab 	Longer PFSMedian PFS: 20.7 vs 10.4 mo(HR 0.40, 95% CI 0.20-0.80)
====Targeted therapy====
*Bevacizumab (Avastin) as follows:
**Cycle 1: 10 mg/kg IV once per day on days 3 & 15
**Cycles 2 to 5: 10 mg/kg IV once per day on days 1, 15, 29, 43
*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
12-week course, then 2-month cycle for 4 cycles
===References===
#Hainsworth JD, Greco FA, Raefsky EL, Thompson DS, Lunin S, Reeves J Jr, White L, Quinn R, DeBusk LM, Flinn IW. Rituximab with or without bevacizumab for the treatment of patients with relapsed follicular lymphoma. Clin Lymphoma Myeloma Leuk. 2014 Aug;14(4):277-83. Epub 2014 Feb 28. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Bortezomib & Rituximab (VR)==
VR: Velcade (Bortezomib), Rituximab
===Regimen variant #1===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Coiffier et al. 2011 (LYM-3001)	2006-2008 	Phase 3 (E-esc)	Rituximab 	Seems to have longer PFS (primary endpoint)Median PFS: 12.8 vs 11 mo(HR 0.82, 95% CI 0.68-0.99)
====Targeted therapy====
*Bortezomib (Velcade) 1.6 mg/m2 IV over 3 to 5 seconds 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 to 5: 375 mg/m2 IV once on day 1
====Supportive therapy====
*No routine antiviral prophylaxis was mandated
35-day cycle for 5 cycles
===Regimen variant #2===
Study 	Dates of enrollment	Evidence
Agathocleous et al. 2010	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:
**Cycles 1 & 4: 375 mg/m2 IV once per day on days 1, 8, 15, 22
35-day cycle for up to 6 cycles
===Regimen variant #3===
Study 	Dates of enrollment	Evidence
de Vos et al. 2009 (M34103-061)	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
35-day cycle for 3 cycles
===Regimen variant #4===
Study 	Dates of enrollment	Evidence
Baiocchi et al. 2011 (OSU-0430)	2005-2009 	Phase 2, less than 20 patients reported
Note: Bortezomib dose was initially 1.5 mg/m2 but was reduced due to excess grade 3 neurotoxicity.
====Targeted therapy====
*Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
*Rituximab (Rituxan) as follows:
**Cycles 2 to 5: 375 mg/m2 IV once per day on days 1 & 8
21-day cycle for up to 5 cycles
====Subsequent treatment====
*OSU-0430, SD or better: optional VR maintenance
===References===
#M34103-061: de Vos S, Goy A, Dakhil SR, Saleh MN, McLaughlin P, Belt R, Flowers CR, Knapp M, Hart L, Patel-Donnelly D, Glenn M, Gregory SA, Holladay C, Zhang T, Boral AL. Multicenter randomized phase II study of weekly or twice-weekly bortezomib plus rituximab in patients with relapsed or refractory follicular or marginal-zone B-cell lymphoma. J Clin Oncol. 2009 Oct 20;27(30):5023-30. Epub 2009 Sep 21. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00085696
#Agathocleous A, Rohatiner A, Rule S, Hunter H, Kerr JP, Neeson SM, Matthews J, Strauss S, Montoto S, Johnson P, Radford J, Lister A. Weekly versus twice weekly bortezomib given in conjunction with rituximab, in patients with recurrent follicular lymphoma, mantle cell lymphoma and Waldenström macroglobulinaemia. Br J Haematol. 2010 Nov;151(4):346-53. Epub 2010 Sep 29. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#OSU-0430: Baiocchi RA, Alinari L, Lustberg ME, Lin TS, Porcu P, Li X, Johnston JS, Byrd JC, Blum KA. Phase 2 trial of rituximab and bortezomib in patients with relapsed or refractory mantle cell and follicular lymphoma. Cancer. 2011 Jun 1;117(11):2442-51. Epub 2010 Dec 14. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00201877
#LYM-3001: Coiffier B, Osmanov EA, Hong X, Scheliga A, Mayer J, Offner F, Rule S, Teixeira A, Walewski J, de Vos S, Crump M, Shpilberg O, Esseltine DL, Zhu E, Enny C, Theocharous P, van de Velde H, Elsayed YA, Zinzani PL; LYM-3001 study investigators. Bortezomib plus rituximab versus rituximab alone in patients with relapsed, rituximab-naive or rituximab-sensitive, follicular lymphoma: a randomised phase 3 trial. Lancet Oncol. 2011 Aug;12(8):773-84. Epub 2011 Jul 1. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00312845
##Subgroup analysis: Zinzani PL, Khuageva NK, Wang H, Garicochea B, Walewski J, Van Hoof A, Soubeyran P, Caballero D, Buckstein R, Esseltine DL, Theocharous P, Enny C, Zhu E, Elsayed YA, Coiffier B. Bortezomib plus rituximab versus rituximab in patients with high-risk, relapsed, rituximab-naïve or rituximab-sensitive follicular lymphoma: subgroup analysis of a randomized phase 3 trial. J Hematol Oncol. 2012 Oct 22;5:67. link to original article link to PMC article EuroPMC
==Lenalidomide monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Leonard et al. 2015 (CALGB 50401)	2006-2011 	Randomized Phase 2 (E-de-esc)	Lenalidomide & Rituximab	Shorter TTP (secondary endpoint)
Note: Lenalidomide dose was escalated only if tolerated.
====Targeted therapy====
*Lenalidomide (Revlimid) as follows:
**Cycle 1: 15 mg PO once per day on days 1 to 21
**Cycle 2: 20 mg PO once per day on days 1 to 21
**Cycles 3 to 12: 25 mg PO once per day on days 1 to 21
====Supportive therapy====
*Aspirin or LMWH recommended for patients at high risk of thrombosis (see paper for details)
28-day cycle for 12 cycles
===References===
#CALGB 50401: Leonard JP, Jung SH, Johnson J, Pitcher BN, Bartlett NL, Blum KA, Czuczman M, Giguere JK, Cheson BD. Randomized Trial of Lenalidomide Alone Versus Lenalidomide Plus Rituximab in Patients With Recurrent Follicular Lymphoma: CALGB 50401 (Alliance). J Clin Oncol. 2015 Nov 1;33(31):3635-40. Epub 2015 Aug 24. link to full article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00238238
==Lenalidomide & Rituximab (R2)==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Leonard et al. 2015 (CALGB 50401)	2006-2011 	Randomized Phase 2 (E-esc)	Lenalidomide	Longer TTP (secondary endpoint)
Note: Lenalidomide dose was escalated only if tolerated.
====Targeted therapy====
*Lenalidomide (Revlimid) as follows:
**Cycle 1: 15 mg PO once per day on days 1 to 21
**Cycle 2: 20 mg PO once per day on days 1 to 21
**Cycles 3 to 12: 25 mg PO once per day on days 1 to 21
*Rituximab (Rituxan) as follows:
**Cycle 1: 375 mg/m2 IV once per day on days 8, 15, 22
**Cycle 2: 375 mg/m2 IV once on day 1
====Supportive therapy====
*Aspirin or LMWH recommended for patients at high risk of thrombosis (see paper for details)
28-day cycle for 12 cycles
===References===
#CALGB 50401: Leonard JP, Jung SH, Johnson J, Pitcher BN, Bartlett NL, Blum KA, Czuczman M, Giguere JK, Cheson BD. Randomized Trial of Lenalidomide Alone Versus Lenalidomide Plus Rituximab in Patients With Recurrent Follicular Lymphoma: CALGB 50401 (Alliance). J Clin Oncol. 2015 Nov 1;33(31):3635-40. Epub 2015 Aug 24. link to full article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00238238
==Obinutuzumab monotherapy==
===Regimen=== 
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Zinzani et al. 2023 (ROSEWOOD)	2017-11 to 2021-06 	Randomized Phase 2 (C)	ZO 	Lower ORR
====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
**Cycles 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29: 1000 mg IV once on day 1
28-day cycle for up to 29 cycles
===References===
#ROSEWOOD: Zinzani PL, Mayer J, Flowers CR, Bijou F, De Oliveira AC, Song Y, Zhang Q, Merli M, Bouabdallah K, Ganly P, Zhang H, Johnson R, Martín García-Sancho A, Provencio Pulla M, Trněný M, Yuen S, Tilly H, Kingsley E, Tumyan G, Assouline SE, Auer R, Ivanova E, Kim P, Huang S, Delarue R, Trotman J. ROSEWOOD: A Phase II Randomized Study of Zanubrutinib Plus Obinutuzumab Versus Obinutuzumab Monotherapy in Patients With Relapsed or Refractory Follicular Lymphoma. J Clin Oncol. 2023 Nov 20;41(33):5107-5117. Epub 2023 Jul 28. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03332017
##PRO analysis: Trotman J, Zinzani PL, Song Y, Delarue R, Kim P, Ivanova E, Korde R, Mayer J, De Oliveira AC, Assouline SE, Flowers CR, Barnes G. Patient-reported outcomes in patients with relapsed or refractory follicular lymphoma treated with zanubrutinib plus obinutuzumab versus obinutuzumab monotherapy: results from the ROSEWOOD trial. Curr Med Res Opin. 2024 Nov;40(11):1863-1871. Epub 2024 Oct 14. link to original article EuroPMC
==R-CHOP==
R-CHOP: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone
===Regimen variant #1, 3 cycles===
Study 	Dates of enrollment	Evidence
Illidge et al. 2016 (SCHRIFT)	2008-05 to 2010-08 	Phase 2
Dosing details for R-CHOP were not described; this is a typical R-CHOP regimen.
====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
21-day cycle for 3 cycles
====Subsequent treatment====
*Ibritumomab tiuxetan consolidation
===Regimen variant #2, 6 cycles with prednisone 100 mg===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Van Oers et al. 2006 (EORTC 20981)	1998-2004 	Phase 3 (E-esc)	CHOP 	Might have longer OS (secondary endpoint)OS36: 82.5% vs 71.9%(HR 0.74, 95% CI 0.52-1.05)Higher ORR (primary endpoint)
Nastoupil et al. 2023 (SELENE) 	2014-03-28 to 2015-11-05	Phase 3 (C) 	1a. BR & Ibrutinib1b. R-CHOP & Ibrutinib	Might have shorter PFS (primary endpoint)Median PFS: 23.8 vs 40.5 mo(HR 1.24, 95% CI 0.96-1.60)
====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
21-day cycle for 6 cycles
====Subsequent treatment====
*EORTC 20981, responders (PR or CR): Rituximab maintenance versus no further treatment
===Regimen variant #3, 6 cycles with prednisone 100 mg/m2===
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
#EORTC 20981: van Oers MH, Klasa R, Marcus RE, Wolf M, Kimby E, Gascoyne RD, Jack A, Van 't Veer M, Vranovsky A, Holte H, van Glabbeke M, Teodorovic I, Rozewicz C, Hagenbeek A. Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. Blood. 2006 Nov 15;108(10):3295-301. Epub 2006 Jul 27. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00004179
##Update: van Oers MH, Van Glabbeke M, Giurgea L, Klasa R, Marcus RE, Wolf M, Kimby E, van t Veer M, Vranovsky A, Holte H, Hagenbeek A. Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin's lymphoma: long-term outcome of the EORTC 20981 phase III randomized intergroup study. J Clin Oncol. 2010 Jun 10;28(17):2853-8. Epub 2010 May 3. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
#SCHRIFT: Illidge TM, McKenzie HS, Mayes S, Bates A, Davies AJ, Pettengell R, Stanton L, Cozens K, Hampson G, Dive C, Zivanovic M, Tipping J, Gallop-Evans E, Radford JA, Johnson PW; UK National Cancer Research Institute Lymphoma Group. Short duration immunochemotherapy followed by radioimmunotherapy consolidation is effective and well tolerated in relapsed follicular lymphoma: 5-year results from a UK National Cancer Research Institute Lymphoma Group study. Br J Haematol. 2016 Apr;173(2):274-82. Epub 2016 Feb 5. link to original article does not contain dosing details iin manuscript EuroPMC NCT00637832
#SELENE: Nastoupil LJ, Hess G, Pavlovsky MA, Danielewicz I, Freeman J, García-Sancho AM, Glazunova V, Grigg A, Hou JZ, Janssens A, Kim SJ, Masliak Z, McKay P, Merli F, Munakata W, Nagai H, Özcan M, Preis M, Wang T, Rowe M, Tamegnon M, Qin R, Henninger T, Curtis M, Caces DB, Thieblemont C, Salles G. Phase 3 SELENE study: ibrutinib plus BR/R-CHOP in previously treated patients with follicular or marginal zone lymphoma. Blood Adv. 2023 Nov 28;7(22):7141-7150. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01974440
==R-FCM==
R-FCM: Rituximab, Fludarabine, Cyclophosphamide, Mitoxantrone
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Forstpointner et al. 2004	1998-2001 	Phase 3 (E-esc)	FCM 	Seems to have longer PFSMedian PFS: NYR vs 21 mo
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day -1 (the day before FCM)
====Chemotherapy====
*Fludarabine (Fludara) 25 mg/m2 IV over 30 minutes once per day on days 1 to 3
*Cyclophosphamide (Cytoxan) 200 mg/m2 IV over 4 hours once per day on days 1 to 3
*Mitoxantrone (Novantrone) 8 mg/m2 IV over 30 minutes once on day 1
28-day cycle for 4 cycles
====Subsequent treatment====
*Forstpointner et al. 2004, PR or CR: Rituximab maintenance versus no further treatment
===References===
#Forstpointner R, Dreyling M, Repp R, Hermann S, Hänel A, Metzner B, Pott C, Hartmann F, Rothmann F, Rohrberg R, Böck HP, Wandt H, Unterhalt M, Hiddemann W; German Low-Grade Lymphoma Study Group. The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2004 Nov 15;104(10):3064-71. Epub 2004 Jul 29. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Update: Forstpointner R, Unterhalt M, Dreyling M, Böck HP, Repp R, Wandt H, Pott C, Seymour JF, Metzner B, Hänel A, Lehmann T, Hartmann F, Einsele H, Hiddemann W; German Low Grade Lymphoma Study Group. Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: Results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood. 2006 Dec 15;108(13):4003-8. Epub 2006 Aug 31. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Rituximab monotherapy==
===Regimen variant #1, induction then consolidation===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Hainsworth et al. 2014	2005-2012 	Randomized Phase 2 (C)	Bevacizumab & Rituximab	Shorter PFSMedian PFS: 10.4 vs 20.7 mo(HR 2.50, 95% CI 1.25-5.00)
====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
12-week course, then 2-month cycle for 4 cycles
===Regimen variant #2, induction only===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Maloney et al. 1994 	Not reported 	Phase 1, less than 20 pts 	 	
Maloney et al. 1997a 	Not reported 	Phase 2 (RT) 	 	
Maloney et al. 1997b 	Not reported 	Phase 1, less than 20 pts 	 	
Witzig et al. 2002a 	Not reported 	Phase 3 (C) 	Ibritumomab tiuxetan	Lower ORR
Ghielmini et al. 2004 (SAKK 35/98FL)	1998-2002 	Non-randomized part of phase 3 RCT	 	
Note: the phase 1 described by Maloney et al. 1994 did not actually employ this dosing level, but is included here for reference purposes.
====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====
*SAKK 35/98FL, patients with SD or better at 12 weeks: Rituximab maintenance versus no further treatment
===Regimen variant #3===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Coiffier et al. 2011 (LYM-3001)	2006-2008 	Phase 3 (C)	VR 	Seems to have shorter PFSMedian PFS: 11 vs 12.8 mo(HR 1.22, 95% CI 1.01-1.47)
====Targeted therapy====
*Rituximab (Rituxan) as follows:
**Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15, 22
**Cycles 2 to 6: 375 mg/m2 IV once on day 1
====Supportive therapy====
*Acetaminophen (Tylenol) 650 mg PO once per infusion; 30 minutes prior to rituximab
*Diphenhydramine (Benadryl) 50 mg PO once per infusion; 30 minutes prior to rituximab
35-day cycle for 6 cycles
===Regimen variant #4===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Kahl et al. 2014 (RESORT)	2003-2008 	Phase 3 (C)	Rituximab; indefinite	Did not meet primary endpoint of TTF
====Preceding treatment====
*Rituximab
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
7-day cycle for 4 cycles, repeated every progression until treatment failure
===References===
#Maloney DG, Liles TM, Czerwinski DK, Waldichuk C, Rosenberg J, Grillo-Lopez A, Levy R. Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma. Blood. 1994 Oct 15;84(8):2457-66. link to original article EuroPMC
#Maloney DG, Grillo-López AJ, White CA, Bodkin D, Schilder RJ, Neidhart JA, Janakiraman N, Foon KA, Liles TM, Dallaire BK, Wey K, Royston I, Davis T, Levy R. IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma. Blood. 1997 Sep 15;90(6):2188-95. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Maloney DG, Grillo-López AJ, Bodkin DJ, White CA, Liles TM, Royston I, Varns C, Rosenberg J, Levy R. IDEC-C2B8: results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin's lymphoma. J Clin Oncol. 1997 Oct;15(10):3266-74. link to original article 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
#SAKK 35/98FL: Ghielmini M, Schmitz SF, Cogliatti SB, Pichert G, Hummerjohann J, Waltzer U, Fey MF, Betticher DC, Martinelli G, Peccatori F, Hess U, Zucca E, Stupp R, Kovacsovics T, Helg C, Lohri A, Bargetzi M, Vorobiof D, Cerny T. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood. 2004 Jun 15;103(12):4416-23. Epub 2004 Feb 19. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00003280
##Update: Martinelli G, Schmitz SF, Utiger U, Cerny T, Hess U, Bassi S, Okkinga E, Stupp R, Stahel R, Heizmann M, Vorobiof D, Lohri A, Dietrich PY, Zucca E, Ghielmini M. Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98. J Clin Oncol. 2010 Oct 10;28(29):4480-4. Epub 2010 Aug 9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#LYM-3001: Coiffier B, Osmanov EA, Hong X, Scheliga A, Mayer J, Offner F, Rule S, Teixeira A, Walewski J, de Vos S, Crump M, Shpilberg O, Esseltine DL, Zhu E, Enny C, Theocharous P, van de Velde H, Elsayed YA, Zinzani PL; LYM-3001 study investigators. Bortezomib plus rituximab versus rituximab alone in patients with relapsed, rituximab-naive or rituximab-sensitive, follicular lymphoma: a randomised phase 3 trial. Lancet Oncol. 2011 Aug;12(8):773-84. Epub 2011 Jul 1. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00312845
##Subgroup analysis: Zinzani PL, Khuageva NK, Wang H, Garicochea B, Walewski J, Van Hoof A, Soubeyran P, Caballero D, Buckstein R, Esseltine DL, Theocharous P, Enny C, Zhu E, Elsayed YA, Coiffier B. Bortezomib plus rituximab versus rituximab in patients with high-risk, relapsed, rituximab-naïve or rituximab-sensitive follicular lymphoma: subgroup analysis of a randomized phase 3 trial. J Hematol Oncol. 2012 Oct 22;5:67. link to original article link to PMC article EuroPMC
#RESORT: Kahl BS, Hong F, Williams ME, Gascoyne RD, Wagner LI, Krauss JC, Habermann TM, Swinnen LJ, Schuster SJ, Peterson CG, Sborov MD, Martin SE, Weiss M, Ehmann WC, Horning SJ. Rituximab extended schedule or re-treatment trial for low-tumor burden follicular lymphoma: Eastern Cooperative Oncology Group protocol E4402. J Clin Oncol. 2014 Oct 1;32(28):3096-102. Epub 2014 Aug 25. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00075946
##Update: Kahl BS, Jegede OA, Peterson C, Swinnen LJ, Habermann TM, Schuster SJ, Weiss M, Fishkin PA, Fenske TS, Williams ME. Long-Term Follow-Up of the RESORT Study (E4402): A Randomized Phase III Comparison of Two Different Rituximab Dosing Strategies for Low-Tumor Burden Follicular Lymphoma. J Clin Oncol. 2024 Mar 1;42(7):774-778. Epub 2024 Jan 9. link to original article link to PMC article EuroPMC
#Hainsworth JD, Greco FA, Raefsky EL, Thompson DS, Lunin S, Reeves J Jr, White L, Quinn R, DeBusk LM, Flinn IW. Rituximab with or without bevacizumab for the treatment of patients with relapsed follicular lymphoma. Clin Lymphoma Myeloma Leuk. 2014 Aug;14(4):277-83. Epub 2014 Feb 28. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Zanubrutinib & Obinutuzumab (ZO)==
ZO: Zanubrutinib & Obinutuzumab
===Regimen=== 
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Zinzani et al. 2023 (ROSEWOOD)	2017-11 to 2021-06 	Randomized Phase 2 (E-esc)	Obinutuzumab	Higher ORR (primary endpoint)ORR: 69% vs 46%
====Targeted therapy====
*Zanubrutinib (Brukinsa) 160 mg PO twice per day
*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
**Cycles 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29: 1000 mg IV once on day 1
28-day cycles
===References===
#ROSEWOOD: Zinzani PL, Mayer J, Flowers CR, Bijou F, De Oliveira AC, Song Y, Zhang Q, Merli M, Bouabdallah K, Ganly P, Zhang H, Johnson R, Martín García-Sancho A, Provencio Pulla M, Trněný M, Yuen S, Tilly H, Kingsley E, Tumyan G, Assouline SE, Auer R, Ivanova E, Kim P, Huang S, Delarue R, Trotman J. ROSEWOOD: A Phase II Randomized Study of Zanubrutinib Plus Obinutuzumab Versus Obinutuzumab Monotherapy in Patients With Relapsed or Refractory Follicular Lymphoma. J Clin Oncol. 2023 Nov 20;41(33):5107-5117. Epub 2023 Jul 28. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03332017
##PRO analysis: Trotman J, Zinzani PL, Song Y, Delarue R, Kim P, Ivanova E, Korde R, Mayer J, De Oliveira AC, Assouline SE, Flowers CR, Barnes G. Patient-reported outcomes in patients with relapsed or refractory follicular lymphoma treated with zanubrutinib plus obinutuzumab versus obinutuzumab monotherapy: results from the ROSEWOOD trial. Curr Med Res Opin. 2024 Nov;40(11):1863-1871. Epub 2024 Oct 14. link to original article EuroPMC
=Relapsed or refractory, non-randomized or retrospective data=
==BVR==
BVR: Bendamustine, Velcade (Bortezomib), Rituximab
VBR: Velcade (Bortezomib), Bendamustine, Rituximab
===Regimen===
Study 	Dates of enrollment	Evidence
Fowler et al. 2011 (VERTICAL)	2008-2009 	Phase 2
Note: Bendamustine was dose-escalated in the first phase of the trial and the 90 mg/m2 dose was the MTD.
====Chemotherapy====
*Bendamustine 90 mg/m2 IV once per day on days 1 & 2, given second
====Targeted therapy====
*Bortezomib (Velcade) 1.6 mg/m2 IV once per day on days 1, 8, 15, 22, given first
*Rituximab (Rituxan) as follows, given third:
**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
====Supportive therapy====
*Antiviral prophylaxis at physician discretion
35-day cycle for 5 cycles
===References===
#VERTICAL: Fowler N, Kahl BS, Lee P, Matous JV, Cashen AF, Jacobs SA, Letzer J, Amin B, Williams ME, Smith S, Saleh A, Rosen P, Shi H, Parasuraman S, Cheson BD. Bortezomib, bendamustine, and rituximab in patients with relapsed or refractory follicular lymphoma: the phase II VERTICAL study. J Clin Oncol. 2011 Sep 1;29(25):3389-95. Epub 2011 Aug 1. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00636792
==Epcoritamab monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence
Hutchings et al. 2021 (EPCORE NHL-1FL)	2020-06-19 to 2023-04-21	Phase 2 (RT)
Note: dates of enrollment are based on the follicular lymphoma cohort.
====Immunotherapy====
*Epcoritamab (Epkinly) as follows:
**Cycle 1: 0.16 mg SC once on day 1, then 0.8 mg SC once on day 8, then 48 mg SC once per day on days 15 & 22
**Cycles 2 & 3: 48 mg SC once per day on days 1, 8, 15, 22
**Cycles 4 to 9: 48 mg SC once per day on days 1 & 15
**Cycle 10 onwards: 48 mg SC once on day 1
28-day cycles
===References===
#EPCORE NHL-1FL: Linton KM, Vitolo U, Jurczak W, Lugtenburg PJ, Gyan E, Sureda A, Christensen JH, Hess B, Tilly H, Cordoba R, Lewis DJ, Okada C, Hutchings M, Clausen MR, Sancho JM, Cochrane T, Leppä S, Chamuleau MED, Gernhardt D, Altıntaş I, Liu Y, Ahmadi T, Dinh MH, Hoehn D, Favaro E, Elliott B, Thieblemont C, Vose JM. Epcoritamab monotherapy in patients with relapsed or refractory follicular lymphoma (EPCORE NHL-1): a phase 2 cohort of a single-arm, multicentre study. Lancet Haematol. 2024 Aug;11(8):e593-e605. Epub 2024 Jun 15. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT03625037
==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
==Ibrutinib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence	Efficacy
Bartlett et al. 2017 (MC1282)	2013-2014 	Phase 2 	ORR: 37.5% (95% CI, 23-54)
Gopal et al. 2018 (DAWN) 	2013-2016 	Phase 2 	ORR: 21% (95% CI, 14-30)
====Targeted therapy====
*Ibrutinib (Imbruvica) 560 mg PO once per day on days 1 to 28
28-day cycles
===References===
#MC1282: Bartlett NL, Costello BA, LaPlant BR, Ansell SM, Kuruvilla JG, Reeder CB, Thye LS, Anderson DM, Krysiak K, Ramirez C, Qi J, Siegel BA, Griffith M, Griffith OL, Gomez F, Fehniger TA. Single-agent ibrutinib in relapsed or refractory follicular lymphoma: a phase 2 consortium trial. Blood. 2018 Jan 11;131(2):182-190. Epub 2017 Oct 26. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01849263
#DAWN: Gopal AK, Schuster SJ, Fowler NH, Trotman J, Hess G, Hou JZ, Yacoub A, Lill M, Martin P, Vitolo U, Spencer A, Radford J, Jurczak W, Morton J, Caballero D, Deshpande S, Gartenberg GJ, Wang SS, Damle RN, Schaffer M, Balasubramanian S, Vermeulen J, Cheson BD, Salles G. Ibrutinib as treatment for patients with relapsed/refractory follicular lymphoma: results from the open-label, multicenter, phase II DAWN study. J Clin Oncol. 2018 Aug 10;36(23):2405-2412. Epub 2018 May 31. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01779791
==Lisocabtagene maraleucel monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence
Morschhauser et al. 2024 (TRANSCEND-FL)	2020-07-14 to 2023-01-27	Phase 2 (RT)
====Preceding treatment====
*Lymphodepletion with FC
====Immunotherapy====
*Lisocabtagene maraleucel (Breyanzi) target dose of 100 x 106 CAR T cells IV once on day 0
One course
===References===
#TRANSCEND-FL: Morschhauser F, Dahiya S, Palomba ML, Martin Garcia-Sancho A, Reguera Ortega JL, Kuruvilla J, Jäger U, Cartron G, Izutsu K, Dreyling M, Kahl B, Ghesquieres H, Ardeshna K, Goto H, Barbui AM, Abramson JS, Borchmann P, Fleury I, Mielke S, Skarbnik A, de Vos S, Kamdar M, Karmali R, Viardot A, Farazi T, Fasan O, Lymp J, Vedal M, Nishii R, Avilion A, Papuga J, Kumar J, Nastoupil LJ. Lisocabtagene maraleucel in follicular lymphoma: the phase 2 TRANSCEND FL study. Nat Med. 2024 Aug;30(8):2199-2207. Epub 2024 Jun 3. Erratum in: Nat Med. 2024 Aug;30(8):2374. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04245839
==Mosunetuzumab monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment	Evidence
Budde et al. 2022 (GO29781)	2019-2020 	Phase 2 (RT)
====Prior treatment criteria====
*2 or more SACT, including an anti-CD20 therapy and an alkylating agent
====Immunotherapy====
*Mosunetuzumab (Lunsumio) as follows:
**Cycle 1: 1 mg IV once on day 1, then 2 mg IV once on day 8, then 60 mg IV once on day 15
**Cycle 2: 60 mg IV once on day 1
**Cycle 3 onwards: 30 mg IV once on day 1
21-day cycles
===References===
#GO29781: Budde LE, Sehn LH, Matasar M, Schuster SJ, Assouline S, Giri P, Kuruvilla J, Canales M, Dietrich S, Fay K, Ku M, Nastoupil L, Cheah CY, Wei MC, Yin S, Li CC, Huang H, Kwan A, Penuel E, Bartlett NL. Safety and efficacy of mosunetuzumab, a bispecific antibody, in patients with relapsed or refractory follicular lymphoma: a single-arm, multicentre, phase 2 study. Lancet Oncol. 2022 Aug;23(8):1055-1065. Epub 2022 Jul 5. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT02500407
==R-CVP==
R-CVP: Rituximab, Cyclophosphamide, Vincristine, Prednisone
===Regimen===
Study 	Dates of enrollment	Evidence
Illidge et al. 2016 (SCHRIFT)	2008-05 to 2010-08 	Phase 2
Dosing details for R-CVP were not described; this is a typical R-CVP regimen.
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 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
21-day cycle for 3 cycles
====Subsequent treatment====
*Ibritumomab tiuxetan consolidation
===References===
#SCHRIFT: Illidge TM, McKenzie HS, Mayes S, Bates A, Davies AJ, Pettengell R, Stanton L, Cozens K, Hampson G, Dive C, Zivanovic M, Tipping J, Gallop-Evans E, Radford JA, Johnson PW; UK National Cancer Research Institute Lymphoma Group. Short duration immunochemotherapy followed by radioimmunotherapy consolidation is effective and well tolerated in relapsed follicular lymphoma: 5-year results from a UK National Cancer Research Institute Lymphoma Group study. Br J Haematol. 2016 Apr;173(2):274-82. Epub 2016 Feb 5. link to original article does not contain dosing details in manuscript EuroPMC NCT00637832
==Tazemetostat monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment	Evidence
Morschhauser et al. 2020 (E7438-G000-101)	2015-2019 	Phase 2 (RT)
====Targeted therapy====
*Tazemetostat (Tazverik) 800 mg PO twice per day on days 1 to 28
28-day cycles
===References===
# E7438-G000-101: Morschhauser F, Tilly H, Chaidos A, McKay P, Phillips T, Assouline S, Batlevi CL, Campbell P, Ribrag V, Damaj GL, Dickinson M, Jurczak W, Kazmierczak M, Opat S, Radford J, Schmitt A, Yang J, Whalen J, Agarwal S, Adib D, Salles G. Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial. Lancet Oncol. 2020 Nov;21(11):1433-1442. Epub 2020 Oct 6. link to original article dosing details in abstract have been reviewed by our editors link to PMC article EuroPMC NCT01897571
==Tisagenlecleucel monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment	Evidence
Fowler et al. 2021 (ELARA)	2018-2020 	Phase 2 (RT)
The range given is the FDA-recommended dose.
====Prior treatment criteria====
*One of the following:
**Refractory to at least 2 lines of therapy including an anti-CD20 antibody and an alkylating agent
**Relapsed within 6 months after completion of at least 2 lines of therapy including an anti-CD20 antibody and an alkylating agent
**Relapsed during anti-CD20 antibody maintenance after completion of at least 2 lines of therapy including an anti-CD20 antibody and an alkylating agent
**Relapsed after autologous HSCT
====Immunotherapy====
*Tisagenlecleucel (Kymriah) 0.6 to 6 x 108 CTL019 transduced viable T-cells IV once on day 0
One course
===References===
# ELARA: Fowler NH, Dickinson M, Dreyling M, Martinez-Lopez J, Kolstad A, Butler J, Ghosh M, Popplewell L, Chavez JC, Bachy E, Kato K, Harigae H, Kersten MJ, Andreadis C, Riedell PA, Ho PJ, Pérez-Simón JA, Chen AI, Nastoupil LJ, von Tresckow B, Ferreri AJM, Teshima T, Patten PEM, McGuirk JP, Petzer AL, Offner F, Viardot A, Zinzani PL, Malladi R, Zia A, Awasthi R, Masood A, Anak O, Schuster SJ, Thieblemont C. Tisagenlecleucel in adult relapsed or refractory follicular lymphoma: the phase 2 ELARA trial. Nat Med. 2022 Feb;28(2):325-332. Epub 2021 Dec 17. link to original article EuroPMC NCT03568461
##Update: Dreyling M, Fowler NH, Dickinson M, Martinez-Lopez J, Kolstad A, Butler J, Ghosh M, Popplewell L, Chavez JC, Bachy E, Kato K, Harigae H, Kersten MJ, Andreadis C, Riedell PA, Ho PJ, Pérez-Simón JA, Chen AI, Nastoupil LJ, von Tresckow B, María Ferreri AJ, Teshima T, Patten PEM, McGuirk JP, Petzer AL, Offner F, Viardot A, Zinzani PL, Malladi R, Paule I, Zia A, Awasthi R, Han X, Germano D, O'Donovan D, Ramos R, Maier HJ, Masood A, Thieblemont C, Schuster SJ. Durable response after tisagenlecleucel in adults with relapsed/refractory follicular lymphoma: ELARA trial update. Blood. 2024 Apr 25;143(17):1713-1725. link to original article link to PMC article EuroPMC
==VR-CP==
VR-CP: Velcade (Bortezomib), Rituximab, Cyclophosphamide, Prednisone
===Regimen===
Study 	Dates of enrollment 	Evidence
Craig et al. 2014 (C05012)	2008-09-04 to 2010-04-07	Phase 2
====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) 1000 mg/m2 IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5
====Supportive therapy====
*Antiviral prophylaxis against VZV recommended for all patients
21-day cycle for 6 cycles
===References===
#C05012: Craig M, Hanna WT, Cabanillas F, Chen CS, Esseltine DL, Neuwirth R, O'Connor OA. Phase II study of bortezomib in combination with rituximab, cyclophosphamide and prednisone with or without doxorubicin followed by rituximab maintenance in patients with relapsed or refractory follicular lymphoma. Br J Haematol. 2014 Sep;166(6):920-8. Epub 2014 Jul 9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00715208
=Rituximab-refractory=
==Ibritumomab tiuxetan protocol==
===Regimen===
Study 	Dates of enrollment	Evidence
Witzig et al. 2002b	1998-1999 	Phase 2 (RT)
====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, Flinn IW, Gordon LI, Emmanouilides C, Czuczman MS, Saleh MN, Cripe L, Wiseman G, Olejnik T, Multani PS, White CA. Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin's lymphoma. J Clin Oncol. 2002 Aug 1;20(15):3262-9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
=Consolidation after subsequent lines of therapy=
==BEAM, then auto HSCT==
BEAM: BiCNU (Carmustine), Etoposide, Ara-C (Cytarabine), Melphalan
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Ladetto et al. 2023 (FIL FLAZ12)	2012-08 to 2019-09 	Phase 3 (C)	Zevalin 	Did not meet primary endpoint of PFS
====Preceding treatment====
*Salvage R-CHOP x 3 or R-DHAP x 3 or R-FM x 3 or R-ICE x 3 or R-IEV x 3 or BR x 3
====Subsequent treatment====
*Rituximab maintenance
===References===
#FIL FLAZ12: Ladetto M, Tavarozzi R, Zanni M, Evangelista A, Ferrero S, Tucci A, Botto B, Bolis S, Volpetti S, Zilioli VR, Puccini B, Arcari A, Pavone V, Gaidano G, Corradini P, Tani M, Cavallo F, Milone G, Ghiggi C, Pinto A, Pastore D, Ferreri AJM, Latte G, Patti C, Re F, Benedetti F, Luminari S, Pennese E, Bossi E, Boccomini C, Anastasia A, Bottelli C, Ciccone G, Vitolo U. Radioimmunotherapy versus autologous hematopoietic stem cell transplantation in relapsed/refractory follicular lymphoma: a Fondazione Italiana Linfomi multicenter, randomized, phase III trial. Ann Oncol. 2024 Jan;35(1):118-129. Epub 2023 Nov 3. link to original article dosing details in supplement have been reviewed by our editors EuroPMC NCT01827605
==FCR, then allo HSCT==
FCR: Fludarabine, Cyclophosphamide, Rituximab
===Regimen===
Study 	Dates of enrollment	Evidence
Khouri et al. 2001 (MDACC ID01-233)	1997-2000 	Phase 2
===References===
#MDACC ID01-233: Khouri IF, Saliba RM, Giralt SA, Lee MS, Okoroji GJ, Hagemeister FB, Korbling M, Younes A, Ippoliti C, Gajewski JL, McLaughlin P, Anderlini P, Donato ML, Cabanillas FF, Champlin RE. Nonablative allogeneic hematopoietic transplantation as adoptive immunotherapy for indolent lymphoma: low incidence of toxicity, acute graft-versus-host disease, and treatment-related mortality. Blood. 2001 Dec 15;98(13):3595-9. link to original article EuroPMC NCT00048737
##Update: Khouri IF, McLaughlin P, Saliba RM, Hosing C, Korbling M, Lee MS, Medeiros LJ, Fayad L, Samaniego F, Alousi A, Anderlini P, Couriel D, de Lima M, Giralt S, Neelapu SS, Ueno NT, Samuels BI, Hagemeister F, Kwak LW, Champlin RE. Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab. Blood. 2008 Jun 15;111(12):5530-6. Epub 2008 Apr 14. Erratum in: Blood. 2009 Feb 12;113(7):1613. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
##Update: Khouri IF, Saliba RM, Erwin WD, Samuels BI, Korbling M, Medeiros LJ, Valverde R, Alousi AM, Anderlini P, Bashir Q, Ciurea S, Gulbis AM, de Lima M, Hosing C, Kebriaei P, Popat UR, Fowler N, Neelapu SS, Samaniego F, Champlin RE, Macapinlac HA. Nonmyeloablative allogeneic transplantation with or without 90yttrium ibritumomab tiuxetan is potentially curative for relapsed follicular lymphoma: 12-year results. Blood. 2012 Jun 28;119(26):6373-8. Epub 2012 May 14. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
==Ibritumomab tiuxetan protocol==
===Regimen===
Study 	Dates of enrollment	Evidence
Illidge et al. 2016 (SCHRIFT)	2008-05 to 2010-08 	Phase 2
====Preceding treatment====
*Salvage R-CHOP x 3 or R-CVP x 3, with at least PR
====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) 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, given immediately after rituximab
**Platelet count 100 to 149 x 109/L: 11.1 MBq/kg (maximum dose of 888 MBq) IV once on day 8, given immediately after rituximab
8-day course
===References===
#SCHRIFT: Illidge TM, McKenzie HS, Mayes S, Bates A, Davies AJ, Pettengell R, Stanton L, Cozens K, Hampson G, Dive C, Zivanovic M, Tipping J, Gallop-Evans E, Radford JA, Johnson PW; UK National Cancer Research Institute Lymphoma Group. Short duration immunochemotherapy followed by radioimmunotherapy consolidation is effective and well tolerated in relapsed follicular lymphoma: 5-year results from a UK National Cancer Research Institute Lymphoma Group study. Br J Haematol. 2016 Apr;173(2):274-82. Epub 2016 Feb 5. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00637832
==Rituximab monotherapy, abbreviated course==
Maintenance regimens of less than one year duration or less than 12 total doses.
===Regimen variant #1, 4 doses===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Ghielmini et al. 2004 (SAKK 35/98FL)	1998-2002 	Phase 3 (E-esc)	Observation	Longer EFS (primary endpoint)Median EFS: 23 vs 12 mo(aHR 0.40, 95% CI 0.26-0.64)
Pettengell et al. 2013 (EBMT Lym-1) 	1999-2006 	Phase 3 (E-esc)	Observation	Longer PFS (primary endpoint)PFS120: 54% vs 37%(HR 0.66, 95% CI 0.47-0.91)
Note: SAKK 35/98 specified that treatment was to be given at week 12, month 5, 7, 9. Pettengell et al. 2013 did not specify when the maintenance rituximab was to begin post-auto HSCT.
====Preceding treatment====
*SAKK 35/98FL: Salvage Rituximab
*EBMT Lym-1: BEAM with auto HSCT
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
2-month cycle for 4 cycles
===Regimen variant #2, 8 doses===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Forstpointner et al. 2004	1998-2001 	Phase 3 (E-esc)	Observation	Seems to have longer PFS1Median PFS: NYR vs 26 mo
1Reported efficacy is based on the FL subgroup in the 2006 update.
Note: first cycle began 3 months after completion of salvage therapy.
====Preceding treatment====
*Salvage R-FCM x 4 versus FCM x 4
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1, 8, 15, 22
6-month cycle for 2 cycles
===References===
#SAKK 35/98FL: Ghielmini M, Schmitz SF, Cogliatti SB, Pichert G, Hummerjohann J, Waltzer U, Fey MF, Betticher DC, Martinelli G, Peccatori F, Hess U, Zucca E, Stupp R, Kovacsovics T, Helg C, Lohri A, Bargetzi M, Vorobiof D, Cerny T. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood. 2004 Jun 15;103(12):4416-23. Epub 2004 Feb 19. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00003280
##Update: Martinelli G, Schmitz SF, Utiger U, Cerny T, Hess U, Bassi S, Okkinga E, Stupp R, Stahel R, Heizmann M, Vorobiof D, Lohri A, Dietrich PY, Zucca E, Ghielmini M. Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98. J Clin Oncol. 2010 Oct 10;28(29):4480-4. Epub 2010 Aug 9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Forstpointner R, Dreyling M, Repp R, Hermann S, Hänel A, Metzner B, Pott C, Hartmann F, Rothmann F, Rohrberg R, Böck HP, Wandt H, Unterhalt M, Hiddemann W; German Low-Grade Lymphoma Study Group. The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2004 Nov 15;104(10):3064-71. Epub 2004 Jul 29. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Update: Forstpointner R, Unterhalt M, Dreyling M, Böck HP, Repp R, Wandt H, Pott C, Seymour JF, Metzner B, Hänel A, Lehmann T, Hartmann F, Einsele H, Hiddemann W; German Low Grade Lymphoma Study Group. Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: Results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood. 2006 Dec 15;108(13):4003-8. Epub 2006 Aug 31. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#EBMT Lym-1: Pettengell R, Schmitz N, Gisselbrecht C, Smith G, Patton WN, Metzner B, Caballero D, Tilly H, Walewski JA, Bence-Bruckler I, To B, Geisler CH, Schots R, Kimby E, Taverna CJ, Kozák T, Dreger P, Uddin R, Ruiz de Elvira C, Goldstone AH. Rituximab purging and/or maintenance in patients undergoing autologous transplantation for relapsed follicular lymphoma: a prospective randomized trial from the lymphoma working party of the European group for blood and marrow transplantation. J Clin Oncol. 2013 May 1;31(13):1624-30. Epub 2013 Apr 1. link to original article EuroPMC NCT00005589
==TEAM, then auto HSCT==
TEAM: Thiotepa, Etoposide, Ara-C (Cytarabine), Melphalan
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Ladetto et al. 2023 (FIL FLAZ12)	2012-08 to 2019-09 	Phase 3 (C)	Zevalin 	Did not meet primary endpoint of PFS
====Preceding treatment====
*Salvage R-CHOP x 3 or R-DHAP x 3 or R-FM x 3 or R-ICE x 3 or R-IEV x 3 or BR x 3
====Subsequent treatment====
*Rituximab maintenance
===References===
#FIL FLAZ12: Ladetto M, Tavarozzi R, Zanni M, Evangelista A, Ferrero S, Tucci A, Botto B, Bolis S, Volpetti S, Zilioli VR, Puccini B, Arcari A, Pavone V, Gaidano G, Corradini P, Tani M, Cavallo F, Milone G, Ghiggi C, Pinto A, Pastore D, Ferreri AJM, Latte G, Patti C, Re F, Benedetti F, Luminari S, Pennese E, Bossi E, Boccomini C, Anastasia A, Bottelli C, Ciccone G, Vitolo U. Radioimmunotherapy versus autologous hematopoietic stem cell transplantation in relapsed/refractory follicular lymphoma: a Fondazione Italiana Linfomi multicenter, randomized, phase III trial. Ann Oncol. 2024 Jan;35(1):118-129. Epub 2023 Nov 3. link to original article dosing details in supplement have been reviewed by our editors EuroPMC NCT01827605
==Cyclophosphamide & TBI, then auto HSCT==
Cy/TBI: Cyclophosphamide & Total Body Irradiation
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Schouten et al. 2003 (CUP)	1993-1997 	Phase 3 (E-esc)	CHOP x 3 	Might have longer OS
===References===
#CUP: Schouten HC, Qian W, Kvaloy S, Porcellini A, Hagberg H, Johnsen HE, Doorduijn JK, Sydes MR, Kvalheim G. High-dose therapy improves progression-free survival and survival in relapsed follicular non-Hodgkin's lymphoma: results from the randomized European CUP trial. J Clin Oncol. 2003 Nov 1;21(21):3918-27. Epub 2003 Sep 29. link to original article EuroPMC
==(90)YFC, then allo HSCT==
(90)YFC: Ibritumomab tiuxetan, Fludarabine, Cyclophosphamide
===Regimen===
Study 	Dates of enrollment	Evidence
Khouri et al. 2001 (MDACC ID01-233)	1997-2000 	Phase 2
===References===
#MDACC ID01-233: Khouri IF, Saliba RM, Giralt SA, Lee MS, Okoroji GJ, Hagemeister FB, Korbling M, Younes A, Ippoliti C, Gajewski JL, McLaughlin P, Anderlini P, Donato ML, Cabanillas FF, Champlin RE. Nonablative allogeneic hematopoietic transplantation as adoptive immunotherapy for indolent lymphoma: low incidence of toxicity, acute graft-versus-host disease, and treatment-related mortality. Blood. 2001 Dec 15;98(13):3595-9. link to original article EuroPMC NCT00048737
##Update: Khouri IF, McLaughlin P, Saliba RM, Hosing C, Korbling M, Lee MS, Medeiros LJ, Fayad L, Samaniego F, Alousi A, Anderlini P, Couriel D, de Lima M, Giralt S, Neelapu SS, Ueno NT, Samuels BI, Hagemeister F, Kwak LW, Champlin RE. Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab. Blood. 2008 Jun 15;111(12):5530-6. Epub 2008 Apr 14. Erratum in: Blood. 2009 Feb 12;113(7):1613. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
##Update: Khouri IF, Saliba RM, Erwin WD, Samuels BI, Korbling M, Medeiros LJ, Valverde R, Alousi AM, Anderlini P, Bashir Q, Ciurea S, Gulbis AM, de Lima M, Hosing C, Kebriaei P, Popat UR, Fowler N, Neelapu SS, Samaniego F, Champlin RE, Macapinlac HA. Nonmyeloablative allogeneic transplantation with or without 90yttrium ibritumomab tiuxetan is potentially curative for relapsed follicular lymphoma: 12-year results. Blood. 2012 Jun 28;119(26):6373-8. Epub 2012 May 14. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
=Maintenance after subsequent lines of therapy=
==Bortezomib & Rituximab (VR)==
VR: Velcade (Bortezomib), Rituximab
===Regimen===
Study 	Dates of enrollment	Evidence
Baiocchi et al. 2011 (OSU-0430)	2005-2009 	Phase 2, less than 20 patients reported
====Preceding treatment====
*VR salvage
====Targeted therapy====
*Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1 & 8
*Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1 & 8
6-month cycle for up to 4 cycles (2 years)
===References===
#OSU-0430: Baiocchi RA, Alinari L, Lustberg ME, Lin TS, Porcu P, Li X, Johnston JS, Byrd JC, Blum KA. Phase 2 trial of rituximab and bortezomib in patients with relapsed or refractory mantle cell and follicular lymphoma. Cancer. 2011 Jun 1;117(11):2442-51. Epub 2010 Dec 14. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00201877
==Rituximab monotherapy, extended course==
Maintenance regimens of one to two years duration or 12 to 16 total doses.
===Regimen variant #1, 3-month cycles===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Van Oers et al. 2006 (EORTC 20981)	1998-2004 	Phase 3 (E-esc)	Observation	Might have longer OS1 (secondary endpoint)OS60: 74.3% vs 64.7%(HR 0.70, 95% CI 0.48-1.03)
1Reported efficacy is based on the 2010 update.
====Preceding treatment====
*Salvage CHOP versus R-CHOP
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
3-month cycle for up to 8 cycles (2 years)
===Regimen variant #2, 2-month cycles===
Study 	Dates of enrollment 	Evidence
Witzens-Harig et al. 2014 (MAXIMA)	2006 to not reported	Non-randomized
====Preceding treatment====
*Salvage Rituximab monotherapy or rituximab and chemotherapy (Most patients, 62%, received an anthracycline-based regimen)
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
2-month cycle for up to 12 cycles (2 years)
===References===
#EORTC 20981: van Oers MH, Klasa R, Marcus RE, Wolf M, Kimby E, Gascoyne RD, Jack A, Van 't Veer M, Vranovsky A, Holte H, van Glabbeke M, Teodorovic I, Rozewicz C, Hagenbeek A. Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. Blood. 2006 Nov 15;108(10):3295-301. Epub 2006 Jul 27. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00004179
##Update: van Oers MH, Van Glabbeke M, Giurgea L, Klasa R, Marcus RE, Wolf M, Kimby E, van t Veer M, Vranovsky A, Holte H, Hagenbeek A. Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin's lymphoma: long-term outcome of the EORTC 20981 phase III randomized intergroup study. J Clin Oncol. 2010 Jun 10;28(17):2853-8. Epub 2010 May 3. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
#MAXIMA: Witzens-Harig M, Foá R, Di Rocco A, van Hazel G, Chamone DF, Rowe JM, Arcaini L, Poddubnaya I, Ho AD, Ivanova V, Vranovsky A, Thurley D, Oertel S. Maintenance with rituximab is safe and not associated with severe or uncommon infections in patients with follicular lymphoma: results from the phase IIIb MAXIMA study. Ann Hematol. 2014 Oct;93(10):1717-24. Epub 2014 May 14. Erratum in: Ann Hematol. 2014 Oct;93(10):1807. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00430352
=Prognosis=
==Follicular lymphoma international prognostic index (FLIPI - 1)==
Each category is assigned 0 or 1 points:
*Age
**Less than 60 years (0 points)
**Greater than or equal to 60 years (1 point)
*Ann Arbor stage
**I or II (0 points)
**III or IV (1 point)
*Hemoglobin level
**Less than 12 g/dL (1 point)
**Greater than or equal to 12 g/dL (0 points)
*Serum LDH level (note that reference ranges can vary widely!)
**Less than or equal to upper limit of normal (0 points)
**Greater than upper limit of normal (1 point)
*Number of nodal sites
**Less than 5 (0 points)
**Greater than or equal to 5 (1 point)
Risk stratification:
*0 or 1 points: Low risk
*2 points: Intermediate risk
*Greater than or equal to 3 points: High risk
</div>
===References===
#Solal-Céligny P, Roy P, Colombat P, White J, Armitage JO, Arranz-Saez R, Au WY, Bellei M, Brice P, Caballero D, Coiffier B, Conde-Garcia E, Doyen C, Federico M, Fisher RI, Garcia-Conde JF, Guglielmi C, Hagenbeek A, Haïoun C, LeBlanc M, Lister AT, Lopez-Guillermo A, McLaughlin P, Milpied N, Morel P, Mounier N, Proctor SJ, Rohatiner A, Smith P, Soubeyran P, Tilly H, Vitolo U, Zinzani PL, Zucca E, Montserrat E. Follicular lymphoma international prognostic index. Blood. 2004 Sep 1;104(5):1258-65. Epub 2004 May 4. link to original article EuroPMC
</div>
==Follicular lymphoma international prognostic index (FLIPI - 2)==
Each category is assigned 0 or 1 points:
*Age
**Less than 60 years (0 points)
**Greater than or equal to 60 years (1 point)
*Hemoglobin level
**Less than 12 g/dL (1 point)
**Greater than or equal to 12 g/dL (0 points)
*β2-microglobulin level (note that reference ranges can vary)
**Less than or equal to upper limit of normal (0 points)
**Greater than upper limit of normal (1 point)
*Longest diameter of the largest involved node
**Less than or equal to 6 cm (0 points)
**Greater than 6 cm (1 point)
*Bone marrow involvement
**No (0 points)
**Yes (1 point)
Risk stratification:
*0 points: Low risk
*1 or 2 points: Intermediate risk
*Greater than or equal to 3 points: High risk
</div>
===References===
#Federico M, Bellei M, Marcheselli L, Luminari S, Lopez-Guillermo A, Vitolo U, Pro B, Pileri S, Pulsoni A, Soubeyran P, Cortelazzo S, Martinelli G, Martelli M, Rigacci L, Arcaini L, Di Raimondo F, Merli F, Sabattini E, McLaughlin P, Solal-Céligny P. Follicular lymphoma international prognostic index 2: a new prognostic index for follicular lymphoma developed by the international follicular lymphoma prognostic factor project. J Clin Oncol. 2009 Sep 20;27(27):4555-62. Epub 2009 Aug 3. link to original article EuroPMC
</div>
=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:Follicular lymphoma regimens
Category:Disease-specific pages
Category:Indolent lymphomas
Category:B-cell lymphomas