Follicular lymphoma

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

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!

• We have moved How I Treat articles to a dedicated page.

85 regimens on this page 140 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 PubMed
  • 2012: McNamara et al. Guidelines on the investigation and management of follicular lymphoma PubMed

ESMO

• 2020: Dreyling et al. Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
  • 2016: Dreyling et al. Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
  • 2014: Dreyling et al. Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
  • 2011: Dreyling et al. Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
  • 2010: Dreyling. Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
  • 2009: Dreyling. Newly diagnosed and relapsed follicular lymphoma: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
  • 2008: Dreyling. Newly diagnosed and relapsed follicular lymphoma: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
  • 2003: Hiddemann. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of newly diagnosed follicular lymphoma PubMed
• 2013: Ghielmini et al. ESMO Guidelines consensus conference on malignant lymphoma 2011 part 1: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL) PubMed

NCCN

• NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - B-cell Lymphomas.

Early disease, definitive therapy

Ibritumomab tiuxetan protocol

Regimen

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

Targeted therapy

• Rituximab (Rituxan) 250 mg/m² IV once per day on days 1 & 8, given first on day 8

Radioconjugate therapy

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

References

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

Radiation therapy

RT: Radiation Therapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kelsey et al. 1994	1974-1981	Non-randomized part of RCT
Yahalom et al. 1993	1980-1988	Non-randomized part of RCT
Lowry et al. 2011	1997-2005	Phase 3 (E-de-esc)	RT x 4000 to 4500 cGy	Did not meet primary endpoint of ORR
MacManus et al. 2018 (TROG 99.03)	2000-2012	Non-randomized part of phase 3 RCT
Hoskin et al. 2014 (FORT)	2006-2011	Phase 3 (C)	RT x 400 cGy	Superior TTP

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

Radiotherapy

• External beam radiotherapy 24 to 3600 cGy

Subsequent treatment

• Yahalom et al. 1993: Adjuvant CHOP versus no further treatment
• Kelsey et al. 1994: Adjuvant Chlorambucil versus no further treatment
• TROG 99.03: Adjuvant CVP or R-CVP versus no further treatment

References

1. Yahalom J, Varsos G, Fuks Z, Myers J, Clarkson BD, Straus DJ. Adjuvant cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy after radiation therapy in stage I low-grade and intermediate-grade non-Hodgkin lymphoma: results of a prospective randomized study. Cancer. 1993 Apr 1;71(7):2342-50. link to original article PubMed
2. Kelsey SM, Newland AC, Hudson GV, Jelliffe AM. A British National Lymphoma Investigation randomised trial of single agent chlorambucil plus radiotherapy versus radiotherapy alone in low grade, localised non-Hodgkins lymphoma. Med Oncol. 1994;11(1):19-25. link to original article PubMed
3. Lowry L, Smith P, Qian W, Falk S, Benstead K, Illidge T, Linch D, Robinson M, Jack A, Hoskin P. Reduced dose radiotherapy for local control in non-Hodgkin lymphoma: a randomised phase III trial. Radiother Oncol. 2011 Jul;100(1):86-92. Epub 2011 Jun 12. link to original article PubMed
4. FORT: Hoskin PJ, Kirkwood AA, Popova B, Smith P, Robinson M, Gallop-Evans E, Coltart S, Illidge T, Madhavan K, Brammer C, Diez P, Jack A, Syndikus I. 4 Gy versus 24 Gy radiotherapy for patients with indolent lymphoma (FORT): a randomised phase 3 non-inferiority trial. Lancet Oncol. 2014 Apr;15(4):457-63. Epub 2014 Feb 24. link to original article PubMed NCT00310167
5. 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 PubMed NCT00115700

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

1. 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 PubMed NCT01332968
   1. 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 PubMed

Bendamustine & Rituximab (BR)

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

Regimen variant #1, 6 cycles

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

Regimen variant #2, 6 cycles with rituximab extension

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

Chemotherapy

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

Targeted therapy

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

28-day cycle for 8 cycles

Subsequent treatment

• Rituximab maintenance x 2 y versus rituximab maintenance x 4 y

Regimen variant #3, 8 cycles

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

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

Chemotherapy

• Bendamustine 90 mg/m² IV once per day on days 1 & 2

Targeted therapy

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

Supportive therapy

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

28-day cycle for up to 8 cycles

References

1. StiL NHL1: Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grünhagen U, Losem C, Kofahl-Krause D, Heil G, Welslau M, Balser C, Kaiser U, Weidmann E, Dürk H, Ballo H, Stauch M, Roller F, Barth J, Hoelzer D, Hinke A, Brugger W; StiL. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013 Apr 6;381(9873):1203-10. Epub 2013 Feb 20. Erratum in: Lancet. 2013 Apr 6;381(9873):1184. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00991211
   1. Update: Abstract: Mathias J. Rummel, MD, Georg Maschmeyer, MD, Arnold Ganser, Andrea Heider, PhD, Ulrich von Grünhagen, MD, PhD5, Christoph Losem, Gerhard Heil, MD, Manfred Welslau, Christina Balser, MD, Ulrich Kaiser, MD, Eckhart Weidmann, Heinz Dürk, MD, Hans Peter Böck, Martina Beate Stauch, MD, Jürgen Barth, Wolfgang Blau, MD, Alexander Burchardt, MD, Frank Kauff, PhD, Axel Hinke, PhD and Wolfram Brugger, MD. Bendamustine Plus Rituximab (B-R) Versus CHOP Plus Rituximab (CHOP-R) As First-Line Treatment in Patients with Indolent and Mantle Cell Lymphomas (MCL) – 7 Year Updated Results from the StiL NHL1 Study. Blood 2014 124:4407. link to abstract
   2. Update: Abstract: Mathias J. Rummel, Georg Maschmeyer, Arnold Ganser, Andrea Heider, Ulrich von Gruenhagen, Christoph Losem, Gerhard Heil, Manfred Welslau, Christina Balser, Ulrich Kaiser, Eckhart Weidmann, Heinz Albert Dürk, Harald Ballo, Martina Stauch, Wolfgang Blau, Alexander Burchardt, Juergen Barth, Frank Kauff, and Wolfram Brugger. Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent lymphomas: Nine-year updated results from the StiL NHL1 study. Journal of Clinical Oncology 2017 35:15_suppl, 7501-7501 link to abstract
2. BRIGHT: Flinn IW, van der Jagt R, Kahl BS, Wood P, Hawkins TE, Macdonald D, Hertzberg M, Kwan YL, Simpson D, Craig M, Kolibaba K, Issa S, Clementi R, Hallman DM, Munteanu M, Chen L, Burke JM. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood. 2014 May 8;123(19):2944-52. Epub 2014 Mar 3. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00877006
   1. Update: Flinn IW, van der Jagt R, Kahl B, Wood P, Hawkins T, MacDonald D, Simpson D, Kolibaba K, Issa S, Chang J, Trotman J, Hallman D, Chen L, Burke JM. First-line treatment of patients with indolent non-Hodgkin lymphoma or mantle-cell lymphoma with bendamustine plus rituximab versus R-CHOP or R-CVP: results of the BRIGHT 5-year follow-up study. J Clin Oncol. 2019 Apr 20;37(12):984-991. Epub 2019 Feb 27. link to original article link to PMC article PubMed
3. MAINTAIN: link to abstract NCT00877214
4. 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 PubMed NCT01332968
   1. 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 PubMed
5. 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 PubMed NCT01650701
   1. 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 PubMed
6. 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 PubMed CTRI/2016/05/006904

Chlorambucil monotherapy

Regimen

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

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

Chemotherapy

• Chlorambucil (Leukeran) 10 mg PO once per day

Continued indefinitely

References

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

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

1. 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 PubMed
2. 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 PubMed

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

1. 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 PubMed NCT01332968
   1. 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 PubMed

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

1. 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 PubMed NCT01332968
   1. 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 PubMed

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 superior 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 #2

Study	Dates of enrollment	Evidence
Fowler et al. 2014 (MDACC 2008-0042)	2008-06-30 to 2011-08-12	Phase 2

Targeted therapy

• Lenalidomide (Revlimid) 20 mg PO once per day on days 1 to 21
• Rituximab (Rituxan) 375 mg/m² IV once on day 1

28-day cycle for up to 12 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 #4

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Morschhauser et al. 2018 (RELEVANCE)	2011-2014	Phase 3 (E-switch-ooc)	1a. R-B 1b. R-CHOP 1c. 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

1. MDACC 2008-0042: Fowler NH, Davis RE, Rawal S, Nastoupil L, Hagemeister FB, McLaughlin P, Kwak LW, Romaguera JE, Fanale MA, Fayad LE, Westin JR, Shah J, Orlowski RZ, Wang M, Turturro F, Oki Y, Claret LC, Feng L, Baladandayuthapani V, Muzzafar T, Tsai KY, Samaniego F, Neelapu SS. Safety and activity of lenalidomide and rituximab in untreated indolent lymphoma: an open-label, phase 2 trial. Lancet Oncol. 2014 Nov;15(12):1311-8. Epub 2014 Oct 15. link to original article dosing details in abstract have been reviewed by our editors link to PMC article PubMed NCT00695786
2. 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 PubMed NCT01307605
3. 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 PubMed NCT01145495
4. 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 PubMed NCT01650701
   1. 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 PubMed

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

• PRIMA_FL, responders (PR or CR): Rituximab maintenance versus no further treatment
• GALLIUM & RELEVANCE: Rituximab maintenance

Regimen variant #4, prednisone 100 mg, 6 to 8 cycles

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

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

Targeted therapy

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

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5

Supportive therapy

• Antiemetics, antipyretics, and antibiotics per local standard of care
• G-CSF according to the American Society of Clinical Oncology guidelines

21-day cycle for 6 to 8 cycles

Regimen variant #5, 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 superior OS (secondary endpoint)	Increased toxicity
Federico et al. 2013 (FOLL05)	2006-2010	Phase 3 (E-esc)	1. R-CVP	Seems to have superior PFS (secondary endpoint)
			2. R-FM	Did not meet primary endpoint of TTF

In FOLL05, PFS was superior to 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 #6, 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	Inferior 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 PFS

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

1. Czuczman MS, Grillo-López AJ, White CA, Saleh M, Gordon L, LoBuglio AF, Jonas C, Klippenstein D, Dallaire B, Varns C. Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol. 1999 Jan;17(1):268-76. link to original article dosing details in manuscript have been reviewed by our editors PubMed
   1. Update: Czuczman MS, Weaver R, Alkuzweny B, Berlfein J, Grillo-López AJ. Prolonged clinical and molecular remission in patients with low-grade or follicular non-Hodgkin's lymphoma treated with rituximab plus CHOP chemotherapy: 9-year follow-up. J Clin Oncol. 2004 Dec 1;22(23):4711 to 6. Epub 2004 Oct 13. link to original article PubMed
2. 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 PubMed
3. 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 abstract have been reviewed by our editors PubMed
4. 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 PubMed NCT00177554
5. 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 PubMed
6. PRIMA_FL: 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 PubMed NCT00140582
   1. 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 PubMed
   2. 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 PubMed
7. JCOG 0203: Watanabe T, Tobinai K, Shibata T, Tsukasaki K, Morishima Y, Maseki N, Kinoshita T, Suzuki T, Yamaguchi M, Ando K, Ogura M, Taniwaki M, Uike N, Takeuchi K, Nawano S, Terauchi T, Hotta T. Phase II/III study of R-CHOP-21 versus R-CHOP-14 for untreated indolent B-cell non-Hodgkin's lymphoma: JCOG 0203 trial. J Clin Oncol. 2011 Oct 20;29(30):3990-8. Epub 2011 Sep 19. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00147121
   1. 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 PubMed
8. 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 PubMed NCT00006721
   1. 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 PubMed
9. StiL NHL1: Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grünhagen U, Losem C, Kofahl-Krause D, Heil G, Welslau M, Balser C, Kaiser U, Weidmann E, Dürk H, Ballo H, Stauch M, Roller F, Barth J, Hoelzer D, Hinke A, Brugger W; StiL. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013 Apr 6;381(9873):1203-10. Epub 2013 Feb 20. Erratum in: Lancet. 2013 Apr 6;381(9873):1184. link to original article PubMed NCT00991211
   1. Update: Abstract: Mathias J. Rummel, MD, Georg Maschmeyer, MD, Arnold Ganser, Andrea Heider, PhD, Ulrich von Grünhagen, MD, PhD5, Christoph Losem, Gerhard Heil, MD, Manfred Welslau, Christina Balser, MD, Ulrich Kaiser, MD, Eckhart Weidmann, Heinz Dürk, MD, Hans Peter Böck, Martina Beate Stauch, MD, Jürgen Barth, Wolfgang Blau, MD, Alexander Burchardt, MD, Frank Kauff, PhD, Axel Hinke, PhD and Wolfram Brugger, MD. Bendamustine Plus Rituximab (B-R) Versus CHOP Plus Rituximab (CHOP-R) As First-Line Treatment in Patients with Indolent and Mantle Cell Lymphomas (MCL) – 7 Year Updated Results from the StiL NHL1 Study. Blood 2014 124:4407. link to abstract
   2. Update: Abstract: Mathias J. Rummel, Georg Maschmeyer, Arnold Ganser, Andrea Heider, Ulrich von Gruenhagen, Christoph Losem, Gerhard Heil, Manfred Welslau, Christina Balser, Ulrich Kaiser, Eckhart Weidmann, Heinz Albert Dürk, Harald Ballo, Martina Stauch, Wolfgang Blau, Alexander Burchardt, Juergen Barth, Frank Kauff, and Wolfram Brugger. Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent lymphomas: Nine-year updated results from the StiL NHL1 study. Journal of Clinical Oncology 2017 35:15_suppl, 7501-7501 link to abstract
10. 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 PubMed NCT00774826
    1. 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 PubMed
11. 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
12. BRIGHT: Flinn IW, van der Jagt R, Kahl BS, Wood P, Hawkins TE, Macdonald D, Hertzberg M, Kwan YL, Simpson D, Craig M, Kolibaba K, Issa S, Clementi R, Hallman DM, Munteanu M, Chen L, Burke JM. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood. 2014 May 8;123(19):2944-52. Epub 2014 Mar 3. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00877006
    1. Update: Flinn IW, van der Jagt R, Kahl B, Wood P, Hawkins T, MacDonald D, Simpson D, Kolibaba K, Issa S, Chang J, Trotman J, Hallman D, Chen L, Burke JM. First-line treatment of patients with indolent non-Hodgkin lymphoma or mantle-cell lymphoma with bendamustine plus rituximab versus R-CHOP or R-CVP: results of the BRIGHT 5-year follow-up study. J Clin Oncol. 2019 Apr 20;37(12):984-991. Epub 2019 Feb 27. link to original article link to PMC article PubMed
13. 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 PubMed NCT01332968
    1. 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 PubMed
14. 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 PubMed NCT01650701
    1. 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 PubMed

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	Superior 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

1. 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 PubMed NCT00136552
   1. 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 PubMed

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	Superior TTP (secondary endpoint) Superior 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 inferior PFS (secondary endpoint)	See paper
			2. R-FM	Inferior PFS1	See paper
Walewski et al. 2019 (PLRG4)	2007-2011	Phase 3 (C)	R-CHOP	Did not meet primary endpoint of EFS
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

• PRIMA_FL, responders (PR or CR): Rituximab maintenance versus no further treatment
• RELEVANCE & PLRG4: Rituximab maintenance

Regimen variant #2, prednisone 100 mg/day

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Flinn et al. 2014 (BRIGHT)	2009-2012	Phase 3 (C)	BR	Seems to have non-inferior CR rate
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 ORR ORR: 88% vs 87%

Patients in BRIGHT were required to be treatment-naive with a need for treatment per any of the following: B symptoms, large tumor mass (lymphomas with a diameter greater than 3 cm in 3 or more regions or diameter greater than 7 cm in 1 region), presence of lymphoma-related complications, or hyperviscosity syndrome attributed to monoclonal gammopathy. 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, prednisone 100 mg/day, cyclophosphamide 1000 mg/m²

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

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

Targeted therapy

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

Chemotherapy

• Cyclophosphamide (Cytoxan) 1000 mg/m² IV once on day 1
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5

Supportive therapy

• Antiemetics, antipyretics, and antibiotics per local standard of care
• G-CSF "according to the American Society of Clinical Oncology guidelines"

21-day cycle for up to 8 cycles

Regimen variant #4, 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

1. 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 PubMed
2. 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 abstract have been reviewed by our editors PubMed
   1. 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 PubMed
3. PRIMA_FL: 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 PubMed NCT00140582
   1. 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 PubMed
   2. 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 PubMed
4. 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 PubMed NCT00774826
   1. 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 PubMed
5. BRIGHT: Flinn IW, van der Jagt R, Kahl BS, Wood P, Hawkins TE, Macdonald D, Hertzberg M, Kwan YL, Simpson D, Craig M, Kolibaba K, Issa S, Clementi R, Hallman DM, Munteanu M, Chen L, Burke JM. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood. 2014 May 8;123(19):2944-52. Epub 2014 Mar 3. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00877006
   1. Update: Flinn IW, van der Jagt R, Kahl B, Wood P, Hawkins T, MacDonald D, Simpson D, Kolibaba K, Issa S, Chang J, Trotman J, Hallman D, Chen L, Burke JM. First-line treatment of patients with indolent non-Hodgkin lymphoma or mantle-cell lymphoma with bendamustine plus rituximab versus R-CHOP or R-CVP: results of the BRIGHT 5-year follow-up study. J Clin Oncol. 2019 Apr 20;37(12):984-991. Epub 2019 Feb 27. link to original article link to PMC article PubMed
6. 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 PubMed NCT01419665
7. 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 PubMed NCT02162771
   1. 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 PubMed
8. 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 PubMed NCT01332968
   1. 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 PubMed
9. 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 PubMed NCT01650701
   1. 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 PubMed
10. PLRG4: Walewski J, Paszkiewicz-Kozik E, Michalski W, Rymkiewicz G, Szpila T, Butrym A, Giza A, Zaucha JM, Kalinka-Warzocha E, Wieczorkiewicz A, Zimowska-Curyło D, Knopińska-Posłuszny W, Tyczyńska A, Romejko-Jarosińska J, Dąbrowska-Iwanicka A, Gruszecka B, Jamrozek-Jedlińska M, Borawska A, Hołda W, Porowska A, Romanowicz A, Hellmann A, Stella-Hołowiecka B, Deptała A, Jurczak W. First-line R-CVP versus R-CHOP induction immunochemotherapy for indolent lymphoma with rituximab maintenance: a multicentre, phase III randomized study by the Polish Lymphoma Research Group PLRG4. Br J Haematol. 2020 Mar;188(6):898-906. Epub 2019 Dec 2. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00801281

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
			2. R-CVP	Superior 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

1. 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 PubMed
2. 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 PubMed NCT00774826
   1. 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 PubMed

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

1. 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 PubMed NCT01144364
2. DM97-261: Nastoupil LJ, McLaughlin P, Feng L, Neelapu SS, Samaniego F, Hagemeister FB, Ayala A, Romaguera JE, Goy AH, Neal E, Wang M, Fayad L, Fanale MA, Oki Y, Westin JR, Rodriguez MA, Cabanillas F, Fowler NH. High ten-year remission rates following rituximab, fludarabine, mitoxantrone and dexamethasone (R-FND) with interferon maintenance in indolent lymphoma: results of a randomized study. Br J Haematol. 2017 Apr;177(2):263-270. Epub 2017 Mar 24. link to original article link to PMC article PubMed NCT00577993

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	Superior OS (secondary endpoint) OS48: 87% vs 74% Superior 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

1. 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 PubMed NCT00269113
   1. 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 PubMed

Rituximab monotherapy

Regimen variant #1, 4 doses

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Colombat et al. 2001	1997-1998	Phase 2
Hainsworth et al. 2000	1998-1999	Phase 2
Hainsworth et al. 2002	1998-1999	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	Superior TTNT (primary endpoint)
			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

• Hainsworth et al. 2002 & CT-P10 3.4, SD or better: Rituximab maintenance
• SAKK 35/98_FL, 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 TTF
Zucca et al. 2019 (SAKK 35/10)	2011-2013	Randomized Phase 2 (C)	Lenalidomide & Rituximab	Might have inferior 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

1. Hainsworth JD, Burris HA 3rd, Morrissey LH, Litchy S, Scullin DC Jr, Bearden JD 3rd, Richards P, Greco FA. Rituximab monoclonal antibody as initial systemic therapy for patients with low-grade non-Hodgkin lymphoma. Blood. 2000 May 15;95(10):3052-6. link to original article PubMed
2. 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 abstract have been reviewed by our editors PubMed
   1. 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 PubMed
3. Hainsworth JD, Litchy S, Burris HA 3rd, Scullin DC Jr, Corso SW, Yardley DA, Morrissey L, Greco FA. Rituximab as first-line and maintenance therapy for patients with indolent non-hodgkin's lymphoma. J Clin Oncol. 2002 Oct 15;20(20):4261-7. link to original article dosing details in manuscript have been reviewed by our editors PubMed
4. SAKK 35/98_FL: 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 PubMed NCT00003280
   1. 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 PubMed
5. 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. PubMed
6. 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 PubMed NCT00112931
7. 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 PubMed NCT00075946
   1. 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 PubMed
8. 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 PubMed NCT01307605
9. NLG ML16865: Kimby E, Östenstad B, Brown P, Hagberg H, Erlanson M, Holte H, Linden O, Johansson AS, Ahlgren T, Wader K, Wahlin BE, Delabie J, Sundström C; Nordic Lymphoma Group. Two courses of four weekly infusions of rituximab with or without interferon-α2a: final results from a randomized phase III study in symptomatic indolent B-cell lymphomas. Leuk Lymphoma. 2015;56(9):2598-607. Epub 2015 Mar 11. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01609010
   1. Pooled update: Lockmer S, Østenstad B, Hagberg H, Holte H, Johansson AS, Wahlin BE, Wader KF, Steen CB, Meyer P, Maisenhølder M, Smedby KE, Brown P, Kimby E. Chemotherapy-free initial treatment of advanced indolent lymphoma has durable effect with low toxicity: results from two Nordic Lymphoma Group trials with more than 10 years of follow-up. J Clin Oncol. 2018 Nov 20;36(33):3315-23. Epub 2018 Oct 4. link to original article PubMed
10. 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 PubMed NCT00227695
    1. 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 PubMed
11. 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 PubMed NCT02260804
12. 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 PubMed NCT02213263
13. 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 PubMed 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	Superior 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

1. 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 PubMed NCT02303119

Watchful waiting

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Horning & Rosenberg 1984	1963-1984	Non-randomized
Young et al. 1988	Not reported in abstract	Phase 3 (E-de-esc)	ProMACE-MOPP, then TNI	Not reported
Ardeshna et al. 2003	1981-1990	Phase 3 (E-de-esc)	Chlorambucil	Did not meet primary endpoint of OS
Brice et al. 1997	1986-1995	Phase 3 (E-de-esc)	1. Interferon alfa 2. Prednimustine	Did not meet primary endpoint of OS
Ardeshna et al. 2014 (CRUK-2004-001621-16)	2004-2009	Phase 3 (C)	1. Rituximab induction	Inferior TTNT
			2. Rituximab induction, then Rituximab maintenance	Inferior TTNT

References

1. Horning SJ, Rosenberg SA. The natural history of initially untreated low-grade non-Hodgkin's lymphomas. N Engl J Med. 1984 Dec 6;311(23):1471-5. link to original article PubMed
2. Young RC, Longo DL, Glatstein E, Ihde DC, Jaffe ES, DeVita VT Jr. The treatment of indolent lymphomas: watchful waiting v aggressive combined modality treatment. Semin Hematol. 1988 Apr;25(2 Suppl 2):11-6. PubMed
3. 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 PubMed
4. Ardeshna KM, Smith P, Norton A, Hancock BW, Hoskin PJ, MacLennan KA, Marcus RE, Jelliffe A, Vaughan G, Hudson GV, Linch DC; British National Lymphoma Investigation. Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial. Lancet. 2003 Aug 16;362(9383):516-22. link to original article PubMed
5. 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 PubMed NCT00112931

Advanced disease, first-line therapy, non-randomized or retrospective data

Bendamustine & Ofatumumab

Regimen

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

The subtypes of indolent lymphoma that this regimen was used for are not specified in the abstract. Given that follicular lymphoma is the most common indolent lymphoma, the regimen is included here.

Chemotherapy

• Bendamustine 90 mg/m² IV once per day on days 1 & 2

Targeted therapy

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

28-day cycle for 6 cycles

References

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

Bortezomib & Rituximab (VR)

VR: Velcade (Bortezomib) & Rituximab

Regimen

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

Targeted therapy

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

35-day cycle for 3 cycles

Subsequent treatment

• VR consolidation

References

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

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

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

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

1. 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 PubMed NCT00772655
   1. 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 PubMed
2. 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 PubMed NCT01493479
3. 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 PubMed

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

1. 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 PubMed NCT00494780

PCR

PCR: Pentostatin, Cyclophosphamide, Rituximab

Regimen

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

Chemotherapy

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

Targeted therapy

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

Supportive therapy

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

21-day cycle for 6 cycles

References

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

R-CMD

R-CMD: Rituximab, Cladribine, Mitoxantrone, Dexamethasone

Regimen

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

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

Targeted therapy

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

Chemotherapy

• Cladribine (Leustatin) 0.10 mg/kg IV once per day on days 1 to 3
• Mitoxantrone (Novantrone) 8 mg/m² IV once on day 1

Glucocorticoid therapy

• Dexamethasone (Decadron) 8 mg/body (route not specified) on days 1 to 3

21-day cycle for 4 cycles

Subsequent treatment

• Rituximab consolidation

References

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

R-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

• PRIMA_FL, responders (PR or CR): Rituximab maintenance versus no further treatment

References

1. PRIMA_FL: 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 PubMed NCT00140582
   1. 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 PubMed
   2. 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 PubMed

VR-CHOP

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

Regimen

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

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

Targeted therapy

• Bortezomib (Velcade) 1.6 mg/m² IV once per day on days 1 & 8
• Rituximab (Rituxan) 375 mg/m² IV once on day 1

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 1.5 mg) IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5

21-day cycle for 6 to 8 cycles

Subsequent treatment

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

References

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

Consolidation after first-line therapy

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

Bortezomib & Rituximab (VR)

VR: Velcade (Bortezomib) & Rituximab

Regimen

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

Preceding treatment

• First-line VR

Targeted therapy

• Bortezomib (Velcade) 1.6 mg/m² IV once on day 1
• Rituximab (Rituxan) 375 mg/m² IV once on day 1

2-month cycle for 4 cycles

References

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

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	Superior 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) given immediately following second dose of rituximab, 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
  • 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

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
  • Platelet count 100 to 149 x 10⁹/L: 0.3 mCi/kg

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) given immediately following second dose of rituximab, 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
  • 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

8-day course

Regimen variant #5

Study	Dates of enrollment	Evidence	Efficacy
Jacobs et al. 2008 (UPCI 03-005)	2004-2007	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%

To be completed; further details are not available in the abstract.

Preceding treatment

• First-line R-CHOP x 4, then CHOP de-intensification x 2

Radioconjugate therapy

• Ibritumomab tiuxetan (Zevalin)

References

1. 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 PubMed EudraCT 2004-002211-92
2. 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 PubMed NCT00185393
   1. 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 PubMed
3. 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 PubMed NCT00177554
4. 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 PubMed
5. 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 PubMed
6. 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 PubMed NCT00722930
7. 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
Hainsworth et al. 2002	1998-1999	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
• Hainsworth et al. 2002: First-line Rituximab
• 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, 4 doses in 4 months

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

Preceding treatment

• First-line R-CMD x 4

Targeted therapy

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

28-day cycle for 4 cycles

Regimen variant #4, 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 #5, 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	Superior 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

1. 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 PubMed
2. Hainsworth JD, Litchy S, Burris HA 3rd, Scullin DC Jr, Corso SW, Yardley DA, Morrissey L, Greco FA. Rituximab as first-line and maintenance therapy for patients with indolent non-hodgkin's lymphoma. J Clin Oncol. 2002 Oct 15;20(20):4261-7. link to original article dosing details in abstract have been reviewed by our editors PubMed
3. SAKK 35/98_FL: 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 PubMed NCT00003280
   1. 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 PubMed
4. 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 PubMed
5. 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 abstract have been reviewed by our editors PubMed NCT00435955
6. 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 PubMed NCT01144364
7. Sakai T, Masaki Y, Otsuki N, Sakamaki I, Kishi S, Miyazono T, Urasaki Y, Murakami J, Satoh T, Nakamura T, Iwao H, Nakajima A, Kawanami T, Miki M, Fujita Y, Tanaka M, Fukushima T, Okazaki T, Ueda T; Hokuriku Hematology Oncology Study Group. Prospective clinical study of R-CMD therapy for indolent B cell lymphoma and mantle cell lymphoma from the Hokuriku Hematology Oncology Study Group. Med Oncol. 2015 Sep;32(9):232. Epub 2015 Aug 15. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed
8. 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 PubMed NCT00227695
   1. 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 PubMed

Maintenance after first-line therapy

Bortezomib & Rituximab (VR)

VR: Velcade (Bortezomib) & Rituximab

Regimen

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

Preceding treatment

• First-line VR-CHOP x 6 to 8

Targeted therapy

• Bortezomib (Velcade) 1.6 mg/m² IV once per day on days 1, 8, 15, 22
• Rituximab (Rituxan) 375 mg/m² IV once per day on days 1, 8, 15, 22

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

References

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

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

1. 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 PubMed NCT01650701
   1. 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 PubMed

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

1. 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 PubMed NCT01332968
   1. 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 PubMed

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	Superior 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	Superior PFS PFS36: 86% vs 72%

¹Reported efficacy is based on the 2019 update.
Starts 8 weeks after the last induction treatment.

Preceding treatment

• PRIMA_FL: 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, q6mo cycles

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

Preceding treatment

• First-line CVP x 6 to 8 cycles

Targeted therapy

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

6-month cycle for 4 cycles (2 years)

Regimen variant #3

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ardeshna et al. 2014 (CRUK-2004-001621-16)	2004-2009	Phase 3 (E-esc)	1. Observation	Superior TTNT (primary endpoint)
			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 #4

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

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

1. 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. PubMed
2. ECOG E1496: Hochster H, Weller E, Gascoyne RD, Habermann TM, Gordon LI, Ryan T, Zhang L, Colocci N, Frankel S, Horning SJ. Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG1496 Study. J Clin Oncol. 2009 Apr 1;27(10):1607-14. Epub 2009 Mar 2. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00003204
   1. Update: Barta SK, Li H, Hochster HS, Hong F, Weller E, Gascoyne RD, Habermann TM, Gordon LI, Colocci N, Bengtson EM, Horning SJ, Kahl BS. Randomized phase 3 study in low-grade lymphoma comparing maintenance anti-CD20 antibody with observation after induction therapy: A trial of the ECOG-ACRIN Cancer Research Group (E1496). Cancer. 2016 Oct;122(19):2996-3004. Epub 2016 Jun 28. link to original article link to PMC article PubMed
3. PRIMA_FL: 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 PubMed NCT00140582
   1. 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 PubMed
   2. 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 PubMed
4. 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 PubMed NCT00112931
5. 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 PubMed NCT00430352
6. MAINTAIN: link to abstract NCT00877214
7. 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 PubMed NCT01200758
8. 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 PubMed NCT01332968
   1. 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 PubMed
9. 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 PubMed NCT02063685

Rituximab monotherapy, very extended course

Maintenance regimens of more than two years duration.

Regimen variant #1, 4 years

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

Preceding treatment

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

Targeted therapy

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

2-month cycle for 24 cycles (4 years)

Regimen variant #2, 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 #3, 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

1. MAINTAIN: link to abstract NCT00877214
2. 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 PubMed NCT00075946
   1. 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 PubMed
3. 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 PubMed NCT00227695
   1. 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 PubMed

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

1. 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 PubMed NCT01200758
2. 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 PubMed NCT02303119

Relapsed or refractory, randomized data

Bendamustine & Rituximab (BR)

BR: Bendamustine, Rituximab

Regimen variant #1, 4 cycles

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

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

Chemotherapy

• Bendamustine 90 mg/m² IV once per day on days 1 & 2

Targeted therapy

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

28-day cycle for 4 cycles

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

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

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

Chemotherapy

• Bendamustine 90 mg/m² IV once per day on days 2 & 3

Targeted therapy

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

28-day cycle for 4 cycles (see note)

Regimen variant #3, 6 cycles

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rummel et al. 2015 (StiL NHL 2-2003)	2003-2010	Phase 3 (E-switch-ic)	FR	Superior PFS (primary endpoint) Median PFS: 34.2 vs 11.7 mo (HR 0.54, 95% CI 0.38-0.72)
Nastoupil et al. 2023 (SELENE)	2014-03-28 to 2015-11-05	Phase 3 (C)	1a. BR & Ibrutinib 1b. R-CHOP & Ibrutinib	Might have inferior 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

1. Rummel MJ, Al-Batran SE, Kim SZ, Welslau M, Hecker R, Kofahl-Krause D, Josten KM, Dürk H, Rost A, Neise M, von Grünhagen U, Chow KU, Hansmann ML, Hoelzer D, Mitrou PS. Bendamustine plus rituximab is effective and has a favorable toxicity profile in the treatment of mantle cell and low-grade non-Hodgkin's lymphoma. J Clin Oncol. 2005 May 20;23(15):3383-9. link to original article dosing details in manuscript have been reviewed by our editors PubMed
2. SDX-105-01 part 1: Robinson KS, Williams ME, van der Jagt RH, Cohen P, Herst JA, Tulpule A, Schwartzberg LS, Lemieux B, Cheson BD. Phase II multicenter study of bendamustine plus rituximab in patients with relapsed indolent B-cell and mantle cell non-Hodgkin's lymphoma. J Clin Oncol. 2008 Sep 20;26(27):4473-9. Epub 2008 Jul 14. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00069758
3. BRB: Matsumoto K, Takayama N, Aisa Y, Ueno H, Hagihara M, Watanabe K, Nakaya A, Chen K, Shimizu T, Tsukada Y, Yamada Y, Nakazato T, Ishida A, Miyakawa Y, Yokoyama K, Nakajima H, Masuda Y, Yano T, Okamoto S; Keio BRB Study Group. A phase II study of bendamustine plus rituximab in Japanese patients with relapsed or refractory indolent B-cell non-Hodgkin lymphoma and mantle cell lymphoma previously treated with rituximab: BRB study. Int J Hematol. 2015 Jun;101(6):554-62. Epub 2015 Mar 19. link to original article dosing details in manuscript have been reviewed by our editors PubMed
4. StiL NHL 2-2003: Rummel M, Kaiser U, Balser C, Stauch M, Brugger W, Welslau M, Niederle N, Losem C, Boeck HP, Weidmann E, von Gruenhagen U, Mueller L, Sandherr M, Hahn L, Vereshchagina J, Kauff F, Blau W, Hinke A, Barth J; StiL. Bendamustine plus rituximab versus fludarabine plus rituximab for patients with relapsed indolent and mantle-cell lymphomas: a multicentre, randomised, open-label, non-inferiority phase 3 trial. Lancet Oncol. 2016 Jan;17(1):57-66. Epub 2015 Dec 5. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT01456351
5. 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 PubMed NCT01974440

Bevacizumab & Rituximab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hainsworth et al. 2014	2005-2012	Randomized Phase 2 (E-esc)	Rituximab	Seems to have superior PFS Median 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

1. 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 PubMed

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 superior 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

1. 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 PubMed NCT00085696
2. 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 PubMed
3. 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 PubMed NCT00201877
4. 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 PubMed NCT00312845
   1. 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 PubMed

Copanlisib & Rituximab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Matasar et al. 2021 (CHRONOS-3)	2015-2019	Phase 3 (E-esc)	Rituximab	Superior PFS (primary endpoint) Median PFS: 21.5 vs 13.8 mo (HR 0.52, 95% CI 0.39-0.69)

Targeted therapy

• Copanlisib (Aliqopa) 60 mg IV over 60 minutes once per day on days 1, 8, 15, given first
• Rituximab (Rituxan) given second as follows:
  • Cycle 1: 375 mg/m² IV once per day on days 1, 8, 15, 22
  • Cycles 3, 5, 7, 9: 375 mg/m² IV once on day 1

28-day cycles

References

1. CHRONOS-3: Matasar MJ, Capra M, Özcan M, Lv F, Li W, Yañez E, Sapunarova K, Lin T, Jin J, Jurczak W, Hamed A, Wang MC, Baker R, Bondarenko I, Zhang Q, Feng J, Geissler K, Lazaroiu M, Saydam G, Szomor Á, Bouabdallah K, Galiulin R, Uchida T, Mongay Soler L, Cao A, Hiemeyer F, Mehra A, Childs BH, Shi Y, Zinzani PL. Copanlisib plus rituximab versus placebo plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma (CHRONOS-3): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2021 May;22(5):678-689. Epub 2021 Apr 10. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT02367040

Ibritumomab tiuxetan protocol

Regimen variant #1, 0.3 mCi/kg

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

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

Targeted therapy

• Rituximab (Rituxan) 250 mg/m² IV once per day on days 1 & 8

Radioconjugate therapy

• Ibritumomab tiuxetan 1.6 mg & Indium-111 5 mCi IV over 10 minutes once on day 1
• Ibritumomab tiuxetan & Yttrium-90 (Zevalin) 0.3 mCi/kg (11 MBq/kg) (maximum dose of 32 mCi/1.2 GBq) IV over 10 minutes once on day 8, given immediately following rituximab

8-day course

Regimen variant #2, 0.4 mCi/kg

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

Targeted therapy

• Rituximab (Rituxan) 250 mg/m² IV once per day on days 1 & 8

Radioconjugate therapy

• Ibritumomab tiuxetan 1.6 mg & Indium-111 5 mCi IV over 10 minutes once on day 1
• Ibritumomab tiuxetan & Yttrium-90 (Zevalin) 0.4 mCi/kg (15 MBq/kg) (maximum dose of 32 mCi/1.2 GBq) IV over 10 minutes once on day 8, given immediately following rituximab

8-day course

References

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

Lenalidomide monotherapy

Regimen variant #1, up to 12 cycles

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Leonard et al. 2015 (CALGB 50401)	2006-2011	Randomized Phase 2 (E-de-esc)	Lenalidomide & Rituximab	Inferior 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

Regimen variant #2, indefinite

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

Targeted therapy

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

28-day cycles

References

1. CC-5013-NHL-001: Witzig TE, Wiernik PH, Moore T, Reeder C, Cole C, Justice G, Kaplan H, Voralia M, Pietronigro D, Takeshita K, Ervin-Haynes A, Zeldis JB, Vose JM. Lenalidomide oral monotherapy produces durable responses in relapsed or refractory indolent non-Hodgkin's Lymphoma. J Clin Oncol. 2009 Nov 10;27(32):5404-9. Epub 2009 Oct 5. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00179673
2. 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 PubMed NCT00238238

Lenalidomide & Rituximab (R²)

Regimen variant #1, len 10

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

Targeted therapy

• Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 28
• Rituximab (Rituxan) as follows:
  • Cycle 3: 375 mg/m² IV once per day on days 1, 8, 15, 22

28-day cycles

Regimen variant #2, len dose escalation 15 -> 25 x 12

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Leonard et al. 2015 (CALGB 50401)	2006-2011	Randomized Phase 2 (E-esc)	Lenalidomide	Superior 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

Regimen variant #3, len 20 x 2

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

Targeted therapy

• Lenalidomide (Revlimid) 20 mg PO once per day on days 1 to 21
• Rituximab (Rituxan) as follows:
  • Cycle 1: 375 mg/m² IV once on day 15
  • Cycle 2: 375 mg/m² IV once per day on days 1, 8, 15, 22

Supportive therapy

• Allopurinol (Zyloprim) as follows:
  • Cycle 1: 300 mg PO once per day
• Aspirin 81 mg PO once per day

28-day cycle for 2 cycles

Subsequent treatment

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

Regimen variant #4, len 20 x 12

FDA-recommended dose

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

Prior treatment criteria

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

Targeted therapy

• Lenalidomide (Revlimid) 20 mg PO once per day on days 1 to 21
• Rituximab (Rituxan) as follows:
  • Cycle 1: 375 mg/m² IV once per day on days 1, 8, 15, 22
  • Cycles 2 to 5: 375 mg/m² IV once on day 1

28-day cycle for 12 cycles

Regimen variant #5, len 20 x 12, staggered rituximab

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

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

Targeted therapy

• Lenalidomide (Revlimid) 20 mg PO once per day on days 1 to 21
• Rituximab (Rituxan) as follows:
  • Cycle 1: 375 mg/m² IV once per day on days 1, 8, 15, 22
  • Cycles 3, 5, 7, 9, 11: 375 mg/m² IV once on day 1

28-day cycle for 12 cycles

Subsequent treatment

• Rituximab maintenance

References

1. RV-PI-NHL-0488: Tuscano JM, Dutia M, Chee K, Brunson A, Reed-Pease C, Abedi M, Welborn J, O'Donnell RT. Lenalidomide plus rituximab can produce durable clinical responses in patients with relapsed or refractory, indolent non-Hodgkin lymphoma. Br J Haematol. 2014 May;165(3):375-81. Epub 2014 Mar 7. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01316523
2. UPCC 02408 ²: Chong EA, Ahmadi T, Aqui NA, Svoboda J, Nasta SD, Mato AR, Walsh KM, Schuster SJ. Combination of lenalidomide and rituximab overcomes rituximab resistance in patients with indolent B-cell and mantle cell lymphomas. Clin Cancer Res. 2015 Apr 15;21(8):1835-42. Epub 2015 Jan 28. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00783367
3. 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 PubMed NCT00238238
4. AUGMENT: Leonard JP, Trneny M, Izutsu K, Fowler NH, Hong X, Zhu J, Zhang H, Offner F, Scheliga A, Nowakowski GS, Pinto A, Re F, Fogliatto LM, Scheinberg P, Flinn IW, Moreira C, Cabeçadas J, Liu D, Kalambakas S, Fustier P, Wu C, Gribben JG; AUGMENT Trial Investigators. AUGMENT: a phase III study of lenalidomide plus rituximab versus placebo plus rituximab in relapsed or refractory indolent lymphoma. J Clin Oncol. 2019 May 10;37(14):1188-1199. Epub 2019 Mar 21. link to original article link to PMC article PubMed NCT01938001
5. EZH-302: NCT04224493
6. InMIND: NCT04680052
7. MAGNIFY: NCT01996865

Obinutuzumab monotherapy

Regimen variant #1, 4 doses

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

Targeted therapy

• Obinutuzumab (Gazyva) 1000 mg IV once on day 1

7-day cycle for 4 cycles

Subsequent treatment

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

Regimen variant #2, 9 doses

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

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

Targeted therapy

• Obinutuzumab (Gazyva) as follows:
  • Cycle 1: 1600 mg (diluted to 10 mg/mL) IV once per day on days 1 & 7
  • Cycles 2 to 8: 800 mg IV once on day 1
  • Initial infusion rate is 50 mg/hour. In the absence of infusion-related reactions (IRRs), the rate is then increased by 50 mg/hour every 30 minutes, up to a maximum of 400 mg/hour.

Supportive therapy

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

21-day cycle for 8 cycles

Regimen variant #3, 20 doses

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Zinzani et al. 2023 (ROSEWOOD)	2017-11 to 2021-06	Randomized Phase 2 (C)	ZO	Inferior 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

1. GAUGUIN: Salles G, Morschhauser F, Lamy T, Milpied N, Thieblemont C, Tilly H, Bieska G, Asikanius E, Carlile D, Birkett J, Pisa P, Cartron G. Phase 1 study results of the type II glycoengineered humanized anti-CD20 monoclonal antibody obinutuzumab (GA101) in B-cell lymphoma patients. Blood. 2012 May 31;119(22):5126-32. Epub 2012 Mar 19. link to original article PubMed NCT00517530
   1. Subgroup analysis: Morschhauser FA, Cartron G, Thieblemont C, Solal-Céligny P, Haioun C, Bouabdallah R, Feugier P, Bouabdallah K, Asikanius E, Lei G, Wenger M, Wassner-Fritsch E, Salles GA. Obinutuzumab (GA101) monotherapy in relapsed/refractory diffuse large B-cell lymphoma or mantle-cell lymphoma: results from the phase II GAUGUIN study. J Clin Oncol. 2013 Aug 10;31(23):2912-9. Epub 2013 Jul 8. link to original article dosing details in manuscript have been reviewed by our editors PubMed
   2. Subgroup analysis: Salles GA, Morschhauser F, Solal-Céligny P, Thieblemont C, Lamy T, Tilly H, Gyan E, Lei G, Wenger M, Wassner-Fritsch E, Cartron G. Obinutuzumab (GA101) in patients with relapsed/refractory indolent non-Hodgkin lymphoma: results from the phase II GAUGUIN study. J Clin Oncol. 2013 Aug 10;31(23):2920-6. Epub 2013 Jul 8. link to original article dosing details in manuscript have been reviewed by our editors PubMed
   3. Subgroup analysis: Cartron G, de Guibert S, Dilhuydy MS, Morschhauser F, Leblond V, Dupuis J, Mahe B, Bouabdallah R, Lei G, Wenger M, Wassner-Fritsch E, Hallek M. Obinutuzumab (GA101) in relapsed/refractory chronic lymphocytic leukemia: final data from the phase 1/2 GAUGUIN study. Blood. 2014 Oct 2;124(14):2196-202. Epub 2014 Aug 20. link to original article dosing details in manuscript have been reviewed by our editors PubMed
2. GAUSS: Sehn LH, Goy A, Offner FC, Martinelli G, Caballero MD, Gadeberg O, Baetz T, Zelenetz AD, Gaidano G, Fayad LE, Buckstein R, Friedberg JW, Crump M, Jaksic B, Zinzani PL, Padmanabhan Iyer S, Sahin D, Chai A, Fingerle-Rowson G, Press OW. Randomized phase II trial comparing obinutuzumab (GA101) with rituximab in patients with relapsed CD20+ indolent B-cell non-Hodgkin lymphoma: final analysis of the GAUSS study. J Clin Oncol. 2015 Oct 20;33(30):3467-74. Epub 2015 Aug 17. link to original article] dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00576758
3. 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 PubMed NCT03332017

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 superior OS (secondary endpoint) OS36: 82.5% vs 71.9% (HR 0.74, 95% CI 0.52-1.05) Superior ORR (primary endpoint)
Nastoupil et al. 2023 (SELENE)	2014-03-28 to 2015-11-05	Phase 3 (C)	1a. BR & Ibrutinib 1b. R-CHOP & Ibrutinib	Might have inferior 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

1. Czuczman MS, Grillo-López AJ, White CA, Saleh M, Gordon L, LoBuglio AF, Jonas C, Klippenstein D, Dallaire B, Varns C. Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol. 1999 Jan;17(1):268-76. link to original article dosing details in manuscript have been reviewed by our editors PubMed
   1. Update: Czuczman MS, Weaver R, Alkuzweny B, Berlfein J, Grillo-López AJ. Prolonged clinical and molecular remission in patients with low-grade or follicular non-Hodgkin's lymphoma treated with rituximab plus CHOP chemotherapy: 9-year follow-up. J Clin Oncol. 2004 Dec 1;22(23):4711 to 6. Epub 2004 Oct 13. link to original article PubMed
2. 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 PubMed NCT00004179
   1. 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 PubMed
3. 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 PubMed NCT00637832
4. 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 PubMed 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 superior PFS Median 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

1. 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 PubMed
   1. 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 PubMed

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	Seems to have inferior PFS
Maloney et al. 2020 (HOMER)	2010-2016	Phase 3 (C)	Ofatumumab	Did not meet primary endpoint of PFS

Targeted therapy

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

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
McLaughlin et al. 1998	1995-1996	Phase 2 (RT)
Witzig et al. 2002a	Not reported	Phase 3 (C)	Ibritumomab tiuxetan	Inferior ORR
Ghielmini et al. 2004 (SAKK 35/98FL)	1998-2002	Non-randomized part of phase 3 RCT
Hainsworth et al. 2005b	1998-2002	Non-randomized part of phase 2 RCT
Sehn et al. 2015 (GAUSS)	2009-2010	Randomized Phase 2 (C)	Obinutuzumab	Might have inferior ORR

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 35/98_FL, patients with SD or better at 12 weeks: Rituximab maintenance versus no further treatment
• Hainsworth et al. 2005b, patients with SD or better: Rituximab maintenance versus re-treatment with rituximab at time of progression
• GAUSS, SD or better: Optional rituximab maintenance

Regimen variant #3

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Coiffier et al. 2011 (LYM-3001)	2006-2008	Phase 3 (C)	VR	Seems to have inferior PFS

Targeted therapy

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

1. 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 PubMed
2. 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 abstract have been reviewed by our editors PubMed
3. 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 PubMed
4. McLaughlin P, Grillo-López AJ, Link BK, Levy R, Czuczman MS, Williams ME, Heyman MR, Bence-Bruckler I, White CA, Cabanillas F, Jain V, Ho AD, Lister J, Wey K, Shen D, Dallaire BK. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998 Aug;16(8):2825-33. link to original article dosing details in manuscript have been reviewed by our editors PubMed
5. Witzig TE, Gordon LI, Cabanillas F, Czuczman MS, Emmanouilides C, Joyce R, Pohlman BL, Bartlett NL, Wiseman GA, Padre N, Grillo-López AJ, Multani P, White CA. Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma. J Clin Oncol. 2002 May 15;20(10):2453-63. link to original article dosing details in manuscript have been reviewed by our editors PubMed
6. SAKK 35/98_FL: 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 PubMed NCT00003280
   1. 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 PubMed
7. Hainsworth JD, Litchy S, Shaffer DW, Lackey VL, Grimaldi M, Greco FA. Maximizing therapeutic benefit of rituximab: maintenance therapy versus re-treatment at progression in patients with indolent non-Hodgkin's lymphoma--a randomized phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol. 2005 Feb 20;23(6):1088-95. Epub 2005 Jan 18. link to original article dosing details in abstract have been reviewed by our editors PubMed
8. 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 PubMed NCT00312845
   1. 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 PubMed
9. 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 PubMed NCT00075946
   1. 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 PubMed
10. 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 PubMed
11. GAUSS: Sehn LH, Goy A, Offner FC, Martinelli G, Caballero MD, Gadeberg O, Baetz T, Zelenetz AD, Gaidano G, Fayad LE, Buckstein R, Friedberg JW, Crump M, Jaksic B, Zinzani PL, Padmanabhan Iyer S, Sahin D, Chai A, Fingerle-Rowson G, Press OW. Randomized phase II trial comparing obinutuzumab (GA101) with rituximab in patients with relapsed CD20+ indolent B-cell non-Hodgkin lymphoma: final analysis of the GAUSS study. J Clin Oncol. 2015 Oct 20;33(30):3467-74. Epub 2015 Aug 17. link to original article] dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00576758
12. HOMER: Maloney DG, Ogura M, Fukuhara N, Davis J, Lasher J, Izquierdo M, Banerjee H, Tobinai K. A phase 3 randomized study (HOMER) of ofatumumab vs rituximab in iNHL relapsed after rituximab-containing therapy. Blood Adv. 2020 Aug 25;4(16):3886-3893. link to original article link to PMC article PubMed NCT01200589
13. CHRONOS-3: Matasar MJ, Capra M, Özcan M, Lv F, Li W, Yañez E, Sapunarova K, Lin T, Jin J, Jurczak W, Hamed A, Wang MC, Baker R, Bondarenko I, Zhang Q, Feng J, Geissler K, Lazaroiu M, Saydam G, Szomor Á, Bouabdallah K, Galiulin R, Uchida T, Mongay Soler L, Cao A, Hiemeyer F, Mehra A, Childs BH, Shi Y, Zinzani PL. Copanlisib plus rituximab versus placebo plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma (CHRONOS-3): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2021 May;22(5):678-689. Epub 2021 Apr 10. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT02367040

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	Superior 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

1. 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 PubMed NCT03332017

Relapsed or refractory, non-randomized or retrospective data

Axicabtagene ciloleucel monotherapy

Regimen

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

Preceding treatment

• Lymphodepletion with FC

Immunotherapy

• Axicabtagene ciloleucel (Yescarta) 2 x 10⁶ CAR T cells/kg IV once on day 0

One course

References

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

Bortezomib monotherapy

Regimen

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

Targeted therapy

• Bortezomib (Velcade) 1.5 mg/m² IV once per day on days 1, 4, 8, 11

Supportive therapy

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

21-day cycles

References

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

BVR

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

Regimen variant #1, 1.3/90/375

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

Chemotherapy

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

Targeted therapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11, given first
• Rituximab (Rituxan) 375 mg/m² IV once on day 1, given second

Supportive therapy

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

28-day cycle for 6 cycles

Regimen variant #2, 1.6/90/375

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

1. ULYM07054: Friedberg JW, Vose JM, Kelly JL, Young F, Bernstein SH, Peterson D, Rich L, Blumel S, Proia NK, Liesveld J, Fisher RI, Armitage JO, Grant S, Leonard JP. The combination of bendamustine, bortezomib, and rituximab for patients with relapsed/refractory indolent and mantle cell non-Hodgkin lymphoma. Blood. 2011 Mar 10;117(10):2807-12. Epub 2011 Jan 14. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00547534
2. 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 PubMed NCT00636792

Copanlisib monotherapy

Regimen variant #1, flat dose

FDA-recommended dose

Study	Dates of enrollment	Evidence	Efficacy
Dreyling et al. 2017 (CHRONOS-1)	2012 to not reported	Phase 2 (RT)	ORR: 59% (95% CI, 49-68)

Note: this is the FDA-recommended dose and the dose used for most of the patients enrolled in this trial; however, the 2017 publication only details the weight-based dosing (see below).

Targeted therapy

• Copanlisib (Aliqopa) 60 mg IV over 60 minutes once per day on days 1, 8, 15

28-day cycles

Regimen variant #2, weight-based

Study	Dates of enrollment	Evidence	Efficacy
Dreyling et al. 2017 (CHRONOS-1)	2012 to not reported	Phase 2 (RT)	ORR: 59% (95% CI, 49-68)

Targeted therapy

• Copanlisib (Aliqopa) 0.8 mg/kg IV over 60 minutes once per day on days 1, 8, 15

28-day cycles

References

1. CHRONOS-1: Dreyling M, Morschhauser F, Bouabdallah K, Bron D, Cunningham D, Assouline SE, Verhoef G, Linton K, Thieblemont C, Vitolo U, Hiemeyer F, Giurescu M, Garcia-Vargas J, Gorbatchevsky I, Liu L, Koechert K, Peña C, Neves M, Childs BH, Zinzani PL. Phase II study of copanlisib, a PI3K inhibitor, in relapsed or refractory, indolent or aggressive lymphoma. Ann Oncol. 2017 Sep 1;28(9):2169-2178. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT01660451

Duvelisib monotherapy

Regimen

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

Targeted therapy

• Duvelisib (Copiktra) 25 mg PO twice per day on days 1 to 28

28-day cycles

References

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

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

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

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

1. 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 PubMed NCT01849263
2. 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 abstract have been reviewed by our editors PubMed NCT01779791

Inotuzumab ozogamicin monotherapy

Regimen

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

Antibody-drug conjugate therapy

• Inotuzumab ozogamicin (Besponsa) 1.8 mg/m² IV once on day 1

28-day cycle for 4 to 8 cycles

References

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

Lenalidomide, Dexamethasone, Rituximab

Regimen

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

Targeted therapy

• Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 28
• Rituximab (Rituxan) as follows:
  • Cycle 3: 375 mg/m² IV once per day on days 1, 8, 15, 22

Glucocorticoid therapy

• Dexamethasone (Decadron) 8 mg (route not specified) once per day on days 1, 8, 15, 22

28-day cycles

References

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

Lisocabtagene maraleucel monotherapy

Regimen

Study	Dates of enrollment	Evidence
Awaiting publication (TRANSCEND-FL)	2020-ongoing	Phase 2 (RT)

Immunotherapy

• Lisocabtagene maraleucel (Breyanzi)

One course

References

1. TRANSCEND-FL: 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

1. 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 PubMed NCT02500407

PEP-C

PEP-C: Prednisone, Etoposide, Procarbazine, Cyclophosphamide

Regimen

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

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

Glucocorticoid therapy

• Prednisone (Sterapred) 20 mg PO once per day, taken after breakfast

Chemotherapy

• Etoposide (Vepesid) 50 mg PO once per day, taken after dinner
• Procarbazine (Matulane) 50 mg PO once per day, taken at bedtime
• Cyclophosphamide (Cytoxan) 50 mg PO once per day, taken after lunch

Supportive therapy

• Ondansetron (Zofran) (dose not specified) with each procarbazine dose

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

References

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

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

1. 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 PubMed NCT00637832

R-DexaBEAM

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

Regimen

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

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

Targeted therapy

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

Glucocorticoid therapy

• Dexamethasone (Decadron) 8 mg PO three times per day on days 1 to 10

Chemotherapy

• Carmustine (BCNU) 60 mg/m² IV once on day 3
• Etoposide (Vepesid) 75 mg/m² IV once per day on days 4 to 7
• Cytarabine (Ara-C) 100 mg/m² IV twice per day on days 4 to 7
• Melphalan (Alkeran) 20 mg/m² IV once on day 2

3- to 4-week cycle for 2 cycles

Subsequent treatment

• R-BEAM with autologous hematopoietic stem cell transplant or R-TBI/Cy with autologous hematopoietic stem cell transplant

References

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

R-FND

R-FND: Rituximab, Fludarabine, Novantrone, Dexamethasone

Regimen

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

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

Targeted therapy

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

Chemotherapy

• Fludarabine (Fludara) 25 mg/m² IV once per day on days 2 to 4
• Mitoxantrone (Novantrone) 10 mg/m² IV once on day 2

Glucocorticoid therapy

• Dexamethasone (Decadron) 20 mg IV or PO once per day on days 1 to 5

28-day cycle for up to 8 cycles

Subsequent treatment

• Interferon alfa maintenance

References

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

R-INO

R-INO: Rituximab, INOtuzumab ozogamicin

Regimen

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

Targeted therapy

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

Antibody-drug conjugate therapy

• Inotuzumab ozogamicin (Besponsa) 1.8 mg/m² IV once on day 2

28-day cycle for up to 8 cycles

References

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

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

1. 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 PubMed NCT01897571

Temsirolimus monotherapy

Regimen

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

Targeted therapy

• Temsirolimus (Torisel) 25 mg IV over 30 minutes once on day 1

7-day cycle for at least 8 cycles

References

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

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

1. 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 PubMed NCT03568461
   1. 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 PubMed

Vorinostat monotherapy

Regimen

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

Targeted therapy

• Vorinostat (Zolinza) 200 mg PO twice per day on days 1 to 14

21-day cycles

References

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

Vorinostat & Rituximab

Regimen

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

Targeted therapy

• Vorinostat (Zolinza) 200 mg PO twice per day on days 1 to 14
• Rituximab (Rituxan) 375 mg/m² IV once on day 1

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

References

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

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

1. 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 PubMed NCT00715208

Rituximab-refractory

Bendamustine monotherapy

Regimen variant #1, q3wk x 6-8

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

Chemotherapy

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

21-day cycle for 6 to 8 cycles

Regimen variant #2, q3wk x up to 8

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rummel et al. 2021 (COMPLEMENT A plus B)	2010-2016	Phase 3 (C)	Bendamustine & Ofatumumab	Did not meet primary endpoint of PFS

Chemotherapy

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

21-day cycle for up to 8 cycles

Regimen variant #3, q4wk x 6

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

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

Chemotherapy

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

28-day cycle for 6 cycles

Regimen variant #4, q3wk x 12

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

Chemotherapy

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

21-day cycle for up to 12 cycles

References

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

Bendamustine & Obinutuzumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Sehn et al. 2016 (GADOLIN)	2010-2014	Phase 3 (E-RT-esc)	Bendamustine	Superior OS1 (secondary endpoint) Median OS: NYR vs 53.9 mo (HR 0.58, 95% CI 0.39-0.86) Superior PFS (primary endpoint) Median PFS: NYR vs 14.9 mo (HR 0.55, 95% CI 0.40-0.74)

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

Chemotherapy

• 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

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

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

1. 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 PubMed

Obinutuzumab monotherapy

Regimen

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

Preceding treatment

• Salvage Bendamustine & Obinutuzumab x 6

Targeted therapy

• Obinutuzumab (Gazyva) 1000 mg IV once on day 1

2-month cycle for 12 cycles

References

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

Consolidation after subsequent lines of therapy

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

Chemotherapy

• Carmustine (BCNU) 300 mg/m² IV once on day -6
• Etoposide (Vepesid) 200 mg/m² IV once per day on days -5 to -2
• Cytarabine (Ara-C) 400 mg/m² IV once per day on days -5 to -2
• Melphalan (Alkeran) 140 mg/m² IV once on day -1

Supportive therapy

• Autologous stem cells re-infused on day 0
• Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day +2, continued until ANC greater than 1500/μL

One course

Subsequent treatment

• Rituximab maintenance

References

1. 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 PubMed NCT01827605

Bortezomib & Rituximab (VR)

VR: Velcade (Bortezomib) & Rituximab

Regimen

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

Preceding treatment

• VR salvage

Targeted therapy

• Bortezomib (Velcade) 1.6 mg/m² IV once on day 1
• Rituximab (Rituxan) 375 mg/m² IV once on day 1

2-month cycle for 4 cycles

References

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

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

Details are best described in the 2008 update.

Chemotherapy

• Fludarabine (Fludara) 30 mg/m² IV once per day on days -5 to -3
• Cyclophosphamide (Cytoxan) 750 mg/m² IV once per day on days -5 to -3

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV once on day -13, then 1000 mg/m² IV once per day on days -6, +1, +8

Immunotherapy

• Allogeneic stem cells transfused on day 0

GVHD prophylaxis

• Antithymocyte globulin, horse ATG (Atgam) by the following donor-based criteria:
  • Matched unrelated donor: 15 mg/kg IV once per day on days -5 to -3
• Tacrolimus (Prograf) adjusted to level of 5 to 10 ng/mL for 6 months in patients in remission
• Methotrexate (MTX) by the following donor-based criteria:
  • Related donors: 5 mg/m² IV once per day on days +1, +3, +6
  • Unrelated donors: 5 mg/m² IV once per day on days +1, +3, +6, +11

One course

References

1. 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 PubMed NCT00048737
   1. 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 PubMed
   2. 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 PubMed

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

1. 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 PubMed 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	Superior 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	Superior 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 35/98_FL: 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 superior PFS1 Median 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

1. SAKK 35/98_FL: 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 PubMed NCT00003280
   1. 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 PubMed
2. 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 PubMed
   1. 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 PubMed
3. 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 PubMed NCT00005589

R-BEAM, then auto HSCT

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

Regimen

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

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

Preceding treatment

• Salvage R-DexaBEAM x 2

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV once per day on days -8 & -2

Chemotherapy

• Carmustine (BCNU) 300 mg/m² IV once on day -7
• Etoposide (Vepesid) 200 mg/m² IV twice per day on days -6 to -3
• Cytarabine (Ara-C) 400 mg/m² IV twice per day on days -6 to -3
• Melphalan (Alkeran) 140 mg/m² IV once on day -2

Supportive therapy

• Autologous stem cells re-infused on day 0

One course

References

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

R-TBI/Cy, then auto HSCT

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

Regimen

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

Preceding treatment

• Salvage R-DexaBEAM x 2

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV once per day on days -8 & -2

Chemotherapy

• Cyclophosphamide (Cytoxan) 60 mg/kg IV once per day on days -3 & -2

Radiotherapy

• Total body irradiation (TBI) with a total dose of 1200 cGy over 3 days (days -6 to -4) in fractions

Supportive therapy

• Autologous stem cells re-infused on day 0

One course

References

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

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

Chemotherapy

• Thiotepa (Thioplex) 5 mg/kg IV every 12 hours on day -7 (total dose: 10 mg/kg)
• Etoposide (Vepesid) 200 mg/m² IV once per day on days -5 to -3
• Cytarabine (Ara-C) 200 mg/m² IV once per day on days -5 to -3
• Melphalan (Alkeran) 140 mg/m² IV once on day -2

Supportive therapy

• Autologous stem cells re-infused on day 0
• Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day +2, continued until ANC greater than 1500/μL

One course

Subsequent treatment

• Rituximab maintenance

References

1. 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 PubMed 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 superior OS

Chemotherapy

• Cyclophosphamide (Cytoxan) 60 mg/kg IV once per day on days -3 & -2

Radiotherapy

• Total body irradiation (TBI) 1200 cGy in fractions on days –6 to –4 (pulmonary dosage was limited to 800 cGy)

Supportive therapy

• Autologous stem cells re-infused on day 0

One course

References

1. 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 PubMed

(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

Targeted therapy

• Rituximab (Rituxan) 250 mg/m² IV once per day on days -14 & -7

Radioconjugate therapy

• Ibritumomab tiuxetan & Indium-111 5 mCi IV once on day -14 for dosimetry
• Ibritumomab tiuxetan & Yttrium-90 (Zevalin) 0.4 mCi/kg (15 MBq/kg) (maximum dose of 32 mCi/1.2 GBq) IV once on day -7

Chemotherapy

• Fludarabine (Fludara) 30 mg/m² IV once per day on days -5 to -3
• Cyclophosphamide (Cytoxan) 750 mg/m² IV once per day on days -5 to -3

Immunotherapy

• Allogeneic stem cells transfused on day 0

GVHD prophylaxis

• Antithymocyte globulin, rabbit ATG (Thymoglobulin) by the following donor-based criteria:
  • Matched unrelated or mismatched donors: 1 mg/kg IV once per day on days -2 & -1
• Tacrolimus (Prograf)
• Methotrexate (MTX)

One course

References

1. 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 PubMed NCT00048737
   1. 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 PubMed
   2. 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 PubMed

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

1. 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 PubMed NCT00201877

Lenalidomide monotherapy

Regimen

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

Preceding treatment

• Salvage Lenalidomide & Rituximab

Targeted therapy

• Lenalidomide (Revlimid) 20 mg PO once per day on days 1 to 21

Supportive therapy

• Aspirin 81 mg PO once per day

28-day cycles

References

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

Obinutuzumab monotherapy

Regimen

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

Preceding treatment

• Salvage Obinutuzumab

Targeted therapy

• Obinutuzumab (Gazyva) 1000 mg IV once on day 1

2-month cycle for 12 cycles

References

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

Rituximab monotherapy, extended course

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

Regimen 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 superior 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
Sehn et al. 2015 (GAUSS)	2009-2010	Non-randomized part of phase 2 RCT

Preceding treatment

• MAXIMA: Salvage Rituximab monotherapy or rituximab and chemotherapy (Most patients, 62%, received an anthracycline-based regimen)
• GAUSS: Salvage Rituximab

Targeted therapy

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

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

References

1. 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 PubMed NCT00004179
   1. 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 PubMed
2. 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 PubMed NCT00430352
3. GAUSS: Sehn LH, Goy A, Offner FC, Martinelli G, Caballero MD, Gadeberg O, Baetz T, Zelenetz AD, Gaidano G, Fayad LE, Buckstein R, Friedberg JW, Crump M, Jaksic B, Zinzani PL, Padmanabhan Iyer S, Sahin D, Chai A, Fingerle-Rowson G, Press OW. Randomized phase II trial comparing obinutuzumab (GA101) with rituximab in patients with relapsed CD20+ indolent B-cell non-Hodgkin lymphoma: final analysis of the GAUSS study. J Clin Oncol. 2015 Oct 20;33(30):3467-74. Epub 2015 Aug 17. link to original article] dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00576758

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

References

1. 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 PubMed

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

References

1. 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 PubMed

Response criteria

NCI Sponsored International Working Group Criteria (1999)

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