Follicular lymphoma

From HemOnc.org - A Hematology Oncology Wiki
Jump to navigation Jump to search

Back to Top

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!
Note: this page has regimens which are specific to follicular lymphoma. Please see the indolent lymphoma page for other regimens that have been tested in the broader population.

  • We have moved How I Treat articles to a dedicated page.
Last updated on 2024-12-02:
57 regimens on this page
90 variants on this page


Guidelines

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

BSH


ESMO


NCCN


Early disease, definitive therapy

Radiation therapy

RT: Radiation Therapy

Regimen

Study Dates of enrollment Evidence
MacManus et al. 2018 (TROG 99.03) 2000-2012 Non-randomized part of phase 3 RCT

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

Radiotherapy

Subsequent treatment

References

  1. 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
    1. Update: MacManus MP, Seymour JF, Tsang H, Fisher R, Keane C, Sabdia MB, Law SC, Gunawardana J, Nath K, Kazakoff SH, Marques-Piubelli ML, Duenas DE, Green MR, Roos D, O'Brien P, McCann A, Tsang R, Davis S, Christie D, Cheah C, Amanuel B, Cochrane T, Butler J, Johnston A, Shanavas M, Li L, Vajdic C, Kridel R, Shelton V, Hershenfield S, Baetz T, Lebrun D, Johnson N, Brodtkorb M, Ludvigsen M, d'Amore F, Thompson ER, Blombery P, Gandhi MK, Tobin JWD. Adjuvant rituximab and elevated intratumoural CD8 expression are associated with sustained disease control after radiotherapy in a randomised trial of systemic therapy in early-stage follicular lymphoma. EBioMedicine. 2024 Dec;110:105468. Epub 2024 Dec 3. link to original article PubMed


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

Targeted therapy

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

28-day cycle for 6 cycles

Subsequent treatment

References

  1. 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

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Marcus et al. 2017 (GALLIUM) 2011-2014 Phase 3 (C) See link See link See link
Morschhauser et al. 2018 (RELEVANCE) 2011-2014 Phase 3 (C) Lenalidomide & Rituximab Did not meet co-primary endpoints of CR rate/PFS Different toxicity
Paikaray et al. 2023 2016-01 to 2019-07 Phase 3 (C) Lenalidomide & Rituximab Did not meet primary endpoint of CR rate

Chemotherapy

Targeted therapy

Supportive therapy

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

28-day cycle for up to 6 cycles

Subsequent treatment

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
  2. 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
  3. 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


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

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

Glucocorticoid therapy

21-day cycle for 8 cycles

Subsequent treatment

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

Glucocorticoid therapy

21-day cycle for 8 cycles

Subsequent treatment

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 #3

Study Dates of enrollment Evidence
Martin et al. 2017 (CALGB 50803) 2010-10 to 2011-09 Phase 2

Targeted therapy

28-day cycle for 12 cycles


Regimen variant #3

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Morschhauser et al. 2018 (RELEVANCE) 2011-2014 Phase 3 (E-switch-ooc) 1a. R-B
1b. R-CHOP
1c. R-CVP 		Did not meet co-primary endpoints of CR rate/PFS Different toxicity

Targeted therapy

28-day cycle for 6 cycles

Subsequent treatment

References

  1. 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
  2. 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
  3. 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

Glucocorticoid therapy

28-day course, then 21-day cycle for 3 cycles

Subsequent treatment


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

Chemotherapy

Glucocorticoid therapy

Supportive therapy

21-day cycle for 3 cycles

Subsequent treatment


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

Chemotherapy

Glucocorticoid therapy

Supportive therapy

21-day cycle for 8 cycles

Subsequent treatment


Regimen variant #4, prednisone 100 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Hiddemann et al. 2005 (GLSG '00) 2000-2003 Phase 3 (E-esc) CHOP Seems to have longer OS (secondary endpoint) Increased toxicity
Federico et al. 2013 (FOLL05) 2006-2010 Phase 3 (E-esc) 1. R-CVP Seems to have longer PFS (secondary endpoint)
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

Chemotherapy

Glucocorticoid therapy

21-day cycle for 6 to 8 cycles


Regimen variant #5, variant rituximab schedule

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Czuczman et al. 1999 Not reported Phase 2
Press et al. 2012 (SWOG S0016) 2001-2008 Phase 3 (C) CHOP, then 131Iodine-Tositumomab Shorter PFS1

1Reported efficacy for SWOG S0016 is based on the 2018 update.
In SWOG S0016, this regimen was intended for patients greater than 18 years with untreated bulky stage II or stage III-IV FL (all grades) expressing CD20.

Targeted therapy

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

Chemotherapy

Glucocorticoid therapy

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
Median PFS: 3.7 vs 4.7 y
(HR 1.08, 95% CI 0.80-1.47)

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

Targeted therapy

Chemotherapy

Glucocorticoid therapy

Supportive therapy

21-day cycle for 6 cycles

References

  1. Czuczman MS, Grillo-López AJ, White CA, Saleh M, Gordon L, LoBuglio AF, Jonas C, Klippenstein D, Dallaire B, Varns C. Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol. 1999 Jan;17(1):268-76. link to original article dosing details in manuscript have been reviewed by our editors PubMed
    1. Update: Czuczman MS, Weaver R, Alkuzweny B, Berlfein J, Grillo-López AJ. Prolonged clinical and molecular remission in patients with low-grade or follicular non-Hodgkin's lymphoma treated with rituximab plus CHOP chemotherapy: 9-year follow-up. J Clin Oncol. 2004 Dec 1;22(23):4711 to 6. Epub 2004 Oct 13. link to original article PubMed
  2. 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 manuscript 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. PRIMAFL: Salles G, Seymour JF, Offner F, López-Guillermo A, Belada D, Xerri L, Feugier P, Bouabdallah R, Catalano JV, Brice P, Caballero D, Haioun C, Pedersen LM, Delmer A, Simpson D, Leppa S, Soubeyran P, Hagenbeek A, Casasnovas O, Intragumtornchai T, Fermé C, da Silva MG, Sebban C, Lister A, Estell JA, Milone G, Sonet A, Mendila M, Coiffier B, Tilly H. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet. 2011 Jan 1;377(9759):42-51. Epub 2010 Dec 20. link to original article dosing details in manuscript have been reviewed by our editors 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. 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
  10. 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
  11. 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
  12. 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 Longer EFS (primary endpoint)
Median EFS: NYR vs 2.9 y
(aHR 0.59, 95% CI 0.44-0.78)

Targeted therapy

  • Rituximab (Rituxan) as follows:
    • Cycles 3 & 4: 375 mg/m2 IV once per day on days 1 and 8
    • Cycles 5 & 6: 375 mg/m2 IV once on day 1

Chemotherapy

Glucocorticoid therapy

28-day cycle for 6 cycles

Subsequent treatment

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 Longer 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 shorter PFS (secondary endpoint) See paper
2. R-FM Shorter PFS1 See paper
Morschhauser et al. 2018 (RELEVANCE) 2011-2014 Phase 3 (C) Lenalidomide & Rituximab Did not meet co-primary endpoints of CR rate/PFS Different toxicity
Kim et al. 2017 (CT-P10 3.3) 2014-07-28 to 2015-12-29 Phase 3 (C) R-CVP (rituximab-abbs) Non-inferior ORR (primary endpoint)
ORR: 92.6% vs 97%

1Reported efficacy for this arm of FOLL05 is based on the 2017 update.

Targeted therapy

Chemotherapy

Glucocorticoid therapy

21-day cycle for up to 8 cycles

Subsequent treatment


Regimen variant #2, prednisone 100 mg/day

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Marcus et al. 2017 (GALLIUM) 2011-2014 Phase 3 (C) See link See link See link
Jurczak et al. 2017 (ASSIST-FL) 2011-12-01 to 2015-01-15 Phase 3 (C) GP2013-CVP Equivalent ORR
ORR: 88% vs 87%

Patients in GALLIUM received rituximab only in cycles 7 & 8.

Targeted therapy

Chemotherapy

Glucocorticoid therapy

Supportive therapy

21-day cycle for up to 8 cycles

Subsequent treatment


Regimen variant #3, 3 cycles

Study Dates of enrollment Evidence
Hainsworth et al. 2005a 2000-2001 Phase 2

Preceding treatment

Targeted therapy

Chemotherapy

Glucocorticoid therapy

21-day cycle for 3 cycles

Subsequent treatment

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 manuscript 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. PRIMAFL: Salles G, Seymour JF, Offner F, López-Guillermo A, Belada D, Xerri L, Feugier P, Bouabdallah R, Catalano JV, Brice P, Caballero D, Haioun C, Pedersen LM, Delmer A, Simpson D, Leppa S, Soubeyran P, Hagenbeek A, Casasnovas O, Intragumtornchai T, Fermé C, da Silva MG, Sebban C, Lister A, Estell JA, Milone G, Sonet A, Mendila M, Coiffier B, Tilly H. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet. 2011 Jan 1;377(9759):42-51. Epub 2010 Dec 20. link to original article dosing details in manuscript have been reviewed by our editors 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. 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
  6. 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
  7. 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
  8. 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-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

Targeted therapy

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 Longer PFS1 (secondary endpoint)

1Reported efficacy for this arm of FOLL05 is based on the 2017 update.
Note: risk/benefit ratio was worse than R-CHOP.

Targeted therapy

Chemotherapy

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

Chemotherapy

Glucocorticoid therapy

1-month cycle for 4 cycles

Subsequent treatment

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


R-MCP

R-MCP: Rituximab, Mitoxantrone, Chlorambucil, Prednisolone

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Herold et al. 2007 (OSHO-39) 1998-2003 Phase 3 (E-esc) MCP Longer OS (secondary endpoint)
OS48: 87% vs 74%

Higher ORR (primary endpoint)

Note: the chlorambucil dose was written in the reference as "3 x 3 mg/m2"; total dose per day is 9 mg/m2.

Targeted therapy

Chemotherapy

Glucocorticoid therapy

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
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

Supportive therapy

7-day cycle for 4 cycles

Subsequent treatment


Regimen variant #2, 8 doses

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kimby et al. 2015 (NLG ML16865) 2002-2008 Phase 3 (C) Rituximab & IFN-α2a Did not meet primary endpoint of TTF
Median TTF: 28 vs 21.5 mo
Zucca et al. 2019 (SAKK 35/10) 2011-2013 Randomized Phase 2 (C) Lenalidomide & Rituximab Might have lower composite CR/CRu rate

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

Targeted therapy

12-week cycle for 2 cycles

References

  1. Colombat P, Salles G, Brousse N, Eftekhari P, Soubeyran P, Delwail V, Deconinck E, Haïoun C, Foussard C, Sebban C, Stamatoullas A, Milpied N, Boué F, Taillan B, Lederlin P, Najman A, Thièblemont C, Montestruc F, Mathieu-Boué A, Benzohra A, Solal-Céligny P. Rituximab (anti-CD20 monoclonal antibody) as single first-line therapy for patients with follicular lymphoma with a low tumor burden: clinical and molecular evaluation. Blood. 2001 Jan 1;97(1):101-6. link to original article dosing details in manuscript have been reviewed by our editors 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
  2. SAKK 35/98FL: Ghielmini M, Schmitz SF, Cogliatti SB, Pichert G, Hummerjohann J, Waltzer U, Fey MF, Betticher DC, Martinelli G, Peccatori F, Hess U, Zucca E, Stupp R, Kovacsovics T, Helg C, Lohri A, Bargetzi M, Vorobiof D, Cerny T. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood. 2004 Jun 15;103(12):4416-23. Epub 2004 Feb 19. link to original article dosing details in manuscript have been reviewed by our editors 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
  3. 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
  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
    1. HRQoL analysis: Marzolini MAV, Qian W, Clifton-Hadley L, Patrick P, Warden J, Stevens L, Pocock CFE, Miall F, Cunningham D, Stephens R, Walewski J, Johnston A, Seymour JF, Linch DC, Ardeshna KM. Quality of life in advanced-stage, asymptomatic, non-bulky follicular lymphoma treated with rituximab shows significant improvement compared with watchful-waiting. Br J Haematol. 2024 Nov 27. Epub ahead of print. link to original article PubMed
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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 Longer PFS (primary endpoint)
PFS48: 58.1% vs 41.2%
(HR 0.585, 95% CI 0.39-0.87)

Targeted therapy

4-week course

Subsequent treatment

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
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. 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
  2. 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
    1. HRQoL analysis: Marzolini MAV, Qian W, Clifton-Hadley L, Patrick P, Warden J, Stevens L, Pocock CFE, Miall F, Cunningham D, Stephens R, Walewski J, Johnston A, Seymour JF, Linch DC, Ardeshna KM. Quality of life in advanced-stage, asymptomatic, non-bulky follicular lymphoma treated with rituximab shows significant improvement compared with watchful-waiting. Br J Haematol. 2024 Nov 27. Epub ahead of print. link to original article PubMed


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

Fludarabine & Rituximab (FR)

FR: Fludarabine & Rituximab

Regimen

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

Chemotherapy

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

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

Radioconjugate therapy

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

Glucocorticoid therapy

Supportive therapy

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


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

28-day cycle for 6 cycles

Subsequent treatment

References

  1. PRIMAFL: Salles G, Seymour JF, Offner F, López-Guillermo A, Belada D, Xerri L, Feugier P, Bouabdallah R, Catalano JV, Brice P, Caballero D, Haioun C, Pedersen LM, Delmer A, Simpson D, Leppa S, Soubeyran P, Hagenbeek A, Casasnovas O, Intragumtornchai T, Fermé C, da Silva MG, Sebban C, Lister A, Estell JA, Milone G, Sonet A, Mendila M, Coiffier B, Tilly H. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet. 2011 Jan 1;377(9759):42-51. Epub 2010 Dec 20. link to original article dosing details in manuscript have been reviewed by our editors 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


Consolidation after first-line therapy

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

Ibritumomab tiuxetan protocol

An abstract presented at ASH 2013 from the ZAR2007 trial has preliminary results that R-CHOP followed by Zevalin is inferior to R-CHOP followed by rituximab maintenance; detailed results are not yet available and therefore only the reference is provided, here.

Regimen variant #1

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Morschhauser et al. 2008 (FIT) 2001-2005 Phase 3 (E-RT-esc) Observation Longer PFS (primary endpoint)
Median PFS: 36.5 vs 13.3 mo
(HR 0.465, 95% CI 0.36-0.605)

Preceding treatment

  • First-line therapy (most received CHOP or CVP; some received "CHOP-like", "rituximab combination", "fludarabine combination", or chlorambucil), with PR/CR

Targeted therapy

Radioconjugate therapy

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

Targeted therapy

Radioconjugate therapy

  • Ibritumomab tiuxetan & Yttrium-90 (Zevalin) by the following laboratory-based criteria:
    • Platelet count more than 150 x 109/L: 14.8 MBq/kg (maximum dose of 1184 MBq) IV over 10 minutes once on day 8, given immediately following second dose of rituximab
    • Platelet count 100 to 149 x 109/L: 11.1 MBq/kg (maximum dose of 1184 MBq) IV over 10 minutes once on day 8, given immediately following second dose of rituximab

8-day course


Regimen variant #3

Study Dates of enrollment Evidence
Hainsworth et al. 2009 2002-04 to 2004-03 Phase 2

See text for further information about Zevalin eligbility criteria. If patient did not meet criteria within 7 weeks after final R-CHOP, Zevalin was omitted.

Preceding treatment

Targeted therapy

Radioconjugate therapy

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

Radioconjugate therapy

  • Ibritumomab tiuxetan & Yttrium-90 (Zevalin) by the following laboratory-based criteria:
    • Platelet count more than 150 x 109/L: 14.8 MBq/kg (maximum dose of 1184 MBq) IV over 10 minutes once on day 8, given immediately following second dose of rituximab
    • Platelet count 100 to 149 x 109/L: 11.1 MBq/kg (maximum dose of 1184 MBq) IV over 10 minutes once on day 8, given immediately following second dose of rituximab

8-day course


Regimen variant #5

Study Dates of enrollment Evidence Efficacy
Jacobs et al. 2008 (UPCI 03-005) 2004-03 to 2007-02 Phase 2 ORR: 89%

Preceding treatment

Targeted therapy

Radioconjugate therapy

8-day course, followed in 1 to 2 weeks by:

Targeted therapy

7-day cycle for 4 cycles


Regimen variant #6

Study Dates of enrollment Evidence Efficacy
Provencio et al. 2013 (GOTEL-FL1LC) 2008-04 to 2010-04 Phase 2 ORR: 93%

Preceding treatment

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

Targeted therapy

Radioconjugate therapy

  • Ibritumomab tiuxetan & Yttrium-90 (Zevalin) by the following laboratory-based criteria:
    • Platelet count more than 150 x 109/L, Granulocyte count more than 1500/uL, and bone marrow with no more than 25% lymphom involvement: 0.4 mCi/kg (maximum dose of 32 mCi) IV once on day 8, given no more than four hours after rituximab
    • Platelet count 100 to 149 x 109/L: 0.3 mCi/kg (maximum dose of 32 mCi) IV once on day 8, given no more than four hours after rituximab

One course

References

  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 dosing details in manuscript have been reviewed by our editors 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

Targeted therapy

14-day course


Regimen variant #2, 4 doses in 4 weeks

Study Dates of enrollment Evidence
Rambaldi et al. 2002 Not reported Phase 2
Ladetto et al. 2008 (GITMO 3320) 2000-2005 Non-randomized part of phase 3 RCT

Preceding treatment

  • Rambaldi et al. 2002 & GITMO 3320: First-line CHOP x 6
  • Zinzani et al. 2004: First-line CHOP x 6 versus FM x 6

Targeted therapy

Supportive therapy

7-day cycle for 4 cycles


Regimen variant #3, 8 doses in 8 months

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Vitolo et al. 2013 (ML17638) 2004-2007 Phase 3 (E-esc) Observation Did not meet primary endpoint of PFS

Preceding treatment

Targeted therapy

2-month cycle for 4 cycles


Regimen variant #4, 8 doses in 9 months

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ghielmini et al. 2004 (SAKK 35/98FL) 1998-2002 Phase 3 (E-esc) Observation Longer EFS (primary endpoint)
Median EFS: 23 vs 12 mo
(aHR 0.40, 95% CI 0.26-0.64)
Taverna et al. 2015 (SAKK 35/03) 2004-2007 Phase 3 (C) Rituximab x 5 y Did not meet primary endpoint of EFS

Note: maintenance treatment began in week 12.

Preceding treatment

Targeted therapy

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. SAKK 35/98FL: Ghielmini M, Schmitz SF, Cogliatti SB, Pichert G, Hummerjohann J, Waltzer U, Fey MF, Betticher DC, Martinelli G, Peccatori F, Hess U, Zucca E, Stupp R, Kovacsovics T, Helg C, Lohri A, Bargetzi M, Vorobiof D, Cerny T. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood. 2004 Jun 15;103(12):4416-23. Epub 2004 Feb 19. link to original article dosing details in manuscript have been reviewed by our editors 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
  3. 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
  4. GITMO 3320: Ladetto M, De Marco F, Benedetti F, Vitolo U, Patti C, Rambaldi A, Pulsoni A, Musso M, Liberati AM, Olivieri A, Gallamini A, Pogliani E, Rota Scalabrini D, Callea V, Di Raimondo F, Pavone V, Tucci A, Cortelazzo S, Levis A, Boccadoro M, Majolino I, Pileri A, Gianni AM, Passera R, Corradini P, Tarella C; GITMO; Intergruppo Italiano Linfomi. Prospective, multicenter randomized GITMO/IIL trial comparing intensive (R-HDS) versus conventional (CHOP-R) chemoimmunotherapy in high-risk follicular lymphoma at diagnosis: the superior disease control of R-HDS does not translate into an overall survival advantage. Blood. 2008 Apr 15;111(8):4004-13. Epub 2008 Jan 31. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00435955
  5. 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
  6. 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

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

Targeted therapy

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

Targeted therapy

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 Longer PFS1 (primary endpoint)
Median PFS: 10.5 vs 4.1 y
(HR 0.61, 95% CI 0.52-0.73)
Davies et al. 2017 (SABRINA) 2011-2013 Phase 3 (C) SC Rituximab Similar efficacy
Luminari et al. 2021 (FOLL12) 2012-2018 Phase 3 (C) Response-adapted strategy Longer PFS
PFS36: 86% vs 72%

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

Preceding treatment

Targeted therapy

8-week cycle for 12 cycles (2 years)


Regimen variant #2, 16 doses in 2 years

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ardeshna et al. 2014 (CRUK-2004-001621-16) 2004-2009 Phase 3 (E-esc) 1. Observation Superior TTNT (primary endpoint)
2. Rituximab induction, no maintenance Did not meet primary endpoint of TTNT

Preceding 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 13: 375 mg/m2 IV once on day 1

28-day course, then 2-month cycle for 12 cycles


Regimen variant #3, 12 doses in 2 years

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Witzens-Harig et al. 2014 (MAXIMA) 2006 to not reported Non-randomized
Marcus et al. 2017 (GALLIUM) 2011-2014 Phase 3 (C) See link See link See link

Preceding treatment

Targeted therapy

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. PRIMAFL: Salles G, Seymour JF, Offner F, López-Guillermo A, Belada D, Xerri L, Feugier P, Bouabdallah R, Catalano JV, Brice P, Caballero D, Haioun C, Pedersen LM, Delmer A, Simpson D, Leppa S, Soubeyran P, Hagenbeek A, Casasnovas O, Intragumtornchai T, Fermé C, da Silva MG, Sebban C, Lister A, Estell JA, Milone G, Sonet A, Mendila M, Coiffier B, Tilly H. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet. 2011 Jan 1;377(9759):42-51. Epub 2010 Dec 20. link to original article dosing details in manuscript have been reviewed by our editors 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
  3. 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
    1. HRQoL analysis: Marzolini MAV, Qian W, Clifton-Hadley L, Patrick P, Warden J, Stevens L, Pocock CFE, Miall F, Cunningham D, Stephens R, Walewski J, Johnston A, Seymour JF, Linch DC, Ardeshna KM. Quality of life in advanced-stage, asymptomatic, non-bulky follicular lymphoma treated with rituximab shows significant improvement compared with watchful-waiting. Br J Haematol. 2024 Nov 27. Epub ahead of print. link to original article PubMed
  4. 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
  5. 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
  6. 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
  7. 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, 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

Targeted therapy

  • Rituximab (Rituxan) as follows:
    • Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15, 22
    • Cycles 2 to 30: 375 mg/m2 IV once on day 1

2-month cycle for up to 30 cycles (5 years)


Regimen variant #2, indefinite

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kahl et al. 2014 (RESORT) 2003-2008 Phase 3 (E-esc) Rituximab; salvage Did not meet primary endpoint of TTF

Preceding treatment

Targeted therapy

13-week cycles

References

  1. 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
  2. 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

Targeted therapy

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

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Nastoupil et al. 2023 (SELENE) 2014-03-28 to 2015-11-05 Phase 3 (C) 1a. BR & Ibrutinib
1b. R-CHOP & Ibrutinib 		Might have shorter PFS (primary endpoint)
Median PFS: 23.8 vs 40.5 mo
(HR 1.24, 95% CI 0.96-1.60)

Chemotherapy

Targeted therapy

28-day cycle for up to 6 cycles

References

  1. 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 Longer 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 longer PFS (primary endpoint)
Median PFS: 12.8 vs 11 mo
(HR 0.82, 95% CI 0.68-0.99)

Targeted therapy

  • Bortezomib (Velcade) 1.6 mg/m2 IV over 3 to 5 seconds once per day on days 1, 8, 15, 22
  • Rituximab (Rituxan) as follows:
    • Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15, 22
    • Cycles 2 to 5: 375 mg/m2 IV once on day 1

Supportive therapy

  • No routine antiviral prophylaxis was mandated

35-day cycle for 5 cycles


Regimen variant #2

Study Dates of enrollment Evidence
Agathocleous et al. 2010 Not reported Phase 2

Targeted therapy

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

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

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


Lenalidomide monotherapy

Regimen

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

Note: Lenalidomide dose was escalated only if tolerated.

Targeted therapy

  • Lenalidomide (Revlimid) as follows:
    • Cycle 1: 15 mg PO once per day on days 1 to 21
    • Cycle 2: 20 mg PO once per day on days 1 to 21
    • Cycles 3 to 12: 25 mg PO once per day on days 1 to 21

Supportive therapy

  • Aspirin or LMWH recommended for patients at high risk of thrombosis (see paper for details)

28-day cycle for 12 cycles

References

  1. 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

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

Note: Lenalidomide dose was escalated only if tolerated.

Targeted therapy

  • Lenalidomide (Revlimid) as follows:
    • Cycle 1: 15 mg PO once per day on days 1 to 21
    • Cycle 2: 20 mg PO once per day on days 1 to 21
    • Cycles 3 to 12: 25 mg PO once per day on days 1 to 21
  • Rituximab (Rituxan) as follows:
    • Cycle 1: 375 mg/m2 IV once per day on days 8, 15, 22
    • Cycle 2: 375 mg/m2 IV once on day 1

Supportive therapy

  • Aspirin or LMWH recommended for patients at high risk of thrombosis (see paper for details)

28-day cycle for 12 cycles

References

  1. 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


Obinutuzumab monotherapy

Regimen

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

Targeted therapy

  • Obinutuzumab (Gazyva) as follows:
    • Cycle 1: 1000 mg IV once per day on days 1, 8, 15
    • Cycles 2 to 6: 1000 mg IV once on day 1
    • Cycles 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29: 1000 mg IV once on day 1

28-day cycle for up to 29 cycles

References

  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
    1. PRO analysis: Trotman J, Zinzani PL, Song Y, Delarue R, Kim P, Ivanova E, Korde R, Mayer J, De Oliveira AC, Assouline SE, Flowers CR, Barnes G. Patient-reported outcomes in patients with relapsed or refractory follicular lymphoma treated with zanubrutinib plus obinutuzumab versus obinutuzumab monotherapy: results from the ROSEWOOD trial. Curr Med Res Opin. 2024 Nov;40(11):1863-1871. Epub 2024 Oct 14. link to original article PubMed


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

Chemotherapy

Glucocorticoid therapy

21-day cycle for 3 cycles

Subsequent treatment


Regimen variant #2, 6 cycles with prednisone 100 mg

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Van Oers et al. 2006 (EORTC 20981) 1998-2004 Phase 3 (E-esc) CHOP Might have longer OS (secondary endpoint)
OS36: 82.5% vs 71.9%
(HR 0.74, 95% CI 0.52-1.05)

Higher ORR (primary endpoint)
Nastoupil et al. 2023 (SELENE) 2014-03-28 to 2015-11-05 Phase 3 (C) 1a. BR & Ibrutinib
1b. R-CHOP & Ibrutinib 		Might have shorter PFS (primary endpoint)
Median PFS: 23.8 vs 40.5 mo
(HR 1.24, 95% CI 0.96-1.60)

Targeted therapy

Chemotherapy

Glucocorticoid therapy

21-day cycle for 6 cycles

Subsequent 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

Glucocorticoid therapy

21-day cycle for 6 cycles

References

  1. Czuczman MS, Grillo-López AJ, White CA, Saleh M, Gordon L, LoBuglio AF, Jonas C, Klippenstein D, Dallaire B, Varns C. Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol. 1999 Jan;17(1):268-76. link to original article dosing details in manuscript have been reviewed by our editors PubMed
    1. Update: Czuczman MS, Weaver R, Alkuzweny B, Berlfein J, Grillo-López AJ. Prolonged clinical and molecular remission in patients with low-grade or follicular non-Hodgkin's lymphoma treated with rituximab plus CHOP chemotherapy: 9-year follow-up. J Clin Oncol. 2004 Dec 1;22(23):4711 to 6. Epub 2004 Oct 13. link to original article PubMed
  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 longer PFS
Median PFS: NYR vs 21 mo

Targeted therapy

Chemotherapy

28-day cycle for 4 cycles

Subsequent 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 Shorter PFS
Median PFS: 10.4 vs 20.7 mo
(HR 2.50, 95% CI 1.25-5.00)

Targeted therapy

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

12-week course, then 2-month cycle for 4 cycles


Regimen variant #2, induction only

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Maloney et al. 1994 Not reported Phase 1, less than 20 pts
Maloney et al. 1997a Not reported Phase 2 (RT)
Maloney et al. 1997b Not reported Phase 1, less than 20 pts
Witzig et al. 2002a Not reported Phase 3 (C) Ibritumomab tiuxetan Lower ORR
Ghielmini et al. 2004 (SAKK 35/98FL) 1998-2002 Non-randomized part of phase 3 RCT

Note: the phase 1 described by Maloney et al. 1994 did not actually employ this dosing level, but is included here for reference purposes.

Targeted therapy

Supportive therapy

7-day cycle for 4 cycles

Subsequent treatment


Regimen variant #3

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Coiffier et al. 2011 (LYM-3001) 2006-2008 Phase 3 (C) VR Seems to have shorter PFS
Median PFS: 11 vs 12.8 mo
(HR 1.22, 95% CI 1.01-1.47)

Targeted therapy

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

Supportive therapy

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

Targeted therapy

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 manuscript 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. 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
  5. SAKK 35/98FL: Ghielmini M, Schmitz SF, Cogliatti SB, Pichert G, Hummerjohann J, Waltzer U, Fey MF, Betticher DC, Martinelli G, Peccatori F, Hess U, Zucca E, Stupp R, Kovacsovics T, Helg C, Lohri A, Bargetzi M, Vorobiof D, Cerny T. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood. 2004 Jun 15;103(12):4416-23. Epub 2004 Feb 19. link to original article dosing details in manuscript have been reviewed by our editors 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
  6. 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
  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. 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


Zanubrutinib & Obinutuzumab (ZO)

ZO: Zanubrutinib & Obinutuzumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Zinzani et al. 2023 (ROSEWOOD) 2017-11 to 2021-06 Randomized Phase 2 (E-esc) Obinutuzumab Higher ORR (primary endpoint)
ORR: 69% vs 46%

Targeted therapy

  • Zanubrutinib (Brukinsa) 160 mg PO twice per day
  • Obinutuzumab (Gazyva) as follows:
    • Cycle 1: 1000 mg IV once per day on days 1, 8, 15
    • Cycles 2 to 6: 1000 mg IV once on day 1
    • Cycles 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29: 1000 mg IV once on day 1

28-day cycles

References

  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
    1. PRO analysis: Trotman J, Zinzani PL, Song Y, Delarue R, Kim P, Ivanova E, Korde R, Mayer J, De Oliveira AC, Assouline SE, Flowers CR, Barnes G. Patient-reported outcomes in patients with relapsed or refractory follicular lymphoma treated with zanubrutinib plus obinutuzumab versus obinutuzumab monotherapy: results from the ROSEWOOD trial. Curr Med Res Opin. 2024 Nov;40(11):1863-1871. Epub 2024 Oct 14. link to original article PubMed


Relapsed or refractory, non-randomized or retrospective data

BVR

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

Regimen

Study Dates of enrollment Evidence
Fowler et al. 2011 (VERTICAL) 2008-2009 Phase 2

Note: Bendamustine was dose-escalated in the first phase of the trial and the 90 mg/m2 dose was the MTD.

Chemotherapy

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

Targeted therapy

  • Bortezomib (Velcade) 1.6 mg/m2 IV once per day on days 1, 8, 15, 22, given first
  • Rituximab (Rituxan) as follows, given third:
    • Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15, 22
    • Cycles 2 to 5: 375 mg/m2 IV once on day 1

Supportive therapy

  • Antiviral prophylaxis at physician discretion

35-day cycle for 5 cycles

References

  1. 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


Epcoritamab monotherapy

Regimen

Study Dates of enrollment Evidence
Hutchings et al. 2021 (EPCORE NHL-1FL) 2020-06-19 to 2023-04-21 Phase 2 (RT)

Note: dates of enrollment are based on the follicular lymphoma cohort.

Immunotherapy

  • Epcoritamab (Epkinly) as follows:
    • Cycle 1: 0.16 mg SC once on day 1, then 0.8 mg SC once on day 8, then 48 mg SC once per day on days 15 & 22
    • Cycles 2 & 3: 48 mg SC once per day on days 1, 8, 15, 22
    • Cycles 4 to 9: 48 mg SC once per day on days 1 & 15
    • Cycle 10 onwards: 48 mg SC once on day 1

28-day cycles

References

  1. EPCORE NHL-1FL: Linton KM, Vitolo U, Jurczak W, Lugtenburg PJ, Gyan E, Sureda A, Christensen JH, Hess B, Tilly H, Cordoba R, Lewis DJ, Okada C, Hutchings M, Clausen MR, Sancho JM, Cochrane T, Leppä S, Chamuleau MED, Gernhardt D, Altıntaş I, Liu Y, Ahmadi T, Dinh MH, Hoehn D, Favaro E, Elliott B, Thieblemont C, Vose JM. Epcoritamab monotherapy in patients with relapsed or refractory follicular lymphoma (EPCORE NHL-1): a phase 2 cohort of a single-arm, multicentre study. Lancet Haematol. 2024 Aug;11(8):e593-e605. Epub 2024 Jun 15. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT03625037


Fludarabine & Rituximab (FR)

FR: Fludarabine & Rituximab

Regimen

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

Chemotherapy

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

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 manuscript have been reviewed by our editors PubMed NCT01779791


Lisocabtagene maraleucel monotherapy

Regimen

Study Dates of enrollment Evidence
Morschhauser et al. 2024 (TRANSCEND-FL) 2020-07-14 to 2023-01-27 Phase 2 (RT)

Preceding treatment

  • Lymphodepletion with FC

Immunotherapy

One course

References

  1. TRANSCEND-FL: Morschhauser F, Dahiya S, Palomba ML, Martin Garcia-Sancho A, Reguera Ortega JL, Kuruvilla J, Jäger U, Cartron G, Izutsu K, Dreyling M, Kahl B, Ghesquieres H, Ardeshna K, Goto H, Barbui AM, Abramson JS, Borchmann P, Fleury I, Mielke S, Skarbnik A, de Vos S, Kamdar M, Karmali R, Viardot A, Farazi T, Fasan O, Lymp J, Vedal M, Nishii R, Avilion A, Papuga J, Kumar J, Nastoupil LJ. Lisocabtagene maraleucel in follicular lymphoma: the phase 2 TRANSCEND FL study. Nat Med. 2024 Aug;30(8):2199-2207. Epub 2024 Jun 3. Erratum in: Nat Med. 2024 Aug;30(8):2374. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed 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


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

Chemotherapy

Glucocorticoid therapy

21-day cycle for 3 cycles

Subsequent treatment

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


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

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


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

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


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

Chemotherapy

Glucocorticoid therapy

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

Ibritumomab tiuxetan protocol

Regimen

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

Targeted therapy

Radioconjugate therapy

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


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

Chemotherapy

Supportive therapy

One course

Subsequent treatment

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


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

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

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

Targeted therapy

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 Longer EFS (primary endpoint)
Median EFS: 23 vs 12 mo
(aHR 0.40, 95% CI 0.26-0.64)
Pettengell et al. 2013 (EBMT Lym-1) 1999-2006 Phase 3 (E-esc) Observation Longer PFS (primary endpoint)
PFS120: 54% vs 37%
(HR 0.66, 95% CI 0.47-0.91)

Note: SAKK 35/98 specified that treatment was to be given at week 12, month 5, 7, 9. Pettengell et al. 2013 did not specify when the maintenance rituximab was to begin post-auto HSCT.

Preceding treatment

Targeted therapy

2-month cycle for 4 cycles


Regimen variant #2, 8 doses

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Forstpointner et al. 2004 1998-2001 Phase 3 (E-esc) Observation Seems to have longer 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

Targeted therapy

6-month cycle for 2 cycles

References

  1. SAKK 35/98FL: Ghielmini M, Schmitz SF, Cogliatti SB, Pichert G, Hummerjohann J, Waltzer U, Fey MF, Betticher DC, Martinelli G, Peccatori F, Hess U, Zucca E, Stupp R, Kovacsovics T, Helg C, Lohri A, Bargetzi M, Vorobiof D, Cerny T. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood. 2004 Jun 15;103(12):4416-23. Epub 2004 Feb 19. link to original article dosing details in manuscript have been reviewed by our editors 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



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

Chemotherapy

Supportive therapy

One course

Subsequent treatment

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 longer OS

Chemotherapy

Radiotherapy

Supportive therapy

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

Radioconjugate therapy

Chemotherapy

Immunotherapy

GVHD prophylaxis

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

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



Rituximab monotherapy, extended course

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

Regimen variant #1, 3-month cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Van Oers et al. 2006 (EORTC 20981) 1998-2004 Phase 3 (E-esc) Observation Might have longer OS1 (secondary endpoint)
OS60: 74.3% vs 64.7%
(HR 0.70, 95% CI 0.48-1.03)

1Reported efficacy is based on the 2010 update.

Preceding treatment

Targeted therapy

3-month cycle for up to 8 cycles (2 years)


Regimen variant #2, 2-month cycles

Study Dates of enrollment Evidence
Witzens-Harig et al. 2014 (MAXIMA) 2006 to not reported Non-randomized

Preceding treatment

Targeted therapy

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


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


Retrieved from "https://hemonc.org/w/index.php?title=Follicular_lymphoma&oldid=101811"