Follicular lymphoma - null regimens

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The purpose of this page is to provide references to "null therapy" such as placebo and observation. These references provide further insight into the historical development of the treatment landscape. See the main FL page for regimens that include active anticancer treatment.
=Early disease, consolidation=
==Observation==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
MacManus et al. 2018 (TROG 99.03)	2000-2012 	Phase 3 (C)	1. CVP2. R-CVP	Seems to have shorter PFS
No further treatment. Note that in TROG 99.03, patients enrolled after 2006 were randomized between this arm and R-CVP.
====Preceding treatment====
*Definitive Radiation therapy
===References===
#TROG 99.03: MacManus M, Fisher R, Roos D, O'Brien P, Macann A, Davis S, Tsang R, Christie D, McClure B, Joseph D, Jayamohan J, Seymour JF. Randomized trial of systemic therapy after involved-field radiotherapy in patients with early-stage follicular lymphoma: TROG 99.03. J Clin Oncol. 2018 Oct 10;36(29):2918-2925. Epub 2018 Jul 5. link to original article EuroPMC NCT00115700
##Update: MacManus MP, Seymour JF, Tsang H, Fisher R, Keane C, Sabdia MB, Law SC, Gunawardana J, Nath K, Kazakoff SH, Marques-Piubelli ML, Duenas DE, Green MR, Roos D, O'Brien P, McCann A, Tsang R, Davis S, Christie D, Cheah C, Amanuel B, Cochrane T, Butler J, Johnston A, Shanavas M, Li L, Vajdic C, Kridel R, Shelton V, Hershenfield S, Baetz T, Lebrun D, Johnson N, Brodtkorb M, Ludvigsen M, d'Amore F, Thompson ER, Blombery P, Gandhi MK, Tobin JWD. Adjuvant rituximab and elevated intratumoural CD8 expression are associated with sustained disease control after radiotherapy in a randomised trial of systemic therapy in early-stage follicular lymphoma. EBioMedicine. 2024 Dec;110:105468. Epub 2024 Dec 3. link to original article EuroPMC
=Consolidation after first-line therapy=
==Observation==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Ghielmini et al. 2004 (SAKK 35/98FL)	1998-2002 	Phase 3 (C)	Rituximab 	Shorter EFS
Morschhauser et al. 2008 (FIT) 	2001-2005 	Phase 3 (C)	Ibritumomab tiuxetan 	Shorter PFSMedian PFS: 13.3 vs 36.5 mo(HR 2.15, 95% CI 1.65-2.78)
Schuster et al. 2011 (BiovaxID) 	2002-2008 	Phase 3 (C)	Patient-specific tumor-derived antigen	Seems to have shorter DFS1
Salles et al. 2010 (PRIMAFL) 	2004-2007 	Phase 3 (C)	Rituximab 	Shorter PFSMedian PFS: 4.1 vs 10.5 years(HR 1.64, 95% CI 1.37-1.92)
Vitolo et al. 2013 (ML17638) 	2004-2007 	Phase 3 (C)	Rituximab 	Did not meet primary endpoint of PFS
1Reported efficacy is based on the co-primary endpoint of DFS in the population that received at least one dose of Id vaccine or control.
No further treatment after induction therapy.
====Preceding treatment====
*SAKK 35/98FL: First-line R x 4
*FIT: First-line therapy (most received CHOP or CVP; some received "CHOP-like", "rituximab combination", "fludarabine combination", or chlorambucil), with PR/CR
*PRIMAFL: First-line R-CHOP or R-CVP or R-FCM
*ML17638: First-line R-FND x 4
===References===
#SAKK 35/98FL: Ghielmini M, Schmitz SF, Cogliatti SB, Pichert G, Hummerjohann J, Waltzer U, Fey MF, Betticher DC, Martinelli G, Peccatori F, Hess U, Zucca E, Stupp R, Kovacsovics T, Helg C, Lohri A, Bargetzi M, Vorobiof D, Cerny T. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood. 2004 Jun 15;103(12):4416-23. Epub 2004 Feb 19. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00003280
##Update: Martinelli G, Schmitz SF, Utiger U, Cerny T, Hess U, Bassi S, Okkinga E, Stupp R, Stahel R, Heizmann M, Vorobiof D, Lohri A, Dietrich PY, Zucca E, Ghielmini M. Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98. J Clin Oncol. 2010 Oct 10;28(29):4480-4. Epub 2010 Aug 9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#FIT: Morschhauser F, Radford J, Van Hoof A, Vitolo U, Soubeyran P, Tilly H, Huijgens PC, Kolstad A, d'Amore F, Gonzalez Diaz M, Petrini M, Sebban C, Zinzani PL, van Oers MH, van Putten W, Bischof-Delaloye A, Rohatiner A, Salles G, Kuhlmann J, Hagenbeek A. Phase III trial of consolidation therapy with yttrium-90-ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma. J Clin Oncol. 2008 Nov 10;26(32):5156-64. Epub 2008 Oct 14. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00185393
##Update: Morschhauser F, Radford J, Van Hoof A, Botto B, Rohatiner AZ, Salles G, Soubeyran P, Tilly H, Bischof-Delaloye A, van Putten WL, Kylstra JW, Hagenbeek A. 90Yttrium-ibritumomab tiuxetan consolidation of first remission in advanced-stage follicular non-Hodgkin lymphoma: updated results after a median follow-up of 7.3 years from the international, randomized, phase III First-Line Indolent Trial. J Clin Oncol. 2013 Jun 1;31(16):1977-83. Epub 2013 Apr 1. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
#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 abstract have been reviewed by our editors EuroPMC NCT00140582
##HRQoL analysis: Zhou X, Wang J, Zhang J, Copley-Merriman C, Torigoe Y, Reyes C, Seymour JF, Offner FC, Trneny M, Salles GA. Symptoms and toxicity of rituximab maintenance relative to observation following immunochemotherapy in patients with follicular lymphoma. Hematology. 2015 Apr;20(3):129-36. Epub 2014 Jul 16. link to original article EuroPMC
##Update: Bachy E, Seymour JF, Feugier P, Offner F, López-Guillermo A, Belada D, Xerri L, Catalano JV, Brice P, Lemonnier F, Martin A, Casasnovas O, Pedersen LM, Dorvaux V, Simpson D, Leppa S, Gabarre J, da Silva MG, Glaisner S, Ysebaert L, Vekhoff A, Intragumtornchai T, Le Gouill S, Lister A, Estell JA, Milone G, Sonet A, Farhi J, Zeuner H, Tilly H, Salles G. Sustained Progression-Free Survival Benefit of Rituximab Maintenance in Patients With Follicular Lymphoma: Long-Term Results of the PRIMA Study. J Clin Oncol. 2019 Nov 1;37(31):2815-2824. Epub 2019 Jul 24. link to original article link to PMC article EuroPMC
#BiovaxID: Schuster SJ, Neelapu SS, Gause BL, Janik JE, Muggia FM, Gockerman JP, Winter JN, Flowers CR, Nikcevich DA, Sotomayor EM, McGaughey DS, Jaffe ES, Chong EA, Reynolds CW, Berry DA, Santos CF, Popa MA, McCord AM, Kwak LW. Vaccination with patient-specific tumor-derived antigen in first remission improves disease-free survival in follicular lymphoma. J Clin Oncol. 2011 Jul 10;29(20):2787-94. Epub 2011 May 31. link to original article link to PMC article EuroPMC NCT00091676
#ML17638: Vitolo U, Ladetto M, Boccomini C, Baldini L, De Angelis F, Tucci A, Botto B, Chiappella A, Chiarenza A, Pinto A, De Renzo A, Zaja F, Castellino C, Bari A, Alvarez De Celis I, Evangelista A, Parvis G, Gamba E, Lobetti-Bodoni C, Ciccone G, Rossi G. Rituximab maintenance compared with observation after brief first-line R-FND chemoimmunotherapy with rituximab consolidation in patients age older than 60 years with advanced follicular lymphoma: a phase III randomized study by the Fondazione Italiana Linfomi. J Clin Oncol. 2013 Sep 20;31(27):3351-9. Epub 2013 Aug 19. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01144364
==Placebo==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Freedman et al. 2009	2004-2006 	Phase 3 (C)	Mitumprotimut-T & GM-CSF	Seems to have longer TTP
No active antineoplastic treatment.
====Preceding treatment====
*First-line Rituximab x 4
===References===
#Freedman A, Neelapu SS, Nichols C, Robertson MJ, Djulbegovic B, Winter JN, Bender JF, Gold DP, Ghalie RG, Stewart ME, Esquibel V, Hamlin P. Placebo-controlled phase III trial of patient-specific immunotherapy with mitumprotimut-T and granulocyte-macrophage colony-stimulating factor after rituximab in patients with follicular lymphoma. J Clin Oncol. 2009 Jun 20;27(18):3036-43. Epub 2009 May 4. link to original article link to PMC article EuroPMC
=Consolidation after subsequent lines of therapy=
==Observation==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Forstpointner et al. 2004 	1998-2001 	Phase 3 (C)	Rituximab 	Seems to have shorter PFS
Ghielmini et al. 2004 (SAKK 35/98FL)	1998-2002 	Phase 3 (C)	Rituximab 	Shorter EFS
Van Oers et al. 2006 (EORTC 20981) 	1998-2004 	Phase 3 (C)	Rituximab 	Might have shorter OS1
Pettengell et al. 2013 (EBMT Lym-1) 	1999-2006 	Phase 3 (C)	Rituximab 	Shorter PFSPFS120: 37% vs 54%(HR 1.52, 95% CI 1.10-2.13)
1Reported efficacy is based on the 2010 update.
No further treatment after second-line therapy.
====Preceding treatment====
*SAKK 35/98FL: Salvage R x 4
*Forstpointner et al. 2004: Salvage R-FCM x 4 versus FCM x 4
*EORTC 20981: Salvage CHOP versus R-CHOP
*EBMT Lym-1: BEAM with auto HSCT consolidation
===References===
#SAKK 35/98FL: Ghielmini M, Schmitz SF, Cogliatti SB, Pichert G, Hummerjohann J, Waltzer U, Fey MF, Betticher DC, Martinelli G, Peccatori F, Hess U, Zucca E, Stupp R, Kovacsovics T, Helg C, Lohri A, Bargetzi M, Vorobiof D, Cerny T. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood. 2004 Jun 15;103(12):4416-23. Epub 2004 Feb 19. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00003280
##Update: Martinelli G, Schmitz SF, Utiger U, Cerny T, Hess U, Bassi S, Okkinga E, Stupp R, Stahel R, Heizmann M, Vorobiof D, Lohri A, Dietrich PY, Zucca E, Ghielmini M. Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98. J Clin Oncol. 2010 Oct 10;28(29):4480-4. Epub 2010 Aug 9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Forstpointner R, Dreyling M, Repp R, Hermann S, Hänel A, Metzner B, Pott C, Hartmann F, Rothmann F, Rohrberg R, Böck HP, Wandt H, Unterhalt M, Hiddemann W; German Low-Grade Lymphoma Study Group. The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2004 Nov 15;104(10):3064-71. Epub 2004 Jul 29. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Update: Forstpointner R, Unterhalt M, Dreyling M, Böck HP, Repp R, Wandt H, Pott C, Seymour JF, Metzner B, Hänel A, Lehmann T, Hartmann F, Einsele H, Hiddemann W; German Low Grade Lymphoma Study Group. Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: Results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood. 2006 Dec 15;108(13):4003-8. Epub 2006 Aug 31. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#EORTC 20981: van Oers MH, Klasa R, Marcus RE, Wolf M, Kimby E, Gascoyne RD, Jack A, Van 't Veer M, Vranovsky A, Holte H, van Glabbeke M, Teodorovic I, Rozewicz C, Hagenbeek A. Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. Blood. 2006 Nov 15;108(10):3295-301. Epub 2006 Jul 27. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00004179
##Update: van Oers MH, Van Glabbeke M, Giurgea L, Klasa R, Marcus RE, Wolf M, Kimby E, van t Veer M, Vranovsky A, Holte H, Hagenbeek A. Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin's lymphoma: long-term outcome of the EORTC 20981 phase III randomized intergroup study. J Clin Oncol. 2010 Jun 10;28(17):2853-8. Epub 2010 May 3. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
#EBMT Lym-1: Pettengell R, Schmitz N, Gisselbrecht C, Smith G, Patton WN, Metzner B, Caballero D, Tilly H, Walewski JA, Bence-Bruckler I, To B, Geisler CH, Schots R, Kimby E, Taverna CJ, Kozák T, Dreger P, Uddin R, Ruiz de Elvira C, Goldstone AH. Rituximab purging and/or maintenance in patients undergoing autologous transplantation for relapsed follicular lymphoma: a prospective randomized trial from the lymphoma working party of the European group for blood and marrow transplantation. J Clin Oncol. 2013 May 1;31(13):1624-30. Epub 2013 Apr 1. link to original article EuroPMC NCT00005589
Category:Follicular lymphoma regimens
Category:Disease-specific pages
Category:Indolent lymphomas
Category:B-cell lymphomas
Category:Null regimens