Critical appraisal of rituximab in the maintenance treatment of advanced follicular lymphoma

Figures & data

Table 1 Results from randomized Phase III trials of induction chemotherapy plus rituximab in the first-line treatment of follicular lymphoma

Study	n	Regimen	RR (%)	CR (%)	TTF/PFS/EFS	OS
Hiddemann et al^Citation41	428	CHOP R-CHOP	90 96a	17 20	3-y TTF 50% 3-y TTF 75%a	3-y 86% 3-y 95%a
Herold et al^Citation42	201	MCP + I R-MCP + I	75 92a	25 50a	4-y PFS 40% 4-y PFS 71%a	4-y 74% 4-y 87%a
Marcus et al^Citation43	321	CVP R-CVP	57 81a	10 41a	TTF 7 m TTF 27 ma	4-y 77% 4-y 83%a
Salles et al^Citation44	358	CHVP + I R-CHVP + I	85 94a	34 63a	5-y EFS 37% 5-y EFS 53%a	5-y 79% 5-y 84%a
Federico et al^Citation45	534	R-CVP R-CHOP R-FM	88 93 91	67 73 72	3-y TTF 46% 3-y TTF 62%a 3-y TTF 59%a	3-y 95% for the whole series
Rummel et al^Citation46	549	R-CHOP B-R	91 93	30 40a	PFS 31.2 m PFS 69.5 ma	4-y 82% 4-y 84%

Note:

a Indicates statistically significant differences.

Abbreviations: B-R, bendamustine and rituximab; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; CHVP, cyclophosphamide, doxorubicin, etoposide, and prednisone; CR, complete response; CVP, cyclophosphamide, vincristine, and prednisone; EFS, event-free survival; I, interferon; m, months; FM, fludarabine and mitoxantrone; MCP, mitoxantrone, chlorambucil, and prednisone; n, number of patients; OS, overall survival; PFS, progression-free survival; R, rituximab; RR, response rate; TTF, time to treatment failure; y, years.

Table 2 Randomized Phase III trials comparing maintenance rituximab versus observation after induction therapy in follicular lymphoma

Study	Disease setting	n	Induction regimen	MR schedule	MR duration	EFS/PFS MR versus OB	OS MR versus OB
Ghielmini et al^Citation54	Untreated/relapsed FL	202	R wk ×4	Once every 2 m	8 m	9.5-y EFS	9.5-y
Martinelli et al^Citation15						24 versus 13 ma	68% versus 54%
Hochster et al^Citation55	Untreated FL	282	CVP ×6–8	Once wk ×4every 6 m	2 y	3-y PFS 64% versus 33%a	3-y 91% versus 86%
Salles et al^Citation56,Citation57	Untreated FL	1,217	R-CVP ×8 R-CHOP ×6 R-FCM ×6	Once every 2 m	2 y	6-y PFS 59% versus 43%a	6-y 89% versus 87%
Vitolo et al^Citation58	Untreated FL	234	R-FND ×4 followed by R wk ×4	Once every 2 m	8 m	2-y PFS 81% versus 69%	3-y whole series 89%
Forstpointner et al^Citation59,Citation62	Relapsed FL/MCL	319b	R-FCM ×4 FCM ×4	Once wk ×4 at 3 and 9 m	9 m	2-y PFSc nr versus 26 ma	3-y 77% versus 57%
van Oers et al^Citation60,Citation61	Relapsed FL	466	R-CHOP ×6 CHOP ×6	Once every 3 m	2 y	3.7 y versus 1.3 ya	5-y 74% versus 64%

Notes:

a Indicates statistically significant differences;

b 113 FL randomized to MR versus OB;

c data for FL patients only.

Abbreviations: CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; CVP, cyclophosphamide, vincristine, and prednisone; EFS, event-free survival; FCM, fludarabine, cyclophosphamide, and mitoxantrone; FL, follicular lymphoma; FND, fludarabine, mitoxantrone, and dexamethasone; m, months; MCL, mantle cell lymphoma; MR, maintenance rituximab; n, number of patients; nr, not reached; OB, observation; OS, overall survival; PFS, progression-free survival; R, rituximab; wk, weekly; y, years.

HiddemannWKnebaMDreylingMFrontline 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 GroupBlood2005106123725373216123223

 PubMed Web of Science ®Google Scholar

HeroldMHaasASrockSRituximab 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 StudyJ Clin Oncol200725151986199217420513

 PubMed Web of Science ®Google Scholar

MarcusRImrieKSolal-CelignyPPhase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisone alone in patients with previously untreated advanced follicular lymphomaJ Clin Oncol200826284579458618662969

 PubMed Web of Science ®Google Scholar

SallesGMounierNDe GuibertSRituximab combined with chemotherapy and interferon in follicular lymphoma patients: results of the GELA-GOELAMS FL2000 studyBlood2008112134824483118799723

 PubMed Web of Science ®Google Scholar

FedericoMLuminariSDondiAR-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 LinfomiJ Clin Oncol201331121506151323530110

 PubMed Web of Science ®Google Scholar

RummelMJNiederleNMaschmeyerGBendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, Phase 3 non-inferiority trialLancet201338198731203121023433739

 PubMed Web of Science ®Google Scholar

GhielminiMSchmitzSFCogliattiSBProlonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly ×4 scheduleBlood2004103124416442314976046

 PubMed Web of Science ®Google Scholar

MartinelliGSchmitzSFUtigerULong-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98J Clin Oncol201028294480448420697092

 PubMed Web of Science ®Google Scholar

HochsterHWellerEGascoyneRDMaintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized Phase III ECOG1496 studyJ Clin Oncol200927101607161419255334

 PubMed Web of Science ®Google Scholar

SallesGSeymourJFOffnerFRituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a Phase 3, randomised controlled trialLancet20113779759425121176949

 PubMed Web of Science ®Google Scholar

SallesGASeymourJFFeugierPUpdated 6 year follow-up of the PRIMA study confirms the benefit of 2-year rituximab maintenance in follicular lymphoma patients responding to frontline immunochemotherapyBlood201312221 abstr 509

 Web of Science ®Google Scholar

VitoloULadettoMBoccominiCRituximab 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 LinfomiJ Clin Oncol201331273351335923960180

 PubMed Web of Science ®Google Scholar

ForstpointnerRDreylingMReppRThe 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 GroupBlood2004104103064307115284112

 PubMed Web of Science ®Google Scholar

ForstpointnerRUnterhaltMDreylingMMaintenance 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)Blood2006108134003400816946304

 PubMed Web of Science ®Google Scholar

van OersMHKlasaRMarcusRERituximab 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 trialBlood2006108103295330116873669

 PubMed Web of Science ®Google Scholar

van OersMHVan GlabbekeMGiurgeaLRituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin’s lymphoma: long-term outcome of the EORTC 20981 phase III randomized intergroup studyJ Clin Oncol201028172853285820439641

 PubMed Web of Science ®Google Scholar