Rituximab-Lenalidomide(R2) Maintenance Is Superior to Rituximab Maintenance after First Line Immunochemotherapy in Mantle Cell Lymphoma: Results of the MCL R2 Elderly Clinical Trial
Authors: Ribrag Vincent , Safar Violaine , Kluin-Nelemans Hanneke , Oberic Lucie , Feugier Pierre , Casasnovas Olivier , Thieblemont Catherine , Daguindau Nicolas , Damaj Gandhi Laurent , Klapper Wolfram , Hoster Eva , Fischer von Weikersthal Ludwig , Haenel Mathias , André Marc , Gomes da Silva Maria , Carcinero Fernando , Marin-Niebla Ana , Taszner Michal , Walewski Jan , Boersma Rinske , Houtenbos Ilse , Delfau-Larue Marie-Helene , Le Gouill Steven , Dreyling Martin H. 
Published: November 2021

Abstract
Background: Mantle cell lymphoma (MCL) formally remains an incurable disease. After immunochemotherapy induction, rituximab (R) maintenance can prolong remission duration, but most patients are highly exposed to relapse. The chemotherapy-free combination of lenalidomide and rituximab combo (R2) has demonstrated its activity in MCL, but has never been used as maintenance after immunochemotherapy and never been compared to RM. In the MCL R2 Elderly clinical trial (EUDRACT: 2012-002542-20), we studied different induction regimens and randomized R and R2 maintenance in responders to first-line induction. Here the results of the maintenance phase are reported.
Methods: Seven countries participated in this open-label, double randomized trial of the European MCL Network. Previously untreated patients(pts) &gt;60 yrs not eligible for high dose therapy with stage II-IV MCL were included. Initially, patients were randomized between 8 cycles of 3-weekly R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) or 6 cycles of alternating 3-weekly R-CHOP and 4-weekly R-HAD (rituximab, cytarabine, dexamethasone). Subsequently, patients in complete or partial remission (CR, CRunconfirmed or PR) underwent a second randomization between maintenance with rituximab every 2 months or R2 (lenalidomide 15 mg or 10 mg during 3 weeks every 4 weeks plus rituximab). Second randomization was stratified for induction regimen, country group, MCL international prognostic index (MIPI) and response (CR/CRu vs PR). Both maintenance regimens were continued for 24 months. Primary outcome was PFS, determined as time from second randomization until progression or death from any cause, censored at the last tumor assessment date. The primary evaluation was done strictly according to ITT. This superiority trial was designed to detect a hazard ratio of 0.64 with a power of 80% (158 events in 443 randomized patients) in a two-sided log-rank test with significance level 5% and no interim analyses. In the run-in period of 6 months, patients responding to R-CHOP induction given outside of the trial could be randomized directly for maintenance treatment.
Results: Randomization was closed in Nov 2019. Out of 624 pts included in the study, 620 were randomized for induction and 514 responded to induction (87 % ORR, CR/CRu 41%) and 495 were randomized for maintenance. Median age was 71 yrs, 70% male, 89% stage IV, 47% intermediate and 46% high risk MIPI. After a median follow-up of 2.1 years from maintenance randomization and with 182 observed PFS events, pts in the R2 maintenance arm had a significantly prolonged PFS in comparison to R alone (p=0.0003). The 2-year PFS was 76.6% (95%CI=[70.1 ; 81.9]) in the R2M arm vs. 60.8% in the R arm (95%CI=[53.7 ; 67.2]). So far, Overall survival (OS) was not different between both arms, with 2-year OS of 87.3% in the R2M arm (95%CI=[81.6 ; 91.4]) and 85.8% (95%CI=[79.8 ; 90.0]) in the R arm. Adverse events (AEs) were more pronounced with R2M. Recurrent (&gt; 5% in one arm) AEs of grade &gt; 3 were: neutropenia (50.0% vs 18.8%), respiratory tract infection (5.5% vs. 0.8%), and skin cancer (5.5% vs 2.0%). In 46% percent of the patients in the R2M arm, the dose of lenalidomide had to be reduced at least once.
Conclusions: R2M in patients responding to induction immunochemotherapy is superior to RM for PFS but not OS. Safety data showed more toxicity in the R2M arm.
Figure 1: PFS (A) and OS (B) by maintenance with rituximab (R) or rituximab-lenalidomide (R2).
Figure 1 Figure 1.

Disclosures
Ribrag: PharmaMar: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding; Argen-X: Research Funding; Astex Pharmaceuticals: Research Funding; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; MSD Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Epizyme: Honoraria, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Nanostring: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Safar: roche: Consultancy, Honoraria; novartis: Consultancy, Honoraria. Oberic: celgene: Consultancy, Honoraria; janssen: Consultancy, Honoraria; takeda: Consultancy, Honoraria; roche: Consultancy, Honoraria; gilead: Consultancy, Honoraria. Feugier: Gilead: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Honoraria; Astrazeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Casasnovas: Amgen: Consultancy; Janssen: Consultancy; BMS: Consultancy; Gilead/Kite: Consultancy, Research Funding; TAKEDA: Consultancy, Research Funding; ROCHE: Consultancy, Research Funding. Thieblemont: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses , Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Hospira: Research Funding; Bayer: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses . Damaj: takeda: Consultancy, Honoraria; roche: Consultancy, Honoraria. Klapper: Takeda: Consultancy, Research Funding; Regeneron: Consultancy, Research Funding; Amgen: Research Funding; Roche: Consultancy, Research Funding. Haenel: GSK: Consultancy; Jazz: Consultancy, Honoraria; Bayer Vital: Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy; Celgene: Consultancy, Honoraria. André: Bristol-Myers-Squibb: Consultancy, Other: Travel/Accommodations/Expenses; Karyopharm: Consultancy; Gilead: Consultancy, Other: Travel/Accommodations/Expenses; Incyte: Consultancy; Roche: Other: Travel/accomodation/expenses, Research Funding; Johnson & Johnson: Research Funding; Celgene: Other: Travel/accomodation/expenses; AbbVie: Other: Travel/accomodation/expenses; Takeda: Consultancy, Research Funding. Gomes da Silva: roche: Consultancy, Honoraria; gilead: Consultancy, Honoraria, Research Funding; janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; novartis: Consultancy, Honoraria; az: Research Funding. Marin-Niebla: Janssen: Consultancy, Honoraria, Other: travel; Roche: Honoraria; Takeda: Consultancy, Honoraria, Other: travel; Kiowa Kirin: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Taszner: Roche, Takeda: Consultancy, Other: Travel. Walewski: GSK: Research Funding; roche: Honoraria, Research Funding, Speakers Bureau; novartis: Honoraria, Research Funding; takeda: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; gilead: Consultancy, Honoraria; amgen: Consultancy, Honoraria; seervier: Consultancy, Honoraria. Dreyling: Celgene: Consultancy, Research Funding, Speakers Bureau; Amgen: Speakers Bureau; Genmab: Consultancy; Gilead/Kite: Consultancy, Research Funding, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Abbvie: Research Funding; Astra Zeneca: Consultancy, Speakers Bureau; BeiGene: Consultancy; Bayer HealthCare Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau.