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379 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

Program: Oral and Poster Abstracts
Type: Oral
Session: 623. Mantle Cell, Follicular, and Other B-Cell Lymphomas: Clinical and Epidemiological: Front-line Induction Therapy and Novel Agents After Relapse
Hematology Disease Topics & Pathways:
Clinical Trials, Clinical Research
Sunday, December 12, 2021: 9:30 AM

Vincent Ribrag, MD1,2, Violaine Safar, MD3*, Hanneke Kluin-Nelemans, MD4*, Lucie Oberic5*, Pierre Feugier, MD, PhD6*, Olivier Casasnovas, MD7,8*, Catherine Thieblemont, MD, PhD9,10, Nicolas Daguindau, MD11*, Gandhi Laurent Damaj, MD, PhD12, Wolfram Klapper13*, Eva Hoster, PhD14*, Ludwig Fischer von Weikersthal15, Mathias Haenel16*, Marc André, MD17*, Maria Gomes da Silva, MD18*, Fernando Carcinero19*, Ana Marin-Niebla, MD, PhD20*, Michal Taszner, MD21*, Jan Walewski, MD22, Rinske Boersma, MD23*, Ilse Houtenbos, MD, PhD24*, Marie-Helene Delfau-Larue25*, Steven Le Gouill26 and Martin H. Dreyling, MD, PhD27

1DITEP-Hematology, Inserm U1170, Institut Gustave Roussy, Villejuif, France
2Université Paris-Saclay, Gustave Roussy, INSERM U1170, Villejuif, France
3Department of Hematology, Lyon-Sud Hospital, Pierre-Benite, France
4Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
5hematologie, IUCT, Toulouse, FRA
6Département d'Hématologie, CHRU Nancy, Hôpitaux de Brabois, Vandoeuvre-lès-Nancy, France
7Hématologie Clinique, CHU Dijon Bourgogne, Dijon, France
8Hematology Department, University Hospital F. Mitterrand and Inserm UMR 1231, Dijon, France
9Diderot University, University de Paris, Paris, France
10Assistance Publique & Hôpitaux de Paris (APHP), Hôpital Saint-Louis, Hémato-oncologie, Université de Paris, Paris, France
11Hematology Department, CH Annecy Genevois, Annecy, France
12CHU de Caen Normandie, Caen, France
13Department of Pathology, Hematopathology Section, University Hospital Schleswig-Holstein, Christian-Albrecht-University of Kiel, Kiel, Germany
14Department of Medicine III, University Hospital, LMU Munich, Munich, Germany
15Gesundheitszentrum St. Marien, Amberg, Bavaria, DEU
16Klinik für Innere Medizin III, KLINIKUM CHEMNITZ GGMBH, Chemnitz, Germany
17CHU de Mont Godinne, Yvoir, Belgium
18Hematology Unit, Portuguese Institue of Oncology, Lisboa, Portugal
19HOSPITAL SAN PEDRO DE ALCANTARA, CACERES, Spain
20Department of Hematology, University Hospital Vall d’Hebron, Experimental Hematology, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital Campus, Passeig Vall d'Hebron 119-129, 08035, Barcelona, Spain
21Medical University of Gdansk, Gdansk, Poland
22Maria Sklodowska-Curie Institute and Oncology Centre, Warsaw, Poland
23Amphia Hospital, Breda, Netherlands
24SPAARNE ZIEKENHUIS, Hoofddorp, NLD
25Hematology Biology Department, Hopital Henri Mondor, Creteil, France
26Service d’hématologie clinique du CHU de Nantes, INSERM CRCINA Nantes-Angers, NeXT Université de Nantes, Nantes, France
27Department of Internal Medicine III, LMU Hospital, Munich, Germany

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) >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 (> 5% in one arm) AEs of grade > 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).

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: Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Bayer: Honoraria; Hospira: Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Amgen: 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; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses , Research Funding; 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 . Damaj: takeda: Consultancy, Honoraria; roche: Consultancy, Honoraria. Klapper: Takeda: Consultancy, Research Funding; Amgen: Research Funding; Roche: Consultancy, Research Funding; Regeneron: 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.

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