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Induction and Maintenance Therapy in Elderly Patients with Mantle Cell Lymphoma: Double-Randomized MCL R2 Elderly Clinical Trial By the European Mantle Cell Lymphoma Network

2023; Elsevier BV; Volume: 142; Issue: Supplement 1 Linguagem: Inglês

10.1182/blood-2023-188788

1528-0020

Vincent Ribrag, Violaine Safar, Hanneke C. Kluin‐Nelemans, Lucie Obéric, Pierre Feugier, Olivier Casasnovas, Catherine Thiéblemont, Nicolas Daguindau, Gandhi Damaj, Eva Hoster, Ludwig Fischer von Weikersthal, Mathias Hänel, Marc André, María Gomes da Silva, Ana Marín‐Niebla, Michał Taszner, Jan Walewski, Rinske Boersma, Marie‐Hélène Delfau‐Larue, Steven Le Gouill, Martin Dreyling,

Lymphoma Diagnosis and Treatment

Background: Mantle cell lymphoma (MCL) formally remains an incurable disease. Recent trials in younger patients have demonstrated the benefit of a cytarabin-containing induction (Hermine, JCO 2022) and a rituximab (Le Gouill, NEJM 2017) as well as a lenalidomide maintenance (Ladetto, Lancet Haematol 2021). The MCL-R2 elderly trial investigated whether an induction with intermediate dose of cytarabine improves long term outcome over R-CHOP alone in elderly patients (>60 yrs). In addition, responders to induction therapy were randomized between a 2 year maintenance with rituximab-lenalidomide (R2) compared to rituximab alone. Here, we present the results of the 2 randomizations. Methods: Patients >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 rituximab maintenance every 2 months or R2 (lenalidomide 15 mg d2-22 every 4 weeks plus rituximab). Second randomization was stratified for induction regimen, study group, age, MCL international prognostic index (MIPI) and response (CR/CRu vs PR). Both maintenance regimens were continued for 24 months. The primary endpoint was EFS for the maintenance and overall survival for Induction therapy. Results: Out of 624 patients from 7 countries, 620 were randomized for induction, 492 responded (78 % ORR, CR/CRu 41%) and 495 were randomized for maintenance. Median age was 71 yrs, 69% male, 85% stage IV, 47% intermediate and 46% high risk MIPI. Response rate at the end of induction was similar in the 2 groups (OR 88% and 86% in the R-CHOP and R-CHOP/RHAD arm, respectively; CR 33% in both arms). No major safety difference were observed between the 2 induction arms. So far, PFS and OS were not different between the two induction regimen (70.6% vs. 66.8%; p=0.28 and 83% vs. 83% ; p=0.92 respectively: Figure 1A). After a median follow-up of 4.2 years from maintenance randomization, patients in the R2 maintenance arm had a significantly improved PFS in comparison to R alone. The 4-year PFS was 60.9% in the R2 arm vs. 42.9 % in the R arm (p= 0.0002, figure 1B). Adverse events (AEs) were more pronounced in the R2 maintenance arm. Recurrent (> 5%) AEs grade >3 were: neutropenia (50.8% vs 19.2%), respiratory tract infection (6.3% vs. 0.8%), and skin cancer (5.9% vs 3.2%). In 46% of patients in the R2 arm, the dose of lenalidomide had to be reduced at least once. Overall survival (OS) was not different between the two maintenance arms, (R2: 87.6% and R: 85.1% at 2 years). The majority of relapsed/refractory patients were treated with a BTK inhibitor alone or in combination (67.5%; 63% after R-CHOP and 71% after RHOP/RHAD). Conclusions: While no efficacy or toxicity differences were observed between the two induction regimens (8x R-CHOP vs 6x R-CHOP/HAD), the combined R2 maintenance significantly prolonged PFS compared to rituximab alone. However, no difference in OS was observed, and toxicity was increased in the R2 arm. Figure 1: OS(A) stratified by the CHOP and R-CHOP/RHAD arms and PFS (B) stratified by maintenance with rituximab (R) or rituximab-lenalidomide (R2) stratified by the four groups according to induction and maintenance arms.