Frontline Therapy with the Ribvd Regimen Elicits High Clinical and Molecular Response Rates and Long PFS in Elderly Patients Mantle Cell Lymphoma (MCL); Final Results of a Prospective Phase II Trial By the Lysa Group
Authors: Gressin Remy , Callanan Mary , Daguindau Nicolas , Tempescul Adrian , Carras Sylvain , Moles Marie Pierre , Cartron Guillaume , Houot Roch , Dartigeas Caroline , Pignon Jean Michel , Corm Selim , Banos Anne , Mounier Christiane , Dupuis Jehan , Macro Margareth , Fleury Joel , Jardin Fabrice , Karlin Lionel , Feugier Pierre , Fornecker Luc Matthieu , Chabrot Cecile , Dorvaux Veronique , Bouabdallah Krimo , Amorin Sandy , Garidi Reda , Voillat Laurent , Joly Bertrand , Le Dû Katell , Morineau Nadine , Zerazhi Hacene , Fontan Jean , Arkam Yazid , Alexis Magda , Delwail Vincent , Vilque Jean Pierre , Ysebaert Loic , Le Gouill Steven , Damaj Ghandi 
Published: October 2019

Abstract

Background:
Eight RCHOP/21 cycles followed by Rituximab maintenance is considered the standard of care for first line therapy in elderly MCL patients in Europe (1). However,complete clinical (CR) and molecular responses (MR) to therapy remain suboptimal(CR rate 30-35%, MR after 8 cycles 67 %). Regimen combining Rituximab and Bendamustine and more recently proteasome inhibitor Bortezomib (Velcade®) with CHOP regimen (VcR-CAP) demonstrated superior CR rates and PFS compared to R-CHOP. We have investigated the RiBVD regimen (Rituximab, Bendamustine,Velcade® and Dexamethasone) in a prospective phase II trial by the LYSA group.
Aims of the study:
The primary objective was to improve the median PFS by 6 months over the current 18 months PFS obtained with RCHOP when given without maintenance (ref Lenz, JCO 2005). The secondary objectives were to investigate the prognostic impact of molecular and FDG-PET responses on survival..
Methods and Material:
All patients aged 65 or older with a diagnosis of MCL were treated by the RiBVD regimen if they fulfilled the following inclusion criteria: AAstage II-IV, PS < 3, no other neoplasm, no active HIV or HBV or HCV infections, no renal (creatinin clearance > 20ml/mn) or cardiac dysfunction, no diabetes. The RiBVD regimen was administered every 4 weeks with Rituximab 375 mg/m² IV on day(D)1, Bendamustine 90 mg/m² IV on D1, 2, Dexamethasone 40 mg IV on D2 and Bortezomib (Velcade®) 1.3 mg/m² subcutaneously on D1, 4, 8 and 11. Primary prophylaxis with valacyclovir was mandatory for Herpes virus reactivation, but there was no recommendation for bacterial prevention. Patients were scheduled to receive a total of 6 cycles, if they achieved at least PR at 4 cycles. The IWG criteria, with and without FDG-PET, were used to define responses after 4 and 6 cycles. FDG-PET response was evaluated in each center with the five-point scale visual method of Deauville. Molecular responses (MR) were evaluated centrally by RQ-PCR using patient specific IGH VDJ targets as previously described (2).
Results:
Seventy six patients were recruited in one year (from November 2011 to December 2012), 74 were evaluable [2 patients were excluded because HBV positivity (n=1) or misdiagnosis (n=1)]. Fifty four samples were centrally reviewed for diagnosis, 45 were classic form of MCL, 9 pleomorphic variant and one patient had a DLBCL. Clinical characteristics of the 74 patients were: Median age 73 yo (64-83), sex ratio M/F = 2 (49/25), AAstage II/III-IV = 4/70, PS 0-1/2 = 63/11, MIPIscore low/intermediate/high= 3/19/50 (2 undetermined). The median follow-up is 21 months. Thirteen patients died because of lymphoma progression (n=7), cardiac arrest (n=2) or in one case each,pneumonia, Progressive Multifocal LeukoEncephalopathy, pancreatic carcinoma or of unknown causes. After 4 cycles the ORR was 86% (n=64) and CR/CRu 57% (n=42). After 6 cycles, the CR/CRu raised to 74% (n=55) the PR rate was 9% (n=7), 2 patients had a stable disease, 4 progressed and 5 had died during the treatment. The complete MR rate after 6 months on blood samples or bone marrow was respectively 83% (43/50) and 74 % (32/43). At 24 months, the PFS was 69% and the OS 80%. The MIPI score (high vs low/int) and the blood MR after 6 cycles were the only two statistically prognostic factors for PFS and OS. Toxicities were essentially hematologic with grade 3 or 4 neutropenia and thrombocytopenia in 51% and 36% of the cases, respectively. The main grade 3 or 4 extra-hematologic toxicities were fatigue (19%), neuropathy (14%), cardiac (7%) or febrile neutropenia (5%).
Conclusion:
The RiBVD regimen can be safely administered as first line therapy to elderly patients with MCL. Toxicities are mild and manageable. With 74% of CR/CRu, a 2 year PFS of 69% and 86% of patients achieving an MRD negative status in the blood after 6 cycles, without maintenance therapy, the RiBVD regimen is identified as a highly effective, well tolerated, first line treatment for elderly MCL patients.
Reference : 1 - Kluin Nelemans HC et al, NEJM 2012, 2 - Gimenez E et al, BJH 2012

Disclosures
Gressin: mundipharma: Consultancy. Off Label Use: Bendamustine and Bortezomib did not have authorization to their use in first line for MCL in France. Karlin:Janssen: Honoraria; celgene: Consultancy, Honoraria; Sandoz: Consultancy. Le Gouill:Mundipharma: Honoraria; Roche: Honoraria; Janssen: Consultancy.