FIRST LINE TREATMENT BY THE RIBVD REGIMEN ELICITS HIGH CLINICAL AND MOLECULAR RESPONSE RATES AND PROLONGED SURVIVAL IN ELDERLY MCL PATIENTS; FINAL RESULTS OF a LYSA GROUP TRIAL

Abstract

Introduction: Eight R-CHOP21 cycles followed by rituximab maintenance is considered as the standard first-line treatment for elderly mantle cell lymphoma (MCL) patients. Complete response (CR) and undetectable minimal residual disease (uMRD) rates remain sub-optimal with tR-CHOP regimen (CR rate 30-35%, MR after 8 cycles 67%) and this translates to shorter response duration. Recently VR-CAP, integrating bortezomib to RCHOP has proved superiority to both RCHOP and the R-BAC regimen (rituximab bendamustine cytarabine) has given also promising results. In this setting, we have explored the association rituximab-bendamustine-bortezomib and dexamethasone in the RiBVD regimen. Methods: In this prospective phase II study, all patients >65 years old with newly-diagnosed MCL were treated by the RiBVD regimen (inclusion criteria: AA stage II-IV, PS < 3, no active HIV, HBV or HCV infections, no renal or cardiac dysfunction, no diabetes). RiBVD was administered every 4 weeks: rituximab, 375 mg/m2 IV on day(D)1; bendamustine at 90 mg/m2 IV on D1 and D2; dexamethasone 40 mg IV on D2 and bortezomib1.3 mg/m2 subcutaneously on D1, 4, 8 and 11. Patients received a total of 6 cycles, if they responded (IWG criteria) after 4 cycles. No maintenance was delivered. MRD was centrally evaluated by RQ-PCR using patient specific IGH VDJ targets, and the FDG-PET response was evaluated visually according to Deauville criteria.The primary objective was to prolong PFS by 6 months (m) compared to the 18 m PFS reported for R-CHOP21. In order to define superiority of the RiBVD, PFS > 65% (H1) was required at 18 m. Treatment failure was considered if PFS at 18 m was 50%. With alpha and beta risks of 5% and 20%, respectively, 69 patients needed to be enrolled. Secondary objectives were to evaluate toxicity, known prognostic indices, response FDG-PET imaging and MRD. Results: Seventy four patients were enrolled; 80% (n = 58) had high MIPI score. ORR and CR were 84% (n = 62/74) and 75% (n = 56/74), respectively. After 6 cycles, 78% (n = 46/59) were FDG-PET negative; 87% (47/54) and 76% (35/46) had uMRD in blood (PB) and bone marrow (BM), respectively. With a median follow-up of 52 m the primary objective was reached (24 m PFS = 70%). Four years OS was 86.6% for uMRD patients at the end of treatment, compared to 28.6%, detectable MRD patients; p < 0.0001). Neither the MIPI score nor FDG-PET responses were predictive of OS. Toxicities were mainly hematologic with grade 3/4 neutropenia in 51% and thrombopenia in 36%. The principal grade 3/4 extra-hematologic toxicities were fatigue (19%), neuropathy (14%), cardiac (7%) or febrile neutropenia (5%). Conclusion: The RiBVD regimen is active and well tolerated in MCL patients who are unable or unwilling to receive dose intensive therapy including high risk patients.