OBINUTUZUMAB PLUS DHAP FOLLOWED BY AUTOLOGOUS STEM CELL TRANSPLANTATION (ASCT) PLUS OBINUTUZUMAB MAINTENANCE PROVIDES A HIGH MRD RESPONSE RATE IN UNTREATED MCL PATIENTS. RESULTS OF LYMA‐101 TRIAL, A LYSA GROUP STUDY (2019)

Introduction: Achievement of prolonged minimal residual disease (MRD) negativity after both induction and ASCT is a strong independent prognostic marker in mantle cell lymphoma (MCL). A high-dose aracytine- (HA) and salt platinum-containing (P) chemotherapy regimen with Rituximab followed by autologous stem cell transplantation (ASCT) consolidation plus 3 years Rituximab maintenance is considered as a standard of care for untreated younger patients with MCL (Le Gouill et al. NEJM 2017). Obinutuzumab is a glycoengineered, type II, anti-CD20 monoclonal antibody designed to improve the antibody-dependent cell mediated cytotoxicity compared to Rituximab. in vitro experiments suggest that Obinutuzumab may provide better anti-MCL activity (Chiron et al., Blood 2016) than Rituximab but no in vivo data are available regarding Obinutuzumab in naive MCL patients. Methods: The LYMA-101 study is a prospective and open phase II trial testing the effect of Obitunuzumab in untreated MCL patients under 66 years of age and eligible for intensive therapy. Induction consisted of 4 cycles of Obinutuzumab-DHAP (O-DHAP) before consolidation with ASCT (BEAM conditioning plus Obinutuzumab) followed by Obinutuzumab maintenance for 3 years then Obinutuzumab on-demand for MRD positive patients. The LYMA-101 primary objective was the MRD negativity rate after 4 cycles of O-DHAP. MRD in the BM was assessed by IGH clonospecific or bcl1-JH PCR, and quantification with a sensitivity of at least 10-4was reach by dd-PCR following Euro-MRD lymphoma group recommendations. We hypothesized that O-DHAP would be considered as an effective induction chemotherapy regimen if MRD negativity was ≥ 70%. We calculated that a minimum of 83 patients should be included (α risk of 0.05 and β of 0.20 one-sided test). Results: We enrolled 86 patients between Nov 2016 and May 2018. One patient withdrew consent before starting treatment. Sixty-three patients (73.3%) were male and median age was 55.5 years (32-65). MIPI and MIPI-b risk scores were low in 47 (54.7%) and 9 (10.5%) cases, intermediate in 24 (27.9%) and 38 (44.2%) cases and high in 14 (16.3%) and 21 (24.4%) cases. Fifteen patients (17.4%) presented with a blastoid variant. At the time of analysis, median FU was 14 months (3.8-24.4). Twelve patients out of 85 were not evaluable for MRD, essentially due to purely nodal disease and no detectable MCL clone in PB or BM. Among the 73 MRD-informative patients, 62 reached MRD negativity in the BM (84.9%) while 6 were MRD positive after O-DHAP. The remaining 5 patients were not evaluated because 4 stopped treatment during induction due to AEs and one progressed then died. 72 patients underwent ASCT and 68 started Obinutuzumab maintenance. Twelve patients stopped treatment before ASCT (including disease progression in 2 cases and AE in 7 cases), 3 before maintenance (2 because of AE, one died during ASCT), and 9 during maintenance (including disease progression in one case, death in another, AE in 4 cases or other malignancies in 2 cases). In the whole population (n=85), 3 patients progressed, three died. At one year, PFS is 93.4% (IC95%, 84.7-97.2) and OS is 96% (IC95%, 88.1-98.7). Conclusion: The Lyma-101 trial successfully achieved its primary endpoint (84.9% of MRD BM negativity after induction) and demonstrates the high efficacy of O-DHAP as induction chemotherapy regimen before ASCT with an unprecedented high level of MRD negativity, which predict better PFS and OS. Longer FU is needed to evaluate patient outcome after O-DHAP/ASCT/Obinutuzumab on-demand maintenance. However, both PFS and OS are highly encouraging at one year. Keywords: mantle cell lymphoma (MCL); minimal residual disease (MRD); obinutuzumab. Disclosures: Le Gouill, S: Consultant Advisory Role: Roche Genentech; Honoraria: Roche Genentech; Research Funding: Roche Genentech.