Cyclosporine Versus Cyclosporine Plus Mycophenolate Mofetil in Reduced Intensity Allogeneic Stem Cell Transplantation for Intermediate-Risk AML: A Multi-Center Randomized Study from the Acute Leukemia French Intergroup, on Behalf of the Filo, ALFA, and SFGM-TC Study Groups

Introduction. The French Backbone Intergroup (BIG-1) prospective trial (NCT02416388) evaluated several therapeutic interventions in 18-60yo patients with newly diagnosed AML. Patients were classified as intermediate (INTER)-risk on the basis of their cytogenetics and molecular profile at diagnosis and early response to therapy. Per protocol, INTER-risk AML patients were referred to allogeneic stem cell transplantation (alloSCT) in first CR after two post-induction chemotherapy cycles. AlloSCT numbers increased over the last two decades with the implementation of reduced Intensity conditioning (RIC) for older patients and/or patients with comorbidities (according to HCT-CI). Fludarabine (Flu)-Busulfan(Bu)-based regimen is the most widely used RIC platform, using ATG and cyclosporine A (CsA) GVHD prophylaxis following Slavin et al (Blood 1998) report. The Flu-TBI-based RIC regimen has been associated with mycophenolate mofetil (MMF) to CsA GVHD prophylaxis (Niederwieser et al, Blood 2003). However, the optimal GVHD prophylaxis in Flu-Bu-ATG RIC regimen remains a matter of debate and no formal comparison between CsA alone and CSA+MMF has ever been done so far. Herein we formally compared these regimens in patients with INTER-risk AML. Patients and Methods. The randomized R3-RIC study was nested in the BIG-1 trial and included CR1 INTER-risk AML patients ≥ 45yo or <45yo with HCT-CI > 2, having a matched sibling donor (MSD) or a 10/10 matched unrelated donor (MUD). Patients receiving an alloSCT using Flu-Bu-ATG RIC regimen were randomized (1:1) to receive either CsA alone or CsA+MMF GVHD prophylaxis, with a stratification based on donor type. Primary objective was day 100 (D100) grade II to IV acute GVHD (aGVHD2-4) with an expected reduction of 15% between both arms. Secondary objectives were aGVHD3-4, chronic GVHD (cGVHD), non-relapse mortality (NRM) and relapse incidence (RI) at 1y, and overall survival (OS). Results. In the whole BIG-1 cohort, 824 patients had INTER-risk AML, of whom 210 patients were randomized in the R3-RIC study from 06/2015 to 10/2022. Mean age was 53y (SD 6.1), 54% were male, 96% received PBSC, from a MSD (39.5%) or a MUD (59%). Female donor to male recipient (FD/MR) combination was observed in 17% of the patients. Median time from diagnosis to alloSCT was 153 days (IQR: 134-169). Age, sex, graft source, donor type, ABO D/R, CMV D/R, FD/MR, time between diagnosis and alloSCT did not significantly differ between the 2 arms. Median follow-up was 5.9 years. D100 cumulative incidence (CI) of aGVHD2-4 was 25.2% (95%CI 17.3-33.9) and 17.1% (95%CI 10.7-24.9) in the CsA and CsA+MMF arms, respectively (SHR=0.64, 95%CI 0.35-1.17, p=0.15). In multivariate analysis (MVA), MSD only significantly reduced D100 aGVHD 2-4 CI (SHR=0.32, 95%CI 0.15-0.68, p=0.003). D180 aGVHD3-4 CI was 5.8% and 3.8% for CsA and CsA+MMF, respectively (SHR=0.65, 95%CI 0.18-2.32, p=0.51). In MVA, sex mismatch FD/MR was the only variable affecting D180 aGVHD3-4 CI (SHR 13.3). 1y-cGVHD CI was 28.2% and 19% for CsA and CsA+MMF, respectively (SHR 0.63, 95%CI 0.35-1.1, p=0.109). In MVA, MSD was associated with a reduced risk of 1y-cGVHD (SHR 0.37). 2y-cGVHD was 34% and 21% for CsA and CsA+MMF, respectively (SHR=0.57, 95%CI 0.33-0.96, p=0.037). In MVA, CsA+MMF arm and MSD were significantly associated with a reduced 2y-cGVHD incidence (SHR=0.57 and 0.43, respectively). 1y-NRM was 5.6% and 3.8% for CsA and CsA+MMF, respectively (SHR=0.35, 95%CI 0.11-1.1, p=0.07). In MVA, neither GVHD prophylaxis arm nor donor type, age, sex, R/D CMV status were independently associated with 1y-NRM. 5y-NRM was 15.6% and 9.2% for CsA and CsA+MMF, respectively. 1y-RI was 19.4% and 25.8% for CsA and CsA+MMF respectively (SHR=1.42, 95%CI 0.8-2.5, p=0.22). MVA did not show any variable affecting 1y-RI. 5y-RI was 25.3% and 32% for CsA and CsA+MMF respectively. 1y-OS was 79.8% and 77.2%, and 6y-OS was 56.3% and 51.1% for CsA and CsA+MMF, respectively (HR=1.19, 95%CI 0.77-1.84, p=0.42). In MVA, R+CMV was associated with a reduced 6y-OS (HR=0.61, 95%CI 0.38-0.97, p=0.038). Conclusion. This study failed to significantly reduce aGVHD2-4 incidence with the addition of MMF to a CsA GVHD prophylaxis in CR1 INTER-risk AML patients receiving a Flu-Bu-ATG RIC regimen. 2y-cGVHD incidence was reduced in patients receiving the CsA+MMF while NRM, RI and OS did not significantly differ.