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
Year: 2024
Type: conference-abstract
Abstract: 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.
Source: Blood
Authors: Edouard Forcade, Raynier Devillier, Jean-François Hamel, Jean-Baptiste Méar, Claude-Éric Bulabois, Jean-Henri Bourhis, Sylvain Chantepie, Pascal Turlure, Patrice Chevallier, Patrice Ceballos, Bruno Lioure, Jacques-Olivier Bay, Jean Valere Malfuson, Stéphanie Nguyen-Quoc, Marianne Schwarz, Jérôme Cornillon, Michael Loschi, Mathieu Leclerc, Marie-Thérèse Rubio, Etienne Daguindau, Natacha Maillard, Amandine Charbonnier, Nathalie Contentin, Hélène Labussière-Wallet, Alban Villate, Ibrahim Yakoub-Agha, Arnaud Pigneux, Mathilde Hunault, Christian Recher, Hervé Dombret, Nicole Raus, Marie Robin, Jean-Yves Cahn, Gerard Socie, Anne Huynh, Régis Peffault De Latour
Institutions: Centre Hospitalier Universitaire de Bordeaux, Aix-Marseille Université, Institut Paoli-Calmettes, Centre Hospitalier Universitaire d'Angers, Centre Hospitalier Universitaire de Rennes, Centre Hospitalier Universitaire de Grenoble, Institut Gustave Roussy, Centre Hospitalier Universitaire de Caen Normandie, Centre Hospitalier Universitaire de Limoges, Centre Hospitalier Universitaire de Nantes, Hôpital Saint Eloi, Hôpitaux Universitaires de Strasbourg, Assistance Publique – Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Centre Hospitalier Universitaire de Saint-Étienne, Centre Hospitalier Universitaire de Nice, Hôpital l'Archet, Centre Hospitalier Universitaire Henri-Mondor, Hôpitaux Universitaires Henri-Mondor, Centre Hospitalier Régional et Universitaire de Nancy, Centre Hospitalier Universitaire de Besançon, Centre Hospitalier Universitaire de Poitiers, Centre Hospitalier Universitaire Amiens-Picardie, Centre Henri Becquerel, Hospices Civils de Lyon, Hôpital Lyon Sud, Centre Hospitalier Universitaire de Tours, Centre Hospitalier Universitaire de Lille, Université d'Angers, Centre Hospitalier Universitaire de Toulouse, Institut universitaire du cancer de Toulouse Oncopole, Hôpital Saint-Louis
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4405039962