GVHD prophylaxis after cord blood transplantation in patients with high-risk AML: a nationwide Japanese cohort study

Cord blood transplantation (CBT) is a curative option for patients with high-risk acute myeloid leukemia (AML), including therapy-related AML (t-AML). However, the optimal prophylaxis for graft-versus-host disease (GVHD) remains unclear. We conducted a nationwide, retrospective cohort study including 3222 adults with high-risk AML (t-AML and non-t-AML) who underwent their first CBT in Japan between 2010 and 2023. GVHD prophylaxis consisted of cyclosporine or tacrolimus combined with mycophenolate mofetil (CSP/TAC+MMF) or methotrexate (CSP/TAC+MTX). MMF regimens were associated with faster neutrophil engraftment than MTX regimens (P<0.001). However, CSP/TAC+MMF was associated with a significantly higher incidence of grades II-IV acute GVHD (4 P<0.001) and chronic GVHD (P<0.001) than CSP/TAC+MTX. Two-year transplant-related mortality and relapse rates were 26%-38% and 41%-46%, respectively. At 2 years post-transplant, overall survival rates were higher with MTX than with MMF (P<0.001). Disease-free survival rates were also higher with MTX than with MMF (P=0.003). Therefore, a modest survival advantage was observed for MTX. Multivariable analysis identified older age (≥55 years), male sex, Karnofsky performance status <80, a higher hematopoietic cell transplantation-comorbidity index, and non-remission at transplantation as adverse prognostic factors. Importantly, MMF was associated with an increased risk of human herpesvirus 6 encephalitis. CSP/TAC+MMF and CSP/TAC+MTX support successful CBT for high-risk AML. While MMF accelerates engraftment, this is offset by greater GVHD and viral complications. These real-world, nationwide data highlight the need to individualize GVHD prophylaxis on the basis of patient and transplant characteristics and provide essential benchmarks for future prospective, multicenter studies.