Epigenetic Priming with Azacitidine Prior to Allogeneic Hematopoietic Stem Cell Transplantation for Myeloid Malignancies: A Phase II Study.

Relapse remains the leading cause of treatment failure following allogeneic hematopoietic stem cell transplantation (alloHCT) for high-risk myeloid malignancies. Epigenetic dysregulation contributes to leukemogenesis and therapeutic resistance. To investigate whether pre-transplant epigenetic priming with azacitidine enhances chemosensitivity and improves alloHCT outcomes. We conducted an open-label, prospective phase II study evaluating azacitidine incorporated into reduced-intensity conditioning in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing alloHCT from matched related or unrelated donors. The primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints included relapse incidence, non-relapse mortality (NRM), and pharmacodynamic evaluation of DNA methylation changes in bone marrow CD34+ cells. Thirty-nine patients were enrolled. Most patients had AML (85%), 62% with adverse-risk AML or high/very high-risk MDS, and 23% had TP53 mutations. Neutrophil and platelet engraftment occurred in 97% of patients at median of 13 and 16 days, respectively. One-year OS and PFS were 64% and 54%, respectively, with NRM of 15% and relapse incidence of 31%. Pharmacodynamic analyses demonstrated azacitidine-induced DNA hypomethylation in bone marrow CD34+ cells, which correlated with improved survival. Higher baseline methylation levels were also associated with superior survival. Azacitidine priming prior to alloHCT is feasible and demonstrates encouraging survival outcomes in high-risk myeloid malignancies. Epigenetic priming induces measurable biologic reduction of DNA methylation that is plausibly linked to improved relapse-free survival. These findings support further evaluation in randomized studies and suggest DNA methylation may serve as a predictive biomarker of response.