Epigenetic Priming with Azacitidine Prior to Allogeneic Hematopoietic Stem Cell Transplantation for Myeloid Malignancies.
Abstract
Background
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.
Objective
Objective
: To investigate whether pre-transplant epigenetic priming with azacitidine enhances chemosensitivity and improves alloHCT outcomes. STUDY
Design
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.
Results
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.
Conclusions
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.