Post-transplant monitoring of NGS-based measurable residual disease and donor chimerism as a prognostic tool in older patients with AML/MDS

PURPOSE: To evaluate the prognostic value of integrated post-transplant monitoring of NGS-based measurable residual disease (MRD) and donor chimerism in older patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), undergoing reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (allo-SCT). MATERIALS AND METHODS: This retrospective study analyzed the clinical outcomes of 113 patients with AML or MDS, aged ≥ 60 years or ≥ 55 years if deemed unfit for standard-intensity conditioning, who underwent RIC allo-SCT. NGS-based MRD testing and donor chimerism were assessed at 3 months post-transplant. RESULTS: A total of 113 patients participated in the study (median age 63 years; 69.9% with AML); among the 105 patients evaluable at 3 months post-transplantation, MRD positivity occurred in 28 patients (26.7%) and predicted inferior overall survival (hazard ratio [HR] 6.373, 95% confidence interval [CI] 3.005-13.517; P < 0.001), while complete donor chimerism (CDC), achieved in 82 patients (78.1%), predicted improved survival (HR 0.356, 95% CI 0.195-0.916; P = 0.028). MRD positivity remained an independent predictor of survival on multivariate analysis (HR 3.315, 95% CI 1.423-7.230, P = 0.005), while CDC showed a trend toward improved survival that did not reach statistical significance (HR 0.494, 95% CI 0.306-1.009, P = 0.051). Two-year overall survival differed markedly across the four MRD/CDC subgroups, ranging from 85.6% [MRD(-)/CDC( +)] to 13.6% [MRD( +)/CDC(-)] (P < 0.001), with the MRD( +)/CDC(-) group showing the highest 2-year relapse incidence (69.7%). CONCLUSION: The combination of NGS-based MRD and chimerism monitoring is a critical prognostic strategy for older patients with AML/MDS undergoing RIC allo-SCT. Early identification of MRD positivity or mixed chimerism allows timely, risk-adapted interventions, including donor lymphocyte infusion, hypomethylating agents, and targeted therapies to reduce relapse and improve survival.