Prognostic value of measurable residual disease in high-risk MDS after intensive chemotherapy in HOVON-SAKK studies

Myelodysplastic syndromes (MDS) are heterogenous disorders in which response assessment remains challenging. In acute myeloid leukemia (AML), measurable residual disease (MRD) by multiparametric flow cytometry (MFC) is prognostic and guides decision-making after two cycles of intensive chemotherapy, but its role in high-risk MDS (hrMDS) is unknown. We aimed to determine the prognostic impact of MFC-MRD (0.1% cutoff) for overall survival (OS) and the cumulative incidence of relapse (CIR) in intensively treated hrMDS. After stringent selection from 3269 patients enrolled in prior HOVON-SAKK MDS/AML trials, we identified 91 ICC 2022-defined hrMDS patients with available MFC-MRD. MFC-MRD positivity was detected in 24% and associated with inferior survival (5-year OS: 22.7% vs. 43.7%; P = 0.010) and higher relapse risk (5-year CIR: 72.7% vs. 47.2%; P = 0.014). In multivariable analyses stratified by trial and adjusted for, among others, the presence of a biallelic TP53 mutation, MFC-MRD positivity remained associated with poorer OS (hazard ratio (HR) 2.12 [95% CI 1.15-3.90]; P = 0.017) and increased CIR (subdistribution HR 2.15 [95% CI 1.11-4.14]; P = 0.022). To account for the potential confounding effect of allogeneic hematopoietic stem cell transplantation, additional sensitivity analyses were performed and confirmed that MRD positivity remained significantly associated with inferior survival outcomes. Lastly, an exploratory cross-disease comparison showed that MRD-negative (MRDneg) hrMDS patients had similar survival outcomes to MRD-positive (MRDpos) AML patients. These findings demonstrate the prognostic value of MFC-MRD in intensively treated hrMDS and provide rationale for prospective trials of MRD-informed transplant and post-remission strategies.