SOHO State of the Art Updates and Next Questions | Progress in Higher-Risk Myelodysplastic Syndromes

Myelodysplastic syndromes (MDS) are clonal myeloid malignancies characterized by ineffective hematopoiesis and cytopenias, and possible risk of transformation to acute myeloid leukemia (AML). Higher-risk MDS (HR-MDS) carries significant morbidity and mortality with limited therapeutic options and poor outcomes following treatment failure. The Molecular International Prognostic Scoring System (IPSS-M) refined HR-MDS prognostication by retaining key clinical and cytogenetic variables from the IPSS-R while incorporating somatic mutation data with the inclusion of 16 additional "main effect" prognostic genes and 15 "residual" genes that confer additional risk when mutated. This molecular integration has reclassified risk categories for MDS, approximately upstaging one-third of patients. Concurrently, updated World Health Organization (WHO) and International Consensus Classification (ICC) frameworks have refined the MDS-AML diagnostic gray zone, with the ICC recognizing 10% to 19% bone marrow blasts as "MDS/AML overlap syndrome," broadening eligibility for clinical trials. A unified WHO and ICC classification framework is anticipated, and emerging AI-based classification tools may further support diagnostic accuracy. Treatment remains centered on hypomethylating agents and allogeneic hematopoietic stem cell transplantation (allo-SCT). Despite early promise, multiple agents have failed to show clinical benefit in phase 3 clinical trials. Most recently, the VERONA trial exploring venetoclax and azacitidine did not meet its overall survival endpoint; however, secondary analyses suggested potential benefits in younger patients, those with > 5% blasts, and those with ASXL1/RUNX1, TP53 mutations, supporting biomarker-driven trial design. Venetoclax-based regimens are currently under investigation as bridging and maintenance strategies for allo-SCT. Emerging targets include CDC-like kinases and CD123, which are under early phase evaluation.