Advances and Challenges in the Management of Myelodysplastic Syndromes

Myelodysplastic syndromes/neoplasms (MDS) represent a biologically and clinically diverse group of myeloid malignancies marked by cytopenias, morphological dysplasia, and an inherent risk of progression to acute myeloid leukemia. Over the past two decades, the field has made significant advances in characterizing the molecular landscape of MDS, leading to refined classification systems to reflect the underlying genetic and biological diversity. In 2025, the treatment of MDS is increasingly individualized, guided by integrated clinical, cytogenetic, and molecular risk stratification tools. For lower-risk MDS, the treatment paradigm has evolved beyond erythropoiesis-stimulating agents (ESAs) with the introduction of novel effective agents such as luspatercept and imetelstat, as well as shortened schedules of hypomethylating agents (HMAs). For higher-risk disease, monotherapy with HMAs continue to be the standard of care as combination therapies of HMAs with novel agents have, to date, failed to redefine treatment paradigms. The recognition of precursor states like clonal hematopoiesis of indeterminate potential (CHIP) and the increasing use of molecular monitoring will hopefully enable earlier intervention/prevention strategies. This review provides a comprehensive overview of the current treatment approach for MDS, highlighting new classifications, prognostic tools, evolving therapeutic options, and ongoing challenges. We discuss evidence-based recommendations, treatment sequencing, and emerging clinical trials, with a focus on translating biological insights into improved outcomes for patients with MDS.