Beyond Hypomethylating Agents: Novel Therapies and Targeted Approaches

Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematopoietic diseases sharing ineffective hematopoiesis, cytopenias, and a high risk of evolution to acute myeloid leukemia (AML). The current MDS classification systems, such as the International Consensus Classification (ICC) and the WHO 2022 classification, have incorporated molecular and cytogenetic markers to improve the stratification of risk and guide therapy. However, treatment options for high-risk MDS (HR-MDS) remain limited, with hypomethylating agents (HMAs) providing only modest survival benefits. Emerging treatments such as immune checkpoint blockade and novel targeted therapies could further improve patient outcomes. While early excitement was significant, clinical trials of the immune checkpoint inhibitors (ICIs) ipilimumab and durvalumab have produced no definitive results, highlighting the need for better patient selection and combination regimens. Emerging drugs luspatercept and imetelstat have been suggested for lower-risk MDS (LR-MDS) by promoting transfusion independence and global hematologic response. In contrast, exploratory agents such as pevonedistat, magrolimab, and sabatolimab are under further investigation for HR-MDS. The future of MDS treatment currently addresses precision medicine, in which molecular characterization guides therapeutic options. Identification of predictive biomarkers for response to targeted therapies and immunotherapies is crucial to optimize patient outcomes. An integrated, patient-centered approach combining genomics, novel therapeutics, and immunomodulation is therefore essential to address the current needs in MDS management.