Beyond HMAs: Novel Targets and Therapeutic Approaches

Myelodysplastic syndromes/neoplasms (MDS) constitute a heterogeneous group of clonal hematopoietic disorders with extremely variable clinical features and outcomes. Management of MDS is largely based on risk stratification of patients into either lower-risk or higher-risk categories using the International Prognostic Scoring System-Revised and, more recently, on the Molecular International Prognostic Scoring System. Lower-risk MDS is often managed with the goal of ameliorating cytopenias and improving quality of life, while higher-risk MDS is treated with therapies aimed at extending survival and delaying progression to acute myeloid leukemia (AML). Therapeutic strategies in lower-risk MDS patients may consist of erythropoiesis stimulating agents, luspatercept, and lenalidomide for selected patients. Furthermore, imetelstat has recently been added to the FDA-approved therapeutic armamentarium for lower-risk MDS. In higher-risk MDS, monotherapy with hypomethylating agents continues to be the standard of care. While several novel hypomethylating agent combinations have and are being studied in large randomized phase 3 clinical trials, including the combination of azacitidine and venetoclax, no combination to date have improved overall survival to azacitidine monotherapy. Moreover, biomarker-directed therapies as well as immonotherapeutic approaches are currently being evaluated in early phase trials. Despite recent advancements, the lack of therapeutic agents, particularly after the failure of first line therapy in higher risk MDS, continues to be a major hurdle in the management of MDS. In this review, we discuss the current treatment landscape of MDS and provide an overview of novel agents currently in clinical development that have the potential to alter our current treatment paradigms.