Myelodysplastic syndromes/neoplasms (MDS) constitute a very heterogeneous group of clonal myeloid neoplasms characterized by a variable clinical course and recurrent genetic abnormalities. Their treatment relies on risk classification as lower or higher-risk categories by the original International Prognostic Scoring System (IPSS) or the current revised (IPSS-R) or molecular IPSS-M. Higher-risk MDS (HR-MDS) are clonal hematopoietic disorders characterized by significant cytopenias, dysplastic changes, and a high propensity for progression to acute myeloid leukemia (AML). Up to 40% of them usually progress to AML within two years of diagnosis. Allogeneic stem cell transplantation (HSCT) remains the only potential cure and standard of care for eligible patients. Despite standard treatments such as Allo-HSCT and hypomethylating agents (HMAs), outcomes remain suboptimal. Recent advances have led to the development of novel therapeutic strategies, such as BCL-2 inhibitors (venetoclax), IDH1/2 inhibitors (ivosidenib, enasidenib), CD47 inhibitors (magrolimab), TIM-3 inhibitors (sabatolimab), XPO1 inhibitors (eltanexor), NEDD8-activating enzyme inhibitors (pevonedistat), TP53-targeted agents (eprenetapopt), liposomal chemotherapy (CPX-351), and oral HMA formulations. Combinations of hypomethylating agents with these new drugs, as first-line treatment, have to date not proven more efficacious than HMA monotherapy. This review summarizes the current therapeutic landscape on novel therapies for HR-MDS, highlighting their mechanism of action, efficacy, and demonstrates the unmet clinical need for more effective therapies.
Keywords: HMA; IDH inhibitors; high‐risk MDS; myelodysplastic syndromes; novel therapies; targeted therapy; venetoclax.
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