Pharmacologic progress in higher-risk MDS: an uphill battle

Myelodysplastic syndromes/neoplasms (MDS) comprise a heterogeneous group of clonal myeloid malignancies characterized by ineffective hematopoiesis and a variably increased risk of progression to acute myeloid leukemia (AML). Higher-risk MDS, as defined by the revised- and molecular International Prognostic Scoring System, remains largely incurable except through allogeneic hematopoietic stem cell transplantation. Management continues to rely primarily on hypomethylating agents, which were approved nearly two decades ago and remain the cornerstone of therapy despite their modest efficacy. Advances in molecular profiling and next-generation sequencing have greatly improved disease classification and prognostication tools. However, with the exception of IDH1 inhibitor ivosidenib, targeted therapies in higher-risk MDS remain the exception to the rule. Although numerous early-phase clinical trials have yielded promising signals, phase III trials have repeatedly failed to replicate these findings. This largely reflects the intrinsic biological complexity and heterogeneity of MDS, as well as logistical challenges in trial design and execution. Examining the history and evolution of investigational pharmacotherapy in higher-risk MDS may help identify where efforts to translate early phase successes into successful phase III trials have faltered. The expanding biological knowledge base and the design of better therapies will hopefully pave the way for future therapeutic breakthroughs.