Novel Therapies for Unmet Clinical Needs in Myelodysplastic Syndromes

Simple Summary Several novel therapies are being developed to improve the management of patients with myelodysplastic syndromes. They include drugs aimed at improving hematopoiesis and differentiation of myeloid precursors, hypomethylating agents, several compounds that target intracellular molecular pathways, and immunotherapies. In this review article, we discuss how the novel drugs may address the several unmet needs of lower- and higher-risk patients. Myelodysplastic syndromes (MDS) are a very heterogeneous disease, with extremely variable clinical features and outcomes. Current management relies on risk stratification based on IPSS and IPSS-R, which categorizes patients into low (LR-) and high-risk (HR-) MDS. Therapeutic strategies in LR-MDS patients mainly consist of erythropoiesis stimulating agents (ESAs), transfusion support, and luspatercept or lenalidomide for selected patients. Current unmet needs include the limited options available after treatment failure, and the consequent transfusion burden with several hospital admissions and poor quality of life. Therapeutic approaches in HR-MDS patients are aimed at changing the natural course of the disease and hypometylating agents (HMA) are the first choice. The only potentially curative treatment is allogeneic stem cell transplant (allo-HCT), restricted to a minority of young and fit candidates. Patients unfit for or those that relapse after the abovementioned options harbor an adverse prognosis, with limited overall survival and frequent leukemic evolution. Recent advances in genetic mutations and intracellular pathways that are relevant for MDS pathogenesis are improving disease risk stratification and highlighting therapeutic targets addressed by novel agents. Several drugs are under evaluation for LR and HR patients, which differ by their mechanism of action, reported efficacy, and phase of development. This review analyzes the current unmet clinical needs for MDS patients and provides a critical overview of the novel agents under development in this setting.

Automated summary

This review article discusses the development of novel therapies for patients with myelodysplastic syndromes (MDS), including drugs aimed at improving hematopoiesis and differentiation, hypomethylating agents, compounds targeting intracellular pathways, and immunotherapies. The current management of MDS relies on risk stratification and has limited options for patients with treatment failure. Recent advances in genetic mutations and intracellular pathways are improving disease risk stratification and highlighting therapeutic targets. Several drugs are under evaluation for MDS patients, which differ in mechanism of action, efficacy, and development phase.