It is time to shift the treatment paradigm in myelodysplastic syndromes: A focus on novel developments and current investigational approaches exploring combinatorial therapy in high-risk MDS

Abstract

Higher risk myelodysplastic syndromes are defined as a subset of disease with higher risk of AML transformation and poor overall survival. For decades, therapeutic options for high-risk MDS have been limited to allogeneic stem cell transplant (the only option for cure but limited to only a handful of patients) or hypomethylating agents, with the goal to alter the natural history of disease, delay progression and improve survival, while addressing cytopenias, transfusion requirements and improving quality of life. Recent developments in DNA sequencing and other technologies have shed significant light into the pathogenesis of MDS and led to rational and targeted drug development across a variety of therapeutic vulnerabilities, including disruption of protein ubiquitination through NAE inhibition, selective modulation of macrophage activity and immune checkpoint inhibition through blockade of TIM-3. This review highlights some of the most promising agents in recent drug development and their therapeutic efficacy in the management of high-risk MDS, and further explores the rationale behind potential combinatorial approaches using an HMA backbone to synergistically improve treatment outcomes.

Keywords: Anti-CD47; Myelodysplastic syndromes; NEDD8-activating enzyme; Novel therapies; TIM-3; TP53.