Therapeutic Options in Myelodysplastic Syndromes: Established and Emerging Therapies

Although hypomethylating agents (HMA) have revolutionised the treatment of myelodysplastic syndromes (MDS), a significant proportion of patients either fail to respond to HMA or their disease progresses after an initial response. Established therapeutic options for these patients remain limited. Fortunately, recent advancements in the knowledge of MDS pathogenesis have allowed for the development of many targeted therapies, including epigenetic regulators, signal transduction regulators, immune checkpoint inhibitors, cell apoptosis regulators, and novel cytotoxic agents. These novel therapeutics have shown varying degrees of promise in clinical trials. Epigenetic regulators, such as second-generation HMA and isocitrate dehydrogenase inhibitors, have shown modest efficacy in early studies, while histone deacetylase inhibitors have, thus far, failed to show significant clinical benefit. Signal transduction modulators, such as transforming growth factor (TGF)-β inhibitors and toll-like receptor inhibitors, appear to alleviate anaemia symptoms, but further studies are needed to determine their effect on survival. Rigosertib, a multikinase inhibitor, improved survival in a small subset of patients with very high-risk MDS. Immune checkpoint inhibitors have shown mixed results. Agents that have recently been approved for use in specific types of high-risk acute myeloid leukaemia, including FMS-like tyrosine receptor kinase 3 inhibitors and CPX-351, are also being studied for use in MDS, with early studies suggesting efficacy. Several other agents are also under investigation with results pending. These novel agents represent potential therapeutic options for patients who have failed HMA and for whom no currently established therapies are available.