Treatment options in advanced myelodysplastic syndrome, with emphasis on epigenetic therapy

Abstract

Medical management of myelodysplastic syndrome (MDS) remains challenging, particularly in advanced stages where the risk of developing acute leukemia is very high and the prospect of survival is generally poor. Over the past decade, epigenetic changes such as alterations in DNA methylation and histone modifications have been well described in MDS and are now recognized as targets of therapy (epigenetic therapy). The aim of epigenetic therapy is to reverse epigenetic changes and reactivate important genes, thereby modifying the malignant phenotype and inducing the clearance of the malignant clone via various mechanisms. Epigenetic-modifying agents may also have mechanisms of anticancer action unrelated to gene reactivation. The hypomethylating agents azacitidine and decitabine induce clinically meaningful remissions or improvements in 30% to 60% of patients with this disease, and both agents have been approved in the United States for the treatment of advanced and/or symptomatic MDS. Histone deacetylase inhibitors belong to another class of epigenetic-modifying agents that also have clinical activity in MDS. They are currently being combined with hypomethylating agents. Among other available therapeutic options, allogeneic stem cell transplantation is the only curative approach for MDS but is also characterized by significant morbidities and mortality. We review epigenetic therapy and other therapeutic approaches for patients with advanced MDS.