Novel therapeutic strategies: hypomethylating agents and beyond

Abstract The treatment of symptomatic and high-risk myelodysplastic syndrome (MDS) spans several therapeutic goals and options. Key to the successful therapy of these heterogeneous diseases is careful characterization and diagnosis, including clinical, cytogenetic, biological, and molecular evaluation of individual patients. Any novel management strategy in MDS must be based on accepted and validated prognostic scoring systems, such as the International Prognostic Scoring System (IPSS), and should take into account predictive parameters of response to the available therapeutic agents and individual comorbidities. For IPSS lower-risk MDS patients, several first-line options are available, including erythropoietic stimulating agents, lenalidomide, and immunosuppressive drugs. Sequential therapy is advisable whenever response is lost, and the activity of azacitidine and decitabine in first- or second-line therapy is relevant, especially in patients with symptomatic cytopenias and anemia. Hypomethylating agents have a central role in therapy of IPSS higher-risk MDS patients. These agents include azacitidine and decitabine, which allow treatment of very elderly and frail patients, resulting in hematological improvement and transfusion independency in roughly half, and for azacitidine a demonstrated significant prolongation of survival. Because hypomethylating agents are not curative, they are not satisfactory for younger MDS patients, for whom a transplantation strategy should be planned. Although hypomethylating agent therapy is used extensively, a growing number of MDS patients fail to respond or progress. The future challenge is not only to find treatment regimens that target the dysplastic clone(s) so that durable remissions are achieved (particularly in high-risk patients with short survival and/or increased leukemic transformation rates), but also to also identify active salvage regimens.