High-risk myelodysplastic syndromes (HR-MDS) are usually defined by the International Prognostic Scoring System (IPSS) risk classes intermediate-2 and high. Untreated patients with HR-MDS have poor prognosis with a median survival of less than one year. The discovery of the clinically-significant activity of DNA methyltransferase inhibitors (DNMTi) in MDS has been a major advancement. In addition to supportive care, clinical trials, and DNMTi therapy, the typical therapeutic options for HR-MDS include allogeneic hematopoietic stem cell transplantation (alloHSCT) and intensive chemotherapy. Since most patients with HR-MDS are not candidates for alloHSCT due to co-morbidities and lack of appropriate donors, DNMTi therapy has become standard of care first-line therapy for HR-MDS. While not curative, DNMTi therapy results in hematologic improvements including transfusion-independence, delayed leukemic progression, and in case of azacitidine, survival prolongation. Many unanswered questions remain regarding the optimal use of DNMTi therapy. More data is needed about the best schedules, doses, possible combinations and sequencing with other drugs, biomarkers and models to predict response, and duration of therapy. Although several cycles of DNMTi therapy are needed before responses are typically seen, the optimal number of cycles and the role of maintenance therapy after achieving best response need further exploration. The survival advantage in HR-MDS with azacitidine therapy extends to any hematological response, but it is not clear if survival is improved for patients whose best response is stable disease. As more data emerges on the mechanism of action of DNMTi and their effects on methylation, immune system, hematopoietic stem cells, synergism with other agents, the deployment of these agents will likely result in better outcomes in HR-MDS. Patients with primary or secondary resistance to DNMTi therapy have dismal prognosis and very limited therapeutic options. Development of novel agents or ways to restore or prevent emergence of resistance remains a high-priority research area. Understanding the mechanisms of resistance may allow for the rational design of drugs that would prevent emergence of resistance or restore sensitivity to DNMTi therapy. Several novel agents are undergoing evaluation for HR-MDS. The elucidation of the complex pathogenetic mechanisms of the disease will hopefully allow for development for more targeted therapies.
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