Introduction: Hypomethylating agents (HMA) remain the mainstay of treatment for patients with higher-risk myelodysplastic syndromes (HR-MDS). However, complete responses to HMAs are seen in <20% of cases and are typically not durable. For most patients, HMA failure is an eventual certainty that is associated with an abysmal prognosis.
Areas covered: PubMed and abstracts from annual meetings were searched in May 2020 to review recent studies on novel HMAs (e.g. ASTX727, CC-486, guadecitabine), molecularly targeted agents (e.g. mutant IDH1/2 inhibitors, BCL-2 inhibitors, APR246), and immune therapies (e.g. MBG453, anti-CD47) for the treatment of HR-MDS patients with HMA failure. Several molecules targeting cell signaling (e.g. rigosertib) are also in development. This manuscript also provides an overview of the state of genetic testing and its implications for an increasingly individualized treatment approach for patients with MDS.
Expert opinion: Advances in the understanding of the genetic and immune pathogenesis of HMA failure will lead to biomarker-driven therapeutic approaches and to an era of individualized therapeutic concepts (e.g. IDH inhibitors and APR246). The improved understanding of molecular mechanisms of pathogenesis and immune evasion are offering further opportunities for the rational design of novel agents. Efforts to optimize frontline HMA-based treatment are of paramount importance.