Life after hypomethylating agents in myelodysplastic syndrome: new strategies

Hypomethylating agents, azacitidine and decitabine, are successfully used for the treatment of myelodysplastic syndromes (MDS). In spite of improvement in survival, MDS is still incurable without hematopoietic stem cell transplant, and in case of absence/loss of response to hypomethylating agents, outcome is poor. The purpose of this article is to provide an overview of the new approach to MDS, elucidate the advancements in understanding factors predictive of response to hypomethylating agents, the progress of research to better stratify individual patients, and optimize therapeutic choices, the availability and efficacy of new drugs.

The prognostic importance of recurrent somatic mutations has been elucidated (i.e., ASXL1, TP53 and SF3B1 mutations) and the power to predict response to hypomethylating therapy ascribed to specific mutations (TET2 mutations). The most challenging agents among the numerous evaluated are those with a strong biological background, targeting specific molecular alterations (IDH2 mutation) or altered signaling pathways. Hematopoietic stem cell transplant remains the only curative option, and wider choice of donor (sibling, unrelated, cord blood, haploidentical) and different approaches to conditioning renders it feasible for a higher percentage of elderly patients with MDS.

Few new molecules have reached phase III, the majority being in phase I/II studies. Most importantly, prognostic tools have profoundly improved whereas attitude of hematologists is changing rapidly.

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