How I treat MDS after hypomethylating agent failure

Valeria Santini


Hypomethylating agents (HMA), azacitidine and decitabine are standard of care for myelodysplastic syndromes. Response to these agents accounts for around 50% of treated patients and duration of response, although variable, is transient. Prediction of response to HMA is possible with clinical and molecular parameters, but alternative approved treatments are not available and in case of HMA failure, there are no standard therapeutic opportunities. It is important to develop a reasoned choice of therapy after HMA failure. This choice should be based on evaluation of type of resistance: primary versus secondary, progression of disease (acute leukemia or higher risk MDS) versus absence of hematological improvement, as well as on molecular and cytogenetic characteristics reassessed at the moment of HMA failure. Rescue strategies may include stem cell transplant, which remains the only curative option, chemotherapy, both feasible in only a minority of cases, and experimental agents. HMA failure patients should be recruited into clinical experimental trials as much as possible. Several novel agents with very different mechanisms of action are currently tested in this setting. Drugs targeting molecular alterations (IDH2 mutations, spliceosome gene mutations) or altered signaling pathways (like BCL2 inhibitors) seem to be the most promising.

  • Submitted March 7, 2018.
  • Accepted December 4, 2018.