Epigenetic therapy of myelodysplastic syndromes and acute myeloid leukemia

This review will discuss issues arising along with the expanding use of hypomethylating treatment (HMT) in the management of acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS).

HMT has been shown to induce responses in MDS and AML, and azacitidine (Vidaza, Celgene) has been shown to prolong survival in higher-risk MDS. Recent studies have supported the idea that disease stability may also be a treatment goal, whereas treatment interruption in responding patients is associated with rapid disease relapse and death. In AML, a modest but significant survival advantage has been shown for HMT by censoring patients at the time of subsequent AML therapy, but the major limitation remains the short duration of responses. Unfortunately, some of the strategies to overcome these limitations have failed, including the combination of HMT to histone-deacetylase inhibitors, which has not definitively shown to significantly prolong survival. Molecules interfering with other pathways impacting the survival and proliferation of blasts, used alone or in combination, including guadecitabine, selinexor, or inhibitors of IDH2 mutations, are more promising approaches.

Hypomethylating drugs are the first successful treatment for elderly patients with higher-risk MDS and are effective for some AML subtypes. Translational studies will hopefully identify patients with a favorable profile of response to these drugs, and help to identify newer targets for combination treatments.