Novel approaches to the use of hypomethylating agents in myeloid malignancies

Epigenetic dysregulation has been increasingly understood to be a key factor in the development of myeloid malignancies, often acting alongside genetic alterations to disrupt normal hematopoiesis. The inherent reversibility of epigenetic changes has provided an excellent opportunity for therapeutic intervention. Hypomethylating agents (HMA) preferentially alter gene expression in heavily methylated malignant myeloid cells by inhibiting DNA methyltransferases thereby altering gene expression. They have since become foundation therapies in myelodysplastic syndrome (MDS) and in older patients with acute myeloid leukemia (AML). However, complete responses to HMA monotherapy are limited and usually non-durable. In recent years, novel approaches have been sought to overcome resistance and expand the role of epigenetic therapies in MDS and AML as well as in less well-studied myeloid malignancies such as myeloproliferative neoplasms (MPNs) and MDS/MPN overlap syndromes. Combination regimens that synergistically pair HMAs or other epigenetically active therapeutics with agents targeting apoptosis, cellular metabolism, and immune evasion have also shown early promise in improving patient outcomes. Oral formulations of HMAs have made maintenance strategies more convenient and tolerable for patients, with demonstrated benefits in AML and ongoing investigations in MDS and post-transplant settings. This review will explore these novel therapeutic strategies in the treatment of myeloid malignancies.