The Immuno-Oncology and Genomic Aspects of DNA-Hypomethylating Therapeutics in Acute Myeloid Leukemia

Hypomethylating agents (HMAs) have been used for decades in the treatment of hematologic neoplasms, and now, have gathered attention again in terms of their combination with potent molecular-targeted agents such as a BCL-6 inhibitor venetoclax and an IDH1 inhibitor ivosidenib, as well as a novel immune-checkpoint inhibitor (anit-CD47 antibody) megrolimab. Several studies have shown that leukemic cells have a distinct immunological microenvironment, which is at least partially due to genetic alterations such as the TP53 mutation and epigenetic dysregulation. HMAs possibly improve intrinsic anti-leukemic immunity and sensitivity to immune therapies such as PD-1/PD-L1 inhibitors and anti-CD47 agents. This review describes the immuno-oncological backgrounds of the leukemic microenvironment and the therapeutic mechanisms of HMAs, as well as current clinical trials of HMAs and/or venetoclax-based combination therapies.

Automated summary

Hypomethylating agents (HMAs) have been used for a long time in the treatment of hematologic neoplasms. Recent studies have shown their potential in combination with targeted agents and immune-checkpoint inhibitors. This review discusses the immuno-oncological backgrounds, therapeutic mechanisms, and current clinical trials of HMAs and/or venetoclax-based combination therapies in leukemia.