The development and clinical use of oral hypomethylating agents in acute myeloid leukemia and myelodysplastic syndromes: dawn of the total oral therapy era.

Intravenous and subcutaneous hypomethylating agents have held a key role in myelodysplastic syndrome, chronic myelomonocytic leukemia and acute myeloid leukemia treatment. Following the approval of the cedazuridine/decitabine combination, ASTX727, as well as development of an oral formulation of azacitidine, CC-486, in the USA in 2020, these agents could gradually replace their injectable counterparts. ASTX727 is approved for the treatment of adult patients with intermediate 1 or high-risk MDS as well as those with chronic myelomonocytic leukemia based on the findings from the ASTX727-01-B and ASCERTAIN trials. Oral azacitidine (CC-486) is approved for maintenance treatment of acute myeloid leukemia after induction chemotherapy for patients unfit for allogeneic hematopoietic cell transplant based on the findings from the QUAZAR AML-001 trial. Oral hypomethylating agent formulations have the potential to offer a convenient alternative to injectable hypomethylating agent. However, their current FDA-approved indications are narrow and efficacy needs to be shown in clinical trials before considering use beyond the approved indications. Areas of special interest include: identification of predictive biomarkers for clinical benefit, post-transplant maintenance therapy, and potential combination therapies with other oral agents such as venetoclax, IDH and FLT3 inhibitors.