A review of the isocitrate dehydrogenase inhibitors in management of adult patients with AML and MDS

Abstract

Introduction: The development of oral therapies impacts the management of acute myeloid leukemia and myelodysplastic syndromes, especially for targetable mutations including IDH1/2.

Areas covered: We discuss IDH1/2 activity and inhibitor therapy in various settings, including monotherapy, combination therapy with hypomethylating agents, and other approaches.

Expert opinion: Olutasidenib, enasidenib, and ivosidenib are approved for relapsed AML. Ivosidenib is approved for relapsed MDS and alone or with azacitidine in newly diagnosed AML. However, unanswered questions exist. In newly diagnosed AML, ivosidenib + azacitidine shows a survival benefit compared to azacitidine, but it is unknown whether ivosidenib + azacitidine demonstrates improved survival compared to ivosidenib. Ivosidenib + azacitidine demonstrated a survival benefit not seen with enasidenib + azacitidine. It is unclear whether newly diagnosed AML should be treated with azacitidine + ivosidenib or azacitidine + venetoclax. Azacitidine + venetoclax shows excellent response rates in IDH mutated disease. Retrospective data show low response rates of IDH inhibitor therapy post-venetoclax whereas HMA + venetoclax retains activity post IDH inhibition. The role of IDH inhibition post-transplant is unclear. Single-arm studies show post-transplant maintenance is safe; however, randomized trials are needed. Similarly, IDH inhibitors can be combined with chemotherapy however randomized studies are needed.

Keywords: IDH mutation; Leukemia; MDS; hematology; oral therapy.