Role of Isocitrate Dehydrogenase Inhibitors in AML Treatment
Posted: Friday, March 6, 2020
A review article published in Biomarker Research highlighted the role of isocitrate dehydrogenase (IDH) inhibitors in the treatment of patients with acute myeloid leukemia (AML) who have mutations in IDH. According to Yuping Gong, PhD, of West China Hospital of Sichuan University, and colleague, clinical trials of IDH inhibitors in this patient population are ongoing.
IDH is involved in the conversion of isocitrate to alpha-ketoglutarate in the Krebs cycle, and when mutated, it can create proteins that promote leukemogenesis. Mutation in the IDH gene occurs in about 20% of patients with AML and is typically present as IDH1 R132, IDH2 R140, or IDH2 R172. Various mutations in the gene are associated with differing prognostic value.
Recently, IDH inhibitors have shown activity in patients with AML. The IDH2 and IDH1 inhibitors enasidenib and ivosidenib, respectively, were approved by the U.S. Food and Drug Administration in 2017 and 2018 to treat relapsed or refractory AML with mutations in IDH2 or IDH1. Enasidenib is able to reduce the production of leukemogenetic proteins, reverse epigenetic changes, and induce differentiation of IDH2-mutant AML cells. Ivosidenib is also able to induce AML cell differentiation, although adverse events were reported in 99% of patients taking the drug.
Using IDH inhibitors as monotherapy is safe in patients with relapsed or refractory AML, but tumors can acquire resistance or show primary resistance. There are currently ongoing trials of IDH inhibitors in combination with hypomethylating agents or standard chemotherapy in the treatment of relapsed or refractory AML. These trials are also being conducted for newly diagnosed patients as well as those who have undergone stem cell transplantation as maintenance therapy.
Disclosure: The study authors reported no conflicts of interest.