Hannah McMurry1, Luke Fletcher2, Elie Traer3. 1. Department of Internal Medicine, Oregon Health & Science University, Portland, OR, 97239, USA. 2. Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA. 3. Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97239, USA. traere@ohsu.edu.
Abstract
PURPOSE OF REVIEW: Mutations in isocitrate dehydrogenase genes (IDH1 and IDH2) are common in acute myeloid leukemia (AML), occurring in up to 30% of AML cases. Mutations in IDH leads to abnormal epigenetic regulation in AML cells and blocks differentiation. Inhibitors of mutated IDH1 and IDH2, ivosidenib and enasidenib, respectively, were recently approved by the FDA for relapsed/refractory AML; ivosidenib is also approved for newly diagnosed AML patients not fit for standard chemotherapy. Here, we discuss the clinical development of IDH inhibitors, their unique side effects, and outline future combination approaches in AML. RECENT FINDINGS: IDH inhibitors are well-tolerated but can induce differentiation of AML cells, which leads to the on-target side effect of differentiation syndrome in up to 20% of patients. Although IDH inhibitors demonstrate efficacy as monotherapy, recent trials have shown that they have higher response rates in combination with hypomethylating agents (HMAs). Current trials of IDH inhibitors include combination with standard induction chemotherapy, as maintenance therapy, and in combination with venetoclax-based regimens. IDH inhibitors are active and have a favorable toxicity profile in AML therapy. Current clinical trials are evaluating how to best incorporate IDH inhibitors into combination therapy to optimize outcomes and duration of response for AML patients with IDH mutations.
PURPOSE OF REVIEW: Mutations in isocitrate dehydrogenase genes (IDH1 and IDH2) are common in acute myeloid leukemia (AML), occurring in up to 30% of AML cases. Mutations in IDH leads to abnormal epigenetic regulation in AML cells and blocks differentiation. Inhibitors of mutated IDH1 and IDH2, ivosidenib and enasidenib, respectively, were recently approved by the FDA for relapsed/refractory AML; ivosidenib is also approved for newly diagnosed AMLpatients not fit for standard chemotherapy. Here, we discuss the clinical development of IDH inhibitors, their unique side effects, and outline future combination approaches in AML. RECENT FINDINGS:IDH inhibitors are well-tolerated but can induce differentiation of AML cells, which leads to the on-target side effect of differentiation syndrome in up to 20% of patients. Although IDH inhibitors demonstrate efficacy as monotherapy, recent trials have shown that they have higher response rates in combination with hypomethylating agents (HMAs). Current trials of IDH inhibitors include combination with standard induction chemotherapy, as maintenance therapy, and in combination with venetoclax-based regimens. IDH inhibitors are active and have a favorable toxicity profile in AML therapy. Current clinical trials are evaluating how to best incorporate IDH inhibitors into combination therapy to optimize outcomes and duration of response for AMLpatients with IDH mutations.
Authors: Amanda B Kagan; Blake S Moses; Bryan T Mott; Ganesha Rai; Nicole M Anders; Michelle A Rudek; Curt I Civin Journal: Front Oncol Date: 2022-01-11 Impact factor: 6.244
Authors: Piotr Obszański; Anna Kozłowska; Jakub Wańcowiat; Julia Twardowska; Monika Lejman; Joanna Zawitkowska Journal: Molecules Date: 2022-06-18 Impact factor: 4.927