Patients with AML with an IDH2 R172K mutation have improved overall survival with venetoclax + azacitidine as compared to those with IDH2 R140Q mutations
Abstract
Introduction: Mutations in the Kreb's cycle enzyme isocitrate dehydrogenase 2 (IDH2) and its homolog, isocitrate dehydrogenase 1 (IDH1) are observed in 20% of patients with acute myeloid leukemia (AML). Mutations in IDH2 primarily occur in two distinct hotspots: IDH2 arginine 140 mutated to glutamine (R140Q) and IDH2 arginine 172 mutated to lysine (R172K). These two mutated forms of IDH2 generate unique subtypes of leukemia when introduced into mouse hematopoietic stem cells (Fortin et al PNAS 2023). Furthermore, clinical data have shown that the two mutations are mutually exclusive and have distinct co-mutation profiles suggesting they represent two distinct forms of leukemia (Middeke et al Blood 2022). A recent retrospective study described that AML patients with IDH2 R172K mutations have slower blast clearance in response to intensive induction chemotherapy regimens (Salman et al Blood Advances 2025). The differential response of AML with distinct IDH2 mutations to lower intensity regimens, specifically, venetoclax+azacitidine (ven/aza), has not been studied.
Results: We analyzed a retrospective sequential cohort of 43 newly-diagnosed AML patients with IDH2 mutations treated with ven/aza at the University of Colorado Cancer Center from 2012 to 2025. 31/43 (72%) had IDH2 R140Q mutations and 12/43 (28%) patients had IDH2 R172K mutations, reflecting mutation frequencies previously documented in the literature. Patients with R172K were significantly younger (57 vs 75, p=…
How strong is the evidence?
Evidence Hub reads this as a cohort study, done in people. Its evidence level is 3 of 5 (Moderate · trial / cohort / secondary analysis). Trials without a large randomized design, cohorts and secondary analyses give moderate evidence.
Read the paper
Related studies
- Diagnosis and management of glutaric aciduria type I – revised recommendations
- EZH2 Codon 641 Mutations are Common in BCL2-Rearranged Germinal Center B Cell Lymphomas
- Consensus guidelines for the diagnosis and management of pyridoxine‐dependent epilepsy due to α‐aminoadipic semialdehyde dehydrogenase deficiency
- Systemic Metabolomic Changes in Blood Samples of Lung Cancer Patients Identified by Gas Chromatography Time-of-Flight Mass Spectrometry
- Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal α-toxin
- Discovery of Novel Recurrent Mutations in Childhood Early T-Cell Precursor Acute Lymphoblastic Leukemia by Whole Genome Sequencing - a Report From the St Jude Children's Research Hospital - Washington University Pediatric Cancer Genome Project
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.