Prognostic Significance of IDH1 and IDH2 mutations in Older Patients with Primary Cytogenetically Normal Acute Myeloid Leukemia

IDH1 and IDH2 mutations are frequently identified in older patients with AML.With the development and application of IDH inhibitor, the prognostic significance of these mutations in old patients is of primary importance. To assess the impact on clinic outcome, we analyzed 224 older (> 60 years) patients with primary cytogenetically normal acute myeloid leukemia (CN-AML) similarly treated with intensive induction chemotherapy. Our analysis identified IDH1 and/or IDH2 (IDH1/2), IDH1 or IDH2 mutations in 63(28%), 29(12.9%) and 35(15.6%) patients, respectively. In general, IDH1 and IDH2 mutations were mutually exclusive, with only one patient having both IDH1 R132C and IDH2 R140Q mutations. IDH2 R172 mutations were exclusive with all other mutations analyzed (NPM1, CEBPA, DNMT3A, IDH1 and FLT3-ITD). There was a strong interaction between IDH2 mutation and NPM1 mutational status. Concurrent presence of IDH2 R140 and NPM1 mutations was independently associated with longer overall survival (OS; P=0.038, HR=0.42) and event free survival (EFS; P=0.034, HR=0.46) compared to the wild type counterpart in multivariable analyses. In contrast, IDH1 mutations were independently associated with shorter OS (P=0.004, HR=1.98) and EFS (P=0.014, HR=1.72) in multivariable analyses. Notably, IDH1 R132 mutations harbored higher levels of total 2-hydroxyglutarate compared to IDH2 R140Q mutations. Patients with IDH1 mutations or IDH2 R140 and NPM1 mutations harbored also distinct miRNA-expression signatures. Future studies will establish whether these difference between IDH1 and IDH2 mutations will be relevant with respect to response of the respective subsets of patients to the emerging therapies with IDH1 and IDH2 inhibitors.