IDH1 and IDH2 Mutations Are Frequent Genetic Alterations in Acute Myeloid Leukemia and Confer Adverse Prognosis in Cytogenetically Normal Acute Myeloid Leukemia With NPM1 Mutation Without FLT3 Internal Tandem Duplication Peter Paschka, Richard F. Schlenk, Verena I. Gaidzik, Marianne Habdank, Jan Kro ¨nke, Lars Bullinger, Daniela Spa ¨th, Sabine Kayser, Manuela Zucknick, Katharina Go ¨tze, Heinz-A. Horst, Ulrich Germing, Hartmut Do ¨hner, and Konstanze Do ¨hner From the University Hospital of Ulm, Ulm; German Cancer Research Center, Heidelberg; University Hospital, Techni- cal University of Munich, Munich; Medi- cal Clinic II, University Hospital of Kiel, Kiel; and Oncology and Clinical Immu- nology, University Hospital Du ¨ sseldorf, Du ¨ sseldorf, Germany. Submitted January 25, 2010; accepted April 28, 2010; published online ahead of print at www.jco.org on June 21, 2010. Supported in part by Grants No. 01GI9981 and 01KG0605 from the Bundesministerium fu ¨ r Bildung und Forschung. Authors’ disclosures of potential con- flicts of interest and author contribu- tions are found at the end of this article. Corresponding author: Konstanze Do ¨ hner, MD, Department of Internal Medicine III, University Hospital of Ulm, Albert-Einstein-Allee 23, D-89081 Ulm, Germany; e-mail: konstanze.doehner@ uniklinik-ulm.de. © 2010 by American Society of Clinical Oncology 0732-183X/10/2822-3636/$20.00 DOI: 10.1200/JCO.2010.28.3762 A B S T R A C T Purpose To analyze the frequency and prognostic impact of isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) mutations in acute myeloid leukemia (AML). Patients and Methods We studied 805 adults (age range, 16 to 60 years) with AML enrolled on German-Austrian AML Study Group (AMLSG) treatment trials AML HD98A and APL HD95 for mutations in exon 4 of IDH1 and IDH2. Patients were also studied for NPM1, FLT3, MLL, and CEBPA mutations. The median follow-up for survival was 6.3 years. Results IDH mutations were found in 129 patients (16.0%) —IDH1 in 61 patients (7.6%), and IDH2 in 70 patients (8.7%). Two patients had both IDH1 and IDH2 mutations. All but one IDH1 mutation caused substitutions of residue R132; IDH2 mutations caused changes of R140 (n = 48) or R172 (n = 22). IDH mutations were associated with older age (P  .001; effect conferred by IDH2 only); lower WBC (P = .04); higher platelets (P  .001); cytogenetically normal (CN) –AML (P .001); and NPM1 mutations, in particular with the genotype of mutated NPM1 without FLT3 internal tandem duplication (ITD; P  .001). In patients with CN-AML with the latter genotype, IDH mutations adversely impacted relapse-free survival (RFS; P = .02) and overall survival (P = .03), whereas outcome was not affected in patients with CN-AML who lacked this genotype. In CN-AML, multivariable analyses revealed a significant interaction between IDH mutation and the genotype of mutated NPM1 without FLT3-ITD (ie, the adverse impact of IDH mutation [RFS]; P = .046 was restricted to this patient subset). Conclusion IDH1 and IDH2 mutations are recurring genetic changes in AML. They constitute a poor prognostic factor in CN-AML with mutated NPM1 without FLT3-ITD, which allows refined risk stratification of this AML subset. J Clin Oncol 28:3636-3643. © 2010 by American Society of Clinical Oncology INTRODUCTION The karyotype of the leukemic cells has remained one of the most important prognostic factors in acute myeloid leukemia (AML). 1,2 However, in the past decade, the discovery of molecular genetic alter- ations increasingly contributes to the refinement of prognostication in AML. The role of genetic alter- ations in AML has been emphasized by the 2008 revised WHO classification of AML, so that an in- creasing number of AML are now being classified on the basis of their underlying cytogenetic and molec- ular genetic changes. For the first time, AML with molecular genetic changes have been incorporated as provisional entities, that is, as AML with mutated NPM1 and AML with mutated CEBPA. 3 It is likely that the identification of novel genetic markers will additionally contribute to our understanding of leukemia biology, to an improvement of indi- vidual risk assessment, and eventually to the de- velopment of novel therapies that target these genetic changes. 3 JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T VOLUME 28  NUMBER 22  AUGUST 1 2010 3636 © 2010 by American Society of Clinical Oncology Downloaded from ascopubs.org by 18.209.56.36 on June 3, 2022 from 018.209.056.036 Copyright © 2022 American Society of Clinical Oncology. All rights reserved.