title: 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.
abstract: OBJECTIVE
  To analyze the frequency and prognostic impact of isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) mutations in acute myeloid leukemia (AML).
  
  
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: University Hospital of Ulm, Ulm, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Paschka
authors.forename: Richard F
authors.initials: RF
authors.lastname: Schlenk
authors.forename: Verena I
authors.initials: VI
authors.lastname: Gaidzik
authors.forename: Marianne
authors.initials: M
authors.lastname: Habdank
authors.forename: Jan
authors.initials: J
authors.lastname: Krönke
authors.forename: Lars
authors.initials: L
authors.lastname: Bullinger
authors.forename: Daniela
authors.initials: D
authors.lastname: Späth
authors.forename: Sabine
authors.initials: S
authors.lastname: Kayser
authors.forename: Manuela
authors.initials: M
authors.lastname: Zucknick
authors.forename: Katharina
authors.initials: K
authors.lastname: Götze
authors.forename: Heinz-A
authors.initials: HA
authors.lastname: Horst
authors.forename: Ulrich
authors.initials: U
authors.lastname: Germing
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
mesh_terms: D000293:Adolescent; D000328:Adult; D005260:Female; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000401:mortality / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D000090243:Nucleophosmin; D011379:Prognosis; D020080:Tandem Repeat Sequences; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3