title: Prognostic impact of isocitrate dehydrogenase enzyme isoforms 1 and 2 mutations in acute myeloid leukemia: a study by the Acute Leukemia French Association group.
abstract: OBJECTIVE
  Recently, whole-genome sequencing in acute myeloid leukemia (AML) identified recurrent isocitrate dehydrogenase enzyme isoform (IDH1) mutations (IDH1m), previously reported to be involved in gliomas as well as IDH2 mutations (IDH2m). The prognosis of both IDH1m and IDH2m in AML remains unclear.
  
  
  METHODS
  The prevalence and the prognostic impact of R132 IDH1 and R172 IDH2 mutations were evaluated in a cohort of 520 adults with AML homogeneously treated in the French Acute Leukemia French Association (ALFA) -9801 and -9802 trials.
  
  
  RESULTS
  The prevalence of IDH1m and IDH2m was 9.6% and 3.0%, respectively, mostly associated with normal cytogenetics (CN). In patients with CN-AML, IDH1m were associated with NPM1m (P = .008), but exclusive of CEBPAm (P = .03). In contrary, no other mutations were detected in IDH2m patients. In CN-AML patients, IDH1m were found in 19% of favorable genotype ([NPM1m or CEBPAm] without fms-related tyrosine kinase 3 [FLT3] internal tandem duplication [ITD]) and were associated with a higher risk of relapse (RR) and a shorter overall survival (OS). Favorable genotype in CN-AML could thus be defined by the association of NPM1m or CEBPAm with neither FLT3-ITD nor IDH1m. In IDH2m CN-AML patients, we observed a higher risk of induction failure, a higher RR and a shorter OS. In multivariate analysis, age, WBC count, the four-gene favorable genotype and IDH2m were independently associated with a higher RR and a shorter OS.
  
  
  CONCLUSIONS
  Contrarily to what is reported in gliomas, IDH1m and IDH2m in AML are associated with a poor prognosis. Screening of IDH1m could help to identify high-risk patients within the subset of CN-AML with a favorable genotype.
authors.affiliation: University of Paris 7, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Boissel
authors.forename: Olivier
authors.initials: O
authors.lastname: Nibourel
authors.forename: Aline
authors.initials: A
authors.lastname: Renneville
authors.forename: Claude
authors.initials: C
authors.lastname: Gardin
authors.forename: Oumedaly
authors.initials: O
authors.lastname: Reman
authors.forename: Nathalie
authors.initials: N
authors.lastname: Contentin
authors.forename: Dominique
authors.initials: D
authors.lastname: Bordessoule
authors.forename: Cécile
authors.initials: C
authors.lastname: Pautas
authors.forename: Thierry
authors.initials: T
authors.lastname: de Revel
authors.forename: Bruno
authors.initials: B
authors.lastname: Quesnel
authors.forename: Pascal
authors.initials: P
authors.lastname: Huchette
authors.forename: Nathalie
authors.initials: N
authors.lastname: Philippe
authors.forename: Sandrine
authors.initials: S
authors.lastname: Geffroy
authors.forename: Christine
authors.initials: C
authors.lastname: Terre
authors.forename: Xavier
authors.initials: X
authors.lastname: Thomas
authors.forename: Sylvie
authors.initials: S
authors.lastname: Castaigne
authors.forename: Hervé
authors.initials: H
authors.lastname: Dombret
authors.forename: Claude
authors.initials: C
authors.lastname: Preudhomme
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D015995:Prevalence; D011379:Prognosis; D020033:Protein Isoforms / Q000235:genetics; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D020033:Protein Isoforms; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human