title: Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia.
abstract: BACKGROUND
  Mutations occur in several genes in cytogenetically normal acute myeloid leukemia (AML) cells: the nucleophosmin gene (NPM1), the fms-related tyrosine kinase 3 gene (FLT3), the CCAAT/enhancer binding protein alpha gene (CEPBA), the myeloid-lymphoid or mixed-lineage leukemia gene (MLL), and the neuroblastoma RAS viral oncogene homolog (NRAS). We evaluated the associations of these mutations with clinical outcomes in patients.
  
  
  METHODS
  We compared the mutational status of the NPM1, FLT3, CEBPA, MLL, and NRAS genes in leukemia cells with the clinical outcome in 872 adults younger than 60 years of age with cytogenetically normal AML. Patients had been entered into one of four trials of therapy for AML. In each study, patients with an HLA-matched related donor were assigned to undergo stem-cell transplantation.
  
  
  RESULTS
  A total of 53% of patients had NPM1 mutations, 31% had FLT3 internal tandem duplications (ITDs), 11% had FLT3 tyrosine kinase-domain mutations, 13% had CEBPA mutations, 7% had MLL partial tandem duplications (PTDs), and 13% had NRAS mutations. The overall complete-remission rate was 77%. The genotype of mutant NPM1 without FLT3-ITD, the mutant CEBPA genotype, and younger age were each significantly associated with complete remission. Of the 663 patients who received postremission therapy, 150 underwent hematopoietic stem-cell transplantation from an HLA-matched related donor. Significant associations were found between the risk of relapse or the risk of death during complete remission and the leukemia genotype of mutant NPM1 without FLT3-ITD (hazard ratio, 0.44; 95% confidence interval [CI], 0.32 to 0.61), the mutant CEBPA genotype (hazard ratio, 0.48; 95% CI, 0.30 to 0.75), and the MLL-PTD genotype (hazard ratio, 1.56; 95% CI, 1.00 to 2.43), as well as receipt of a transplant from an HLA-matched related donor (hazard ratio, 0.60; 95% CI, 0.44 to 0.82). The benefit of the transplant was limited to the subgroup of patients with the prognostically adverse genotype FLT3-ITD or the genotype consisting of wild-type NPM1 and CEBPA without FLT3-ITD.
  
  
  CONCLUSIONS
  Genotypes defined by the mutational status of NPM1, FLT3, CEBPA, and MLL are associated with the outcome of treatment for patients with cytogenetically normal AML.
authors.affiliation: University Hospital of Ulm, Ulm, Germany.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Schlenk
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
authors.forename: Jürgen
authors.initials: J
authors.lastname: Krauter
authors.forename: Stefan
authors.initials: S
authors.lastname: Fröhling
authors.forename: Andrea
authors.initials: A
authors.lastname: Corbacioglu
authors.forename: Lars
authors.initials: L
authors.lastname: Bullinger
authors.forename: Marianne
authors.initials: M
authors.lastname: Habdank
authors.forename: Daniela
authors.initials: D
authors.lastname: Späth
authors.forename: Michael
authors.initials: M
authors.lastname: Morgan
authors.forename: Axel
authors.initials: A
authors.lastname: Benner
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schlegelberger
authors.forename: Gerhard
authors.initials: G
authors.lastname: Heil
authors.forename: Arnold
authors.initials: A
authors.lastname: Ganser
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
mesh_terms: D000293:Adolescent; D000328:Adult; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics; D005260:Female; D005819:Genetic Markers; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009154:Mutation; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D000090243:Nucleophosmin; D009856:Oncogene Proteins, Viral / Q000235:genetics; D012074:Remission Induction; D033581:Stem Cell Transplantation; D016896:Treatment Outcome; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D005819:Genetic Markers; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D009856:Oncogene Proteins, Viral; D000090243:Nucleophosmin; D051788:Myeloid-Lymphoid Leukemia Protein; D051941:fms-Like Tyrosine Kinase 3