title: Clinical features of de novo acute myeloid leukemia with concurrent DNMT3A, FLT3 and NPM1 mutations.
abstract: BACKGROUND
  De novo acute myeloid leukemia (AML) with concurrent DNMT3A, FLT3 and NPM1 mutations (AML DNMT3A/FLT3/NPM1 ) has been suggested to represent a unique AML subset on the basis of integrative genomic analysis, but the clinical features of such patients have not been characterized systematically.
  
  
  METHODS
  We assessed the features of patients (n = 178) harboring mutations in DNMT3A, FLT3 and/or NPM1, including an index group of AML DNMT3A/FLT3/NPM1 patients.
  
  
  RESULTS
  Patients with AML DNMT3A/FLT3/NPM1 (n = 35) were significantly younger (median, 56.0 vs. 62.0 years; p = 0.025), mostly women (65.7% vs. 46.9%; p = 0.045), and presented with a higher percentage of bone marrow blasts (p < 0.001) and normal cytogenetics (p = 0.024) in comparison to patients within other mutation groups in this study. Among patients <60 years old, those with AML DNMT3A/FLT3/NPM1 had a shorter event-free survival (EFS) (p = 0.047). DNMT3A mutations and not FLT3 or NPM1 mutations were independently associated with overall survival (OS) (p = 0.026). Within mutation subgroups, patients with AML DNMT3A/NPM1 had a significantly shorter OS compared to those with AML FLT3-ITD/NPM1 (p = 0.047) suggesting that the adverse impact of DNMT3A mutations is more pronounced than that of FLT3-ITD among patients with NPM1 mutation.
  
  
  CONCLUSIONS
  DNMT3A has a significant dominant effect on the clinical features and outcomes of de novo AML patients with concurrent DNMT3A, FLT3 and NPM1 mutations.
authors.forename: Sanam
authors.initials: S
authors.lastname: Loghavi
authors.forename: Zhuang
authors.initials: Z
authors.lastname: Zuo
authors.forename: Farhad
authors.initials: F
authors.lastname: Ravandi
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.forename: Carlos
authors.initials: C
authors.lastname: Bueso-Ramos
authors.forename: Liping
authors.initials: L
authors.lastname: Zhang
authors.forename: Rajesh R
authors.initials: RR
authors.lastname: Singh
authors.forename: Keyur P
authors.initials: KP
authors.lastname: Patel
authors.forename: L Jeffrey
authors.initials: LJ
authors.lastname: Medeiros
authors.forename: Francesco
authors.initials: F
authors.lastname: Stingo
authors.forename: Mark
authors.initials: M
authors.lastname: Routbort
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes
authors.forename: Rajyalakshmi
authors.initials: R
authors.lastname: Luthra
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Khoury
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D000090243:Nucleophosmin; D016133:Polymerase Chain Reaction; D016016:Proportional Hazards Models; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: C000717967:DNMT3A protein, human; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3