title: Gene mutations and response to treatment with all-trans retinoic acid in elderly patients with acute myeloid leukemia. Results from the AMLSG Trial AML HD98B.
abstract: BACKGROUND
  In a previous randomized trial, AML HD98B, we showed that administration of all-trans retinoic acid in addition to intensive chemotherapy improved the outcome of older patients with acute myeloid leukemia. The objectives of this study were to evaluate the prognostic impact of gene mutations and to identify predictive genetic factors for the all-trans retinoic acid treatment effect.
  
  
  METHODS
  Data from mutation analyses of the NPM1, CEBPA, FLT3, and MLL genes were correlated with outcome in patients 61 years and older treated within the AML HD98B trial.
  
  
  RESULTS
  The frequencies of mutations were: NPM1, 23%; CEBPA, 8.5% (analysis restricted to patients with a normal karyotype); FLT3 internal tandem duplications (ITD), 17%; FLT3 tyrosine kinase domain mutations, 5%; and MLL partial tandem duplications, 4.5%. The genotype mutant NPM1 was positively and adverse cytogenetics as well as higher white blood cell count negatively correlated with achievement of complete remission. In Cox regression analysis, a significant interaction between the genotype mutant NPM1 without FLT3-ITD and treatment with all-trans retinoic acid was identified, in that the beneficial effect of all-trans retinoic acid on relapse-free and overall survival was restricted to this subgroup of patients. Other significant factors for survival were age, adverse cytogenetics, and logarithm of white cell count.
  
  
  CONCLUSIONS
  In elderly patients with acute myeloid leukemia, NPM1 mutations are associated with achievement of complete remission, and the genotype 'mutant NPM1 without FLT3-ITD' appears to be a predictive marker for response to all-trans retinoic acid given as an adjunct to intensive chemotherapy (ClinicalTrials.gov Identifier: NCT00151242).
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany. richard.schlenk@uniklinik-ulm.de
authors.forename: Richard F
authors.initials: RF
authors.lastname: Schlenk
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
authors.forename: Michael
authors.initials: M
authors.lastname: Kneba
authors.forename: Katharina
authors.initials: K
authors.lastname: Götze
authors.forename: Frank
authors.initials: F
authors.lastname: Hartmann
authors.forename: Francesco
authors.initials: F
authors.lastname: Del Valle
authors.forename: Heinz
authors.initials: H
authors.lastname: Kirchen
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Koller
authors.forename: Jörg T
authors.initials: JT
authors.lastname: Fischer
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: Silja
authors.initials: S
authors.lastname: Groner
authors.forename: Bernhard
authors.initials: B
authors.lastname: Krebs
authors.forename: Sabine
authors.initials: S
authors.lastname: Kayser
authors.forename: Andrea
authors.initials: A
authors.lastname: Corbacioglu
authors.forename: Andreas
authors.initials: A
authors.lastname: Anhalt
authors.forename: Axel
authors.initials: A
authors.lastname: Benner
authors.forename: Stefan
authors.initials: S
authors.lastname: Fröhling
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D000090243:Nucleophosmin; D010865:Pilot Projects; D015996:Survival Rate; D016896:Treatment Outcome; D014212:Tretinoin / Q000627:therapeutic use*
chemical_list: D015415:Biomarkers; C000716967:NPM1 protein, human; D000090243:Nucleophosmin; D014212:Tretinoin