title: Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm.
abstract: To assess the prognostic relevance of activating mutations of the FLT3 gene in homogeneously treated adults 16 to 60 years of age with acute myeloid leukemia (AML) and normal cytogenetics, pretreatment samples from 224 patients entered into 2 consecutive multicenter treatment trials were analyzed for FLT3 internal tandem duplications (ITDs) and Asp835 mutations. Treatment included intensive double-induction therapy and postremission therapy with high cumulative doses of high-dose cytarabine. ITDs were detected in 32% of the patients and were related to de novo AML and to high white blood cell (WBC) counts, percentages of peripheral blood (PB) and bone marrow (BM) blasts, and serum lactate dehydrogenase levels. Asp835 mutations were present in 14% of the patients and were associated with WBC counts and percentages of PB and BM blasts that were higher than those of patients without FLT3 mutations. With a median follow-up of 34 months, remission duration and overall survival (OS) were significantly shorter for patients with Asp835 mutations or an ITD than for those without FLT3 mutations (P =.03 and P =.0004, respectively). These results were attributable mainly to the negative prognostic effect of FLT3 ITDs. On multivariate analysis, mutant FLT3 was an independent marker affecting remission duration and OS (hazard ratio, 2.35 and 2.11, respectively). Fluorescence in situ hybridization did not detect monoallelic FLT3 deletions in ITD-positive patients. FLT3 mutations identify a subset of young AML patients with normal cytogenetics who do not benefit from intensive chemotherapy, including double-induction and postremission therapy with high-dose cytarabine.
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Fröhling
authors.forename: Richard F
authors.initials: RF
authors.lastname: Schlenk
authors.forename: Jochen
authors.initials: J
authors.lastname: Breitruck
authors.forename: Axel
authors.initials: A
authors.lastname: Benner
authors.forename: Sylvia
authors.initials: S
authors.lastname: Kreitmeier
authors.forename: Karen
authors.initials: K
authors.lastname: Tobis
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000483:Alleles; D019943:Amino Acid Substitution; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D003062:Codon / Q000235:genetics; D003561:Cytarabine / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D017353:Gene Deletion; D020440:Gene Duplication; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000401:mortality; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D016019:Survival Analysis; D016896:Treatment Outcome; D051941:fms-Like Tyrosine Kinase 3
chemical_list: D000964:Antimetabolites, Antineoplastic; D003062:Codon; D011518:Proto-Oncogene Proteins; D003561:Cytarabine; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3