title: Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis.
abstract: Constitutive activation of the FLT3 receptor tyrosine kinase, either by internal tandem duplication (ITD) of the juxtamembrane region or by point mutations in the second tyrosine kinase domain (TKD), has been described in patients with acute myelogenous leukemia (AML). We analyzed the prevalence and the potential prognostic impact of FLT3 mutations in 979 AML patients. Results were correlated with cytogenetic data and the clinical response. FLT3-ITD mutations were found in 20.4% and FLT3-TKD mutations in 7.7% of the patients. Each mutation was associated with similar clinical characteristics and was more prevalent in patients with normal karyotype. Significantly more FLT3 aberrations were found in patients with FAB M5, and fewer were found in patients with FAB M2 and M6. Although less frequent in patients with cytogenetic aberrations, FLT3-ITDs were found in 13 of 42 patients with t(15;17) and in 9 of 10 patients with t(6;9). The prevalence of the ITD allele on the DNA level was heterogeneous, ranging from faint mutant bands in some patients to predominant mutant bands in others. Based on quantitative analysis, the mutant-wild-type (wt) ratio ranged from 0.03 to 32.56 (median, 0.78). Patients with a high mutant/wt ratio (ie, greater than 0.78) had significantly shorter overall and disease-free survival, whereas survival in patients with ratios below 0.78 did not differ from those without FLT3 aberrations. Multivariate analysis confirmed a high mutant/wt ratio to be a strong independent prognostic factor. Taken together, these data confirm that FLT mutations represent a common alteration in adult AML. Constitutive activation may be associated with monocytoid differentiation. A high mutant/wt ratio in ITD-positive patients appears to have a major impact on the prognostic relevance.
authors.affiliation: Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus der Technischen Universität, Dresden, Germany. thiede@mk1.med.tu-dresden.de
authors.forename: Christian
authors.initials: C
authors.lastname: Thiede
authors.forename: Christine
authors.initials: C
authors.lastname: Steudel
authors.forename: Brigitte
authors.initials: B
authors.lastname: Mohr
authors.forename: Markus
authors.initials: M
authors.lastname: Schaich
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schäkel
authors.forename: Uwe
authors.initials: U
authors.lastname: Platzbecker
authors.forename: Martin
authors.initials: M
authors.lastname: Wermke
authors.forename: Martin
authors.initials: M
authors.lastname: Bornhäuser
authors.forename: Markus
authors.initials: M
authors.lastname: Ritter
authors.forename: Andreas
authors.initials: A
authors.lastname: Neubauer
authors.forename: Gerhard
authors.initials: G
authors.lastname: Ehninger
authors.forename: Thomas
authors.initials: T
authors.lastname: Illmer
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D019943:Amino Acid Substitution; D015331:Cohort Studies; D020732:Cytogenetic Analysis; D004789:Enzyme Activation / Q000235:genetics; D005820:Genetic Testing; D005858:Germany / Q000453:epidemiology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000145:classification / Q000201:enzymology / Q000235:genetics*; D008875:Middle Aged; D017354:Point Mutation; D015995:Prevalence; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D016019:Survival Analysis; D020080:Tandem Repeat Sequences; D051941:fms-Like Tyrosine Kinase 3
chemical_list: D011518:Proto-Oncogene Proteins; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3