Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis
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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.