The results suggest that these mutations contribute to the leukemic process and that the FLT3 receptor represents a therapeutic target in AML.(Blood.2001;98:885-887)
An analysis in the 201 patients newly diagnosed with AML (excluding M3) revealed that, in contrast to the FLT3/ITD mutation (n = 46), D835 mutations (n = 8) were not significantly related to the leukocytosis, but tended to worsen disease-free survival.
Improved prognostic significance of cytokine-induced proliferation in vitro in patients with de novo acute myeloid leukemia of intermediate risk: impact of internal tandem duplications in the Flt3 gene.
Our observations of independent Flt3-ITD and the detection of new Flt3-abnormalities at the time of relapse suggest that (i) Flt3-gene abnormalities may be even more important in the pathogenesis of chemotherapy-resistant AML than suggested from previous studies of newly diagnosed AML, and (ii) monitoring of minimal residual disease by using patient-specific real-time polymerase chain reaction assays for Flt3-abnormalities may not be reliable.
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.
We retrospectively evaluated the effect of reinforced courses of chemotherapy on the prognostic value of FLT3-ITDs in 159 AML patients prospectively enrolled in the ALFA-9000 trial, which randomly compared three reinforced induction regimens (standard 3+7 including high-dose daunorubicin, double induction, and timed-sequential therapy).
Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis.
The incidence of FLT3/ITD was 11.3% (9 out of 80 patients) in AML, with 25% (3 out of 12 patients) in acute promyelocytic leukemia (APL) and 8.8% (6 out of 68 patients) in non-M3 AML.
Data suggest a multistep pathogenesis for AML in which class I mutations, such as activating point mutations in receptor tyrosine kinases (eg, FLT3 and c-KIT), provide a proliferative and/or survival signal to hematopoietic progenitors.
Our results suggest that FLT3/ITD may contribute as the initial transforming event in AML, and relapse can reflect the selection and outgrowth of a mutant clone or evolution of a new clone harboring this mutation.
In human FLT3-ITD-positive AML cell lines, CT53518 induced apoptosis and inhibited FLT3-ITD phosphorylation, cellular proliferation, and signaling through the MAP kinase and PI3 kinase pathways.
To date, constitutively activating point mutations reported in hematopoietic growth factor receptors in patients with acute myeloid leukemia (AML) have been restricted to receptors with intrinsic tyrosine kinase activity such as c-kit and FLT3.
FLT3 mutations, either internal tandem duplications (ITDs) or aspartate residue 835 (D835) point mutations, are present in approximately one third of patients with acute myeloid leukemia (AML) and have been associated with an increased relapse rate.
CEP-701 and other FLT3 inhibitors may be useful for overcoming the block to differentiation (as well as the block to apoptosis) in the leukemic cells of patients with AML.