Prognostic significance of FLT3 ITD and D835 mutations in AML patients

Both ITD and D835 mutations of the fms-like tyrosine kinase (FLT3) gene cause constitutive activation of the receptor, in the absence of ligand. We have examined a cohort of 91 patients, AML (80) and MDS (11), to determine the prevalence of these mutations and any correlations between the two mutations and disease prognosis. FLT3/ITD (ITD+) or D835 mutations (D835+) were not detected in MDS patients examined. However, 10% (8/80) and 7.5% (6/80) of AML patients were ITD+ and D835+, respectively. ITD+ patients have a higher rate of relapse than patients with wild-type (WT) FLT3. Median overall survival was 4.6 months (range 0.6-36.2) for ITD+ and 19.85 months (range 0.2-197.5) for WT patients (P=0.0066), and disease-free survival (DFS) was also worse for ITD+ patients than FLT3/WT patients (P=0.047). FLT3/ITD is also a significant prognostic marker for overall survival (OS) and DFS in patients in the standard karyotype group (P=0.0040, 0.0365, respectively). ITD is more prevalent in patients in the standard karyotype category (7/41, 17.1%) as compared to patients in the poor-risk category (1/32, 3.1%). Similar to ITD, D835 mutations were found to be more frequent in patients with standard-risk rather than poor-risk cytogenetic category. WBC count (mean 63.8 x 10(9)/l) was significantly higher in ITD+ patients than patients with D835 mutations (mean 34.8 x 10(9)/l) and WT patients (mean 26.4 x 10(9)/l) (P=0.004). D835 mutants did not appear to have a worse median OS or DFS compared with the WT group. We conclude that FLT3/ITD mutations may be an important prognostic marker in AML, especially in the standard/good risk karyotype groups, where it may allow risk-directed therapy.