Mead AJ et al. (2007) FLT3 tyrosine kinase domain mutations are biologically distinct from and have a significantly more favorable prognosis than FLT3 internal tandem duplications in patients with acute myeloid leukemia. Blood 110: 1262–1270

In patients with acute myeloid leukemia (AML), internal tandem duplications (ITDs) within the tyrosine kinase protein FLT3 correlate with increased relapse rates and poor overall survival (OS); however, the prognostic impact of mutations in the tyrosine kinase domain (TKD) of FLT3 is currently unknown.

In a recent study, 1,107 young adults with AML of known FLT3-ITD mutation status were screened for FLT3-TDK mutations. Overall, FLT3-TDK mutations were identified in 127 patients, and their presence was associated with an increased white blood cell count (P = 0.006). Patients with inv(16) chromosomal translocation were significantly more likely to harbor FLT3-TDK mutations than were patients without this translocation (P = 0.005). By contrast, FLT3-TDK mutations were rare in subjects with adverse cytogenetics (P = 0.008) and in patients with secondary AML. The 5-year OS rate was higher in patients with FLT3-TDK mutations than in TKD-mutation-negative patients (53% and 37%, respectively; P = 0.002). Comparison of FLT3-TDK versus FLT3-ITD mutation carriers showed statistically significant differences in OS (odds ratio 0.53; P <0.001) and cumulative incidence of relapse (odds ratio 0.45; P <0.001). In multivariate analysis, patients with a high proportion of mutated FLT3 alleles (i.e. greater than the median level of 25%) had a higher rate of OS at 10 years than did wild-type patients or patients who had a low relative FLT3 mutation level (P = 0.004).

The authors suggest that distinct mutations of FLT3 correlate with different clinical outcomes and that this finding might have implications for the management of patients with AML.