Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations in acute promyelocytic leukemia: a systematic review

Abstract

The fms-like tyrosine kinase 3 (FLT3) gene aberrations, internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations, are frequent in acute promyelocytic leukemia (APL). To evaluate their prognostic significance, we performed a systematic review and meta-analysis. Eleven studies covering a total of 1063 subjects were included in this review. Incidence of ITD and TKD mutations was 12-38% and 2-20%, respectively. In 9 of 11 studies, ITD was associated with high WBC count at the time of diagnosis, which is a known prognostic indicator in APL. Patients with ITD had inferior 3-year overall survival compared to patients without ITD (risk ratio 1.42, 95% CI: 1.04-1.95). Similarly, ITD was also associated with adverse 3-year disease-free survival (risk ratio 1.48, 95% CI: 1.02-2.15). There were only two studies that evaluated the association of TKD mutation in APL; both showed a trend towards worse survival in patients with mutated TKD. In conclusion, FLT3 ITD is associated with high WBC at diagnosis in patients with APL. Although the available literature is limited to observational studies, our systematic review suggests that FLT3 mutations, especially ITD, can adversely affect overall survival and disease-free survival in APL.