Importance of early detection and follow-up of FLT3 mutations in patients with acute myeloid leukemia

Abstract

Mutations in the fms-like tyrosine kinase 3 (FLT3) gene, such as internal tandem duplication (FLT3/ITD) in the juxtamembrane domain and point mutations in the tyrosine kinase domain, are the most common abnormalities in acute myeloid leukemia (AML). FLT3/ITD and FLT3/D835 mutations were analyzed in 113 Serbian adult AML patients using polymerase chain reaction. Twenty patients were found to be FLT3/ITD positive (17.7%). The mutations occurred most frequently in M5 and M0 subtypes of AML. They were mainly associated with the normal karyotype. All patients harboring FLT3/ITD had a higher number of white blood cells than patients without it (p=0.027). FLT3/ITD mutations were associated with lower complete remission (CR) rate (chi(2)=5.706; p=0.017) and shorter overall survival (OS; Log rank=8.76; p=0.0031). As for disease-free survival, the difference between FLT3/ITD-positive and FLT3/ITD-negative patients was not statistically significant (Log rank=0.78; p=0.3764). In multivariate analysis, the presence of FLT3/ITD mutations was the most significant prognostic factor for both OS and CR rate (p=0.0287; relative risk=1.73; 95% CI=1.06-2.82). However, in the group of patients with the intermediate-risk karyotype, the mere presence of FLT3/ITD was not associated with inferior clinical outcome. FLT3/D835 point mutation was found in four patients (3.5%) only. Follow-up of the FLT3/ITD-positive patients revealed stability of this mutation during the course of the disease. However, changes in the pattern of FLT3/D835 mutations in initial and relapsed AML were observed. Our results indicate an association of FLT3/ITD with the adverse outcome in AML patients treated with standard induction chemotherapy. Because FLT3/ITD mutation is a target for specific therapeutic inhibition, its early detection could be helpful in clinical practice.