title: 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.
authors.affiliation: Institute of Hematology, Clinical Center of Serbia, Belgrade, Serbia.
authors.forename: Natasa
authors.initials: N
authors.lastname: Colovic
authors.forename: Natasa
authors.initials: N
authors.lastname: Tosic
authors.forename: Sanja
authors.initials: S
authors.lastname: Aveic
authors.forename: Marija
authors.initials: M
authors.lastname: Djuric
authors.forename: Natasa
authors.initials: N
authors.lastname: Milic
authors.forename: Vladimir
authors.initials: V
authors.lastname: Bumbasirevic
authors.forename: Milica
authors.initials: M
authors.lastname: Colovic
authors.forename: Sonja
authors.initials: S
authors.lastname: Pavlovic
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D002869:Chromosome Aberrations; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D017354:Point Mutation; D012008:Recurrence; D012307:Risk Factors; D033581:Stem Cell Transplantation; D015996:Survival Rate; D014184:Transplantation, Homologous; D015022:Yugoslavia; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3