title: Prognostic relevance of FLT3-TKD mutations in AML: the combination matters--an analysis of 3082 patients.
abstract: We characterized the mutational status of the FLT3 tyrosine kinase domain (FLT3-TLD) in 3082 patients with newly diagnosed AML. FLT3-TKD mutations were detected in 147 of 3082 (4.8%) patients. Similar to the FLT3 juxtamembrane domain mutations (FLT3-LM), there was a high correlation of FLT3-TKD mutations with normal karyotype (88 of 1472; 6.0%). FLT3-TKD mutations were most frequent in the AML FAB subtypes M5b (15 of 114; 13.2%), M3v (6 of 51; 11.8%), and M4 (39 of 484; 8.1%). Similar to FLT3-LM, the FLT3-TKD mutations show elevated peripheral leukocytes compared with FLT3wt AML. FLT3-TKD had a high incidence in cases with NPM1 mutations (23 of 262; 8.8%), CEBPA mutations (6 of 76; 7.9%), and NRAS mutations (6 of 78; 7.7%). FLT3-TKD in combination with FLT3-LM (17 of 594 patients; 2.9%) and KITD816 (1 of 44; 2.3%) was rare. Unlike the FLT3-LM, which are associated with inferior survival, prognosis was not influenced by FLT3-TKD in the total cohort of 1720 cases, where follow-up data were available (97 FLT3-TKD; 1623 FLT3-WT). In t(15;17)/PML-RARA with FLT3-TKD mutations, in FLT3-LM/TKD double-mutated, and in MLL-PTD/TKD double-mutated cases prognosis was unfavorably influenced by FLT3-TKD mutations. In contrast, we found an additional favorable impact of FLT3-TKD on EFS in prognostically favorable AML with NPM1- or CEBPA mutations.
authors.affiliation: Bone Marrow Transplant Unit, University Hospital of Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Bacher
authors.forename: Claudia
authors.initials: C
authors.lastname: Haferlach
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kern
authors.forename: Torsten
authors.initials: T
authors.lastname: Haferlach
authors.forename: Susanne
authors.initials: S
authors.lastname: Schnittger
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004252:DNA Mutational Analysis; D005819:Genetic Markers; D006801:Humans; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics; D000090243:Nucleophosmin; D011379:Prognosis; D017434:Protein Structure, Tertiary; D012008:Recurrence; D015996:Survival Rate; D013816:Thermodynamics; D051941:fms-Like Tyrosine Kinase 3 / Q000737:chemistry* / Q000235:genetics*
chemical_list: D005819:Genetic Markers; C000716967:NPM1 protein, human; D009363:Neoplasm Proteins; D000090243:Nucleophosmin; D051941:fms-Like Tyrosine Kinase 3