title: 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.
abstract: The prognostic impact of tyrosine kinase domain (TKD) mutations of the fms-like tyrosine kinase-3 (FLT3) gene in acute myeloid leukemia (AML) is currently uncertain. To resolve this issue we screened 1107 young adult nonacute promyelocytic leukemia AML patients with known FLT3 internal tandem duplication (ITD) status for FLT3/TKDs; they were detected in 127 (11%) cases. Mutations were associated with a high white cell count (P =.006) and patients with inv(16) (P = .005) but were infrequent in patients with adverse cytogenetics and secondary AML. Overall survival (OS) at 5 years was 53% and 37% for FLT3/TKD mutant and wild-type patients respectively (odds ratio, 0.72; 95% confidence interval, 0.58 to 0.89; P = .002). For both the cumulative incidence of relapse and OS the difference in outcome between FLT3/ITDs and FLT3/TKDs was highly significant (P < .001). In multivariate analysis, impact of FLT3/TKDs on OS when including all mutant-positive patients was not significant, but patients with high-level mutations (more than 25% mutant) had a significantly improved outcome (P = .004). The novel finding that biologically distinct activating mutations of the same gene can be associated with markedly different clinical outcomes has implications for risk stratification and therapy and is significant to the understanding of chemoresistance in AML.
authors: Department of Haematology, Royal Free and University College Medical School, London, United Kingdom. adam.mead@ucl.ac.uk
authors: Adam J
authors: AJ
authors: Mead
authors: David C
authors: DC
authors: Linch
authors: Robert K
authors: RK
authors: Hills
authors: Keith
authors: K
authors: Wheatley
authors: Alan K
authors: AK
authors: Burnett
authors: Rosemary E
authors: RE
authors: Gale
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000483:Alleles; D019943:Amino Acid Substitution; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D003561:Cytarabine / Q000627:therapeutic use; D004252:DNA Mutational Analysis; D005260:Female; D005500:Follow-Up Studies; D020440:Gene Duplication; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D011379:Prognosis; D015996:Survival Rate; D020080:Tandem Repeat Sequences / Q000235:genetics*; D016896:Treatment Outcome; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: D000964:Antimetabolites, Antineoplastic; D003561:Cytarabine; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3