Submitted April 11, 2006
Accepted April 19, 2007
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
Adam J Mead*, David C Linch, Robert K Hills, Keith Wheatley, Alan K Burnett, and Rosemary E Gale
Department of Haematology, Royal Free and University College Medical School, London, United Kingdom
Department of Haematology, School of Medicine, Cardiff University, Cardiff, United Kingdom
Clinical Trials Unit, University of Birmingham, Birmingham, United Kingdom
* Corresponding author; email: adam.mead{at}ucl.ac.uk.
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 non-acute 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 intervals 0.58-0.89, 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<.0001). 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 chemo-resistance in AML.
