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Blood. 2007 Aug
15;110(4):1262-70. Epub 2007 Apr 24.
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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.
Mead AJ, Linch DC, Hills RK,
Wheatley K, Burnett AK, Gale RE.
Department of Haematology,
Royal Free and University College Medical
School, London, United Kingdom. adam.mead@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 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.
PMID: 17456725 [PubMed - indexed
for MEDLINE]