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The importance of relative mutant level for evaluating impact on outcome of KIT, FLT3 and CBL mutations in core-binding factor acute myeloid leukemia

Allen, C., Hills, Robert Kerrin, Lamb, K., Evans, C., Tinsley, S., Sellar, R., O'Brien, M., Yin, J. L., Burnett, A. K., Linch, D. C. and Gale, R. E. 2013. The importance of relative mutant level for evaluating impact on outcome of KIT, FLT3 and CBL mutations in core-binding factor acute myeloid leukemia. Leukemia 27 (9) , pp. 1891-1901. 10.1038/leu.2013.186

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Abstract

Several different mutations collaborate with the fusion proteins in core-binding factor acute myeloid leukemia (CBF-AML) to induce leukemogenesis, but their prognostic significance remains unclear. We screened 354 predominantly younger (<60 years) adults with t(8;21) (n=199) or inv(16) (n=155) entered into UK MRC trials for KIT, FLT3 tyrosine kinase domain (FLT3TKD), N-RAS, K-RAS and c-CBL mutations and FLT3 internal tandem duplications (FLT3ITD) and assessed the impact of relative mutant level on outcome. Overall, 28% had KIT, 6% FLT3ITD, 10% FLT3TKD, 27% RAS and 6% CBL mutations. Mutant levels for all genes/loci were highly variable. KIT mutations were associated with a higher cumulative incidence of relapse but in multivariate analysis this was only significant for cases with a higher mutant level of 25% or greater (95% confidence interval (CI)=1.01–1.52, P=0.04). Similarly, only FLT3ITD-HIGH was a significant adverse factor for overall survival (OS; CI=1.27–5.39, P=0.004). Conversely, FLT3TKD-HIGH and CBLHIGH were both favorable factors for OS (CI= 0.31–0.89, P=0.01 and CI=0.05–0.85, P=0.02, respectively). KIT mutations were frequently lost at relapse, which is relevant to minimal residual disease detection and the clinical use of KIT inhibitors. These results indicate that relative mutant level should be taken into account when evaluating the impact of mutations in CBF-AML.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
R Medicine > RJ Pediatrics
Uncontrolled Keywords: acute myeloid leukemia; core-binding factor; KIT; FLT3; RAS; CBL
Publisher: Nature Publishing Group
ISSN: 0887-6924
Date of Acceptance: 14 June 2013
Last Modified: 19 Oct 2019 03:00
URI: http://orca-mwe.cf.ac.uk/id/eprint/75276

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