Open AccessThe importance of relative mutant level for evaluating impact on outcome of KIT, FLT3 and CBL mutations in core-binding factor acute myeloid leukemia
Author(s) -
Christopher Allen,
Robert Kerrin Hills,
Katarina Lamb,
Catherine M Evans,
Steven Tinsley,
Rob S. Sellar,
Michelle A. O'Brien,
John Liu Yin,
Alan Kenneth Burnett,
David C. Linch,
Rosemary E. Gale
Publication year - 2013
Publication title -
leukemia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.539
H-Index - 192
eISSN - 1476-5551
pISSN - 0887-6924
DOI - 10.1038/leu.2013.186
Subject(s) - myeloid leukemia , core binding factor , medicine , fms like tyrosine kinase 3 , oncology , mutant , mutation , minimal residual disease , cumulative incidence , leukemia , confidence interval , myeloid , cancer research , biology , immunology , gene , genetics , transcription factor , transplantation
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 (FLT3(TKD)), N-RAS, K-RAS and c-CBL mutations and FLT3 internal tandem duplications (FLT3(ITD)) and assessed the impact of relative mutant level on outcome. Overall, 28% had KIT, 6% FLT3(ITD), 10% FLT3(TKD), 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 FLT3(ITD-HIGH) was a significant adverse factor for overall survival (OS; CI=1.27-5.39, P=0.004). Conversely, FLT3(TKD-HIGH) and CBL(HIGH) 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.