David C. Linch

Frequency of CBFβ/MYH11 fusion transcripts in patients entered into the U.K. MRC AML trials

It has been established that cytogenetic findings at diagnosis of acute myeloid leukaemia (AML) are a powerful prognostic indicator. Patients who have the inv(16)(p13q22), closely associated with the FAB subtype M4Eo, are deemed to have good‐risk disease. This subtle translocation may be difficult to detect in poor‐quality metaphase preparations and if missed could lead to the incorrect assignment of risk group and influence further treatment strategies.

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

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.

In Reply [to 'Comparing Apples and Oranges in Normal Karyotype Acute Myeloid Leukemia' by Bruno C. Medeiros] [Letter]

We thank Medeiros for his interest in our recent study of Wilms’ tumor 1 (WT1) mutations in acute myeloid leukemia. The data are broadly similar to an accompanying article by Paschka et al1 with regard to the frequency of WTI mutations in younger patients with acute myeloid leukemia with a normal karyotype, and to the adverse impact of such mutations independent of the mutational status of NPM1 and FLT3 internal tandem duplications (FLT3-ITDs). As noted by Medeiros, and in contrast to the study of Paschka et al, we chose not to include an analysis of the individual subsets of patients defined by the combination of the mutational status of NPM1 and FLT3-ITDs as part of our original submission. We were reluctant to present this data because we had seen no significant interaction between the impact of a WT1 mutation and the presence of an NPM1 mutation or an FLT3-ITD, and the individual subsets defined by these two parameters included too few patients with a WT1 mutation to facilitate robust interpretation.