Investigations of FLT3 internal tandem duplications in patients with acute myeloid leukaemia

In acute myeloid leukaemia (AML), further prognostic determinants are required in addition to cytogenetics to predict patients at increased risk of relapse. Recent studies have indicated an internal tandem duplication (ITD) in the FLT3 gene may adversely affect clinical outcome. The studies reported in this thesis evaluated the impact of a FLT3/ITD on outcome in 854 patients treated in UK MRC AML trials. A FLT3/ITD was present in 27% patients and was associated with leucocytosis and a high percentage of bone marrow blast cells. With respect to clinical outcome it predicted for increased relapse risk (RR), adverse disease-free survival (DFS), event-free survival (EFS) and overall survival (OS). In multivariate analysis, presence of a mutation was the most significant prognostic factor predicting for RR and DFS. In order to evaluate whether FLT3 mutations can be used as markers of minimal residual disease, paired presentation and relapse samples were studied. Twenty four patients were wild type FLT3 at diagnosis and 4 acquired a FLT3 mutation at relapse. Of 20 patients positive at diagnosis, 5 who were all originally ITD+, had no detectable mutation at relapse. Furthermore, another patient had a completely different ITD at relapse which could not be detected in the presentation sample. These results suggest that, at least in some patients, FLT3 mutations are secondary events in leukaemogenesis, are unstable and thus should be used cautiously for the detection of minimal residual disease. Given the high frequency of activating FLT3 mutations in patients with AML, FLT3 and its downstream pathway are attractive targets for directed inhibition. Several promising tyrosine kinase inhibitors have recently been identified and in vitro data reported here suggest that FLT3 inhibitors may have a role either as monotherapy or in combination with conventional cytotoxic agents in the treatment of AML.