The prognostic significance of IDH1 mutations in younger adult patients with acute myeloid leukaemia is dependent on FLT3/ITD status [Abstract]
Green CL., Evans CM., Hills RK., Burnett AK., Linch DC., Gale RE.
Mutations in the isocitrate dehydrogenase (IDH1) gene were originally identified in patients with glioma but were recently detected in acute myeloid leukaemia (AML) patients following whole-genome sequencing of a single patient. Unlike glioma, where they improved outcome, in AML they were associated with a trend for worse outcome. To investigate this further we used dHPLC to screen 1333 young adult patients, excluding acute promyelocytic leukaemia, treated in the MRC AML10 and 12 trials and with known FLT3/ITD and NPM1 status. A mutation was detected in 107 patients(8%). IDH11patients were significantly older (po.0001) but there was no difference according to type of leukaemia or presenting white cell count. Most IDH11patients (91%) had intermediate-risk cytogenetics; 74% had a normal karyotype. Mutations were significantly correlated with an NPM1 mutation (po.0001) but not a FLT3/ITD (p5.9). In univariate and multivariate analysis, the remission rate, relapse rate (RR) and overall survival (OS) did not differ according to IDH1 mutation status. There was also no difference in outcome if the results were stratified according to NPM1 status: RR at 10 years for IDH11and IDH1- patients was 67% vs 61% for NPM1- (p5.7), 62% vs 47% for NPM11patients(p5.09). However, when cases were stratified according to FLT3/ ITD status, there was a trend for a higher RR in FLT3/ITD- patients (67% vs 51%, p5.06) but not in FLT3/ITD1patients (54% vs 68%, p5.09). In multivariate analysis, an IDH1 mutation was an independent adverse factor for relapse in FLT3/ITD- patients (p5.008) and a favourable factor in FLT3/ITD1patients (p5.02)with significant heterogeneity (p5.002). OS data was compatible with the results for relapse. These results suggest that metabolic changes induced by an IDH1 mutation may influence chemoresistance in a manner that is context-dependent.