Publication Date:
2014-12-06
Description:
NPM1 mutation (NPM1c) defines the commonest molecular subtype of AML, which is molecularly heterogeneous, with outcome influenced by the pattern of cooperating mutations. This has generated interest in molecular profiling to guide treatment approach, particularly concerning allogeneic transplantation (SCT) in first complete remission (CR1). Patients with NPM1c AML with FLT3-ITD and/or DNMT3A mutations have been associated with poorer outcome and are widely considered candidates for SCT. Conversely, those with the NPM1c/FLT3-ITDneg genotype are no longer routinely transplanted in CR1, due to their generally favorable outcome. Given the molecular heterogeneity, use of real time quantitative PCR (RT-qPCR) to detect residual leukemia (MRD) could improve outcome prediction. However, its value has been questioned by recent studies providing evidence that relapse can arise from preleukemic clones. To address these issues we analysed sequential samples from 346 patients (median age 50y, 6-81y) with NPM1c AML treated in the UK NCRI AML17 trial (median follow-up 35mo). An established RT-qPCR assay with mutation-specific primers was used, allowing MRD detection in all patients, covering 27 NPM1 mutations. Assays were confirmed to be mutant specific, with a median sensitivity of 1 in 105 (1 in 103.7-7.1). Overall 2,569 follow-up samples (902 BM, 1667 PB) were analysed (median 6 samples/pt). To determine if MRD assessment provided independent prognostic information, targeted sequencing (Haloplex, Agilent Technologies) of 51 genes was undertaken in 223 cases with available diagnostic DNA. The panel included established recurrent mutation targets in NPM1c AML and 14 genes found to be mutated in whole exome sequencing of 27 cases with differing kinetics of relapse or sustained molecular remission (CRm). For patients in documented morphological CR, early MRD assessment distinguished those at markedly differing risk of relapse and overall survival (OS). For patients with NPM1 mutant transcripts still detectable in peripheral blood (PB) following chemotherapy course 2 (30 of 194, 15%), cumulative incidence of relapse was 77% at 3 years, compared to 28% in those testing PCR negative (p
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
,
Medicine
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