Clinical relevance of mutant allele burden during follow-up in acute myeloid leukemia. A study by the French ALFA group.

Assessment of minimal residual disease has emerged as a powerful prognostic factor in acute myeloid leukemia. In this study, we investigated the potential of mutations as targets for minimal residual disease assessment in acute myeloid leukemia, since these mutations collectively occur in 15-20% of cases of acute myeloid leukemia and now represent druggable targets. We employed droplet digital polymerase chain reaction assays to quantify , , and mutations on genomic DNA in 322 samples from 103 adult patients with primary mutant acute myeloid leukemia and enrolled on Acute Leukemia French Association (ALFA) - 0701 or -0702 clinical trials. The median mutant allele fraction in bone marrow samples was 42.3% (range, 8.2 - 49.9%) at diagnosis of acute myeloid leukemia, and below the detection limit of 0.2% (range, <0.2 - 39.3%) in complete remission after induction therapy. In univariate analysis, the presence of a normal karyotype, a mutation, and an mutant allele fraction <0.2% in bone marrow after induction therapy were statistically significant predictors of longer disease-free survival. In multivariate analysis, these three variables remained significantly predictive of disease-free survival. In 7/103 (7%) patients, mutations persisted at high levels in complete remission, consistent with the presence of an mutation in pre-leukemic hematopoietic stem cells. Five out of these seven patients subsequently relapsed or progressed toward myelodysplastic syndrome, suggesting that patients carrying the mutation in a pre-leukemic clone may be at high risk of hematologic evolution.