DNMT3A mutant transcript levels persist in remission and do not predict outcome in patients with acute myeloid leukemia

Abstract

We investigated the prognostic impact of minimal residual disease (MRD) monitoring in acute myeloid leukemia patients harboring DNA methyltransferase 3A-R882H/-R882C mutations (DNMT3A(mut)). MRD was determined by real-time quantitative PCR (RQ-PCR) in 1494 samples of 181 DNMT3A(mut) patients. At the time of diagnosis, DNMT3A(mut) transcript levels did not correlate with presenting clinical characteristics and concurrent gene mutations as well as the survival end points. In Cox regression analyses, bone marrow (BM) DNMT3A(mut) transcript levels (log10-transformed continuous variable) were not associated with the rate of relapse or death. DNMT3A(mut) transcript levels were significantly higher in BM than in blood after induction I (P = 0.01), induction II (P = 0.05), consolidation I (P = 0.004) and consolidation II (P = 0.008). With regard to the clinically relevant MRD time points, after two cycles of induction and at the end of therapy, DNMT3A(mut) transcript levels had no impact on the end point remission duration and overall survival. Of note, only a minority of the patients achieved RQ-PCR negativity, whereas most had constantly high DNMT3A(mut) transcript levels, a finding which is consistent with the persistence of clonal hematopoiesis in hematological remission.