Quantification of Measurable Residual Disease Using Duplex Sequencing in Adults with Acute Myeloid Leukemia

Duplex sequencing (DS) is an error-corrected next generation sequencing (NGS) method that generates double-stranded consensus sequences to reduce artifacts. DS detection of measurable residual disease (MRD) in adult acute myeloid leukemia (AML) was investigated and compared to multiparametric flow cytometry (MFC). Among 67 adult patients treated intensively to first complete remission on the randomized phase 3 SWOG 0106 clinical trial, 62 had a mutation in a 29 gene panel at time of diagnosis that could be tracked in remission. 43 patients harbored at least 1 residual time of diagnosis mutation in remission, with median variant allele frequency (VAF) of 0.059% (range 0.005-41.8%). DS MRD positivity was defined as a non-DNMT3A/TET2/ASXL1 residual mutation with VAF > 0.1% and/or FLT3-ITD/NPM1 VAF > 0.01%. 22 patients (35%) were DS MRD positive. Hazard ratios (HR) of 8.8, 5.4 and 5.6 were observed for increased rates of relapse, decreased rates of relapse-free survival and decreased overall survival, respectively. HRs were highly significant and were greater than those from MFC MRD positivity, suggesting utility of DS for AML MRD detection.