The evaluation of measurable residual disease (MRD) in acute myeloid leukemia (AML) using comprehensive mutation analysis by next-generation sequencing (NGS) has been investigated in several studies. However controversial results exist regarding the detection of persisting mutations in DNMT3A, TET2, and ASXL1 (DTA). Benchmarking of NGS-MRD taking into account other molecular MRD strategies has to be done. Here, we performed error-corrected-NGS-MRD in 189 patients homogeneously treated in the ALFA-0702 study (NCT00932412). Persistence of non-DTA mutations (HR = 2.23 for RFS and 2.26 for OS), and DTA mutations (HR = 2.16 for OS) were associated with poorer prognosis in multivariate analysis. Persistence of at least two mutations in complete remission (CR) was associated with a higher cumulative incidence of relapse (CIR) (HR = 3.71, p < 0.0001), lower RFS (HR = 3.36, p < 0.0001) and OS (HR = 3.81, p = 0.00023) whereas persistence of only one mutation was not. In 100 analyzable patients, WT1-MRD, but not NGS-MRD, was an independent factor for RFS and OS. In the subset of 67 NPM1 mutated patients, both NPM1 mutation detection (p = 0.0059) and NGS-MRD (p = 0.035) status were associated with CIR. We conclude that detectable NGS-MRD including DTA mutations correlates with unfavorable prognosis in AML. Its integration with alternative MRD strategies in AML management warrants further investigations.
通过二代测序进行全面突变分析以评估急性髓系白血病可测量残留病的方法已在多项研究中得到探讨。然而，关于DNMT3A、TET2和ASXL1基因中持续存在的DTA突变检测仍存在争议性结果。需要结合其他分子残留病检测策略对二代测序-MRD进行基准评估。本研究对ALFA-0702试验（NCT00932412）中接受统一治疗的189例患者进行了纠错二代测序-MRD检测。多变量分析显示，非DTA突变的持续存在（RFS风险比=2.23，OS风险比=2.26）及DTA突变的持续存在（OS风险比=2.16）均与不良预后相关。完全缓解期存在至少两个突变与更高的累积复发率（风险比=3.71，p<0.0001）、更低的无复发生存率（风险比=3.36，p<0.0001）和总生存率（风险比=3.81，p=0.00023）显著相关，而单个突变的持续存在则无此关联。在100例可分析患者中，WT1-MRD（而非二代测序-MRD）是无复发生存和总生存的独立影响因素。在67例NPM1突变患者亚组中，NPM1突变检测（p=0.0059）与二代测序-MRD状态（p=0.035）均与累积复发率相关。本研究结论：包括DTA突变在内的可检测二代测序-MRD与急性髓系白血病不良预后相关，其与其他残留病检测策略在临床管理中的整合应用值得进一步研究。
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