Quantification of measurable residual disease using duplex sequencing in adults with acute myeloid leukemia.
Quantification of measurable residual disease using duplex sequencing in adults with acute myeloid leukemia.
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使用双链测序对成人急性髓系白血病的可测量残留疾病进行量化。
DOI：
10.1101/2023.03.26.23287367
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Hourigan,ChristopherS
中科院分区：
文献类型：
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作者：
Dillon,LauraW;Higgins,Jake;Nasif,Hassan;Othus,Megan;Beppu,Lan;Smith,ThomasH;Schmidt,Elizabeth;Valentine3rd,CharlesC;Salk,JesseJ;Wood,BrentL;Erba,HarryP;Radich,JeraldP;Hourigan,ChristopherS
可测量残留病灶 (MRD) 的存在与急性髓系白血病 (AML) 的治疗结果密切相关。尽管与临床结果相关，但 MRD 评估尚未标准化或常规纳入临床试验。不同的 MRD 评估技术之间存在差异，仍然需要对具有不同突变谱的 AML 患者进行集中、高质量的多参数流式细胞术 (MFC) 和超灵敏下一代测序 (NGS) 进行比较。在随机 3 期 SWOG-S0106 临床试验中，在 62 名年龄为 18-60 岁的 AML 患者中，在强化诱导治疗后首次完全缓解时，将 MFC 检测的 MRD 与利用双链测序 (DS) 的 29 基因组进行比较，双链测序 (DS) 是一种生成双链共有序列以减少假阳性错误的 NGS 方法。使用 DS，在 22 名 (35%) 患者中发现了使用定义标准检测到的持续突变，该突变与较高的复发率（第 5 年时的 68% 与 13%；HR，8.8；95% CI，3.2-24.5；P<0.001）和生存率降低（第 5 年的 32% 与 82%；HR，5.6；95% CI， 2.3-13.8；P<0.001)。由 DS 定义的 MRD 明显优于 MFC，在 10 名患者 (16%) 中观察到 MFC，并且与较高的复发率（第 5 年时为 50% vs 30%；HR，2.4；95% CI，0.9-6.7；P=0.087）和生存率降低（第 5 年时为 40% vs 68%；HR，2.5；95% CI， 1.0-6.3；P=0.059)。此外，缓解时 DS MRD 状态的预后意义在试验的两个随机组中相似，可预测 S0106 临床试验的结果。这些发现表明 DS 是一种强大的工具，可用于患者管理和临床试验中的早期治疗评估。
The presence of measurable residual disease (MRD) is strongly associated with treatment outcomes in acute myeloid leukemia (AML). Despite the correlation with clinical outcomes, MRD assessment has yet to be standardized or routinely incorporated into clinical trials. Discrepancies have been observed between different techniques for MRD assessment and there remains a need to compare centralized, high-quality multiparametric flow cytometry (MFC) and ultrasensitive next-generation sequencing (NGS) in AML patients with diverse mutational profiles. In 62 patients with AML, aged 18-60, in first complete remission after intensive induction therapy on the randomized phase 3 SWOG-S0106 clinical trial, MRD detection by MFC was compared with a 29 gene panel utilizing duplex sequencing (DS), an NGS method that generates double-stranded consensus sequences to reduce false positive errors. Using DS, detection of a persistent mutation utilizing defined criteria was seen in 22 (35%) patients and was strongly associated with higher rates of relapse (68% vs 13% at year 5; HR, 8.8; 95% CI, 3.2-24.5; P<0.001) and decreased survival (32% vs 82% at year 5; HR, 5.6; 95% CI, 2.3-13.8; P<0.001). MRD as defined by DS strongly outperformed MFC, which was observed in 10 (16%) patients and marginally associated with higher rates of relapse (50% vs 30% at year 5; HR, 2.4; 95% CI, 0.9-6.7; P=0.087) and decreased survival (40% vs 68% at year 5; HR, 2.5; 95% CI, 1.0-6.3; P=0.059). Furthermore, the prognostic significance of DS MRD status at the time of remission was similar on both randomized arms of the trial, predicting S0106 clinical trial outcomes. These findings suggest that DS is a powerful tool that could be used in patient management and for early treatment assessment in clinical trials.