Next-generation sequencing-based posttransplant monitoring of acute myeloid leukemia identifies patients at high risk of relapse
Next-generation sequencing-based posttransplant monitoring of acute myeloid leukemia identifies patients at high risk of relapse
复制标题
基于下一代测序的急性髓系白血病移植后监测可识别复发风险高的患者
DOI：
10.1182/blood-2018-04-848028
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发表时间：
2018-10-11
期刊：
影响因子：
20.3
通讯作者：
Kim, Dennis Dong Hwan
中科院分区：
文献类型：
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作者：
Kim, TaeHyung;Moon, Joon Ho;Kim, Dennis Dong Hwan
新一代测序 (NGS) 已用于定义临床相关的体细胞突变并对急性髓系白血病 (AML) 的亚型进行分类。化疗后持续的等位基因负荷与较高的复发率相关，但尚未对接受同种异体造血细胞移植（HCT）后的 AML 患者等位基因负荷的存在进行纵向研究。因此，我们的目的是评估 NGS 监测接受 HCT 的 AML 患者的可行性。使用靶向基因组，我们使用诊断时、HCT 前和 HCT 后第 21 天（HCTD21 后）收集的样本对 104 名接受 HCT 的 AML 患者进行了 NGS。 NGS 在诊断时在 104 名患者中的 90 名中检测到了 256 个突变，这些突变在化疗和 HCT 后显示出逐步清除。在一部分患者中，HCT 前和 HCT 后仍可检测到突变。大多数 HCT 后突变源自诊断时最初检测到的突变。复发患者的 HCTD21 后等位基因负荷高于非复发患者。复发患者的 HCTD21 后突变均在复发时扩大。对变异等位基因频率 (VAF) 的评估显示，HCTD21 后的总体 VAF（VAF(0.2%)-HCTD21 后）与复发风险增加（3 年时 56.2% vs 16.0%；P < .001）和总生存率较差（OS；3 年时 36.5% vs 67.0%；P = .006）相关。多变量分析证实，HCTD21 后的 VAF(0.2%) 是 OS（风险比 [HR]，3.07；P = .003）和复发率（HR，4.75；P < .001）的不良预后因素，与修订后的欧洲 LeukemiaNet 风险组无关。总体而言，目前的研究表明，基于 NGS 的 AML 患者移植后监测是可行的，并且可以区分复发的高风险患者。
Next-generation sequencing (NGS) has been applied to define clinically relevant somatic mutations and classify subtypes in acute myeloid leukemia (AML). Persistent allelic burden after chemotherapy is associated with higher relapse incidence, but presence of allelic burden in AML patients after receiving allogeneic hematopoietic cell transplantation (HCT) has not been examined longitudinally. As such, we aimed to assess the feasibility of NGS in monitoring AML patients receiving HCT. Using a targeted gene panel, we performed NGS in 104 AML patients receiving HCT using samples collected at diagnosis, pre-HCT, and post-HCT at day 21 (post-HCTD21). NGS detected 256 mutations in 90 of 104 patients at diagnosis, which showed stepwise clearances after chemotherapy and HCT. In a subset of patients, mutations were still detectable pre-HCT and post-HCT. Most post-HCT mutations originate from mutations initially detected at diagnosis. Post-HCTD21 allelic burdens in relapsed patients were higher than in nonrelapsed patients. Post-HCTD21 mutations in relapsed patients all expanded at relapse. Assessment of variant allele frequency (VAF) revealed that overall VAF post-HCTD21 (VAF(0.2%)-post-HCTD21) is associated with an increased risk of relapse (56.2% vs 16.0% at 3 years; P < .001) and worse overall survival (OS; 36.5% vs 67.0% at 3 years; P = .006). Multivariate analyses confirmed that VAF(0.2%)-post-HCTD21 is an adverse prognostic factor for OS (hazard ratio [HR], 3.07; P =.003) and relapse incidence (HR, 4.75; P < .001), independent of the revised European LeukemiaNet risk groups. Overall, current study demonstrates that NGS-based posttransplant monitoring in AML patients is feasible and can distinguish high-risk patients for relapse.