Background: Disease relapse is a primary cause of treatment failure after hematopoietic stem cell transplantation in the treatment of malignancy. Consolidation therapy early after transplantation may reduce this risk, but it is difficult to administer in the setting of various post-transplant complications. We proposed that testing donor cell chimerism and for persistent minimal residual disease (MRD) with next-generation sequencing (NGS) of plasma cell-free DNA (cfDNA) early after transplantation would identify those patients at higher risk of relapse who would possibly benefit from consolidation therapy.Methods: We enrolled 20 subjects with known tumor-associated somatic mutations into this prospective pilot study, testing plasma samples before and at 28, 56, and 84 days after transplantation. Pre- and post-transplant bone marrow samples were also analyzed. All samples were subjected to an agnostic, commercially available panel covering 302 genes.Results: Significantly more mutations (p< 0.0001) were detected in the plasma cfDNA than in the bone marrow cells in pre-transplant testing (92 versus 61 mutations, respectively), most likely reflecting sampling variation when bone marrow was used. Two subjects were negative for MRD in staging studies immediately before transplants. Most (19/20) subjects had intermittent or sustained MRD detected in post-transplant plasma cfDNA testing, albeit with much lower average variant allele frequencies (VAFs). Six out of 20 subjects suffered relapses within 12 months after transplantation, and all 6 could be identified by adverse-risk driver mutations that persisted after transplantation. No patients who cleared the adverse-risk mutations relapsed. Donor chimerism using cfDNA fell for all relapsed patients and contributed to the identification of patients at early risk for relapse.Conclusions: These data demonstrate that testing plasma cfDNA for persistent leukemia-associated somatic mutations and donor chimerism as early as 28 days after transplantation will identify a subset of patients with high-risk mutations who are at high risk of relapse. This early assessment of relapse risk may facilitate modifications to the treatment plan, reducing the risk of treatment failure.
背景：在恶性肿瘤的造血干细胞移植治疗中，疾病复发是导致治疗失败的主要原因。移植后早期进行巩固治疗可能降低这一风险，但在移植后多种并发症的情况下难以实施。我们提出，在移植后早期通过血浆游离DNA（cfDNA）进行下一代测序（NGS）检测供体细胞嵌合状态及持续存在的最小残留病（MRD），可识别出复发风险较高、可能从巩固治疗中获益的患者。 方法：在这项前瞻性初步研究中，我们纳入了20名已知存在肿瘤相关体细胞突变的受试者，分别在移植前及移植后第28、56和84天采集血浆样本进行检测。同时分析了移植前后的骨髓样本。所有样本均采用覆盖302个基因的商业化通用检测面板进行分析。 结果：移植前检测显示，血浆cfDNA中检出的突变数量显著多于骨髓细胞（分别为92个与61个突变，p<0.0001），这很可能反映了骨髓取样存在的变异。两名受试者在移植前的分期研究中MRD检测为阴性。大多数受试者（19/20）在移植后血浆cfDNA检测中呈现间歇性或持续性的MRD阳性，但其平均变异等位基因频率（VAF）显著降低。20名受试者中有6名在移植后12个月内复发，这6名患者均通过移植后持续存在的不良风险驱动突变得以识别。所有清除不良风险突变的患者均未复发。利用cfDNA检测的供体嵌合率在所有复发患者中均出现下降，这有助于早期识别具有复发风险的患者。 结论：这些数据表明，早在移植后28天通过血浆cfDNA检测持续存在的白血病相关体细胞突变及供体嵌合状态，能够识别出携带高风险突变、具有高复发风险的患者亚群。这种对复发风险的早期评估可能有助于调整治疗方案，从而降低治疗失败的风险。
肿瘤(癌症)患者之家