通过磁共振成像 (MRI) 对中枢神经系统淋巴瘤 (CNSL) 进行最先进的反应评估具有挑战性，并且不足以预测治疗结果。因此，开发新的 CNSL 风险分层策略是一个高度未满足的医疗需求。我们对 67 名患者的 146 份血浆和脑脊液 (CSF) 样本应用超灵敏循环肿瘤 (ct)DNA 测序，旨在开发一种考虑 CNSL 临床和分子特征的完全无创动态风险模型。我们的超灵敏方法能够检测血浆 ctDNA 中 CNSL 衍生的突变，与 CSF 和肿瘤组织高度一致。基线时血浆 ctDNA 检测不到与良好的结果相关。我们随着时间的推移追踪了血浆来源的 ctDNA 中的肿瘤特异性突变，并根据这些信息开发了一种新型 CNSL 生物标志物：外周残留病 (PRD)。治疗后 PRD 的持续存在高度预测复发。将既定的基线临床风险因素与治疗期间的放射学反应和 PRD 评估相结合，开发并独立验证了一种新的风险分层工具：CNSL 分子预后指数 (MOP-C)。 MOP-C 被证明可以高度预测 CNSL 患者的结局（每个风险组的无失败生存风险比 (HR) 6.60；95% 置信区间 (CI) 3.12-13.97；p < 0.0001），并且可在 www.mop-c.com 上公开获取。猫扑c.com。我们的结果强调了 ctDNA 测序在 CNSL 中的作用。 MOP-C 有潜力提高 CNSL 患者临床风险分层和放射学反应评估的现行标准，最终为个体化治疗铺平道路。版权所有 © 2023 美国血液学会。

State-of-the-art response assessment of central nervous system lymphoma (CNSL) by magnetic resonance imaging (MRI) is challenging and an insufficient predictor of treatment outcomes. Accordingly, the development of novel risk stratification strategies in CNSL is a high unmet medical need. We applied ultrasensitive circulating tumor (ct)DNA sequencing to 146 plasma and cerebrospinal fluid (CSF) samples from 67 patients, aiming to develop an entirely noninvasive dynamic risk model considering clinical and molecular features of CNSL. Our ultrasensitive method allowed for the detection of CNSL-derived mutations in plasma ctDNA with high concordance to CSF and tumor tissue. Undetectable plasma ctDNA at baseline was associated with favorable outcomes. We tracked tumor-specific mutations in plasma-derived ctDNA over time and developed a novel CNSL biomarker based on this information: peripheral residual disease (PRD). Persistence of PRD post-treatment was highly predictive of relapse. Integrating established baseline clinical risk factors with assessment of radiographic response and PRD during treatment resulted in the development and independent validation of a novel tool for risk stratification: Molecular prognostic index for CNSL (MOP-C). MOP-C proved to be highly predictive of outcomes in CNSL patients (failure-free survival hazard ratio (HR) per risk group 6.60; 95% confidence interval (CI) 3.12-13.97; p < 0.0001) and is publicly available at www.mop-c.com. Our results highlight the role of ctDNA sequencing in CNSL. MOP-C has the potential to improve the current standard of clinical risk stratification and radiographic response assessment in patients with CNSL, ultimately paving the way towards individualized treatment.Copyright © 2023 American Society of Hematology.