Background:Patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who are ineligible for high-dose chemotherapy have limited treatment options and poor life expectancy. The purpose of this study is to identify a serum metabolomic profile that may be predictive of outcome in patients with R/R-DLBCL.Methods:This study included 69 R/R DLBCL patients from the R2-GDP-GOTEL trial (EudraCT 2014-001620-299). Serum samples were collected at baseline, and the mean length of follow-up was 41 months. Serum metabolites were analyzed by nuclear magnetic resonance (NMR). Metabolites were correlated with treatment response, progression-free survival (PFS), and overall survival (OS).Results:Serum levels of 3-hydroxybutyrate (3OHB) and acetone were significantly (p< 0.001) associated with PFS (3OHB: hazard ratio [HR] 7.7, 95% confidence interval [CI] 2.5–24.1; acetone: HR 9.32, 95% CI 2.75–31.6) and OS (3OHB: HR 9.32, 95% CI 2.75–31.6; acetone: HR 1.92, 95% CI 1.36–2.69). Serum values of 141 µM for 3OHB and 40 µM for acetone were the optimal cutoffs associated with the survival outcomes. Elevated 3OHB levels (>141 μM) were specific to the ABC subtype of DLBCL, while acetone levels were elevated in both types of DLCBL but more pronounced in ABC cases. In a multivariate survival analysis, including the International Prognostic Index (IPI) score and refractoriness status (R/R), 3OHB and acetone remained significant. To aid oncologists employing the R2-GDP regime, we constructed PFS and OS nomograms for R/R-DLBCL risk stratification, incorporating 3OHB levels or acetone levels, IPI score, and refractoriness status. The nomogram with 3OHB and refractoriness status showed a time-dependent AUC of 0.86 for 6-month PFS and 0.84 for 12-month OS. These nomograms provide a comprehensive tool for individualized risk assessment and treatment optimization.Conclusions:The ketone bodies 3OHB and acetone are potential prognostic biomarkers of poor outcome in R/R DLBCL patients treated with the R2-GDP regimen, independently of IPI score and chemorefractoriness status.
背景：对于不适合接受高剂量化疗的复发或难治性弥漫性大B细胞淋巴瘤患者，其治疗选择有限且预期寿命较短。本研究旨在识别一种可能预测R/R-DLBCL患者预后的血清代谢组学特征。 方法：本研究纳入了来自R2-GDP-GOTEL试验（EudraCT 2014-001620-299）的69例R/R DLBCL患者。在基线时收集血清样本，平均随访时间为41个月。采用核磁共振技术分析血清代谢物。将代谢物水平与治疗反应、无进展生存期和总生存期进行相关性分析。 结果：血清3-羟基丁酸和丙酮水平与PFS（3OHB：风险比7.7，95%置信区间2.5–24.1；丙酮：HR 9.32，95% CI 2.75–31.6）和OS（3OHB：HR 9.32，95% CI 2.75–31.6；丙酮：HR 1.92，95% CI 1.36–2.69）显著相关（p<0.001）。3OHB 141 µM和丙酮40 µM的血清值是预测生存结局的最佳截断值。3OHB水平升高（>141 µM）是DLBCL中ABC亚型特有的，而丙酮水平在两种DLBCL类型中均升高，但在ABC型病例中更为显著。在多变量生存分析中，纳入国际预后指数评分和难治状态后，3OHB和丙酮仍具有显著意义。为辅助肿瘤学家应用R2-GDP方案，我们构建了用于R/R-DLBCL风险分层的PFS和OS列线图，整合了3OHB或丙酮水平、IPI评分和难治状态。包含3OHB和难治状态的列线图显示，6个月PFS的时间依赖性AUC为0.86，12个月OS为0.84。这些列线图为个体化风险评估和治疗优化提供了综合工具。 结论：酮体3OHB和丙酮是接受R2-GDP方案治疗的R/R DLBCL患者不良预后的潜在预后生物标志物，其预测价值独立于IPI评分和化疗耐药状态。
肿瘤(癌症)患者之家