Department of Medicine, Divisions of Oncology and Hematology, Stanford University, Stanford, CA.
Department of Hematology, University Hospital of Essen, Essen, Germany.
J Clin Oncol. 2021 Aug 10;39(23):2605-2616. doi: 10.1200/JCO.20.02573. Epub 2021 Apr 28.
Patients with Diffuse Large B-cell Lymphoma (DLBCL) in need of immediate therapy are largely under-represented in clinical trials. The diagnosis-to-treatment interval (DTI) has recently been described as a metric to quantify such patient selection bias, with short DTI being associated with adverse risk factors and inferior outcomes. Here, we characterized the relationships between DTI, circulating tumor DNA (ctDNA), conventional risk factors, and clinical outcomes, with the goal of defining objective disease metrics contributing to selection bias.
We evaluated pretreatment ctDNA levels in 267 patients with DLBCL treated across multiple centers in Europe and the United States using Cancer Personalized Profiling by Deep Sequencing. Pretreatment ctDNA levels were correlated with DTI, total metabolic tumor volumes (TMTVs), the International Prognostic Index (IPI), and outcome.
Short DTI was associated with advanced-stage disease ( .001) and higher IPI ( .001). We also found an inverse correlation between DTI and TMTV ( 0.37; .001). Similarly, pretreatment ctDNA levels were significantly associated with stage, IPI, and TMTV (all .001), demonstrating that both DTI and ctDNA reflect disease burden. Notably, patients with shorter DTI had higher pretreatment ctDNA levels ( .001). Pretreatment ctDNA levels predicted short DTI independent of the IPI ( .001). Although each risk factor was significantly associated with event-free survival in univariable analysis, ctDNA level was prognostic of event-free survival independent of DTI and IPI in multivariable Cox regression (ctDNA: hazard ratio, 1.5; 95% CI [1.2 to 2.0]; IPI: 1.1 [0.9 to 1.3]; -DTI: 1.1 [1.0 to 1.2]).
Short DTI largely reflects baseline tumor burden, which can be objectively measured using pretreatment ctDNA levels. Pretreatment ctDNA levels therefore have utility for quantifying and guarding against selection biases in prospective DLBCL clinical trials.
需要立即进行治疗的弥漫性大 B 细胞淋巴瘤 (DLBCL) 患者在临床试验中代表性严重不足。诊断至治疗的间隔 (DTI) 最近被描述为量化这种患者选择偏倚的指标，较短的 DTI 与不良风险因素和较差的结果相关。在这里，我们描述了 DTI、循环肿瘤 DNA (ctDNA)、常规风险因素与临床结果之间的关系，旨在确定导致选择偏倚的客观疾病指标。
我们使用深度测序的癌症个体化分析对来自欧洲和美国多个中心的 267 例 DLBCL 患者进行了治疗前 ctDNA 水平评估。将治疗前 ctDNA 水平与 DTI、总代谢肿瘤体积 (TMTV)、国际预后指数 (IPI) 和结果进行了相关性分析。
较短的 DTI 与晚期疾病相关（P<.001），且 IPI 更高（P<.001）。我们还发现 DTI 与 TMTV 之间呈负相关（P=.001）。同样，治疗前 ctDNA 水平与分期、IPI 和 TMTV 显著相关（均 P<.001），表明 DTI 和 ctDNA 均反映了疾病负担。值得注意的是，较短 DTI 的患者治疗前 ctDNA 水平更高（P<.001）。在多变量 Cox 回归分析中，ctDNA 水平独立于 IPI 预测了较短的 DTI（P<.001）。尽管在单变量分析中每个风险因素与无事件生存均显著相关，但 ctDNA 水平在多变量 Cox 回归分析中独立于 DTI 和 IPI 预测了无事件生存（ctDNA：危险比，1.5；95%CI [1.2 至 2.0]；IPI：1.1 [0.9 至 1.3]；-DTI：1.1 [1.0 至 1.2]）。
较短的 DTI 在很大程度上反映了基线肿瘤负担，可通过治疗前 ctDNA 水平进行客观测量。因此，治疗前 ctDNA 水平可用于量化和防范前瞻性 DLBCL 临床试验中的选择偏倚。
