Lymphodepletion chemotherapy followed by infusion of CD19-specific chimeric antigen receptor-modified (CAR) T cells has produced impressive antitumor responses in patients with refractory CD19+ B-cell malignancies but is often associated with cytokine release syndrome (CRS). Our understanding of CRS continues to evolve, and identification of the kinetics of CRS and predictive clinical and laboratory biomarkers of severity are needed to evaluate strategies to mitigate toxicity. We report the clinical presentation of and identify biomarkers of severe CRS in 133 adult patients who received CD19 CAR T cells. CRS developed in 70% of patients, including 62.5% with grade 1 to 3 CRS (grade 1, 26%; grade 2, 32%; grade 3, 4.5%), 3.8% with grade 4, and 3.8% with grade 5. A majority of cases of grade ≥4 CRS occurred during CAR T-cell dose finding. Multivariable analysis of baseline characteristics identified high marrow tumor burden, lymphodepletion using cyclophosphamide and fludarabine, higher CAR T-cell dose, thrombocytopenia before lymphodepletion, and manufacturing of CAR T cells without selection of CD8+ central memory T cells as independent predictors of CRS. Severe CRS was characterized by hemodynamic instability, capillary leak, and consumptive coagulopathy. Angiopoietin-2 and von Willebrand factor, which are biomarkers of endothelial activation, were increased during severe CRS and also before lymphodepletion in patients who subsequently developed CRS. We describe a classification-tree algorithm to guide studies of early intervention after CAR T-cell infusion for patients at high risk of severe CRS. These data provide a framework for early intervention studies to facilitate safer application of effective CD19 CAR T-cell therapy.

中文翻译：

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CD19嵌合抗原受体修饰的T细胞治疗后严重细胞因子释放综合征的动力学和生物标志物

淋巴去除化疗后输注 CD19 特异性嵌合抗原受体修饰 (CAR) T 细胞在难治性 CD19+ B 细胞恶性肿瘤患者中产生了令人印象深刻的抗肿瘤反应，但通常与细胞因子释放综合征 (CRS) 相关。我们对 CRS 的理解不断发展，需要确定 CRS 的动力学以及预测的临床和实验室严重程度的生物标志物，以评估减轻毒性的策略。我们报告了 133 名接受 CD19 CAR T 细胞的成年患者的严重 CRS 的临床表现和生物标志物。70% 的患者发生 CRS，其中 62.5% 的患者发生 1-3 级 CRS（1 级，26%；2 级，32%；3 级，4.5%），4 级发生率为 3.8%，5 级发生率为 3.8%。大多数 ≥ 4 级 CRS 病例发生在 CAR T 细胞剂量发现期间。基线特征的多变量分析确定了高骨髓肿瘤负荷、使用环磷酰胺和氟达拉滨的淋巴清除、更高的 CAR T 细胞剂量、淋巴细胞清除前的血小板减少以及未选择 CD8+中枢记忆 T 细胞作为 CRS 独立预测因子的 CAR T 细胞的制造。严重 CRS 的特征是血流动力学不稳定、毛细血管渗漏和消耗性凝血病。血管生成素 2 和血管性血友病因子是内皮激活的生物标志物，在严重 CRS 期间以及随后发展为 CRS 的患者的淋巴耗竭之前增加。我们描述了一种分类树算法，以指导对重度 CRS 高风险患者进行 CAR T 细胞输注后的早期干预研究。