Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston.
Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
JAMA Neurol. 2020 Dec 1;77(12):1536-1542. doi: 10.1001/jamaneurol.2020.2703.
Chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory hematologic malignant neoplasm causes severe neurologic adverse events ranging from encephalopathy and aphasia to cerebral edema and death. The cause of neurotoxicity is incompletely understood, and its unpredictability is a reason for prolonged hospitalization after CAR T-cell infusion.
To identify clinical and laboratory parameters predictive of neurotoxicity and to develop a prognostic score associated with its risk.
DESIGN, SETTING, AND PARTICIPANTS: This single-center diagnostic/prognostic accuracy study was conducted at Brigham and Women's Hospital/Dana Farber Cancer Institute from April 2015 to February 2020. A consecutive sample of all patients undergoing CAR T-cell therapy with axicabtagene ciloleucel for relapsed or refractory lymphoma were assessed for inclusion (n = 213). Patients who had previously received CAR T cells or who were treated for mantle cell lymphoma were excluded (n = 9). Patients were followed up for a minimum of 30 days from the date of CAR T-cell infusion.
The primary outcomes were measures of performance (accuracy, sensitivity, specificity, area under the curve) of a diagnostic tool to predict the occurrence of CAR-associated neurotoxicity, as graded by the Common Terminology Criteria for Adverse Events criteria.
Two hundred four patients (127 men [62.2%]; mean [SD] age, 60.0 [12.1] years) were included in the analysis, of which 126 (61.8%) comprised a derivation cohort and 78 (38.2%), an internal validation cohort. Seventy-three patients (57.9%) in the derivation cohort and 45 patients (57.7%) in the validation cohort experienced neurotoxicity. Clinical and laboratory values obtained early in admission were used to develop a multivariable score that can predict the subsequent development of neurotoxicity; when tested on an internal validation cohort, this score had an area under the curve of 74%, an accuracy of 77%, a sensitivity of 82%, and a specificity of 70% (positive:negative likelihood ratio, 2.71:0.26).
The score developed in this study may help predict which patients are likely to experience CAR T-cell-associated neurotoxicity. The score can be used for triaging and resource allocation and may allow a large proportion of patients to be discharged from the hospital early.
嵌合抗原受体 (CAR) T 细胞疗法治疗复发或难治性血液恶性肿瘤会引起严重的神经系统不良事件，范围从脑病和失语症到脑水肿和死亡。神经毒性的原因尚不完全清楚，其不可预测性是 CAR T 细胞输注后延长住院时间的一个原因。
确定与神经毒性相关的预测临床和实验室参数，并开发与风险相关的预后评分。
设计、地点和参与者：这项单中心诊断/预后准确性研究于 2015 年 4 月至 2020 年 2 月在布莱根妇女医院/达纳-法伯癌症研究所进行。对接受 axicabtagene ciloleucel 治疗复发或难治性淋巴瘤的连续 CAR T 细胞治疗患者进行评估（n=213）。排除了之前接受过 CAR T 细胞治疗或接受套细胞淋巴瘤治疗的患者（n=9）。从 CAR T 细胞输注之日起，患者至少随访 30 天。
主要结果是预测与 CAR 相关的神经毒性发生的诊断工具的性能（准确性、敏感性、特异性、曲线下面积）的测量值，该工具通过不良事件通用术语标准进行分级。
204 名患者（127 名男性[62.2%]；平均[标准差]年龄 60.0[12.1]岁）纳入分析，其中 126 名（61.8%）为推导队列，78 名（38.2%）为内部验证队列。推导队列中有 73 名（57.9%）患者和验证队列中有 45 名（57.7%）患者发生神经毒性。入院早期获得的临床和实验室值用于开发可预测随后发生神经毒性的多变量评分；在内部验证队列中进行测试时，该评分的曲线下面积为 74%，准确性为 77%，敏感性为 82%，特异性为 70%（阳性：阴性似然比，2.71:0.26）。
本研究中开发的评分可能有助于预测哪些患者可能经历 CAR T 细胞相关的神经毒性。该评分可用于分诊和资源分配，并可能使很大一部分患者能够提前出院。
