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Immune effector cell–associated neurotoxicity syndrome after chimeric antigen receptor T-cell therapy for lymphoma: predictive biomarkers and clinical outcomes
Neuro-Oncology ( IF 16.4 ) Pub Date : 2020-08-05 , DOI: 10.1093/neuonc/noaa183
Noa G Holtzman 1, 2 , Hao Xie 3 , Soren Bentzen 4 , Vivek Kesari 5 , Ali Bukhari 1 , Firas El Chaer 1 , Forat Lutfi 1 , Jonathan Siglin 1 , Elizabeth Hutnick 1 , Natalie Gahres 1 , Kathleen Ruehle 1 , Haroon Ahmad 6 , Carl Shanholtz 7 , Mehmet H Kocoglu 1 , Ashraf Z Badros 1 , Jean A Yared 1 , Nancy M Hardy 1 , Aaron P Rapoport 1 , Saurabh Dahiya 1
Affiliation  

Abstract
Background
CD19-directed chimeric antigen receptor (CAR) T-cell therapy (CAR-T) has emerged as effective for relapsed/refractory large B-cell lymphoma (R/R LBCL). The neurologic toxicity seen with CAR-T, referred to as immune effector cell–associated neurotoxicity syndrome (ICANS), is poorly understood. To better elucidate the clinical characteristics, treatment outcomes, and correlative biomarkers of ICANS, we review here a single-center analysis of ICANS after CAR T-cell therapy in R/R LBCL.
Methods
Patients (n = 45) with R/R LBCL treated with axicabtagene ciloleucel (axi-cel) were identified. Data regarding treatment course, clinical outcomes, and correlative studies were collected. Patients were monitored and graded for ICANS via CARTOX-10 scoring and Common Terminology Criteria for Adverse Events (CTCAE) v4.03 criteria, respectively.
Results
Twenty-five (56%) patients developed ICANS, 18 (72%) of whom had severe (CTCAE grades 3–4) ICANS. Median time to development of ICANS was 5 days (range, 3–11). Elevated pre-infusion (day 0 [D0]) fibrinogen (517 vs 403 mg/dL, upper limit of normal [ULN] 438 mg/dL, P = 0.01) and D0 lactate dehydrogenase (618 vs 506 units/L, ULN 618 units/L, P = 0.04) were associated with ICANS. A larger drop in fibrinogen was associated with ICANS (393 vs 200, P < 0.01). Development of ICANS of any grade had no effect on complete remission (CR), progression-free survival (PFS), or overall survival (OS). Duration and total dose of steroid treatment administered for ICANS did not influence CR, PFS, or OS.
Conclusions
ICANS after CAR-T with axi-cel for R/R LBCL was seen in about half of patients, the majority of which were high grade. Contrary to previous reports, neither development of ICANS nor its treatment were associated with inferior CR, PFS, or OS. The novel finding of high D0 fibrinogen level can identify patients at higher risk for ICANS.


中文翻译:


嵌合抗原受体 T 细胞治疗淋巴瘤后免疫效应细胞相关神经毒性综合征:预测生物标志物和临床结果


 抽象的
 背景

CD19 定向嵌合抗原受体 (CAR) T 细胞疗法 (CAR-T) 已成为治疗复发/难治性大 B 细胞淋巴瘤 (R/R LBCL) 的有效方法。 CAR-T 所见的神经毒性,称为免疫效应细胞相关神经毒性综合征 (ICANS),人们知之甚少。为了更好地阐明 ICANS 的临床特征、治疗结果和相关生物标志物,我们在此回顾了 R/R LBCL CAR T 细胞治疗后 ICANS 的单中心分析。
 方法

确定了接受 axicabtagene ciloleucel (axi-cel) 治疗的 R/R LBCL 患者 ( n = 45)。收集有关治疗过程、临床结果和相关研究的数据。分别通过 CARTOX-10 评分和不良事件通用术语标准 (CTCAE) v4.03 标准对患者进行 ICANS 监测和分级。
 结果

25 名 (56%) 患者出现 ICANS,其中 18 名 (72%) 患有严重(CTCAE 3-4 级)ICANS。 ICANS 开发的中位时间为 5 天(范围:3-11 天)。输注前(第 0 天 [D0])纤维蛋白原升高(517 vs 403 mg/dL,正常上限 [ULN] 438 mg/dL, P = 0.01)和 D0 乳酸脱氢酶(618 vs 506 单位/L,ULN 618)单位/升, P = 0.04)与 ICANS 相关。纤维蛋白原的较大下降与 ICANS 相关(393 vs 200, P < 0.01)。任何级别的 ICANS 的发展对完全缓解 (CR)、无进展生存期 (PFS) 或总生存期 (OS) 没有影响。 ICANS 类固醇治疗的持续时间和总剂量不影响 CR、PFS 或 OS。
 结论

大约一半的患者在使用 axi-cel 进行 CAR-T 治疗 R/R LBCL 后出现 ICANS,其中大多数为高级别患者。与之前的报告相反,ICANS 的开发及其治疗均与 CR、PFS 或 OS 较差相关。高 D0 纤维蛋白原水平的新发现可以识别 ICANS 风险较高的患者。
更新日期:2020-08-05
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