Grading of neurological toxicity in patients treated with tisagenlecleucel in the JULIET trial
Grading of neurological toxicity in patients treated with tisagenlecleucel in the JULIET trial
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DOI：
10.1182/bloodadvances.2019001305
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发表时间：
2020-04-14
期刊：
影响因子：
7.5
通讯作者：
Locke, Frederick L.
中科院分区：
文献类型：
--
作者：
Maziarz, Richard T.;Schuster, Stephen J.;Locke, Frederick L.
嵌合抗原受体 T (CAR-T) 细胞疗法对复发/难治性弥漫性大 B 细胞淋巴瘤 (r/r DLBCL) 患者取得持久缓解，但可能与神经毒性 (NT) 相关。我们回顾性评估了 3 种可用分级量表（美国国家癌症研究所不良事件通用术语标准 v4.03 [CTCAE]、改良 CART 相关脑病综合征 [mCRES] 和美国移植和细胞治疗协会 [ASTCT] 量表）之间的差异和一致性，这些量表应用于来自 JULIET 的同一组 NT 数据（一项 2 期、单臂、多中心试验，以确定CTL019 在成人复发或难治性 DLBCL 患者中的疗效和安全性试验。来自 2 期、单组、全球、关键 JULIET 试验 (NCT02445248) 的个体患者水平 NT 数据由 4 名具有管理 3 种不同 CD19 靶向 CAR 结构患者经验的医学专家使用 CTCAE、ASTCT 和 mCRES 进行回顾性独立分级。根据美国食品和药物管理局使用 CTCAE 对 NT 的定义，截至 2017 年 9 月，输注 tisagenledeucel 的 106 名患者中有 62 名患有 NT。在 111 名输注 tisagenledeucel 的患者中（截至 2017 年 12 月），4 位专家根据 CTCAE 确定了 SO 患者（45%），根据 mCRES 确定了 19 名（17%）为任何级别的 NT，19 名患者根据 mCRES 确定为任何级别的 NT。 (17%) 根据 ASTCT。根据 mCRES/ASTCT 标准重新评估，将 31 个被 CTCAE 视为 NT 的事件降级至 0 级。这是第一项将 CTCAE、mCRES 和 ASTCT 标准回顾性应用于同一患者数据集的研究。我们得出的结论是，CTCAE v4.03 不是为 CART 细胞治疗相关 NT 分级而设计的，而且不是最理想的。 CRES 和 ASTCT 量表可测量免疫效应细胞相关的神经毒性综合征，可对 CART 细胞治疗后的 NT 进行更准确的评估。
Chimeric antigen receptor-T (CAR-T) cell therapy achieves durable responses in patients with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL), but may be associated with neurological toxicity (NT). We retrospectively assessed differences and concordance among 3 available grading scales (the National Cancer Institute Common Terminology Criteria for Adverse Events v4.03 [CTCAE], modified CART Related Encephalopathy Syndrome [mCRES], and American Society for Transplantation and Cellular Therapy [ASTCT] scales) applied to the same set of NT data from the JULIET (A Phase 2, Single Arm, Multicenter Trial to Determine the Efficacy and Safety of CTL019 in Adult Patients With Relapsed or Refractory DLBCL) trial. Individual patient-level NT data from the phase 2, single-group, global, pivotal JULIET trial (NCT02445248) were retrospectively and independently graded, using CTCAE, ASTCT, and mCRES, by 4 medical experts with experience managing patients with 3 different CD19-targeted CAR constructs. According to the US Food and Drug Administration definition of NT using CTCAE, 62 of 106 patients infused with tisagenledeucel had NT as of September 2017. Among 111 patients infused with tisagenledeucel (as of December 2017), the 4 experts identified SO patients (45%) who had any-grade NT per CTCAE, 19 (17%) per mCRES, and 19 (17%) per ASTCT. Reevaluation according to the mCRES/ASTCT criteria downgraded 31 events deemed NT by CTCAE to grade 0. This is the first study to retrospectively apply CTCAE, mCRES, and ASTCT criteria to the same patient data set. We conclude that CTCAE v4.03 was not designed for, and is suboptimal for, grading CART cell therapy-associated NT. The CRES and ASTCT scales, which measure immune effector cell-associated neurotoxicity syndrome, offer more accurate assessments of NT after CART cell therapy.