Lymphomatous infiltration of the peripheral nervous system (PNS), termed neurolymphomatosis, represents a distinct extranodal non-Hodgkin lymphoma variant with dismal outcome. CD19-directed chimeric antigen receptor (CD19-CAR) T-cell therapy has emerged as a safe and effective treatment for B-cell lymphomas. We aimed to assess toxicity and efficacy of CD19-CAR T-cells in neurolymphomatosis. Neurolymphomatosis patients treated with CD19 CAR T-cells were retrospectively identified at Massachusetts General Hospital over a six-year period. Toxicities were graded according to the ASTCT classification, management, and response rates were recorded. Eleven neurolymphomatosis patients were identified with a median of 2 lines of PNS-directed treatments (range: 1-3) prior to receiving CD19-CAR T-cells. Neurolymphomatosis localized to the nerve roots (8/11, 73%), plexus (5/11, 45%), peripheral (4/11, 36%) and cranial nerves (5/11, 45%). Low grade cytokine release syndrome (CRS) was detected in 8/11 (73%; grade 1: N = 7; grade 2: N = 1) cases. Low- and high-grade immune cell-associated neurotoxicity syndrome (ICANS) were recorded in 5/11 (45%; grade 1: N = 4; grade 2: N = 1) and 1/11 (9%; grade 4) patients, respectively. CRP levels at infusion were predictive of ICANS (area under the curve: 0.96, p = 0.01). Seven of eleven neurolymphomatosis patients (64%) responded to CD19-CAR T-cells. Complete remissions (CR) were achieved in three cases (27%), with 2 patients in sustained CR nine and 46 months after CD19-CAR infusion. Median progression-free survival (PFS) was 4 months. Collectively, CD19-CAR T-cell treatment was well tolerated and showed promising efficacy in recurrent neurolymphomatosis, a difficult to treat condition with unmet medical need. Findings suggest that CD19-CAR may sufficiently penetrate the blood-nerve barrier. Toxicity and outcomes were overall similar to CAR-T cell therapy in CNS lymphoma.

中文翻译：

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CD19 定向嵌合抗原受体 T 细胞治疗继发性神经淋巴瘤病后的毒性和结局


周围神经系统 （PNS） 淋巴瘤浸润，称为神经淋巴瘤病，代表一种独特的结外非霍奇金淋巴瘤变体，结果令人沮丧。CD19 定向嵌合抗原受体 （CD19-CAR） T 细胞疗法已成为一种安全有效的 B 细胞淋巴瘤治疗方法。我们旨在评估 CD19-CAR T 细胞在神经淋巴瘤病中的毒性和疗效。在麻省总医院回顾性确定了接受 CD19 CAR T 细胞治疗的神经淋巴瘤病患者，为期 6 年。根据 ASTCT 分类对毒性进行分级，记录管理和反应率。在接受 CD19-CAR T 细胞之前，确定 11 例神经淋巴瘤病患者接受 2 线 PNS 定向治疗的中位数 （范围：1-3）。神经淋巴瘤病局限于神经根 （8/11， 73%）、神经丛 （5/11， 45%）、外周神经 （4/11， 36%） 和颅神经 （5/11， 45%）。在 8/11 （73%;1 级：N = 7;2 级：N = 1） 病例中检测到低级别细胞因子释放综合征 （CRS）。低级别和高级别免疫细胞相关神经毒性综合征 （ICANS） 分别见于 5/11 （45%;1 级：N = 4;2 级：N = 1） 和 1/11 （9%;4 级）患者。输注时 CRP 水平可预测 ICANS （曲线下面积： 0.96，p = 0.01）。11 例神经淋巴瘤病患者中有 7 例 （64%） 对 CD19-CAR T 细胞有反应。3 例 （27%） 达到完全缓解 （CR），其中 2 例患者在输注 CD19-CAR 后 9 个月和 46 个月持续 CR。中位无进展生存期 （PFS） 为 4 个月。总的来说，CD19-CAR T 细胞治疗具有良好的耐受性，并在复发性神经淋巴瘤病中显示出有希望的疗效，这是一种难以治疗的疾病，医疗需求未得到满足。 研究结果表明 CD19-CAR 可能充分穿透血液神经屏障。CNS 淋巴瘤的毒性和结局总体上与 CAR-T 细胞疗法相似。