BACKGROUND CNS relapse of acute lymphocytic leukaemia is difficult to treat. Durable remissions of relapsed or refractory B-cell acute lymphocytic leukaemia have been observed following treatment with CD19-directed chimeric antigen receptor (CAR) T cells; however, most trials have excluded patients with active CNS disease. We aimed to assess the safety and activity of CAR T-cell therapy in patients with a history of CNS relapsed or refractory B-cell acute lymphocytic leukaemia. METHODS In this post-hoc analysis, we included 195 patients (aged 1-29 years; 110 [56%] male and 85 [44%] female) with relapsed or refractory CD19-positive acute lymphocytic leukaemia or lymphocytic lymphoma from five clinical trials (Pedi CART19, 13BT022, ENSIGN, ELIANA, and 16CT022) done at the Children's Hospital of Philadelphia (Philadelphia, PA, USA), in which participants received CD19-directed CAR T-cell therapy between April 17, 2012, and April 16, 2019. The trials required control of CNS disease at enrolment and infusion and excluded treatment in the setting of acute neurological toxic effects (>grade 1 in severity) or parenchymal lesions deemed to increase the risk of neurotoxicity. 154 patients from Pedi CART19, ELIANA, ENSIGN, and 16CT022 received tisagenlecleucel and 41 patients from the 13BT022 trial received the humanised CD19-directed CAR, huCART19. We categorised patients into two strata on the basis of CNS status at relapse or within the 12 months preceding CAR T-cell infusion-either CNS-positive or CNS-negative disease. Patients with CNS-positive disease were further divided on the basis of morphological bone marrow involvement-either combined bone marrow and CNS involvement, or isolated CNS involvement. Endpoints were the proportion of patients with complete response at 28 days after infusion, Kaplan-Meier analysis of relapse-free survival and overall survival, and the incidence of cytokine release syndrome and neurotoxicity. FINDINGS Of all 195 patients, 66 (34%) were categorised as having CNS-positive disease and 129 (66%) as having CNS-negative disease, and 43 (22%) were categorised as having isolated CNS involvement. The median length of follow-up was 39 months (IQR 25-49) in the CNS-positive stratum and 36 months (18-49) in the CNS-negative stratum. The proportion of patients in the CNS-positive stratum with a complete response at 28 days after infusion was similar to that in the CNS-negative stratum (64 [97%] of 66 vs 121 [94%] of 129; p=0·74), with no significant difference in relapse-free survival (60% [95% CI 49-74] vs 60% [51-71]; p=0·50) or overall survival (83% [75-93] vs 71% [64-79]; p=0·39) at 2 years between the two groups. Overall survival at 2 years was significantly higher in patients with isolated CNS involvement compared with those with bone marrow involvement (91% [82-100] vs 71% [64-78]; p=0·046). The incidence and severity of neurotoxicity (any grade, 53 [41%] vs 38 [58%]; grade 1, 24 [19%] vs 20 [30%]; grade 2, 14 [11%] vs 10 [15%]; grade 3, 12 [9%] vs 6 [9%], and grade 4, 3 [2%] vs 2 [3%]; p=0·20) and cytokine release syndrome (any grade, 110 [85%] vs 53 [80%]; grade 1, 12 [9%] vs 2 [3%]; grade 2, 61 [47%] vs 38 [58%]; grade 3, 18 [14%] vs 7 [11%] and grade 4, 19 [15%] vs 6 [9%]; p=0·26) did not differ between the CNS-negative and the CNS-positive disease strata. INTERPRETATION Tisagenlecleucel and huCART19 are active at clearing CNS disease and maintaining durable remissions in children and young adults with CNS relapsed or refractory B-cell acute lymphocytic leukaemia or lymphocytic lymphoma, without increasing the risk of severe neurotoxicity; although care should be taken in the timing of therapy and disease control to mitigate this risk. These preliminary findings support the use of these CAR T-cell therapies for patients with CNS relapsed or refractory B-cell acute lymphocytic leukaemia. FUNDING Children's Hospital of Philadelphia Frontier Program.

中文翻译：

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CD19 靶向嵌合抗原受体 T 细胞疗法治疗 CNS 复发或难治性急性淋巴细胞白血病：对五项临床试验汇总数据的事后分析。


背景技术急性淋巴细胞白血病的中枢神经系统复发很难治疗。在使用 CD19 定向嵌合抗原受体 (CAR) T 细胞治疗后，观察到复发性或难治性 B 细胞急性淋巴细胞白血病的持久缓解；然而，大多数试验都排除了患有活动性中枢神经系统疾病的患者。我们的目的是评估 CAR T 细胞疗法对有 CNS 复发或难治性 B 细胞急性淋巴细胞白血病病史的患者的安全性和活性。方法 在这项事后分析中，我们纳入了来自五项临床试验的 195 名复发或难治性 CD19 阳性急性淋巴细胞白血病或淋巴细胞淋巴瘤患者（年龄 1-29 岁；110 名 [56%] 男性和 85 名 [44%] 女性）。 （Pedi CART19、13BT022、ENSIGN、ELIANA 和 16CT022）在费城儿童医院（美国宾夕法尼亚州费城）完成，参与者于 2012 年 4 月 17 日至 4 月 16 日期间接受 CD19 定向 CAR T 细胞治疗， 2019.试验要求在入组和输注时控制中枢神经系统疾病，并排除在急性神经毒性作用（严重程度为>级1）或被认为增加神经毒性风险的实质病变的情况下的治疗。来自 Pedi CART19、ELIANA、ENSIGN 和 16CT022 的 154 名患者接受了 tisagenlecleucel，来自 13BT022 试验的 41 名患者接受了人源化 CD19 定向 CAR，huCART19。我们根据复发时或 CAR T 细胞输注前 12 个月内的 CNS 状态将患者分为两类：CNS 阳性或 CNS 阴性疾病。 CNS 阳性疾病患者根据形态学骨髓受累进一步分为：骨髓和 CNS 联合受累，或单独 CNS 受累。 终点是输注后 28 天完全缓解的患者比例、无复发生存期和总生存期的 Kaplan-Meier 分析，以及细胞因子释放综合征和神经毒性的发生率。结果 在所有 195 名患者中，66 名 (34%) 被归类为患有 CNS 阳性疾病，129 名 (66%) 被归类为患有 CNS 阴性疾病，43 名 (22%) 被归类为患有孤立的 CNS 受累。 CNS 阳性组的中位随访时间为 39 个月（IQR 25-49），CNS 阴性组为 36 个月（18-49）。输注后 28 天出现完全缓解的 CNS 阳性患者比例与 CNS 阴性患者相似（66 例中的 64 例 [97%] vs 129 例中的 121 例 [94%]；p=0· 74），无复发生存率（60% [95% CI 49-74] vs 60% [51-71]；p=0·50）或总生存率（83% [75-93] vs 71% [64-79]；p=0·39) 2 年时两组之间。与骨髓受累患者相比，单纯中枢神经系统受累患者的 2 年总生存率显着更高（91% [82-100] vs 71% [64-78]；p=0·046）。神经毒性的发生率和严重程度（任何级别，53 [41%] vs 38 [58%]；1 级，24 [19%] vs 20 [30%]；2 级，14 [11%] vs 10 [15%] ]；3级、12级[9%] vs 6级[9%]，4级、3级[2%] vs 2级[3%]；p=0·20）和细胞因子释放综合征（任何级别，110[85] %] vs 53 [80%]；1级、12 [9%] vs 2 [3%]； 61 [47%] vs 38 [58%]； 11%] 和 4、19 级 [15%] 与 6 级 [9%]；p=0·26）在 CNS 阴性和 CNS 阳性疾病层之间没有差异。 解读 Tisagenlecleucel 和 huCART19 能够有效清除患有中枢神经系统复发或难治性 B 细胞急性淋巴细胞白血病或淋巴细胞淋巴瘤的儿童和年轻人的中枢神经系统疾病并维持持久缓解，且不会增加严重神经毒性的风险；尽管应注意治疗时机和疾病控制，以减轻这种风险。这些初步研究结果支持使用这些 CAR T 细胞疗法治疗 CNS 复发或难治性 B 细胞急性淋巴细胞白血病患者。资助费城儿童医院前沿计划。