Moffitt Cancer Center, Tampa, Florida.
M.D. Anderson Cancer Center, Houston, Texas.
Transplant Cell Ther. 2024 Nov;30(11):1065-1079. doi: 10.1016/j.jtct.2024.08.018. Epub 2024 Aug 24.
Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Most patients treated with axi-cel experience cytokine release syndrome (CRS) and/or adverse neurologic events (NEs). To explore potential approaches for reducing CAR T-cell-related toxicities with axi-cel, several safety expansion cohorts were added to the pivotal ZUMA-1 trial. ZUMA-1 Cohort 3 was an exploratory safety cohort that investigated the use of the IL-6 receptor-blocking antibody tocilizumab and anticonvulsant levetiracetam as prophylaxis against CRS and NEs in patients treated with axi-cel. Patients with R/R LBCL were enrolled in Cohort 3 and received conditioning chemotherapy on d -5 through -3 followed by a single infusion of axi-cel (2 × 10 cells/kg) on d 0. Prophylactic tocilizumab (8 mg/kg) was administered 48 h after axi-cel infusion. Primary endpoints were incidence and severity of CRS and NEs. Key secondary endpoints included the incidence of adverse events, objective response rate (ORR), duration of response, progression-free survival, overall survival (OS), and biomarker analyses (eg, circulating CAR T cells, cytokines, chemokines). Forty-two patients were enrolled in Cohort 3, 38 of whom received axi-cel. In the 24-month analysis, any-grade CRS and NEs occurred in 92% and 87% of patients, and Grade ≥3 CRS and NEs occurred in 3% and 42% of patients, respectively. One Grade 5 NE (cerebral edema) occurred. With 24-mo minimum follow-up, the ORR was 63%, and 39.5% of patients had ongoing response. With 48-month follow-up, median OS was 34.8 mo (95% CI, 5.4-not estimable). CAR T-cell expansion in ZUMA-1 Cohort 3 was comparable with pivotal Cohorts 1 and 2. Consistent with tocilizumab-mediated inhibition of IL-6R, serum IL-6 levels were increased relative to Cohorts 1 and 2. Grade ≥3 NEs were associated with elevated IL-6 levels, proinflammatory cytokines, and myeloid cells in the cerebrospinal fluid. Based on these findings, prophylactic tocilizumab is not recommended to prevent CAR T-cell-related adverse events, and beneficial effects of prophylactic levetiracetam remain uncertain in patients with R/R LBCL.
阿基仑赛（axi-cel）是一种自体抗 CD19 嵌合抗原受体（CAR）T 细胞疗法，已获批用于治疗复发/难治性（R/R）大 B 细胞淋巴瘤（LBCL）患者。大多数接受 axi-cel 治疗的患者会出现细胞因子释放综合征（CRS）和/或不良神经系统事件（NE）。为了探索降低 axi-cel 相关 CAR T 细胞毒性的潜在方法，ZUMA-1 试验中增加了几个安全性扩展队列。ZUMA-1 队列 3 是一个探索性安全性队列，研究了在接受 axi-cel 治疗的患者中使用白细胞介素 6 受体阻断抗体托珠单抗和抗惊厥药左乙拉西坦预防 CRS 和 NE 的作用。R/R LBCL 患者入组队列 3，并在 d-5 至 d-3 接受预处理化疗，随后在 d 0 输注单剂量 axi-cel（2×10 细胞/kg）。axi-cel 输注后 48 小时给予预防性托珠单抗（8 mg/kg）。主要终点为 CRS 和 NE 的发生率和严重程度。关键次要终点包括不良事件发生率、客观缓解率（ORR）、缓解持续时间、无进展生存期、总生存期（OS）和生物标志物分析（例如，循环 CAR T 细胞、细胞因子、趋化因子）。队列 3 共入组 42 例患者，其中 38 例接受了 axi-cel 治疗。在 24 个月的分析中，92%和 87%的患者出现任何级别的 CRS 和 NE，3%和 42%的患者分别出现≥3 级 CRS 和 NE。1 例 5 级 NE（脑水肿）。在 24 个月的最小随访中，ORR 为 63%，39.5%的患者有持续缓解。48 个月随访时，中位 OS 为 34.8 个月（95%CI，5.4-不可估计）。ZUMA-1 队列 3 的 CAR T 细胞扩增与关键队列 1 和 2 相似。与队列 1 和 2 相比，托珠单抗介导的 IL-6R 抑制作用使血清 IL-6 水平升高。≥3 级 NE 与升高的 IL-6 水平、促炎细胞因子和脑脊液中的髓样细胞有关。基于这些发现，不建议预防性使用托珠单抗预防 CAR T 细胞相关不良事件，预防性左乙拉西坦对 R/R LBCL 患者的有益作用仍不确定。
