Tocilizumab Prophylaxis Following Axicabtagene Ciloleucel in Relapsed or Refractory Large B-Cell Lymphoma

IF 3.6 3区 医学 Q2 HEMATOLOGY Transplantation and Cellular Therapy Pub Date : 2024-11-01 DOI:10.1016/j.jtct.2024.08.018
Frederick L. Locke , Sattva S. Neelapu , Nancy L. Bartlett , Lazaros J. Lekakis , Caron A. Jacobson , Ira Braunschweig , Olalekan O. Oluwole , Tanya Siddiqi , Yi Lin , John M. Timmerman , Marie José Kersten , Yan Zheng , Teresa Zhang , Jenny Nater , Rhine Shen , Harry Miao , Jenny J. Kim , David B. Miklos
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Abstract

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 × 106 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.
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Axicabtagene Ciloleucel 治疗复发性或难治性大 B 细胞淋巴瘤后的托珠单抗预防疗法
背景:Axicabtagene ciloleucel(axi-cel)是一种自体抗CD19嵌合抗原受体(CAR)T细胞疗法,已被批准用于复发/难治性(R/R)大B细胞淋巴瘤(LBCL)患者。大多数接受axi-cel治疗的患者都会出现细胞因子释放综合征(CRS)和/或不良神经事件(NEs)。为了探索减少axi-cel治疗CAR T细胞相关毒性的潜在方法,关键性ZUMA-1试验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IL-6受体阻断抗体tocilizumab和抗惊厥药左乙拉西坦预防CRS和NEs:研究设计:R/R LBCL患者被纳入队列3,在第5天至第3天接受条件化疗,然后在第0天单次输注axi-cel(2×106个细胞/千克)。输注axi-cel 48小时后注射预防性托珠单抗(8毫克/千克)。主要终点是CRS和NEs的发生率和严重程度。主要次要终点包括不良事件发生率、客观反应率(ORR)、反应持续时间、无进展生存期、总生存期(OS)和生物标志物分析(如循环CAR T细胞、细胞因子、趋化因子):42名患者加入了队列3,其中38人接受了axi-cel治疗。在24个月的分析中,分别有92%和87%的患者发生了任何等级的CRS和NE,分别有3%和42%的患者发生了≥3级的CRS和NE。有一名患者出现了 5 级 NE(脑水肿)。在最短24个月的随访中,ORR为63%,39.5%的患者持续有反应。随访48个月,中位OS为34.8个月(95% CI,5.4-无法估计)。ZUMA-1第3组的CAR T细胞扩增情况与关键组1和2相当。与托西珠单抗介导的IL-6R抑制作用一致,血清中的IL-6水平相对于队列1和队列2有所增加。≥3级NE与脑脊液中IL-6水平、促炎细胞因子和髓细胞升高有关:基于这些研究结果,不推荐使用预防性托西珠单抗来预防CAR T细胞相关不良事件,而预防性左乙拉西坦对R/R LBCL患者的益处仍不确定。
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来源期刊
CiteScore
7.00
自引率
15.60%
发文量
1061
审稿时长
51 days
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