Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma
Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma
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DOI：
10.1056/nejmoa1804980
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发表时间：
2019-01-03
影响因子：
158.5
通讯作者：
Maziarz, Richard T.
中科院分区：
文献类型：
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作者：
Schuster, Stephen J.;Bishop, Michael R.;Maziarz, Richard T.
原发或二线治疗无效或干细胞移植后复发的弥漫性大B细胞淋巴瘤患者预后差。嵌合抗原受体（CAR）T细胞疗法tisagenlecleucel靶向并消除表达CD 19的B细胞，并在单中心2a期研究中显示出对B细胞淋巴瘤的疗效。在复发性或难治性弥漫性大B-细胞淋巴瘤，不适合自体造血干细胞移植或在自体造血干细胞移植后出现疾病进展。主要终点是最佳总体缓解率（即，具有完全或部分反应的患者的百分比）。共有93名患者接受了输注，并被纳入疗效评估。从输注至数据截止的中位时间为14个月（范围：0.1 - 26）。最佳总体缓解率为52 0 10（95%置信区间，41至62）; 40%的患者完全缓解，12%的患者部分缓解。缓解率在预后亚组中是一致的。在初次缓解后12个月，无复发生存率估计为65%（完全缓解患者为79%）。特别关注的最常见3级或4级不良事件包括细胞因子释放综合征（22%）、神经系统事件（12%）、持续超过28天的血细胞减少（32%）、感染（20%）和发热性中性粒细胞减少（14%）。3例患者在输注后30天内死于疾病进展。没有死亡归因于tisagenlecleucel、细胞因子释放综合征或脑水肿。CD 19或免疫检查点相关蛋白的肿瘤表达的反应组之间没有差异被发现。CONCLUSIONSIn this international study of CAR T-cell therapy in recursed or refractory diffuse large B-cell lymphoma in adults，high rates of durable responses were produced with use of tisagenlecleucel.
BACKGROUNDPatients with diffuse large B-cell lymphoma that is refractory to primary and second-line therapies or that has relapsed after stern-cell transplantation have a poor prognosis. The chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel targets and eliminates CD19-expressing B cells and showed efficacy against B-cell lymphomas in a single-center, phase 2a study.METHODSWe conducted an international, phase 2, pivotal study of centrally manufactured tisagenlecleucel involving adult patients with relapsed or refractory diffuse large B-cell lymphoma who were ineligible for or had disease progression after autologous hematopoietic stem-cell transplantation. The primary end point was the best overall response rate (i.e., the percentage of patients who had a complete or partial response), as judged by an independent review committee.RESULTSA total of 93 patients received an infusion and were included in the evaluation of efficacy. The median time from infusion to data cutoff was 14 months (range, 0.1 to 26). The best overall response rate was 52 0 10 (95% confidence interval, 41 to 62); 40% of the patients had complete responses, and 12% had partial responses. Response rates were consistent across prognostic subgroups. At 12 months after the initial response, the rate of relapse-free survival was estimated to be 65% (79% among patients with a complete response). The most common grade 3 or 4 adverse events of special interest included cytokine release syndrome (22%), neurologic events (12%), cytopenias lasting more than 28 days (32%), infections (20%), and febrile neutropenia (14%). Three patients died from disease progression within 30 days after infusion. No deaths were attributed to tisagenlecleucel, cytokine release syndrome, or cerebral edema. No differences between response groups in tumor expression of CD19 or immune checkpoint-related proteins were found.CONCLUSIONSIn this international study of CAR T-cell therapy in relapsed or refractory diffuse large B-cell lymphoma in adults, high rates of durable responses were produced with the use of tisagenlecleucel.