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Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. ​

文献信息 ​

DOI10.1056/NEJMoa1804980
PMID30501490
期刊The New England journal of medicine
影响因子78.5
JCR 分区Q1
发表年份2019
被引次数1950
关键词CAR T细胞治疗, 弥漫性大B细胞淋巴瘤, 复发性, 耐药性, tisagenlecleucel
文献类型Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't
ISSN0028-4793
页码45-56
期号380(1)
作者Stephen J Schuster, Michael R Bishop, Constantine S Tam, Edmund K Waller, Peter Borchmann, Joseph P McGuirk, Ulrich Jäger, Samantha Jaglowski, Charalambos Andreadis, Jason R Westin, Isabelle Fleury, Veronika Bachanova, S Ronan Foley, P Joy Ho, Stephan Mielke, John M Magenau, Harald Holte, Serafino Pantano, Lida B Pacaud, Rakesh Awasthi, Jufen Chu, Özlem Anak, Gilles Salles, Richard T Maziarz

一句话小结 ​

本研究评估了CAR T细胞疗法tisagenlecleucel在复发或难治性弥漫性大B细胞淋巴瘤患者中的疗效，结果显示52%的患者获得最佳总体反应，且12个月无复发生存率为65%。这一研究为改善该类患者的治疗提供了有效的治疗方案，具有重要的临床意义。

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CAR T细胞治疗 · 弥漫性大B细胞淋巴瘤 · 复发性 · 耐药性 · tisagenlecleucel

摘要 ​

背景
对初始和二线治疗无反应或在干细胞移植后复发的弥漫性大B细胞淋巴瘤患者预后较差。嵌合抗原受体（CAR）T细胞疗法tisagenlecleucel针对并消除表达CD19的B细胞，并在一项单中心的2a期研究中显示出对B细胞淋巴瘤的疗效。

方法
我们进行了一项国际性、2期的关键性研究，涉及经中心制造的tisagenlecleucel，研究对象为因自体造血干细胞移植不合格或在移植后病情进展的复发或难治性弥漫性大B细胞淋巴瘤成年患者。主要终点是由独立审查委员会评估的最佳总体反应率（即完全或部分反应的患者比例）。

结果
共93名患者接受了输注，并被纳入疗效评估。输注到数据截止的中位时间为14个月（范围，0.1至26）。最佳总体反应率为52%（95%置信区间，41至62）；40%的患者获得了完全反应，12%获得了部分反应。各预后亚组的反应率一致。首次反应后12个月，估计无复发生存率为65%（在完全反应患者中为79%）。最常见的3级或4级特殊关注不良事件包括细胞因子释放综合症（22%）、神经系统事件（12%）、持续超过28天的细胞减少症（32%）、感染（20%）和发热性中性粒细胞减少症（14%）。有3名患者在输注后30天内因病情进展死亡。没有死亡被归因于tisagenlecleucel、细胞因子释放综合症或脑水肿。未发现反应组之间在肿瘤CD19或免疫检查点相关蛋白表达上的差异。

结论
在这项针对成年复发或难治性弥漫性大B细胞淋巴瘤的国际CAR T细胞疗法研究中，使用tisagenlecleucel产生了高比例的持久反应。（本研究由诺华资助；JULIET临床试验编号，NCT02445248。）

英文摘要 ​

BACKGROUND Patients with diffuse large B-cell lymphoma that is refractory to primary and second-line therapies or that has relapsed after stem-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.

METHODS We 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.

RESULTS A 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% (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.

CONCLUSIONS In 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. (Funded by Novartis; JULIET ClinicalTrials.gov number, NCT02445248 .).

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主要研究问题 ​

  1. Tisagenlecleucel的疗效与其他CAR T细胞疗法相比如何？
  2. 在使用Tisagenlecleucel治疗的患者中，哪些因素可能影响其最佳总体反应率？
  3. 有哪些针对Tisagenlecleucel的长期副作用需要关注，特别是在不同患者群体中？
  4. Tisagenlecleucel在不同年龄段患者中的疗效和安全性是否存在显著差异？
  5. 在治疗复发或难治性弥漫性大B细胞淋巴瘤时，Tisagenlecleucel的使用是否会影响后续治疗的选择？

核心洞察 ​

1. 研究背景和目的 ​

弥漫性大B细胞淋巴瘤（DLBCL）是一种具有高度侵袭性的淋巴系统恶性肿瘤，尤其在初次和二线治疗无效或在自体干细胞移植后复发的患者中，其预后较差。针对这种情况，CAR T细胞疗法（嵌合抗原受体T细胞疗法）被提出为一种新的治疗选择。该研究的目的是评估tisagenlecleucel（CAR T细胞疗法的一种）在成人复发或难治性DLBCL患者中的疗效和安全性。

2. 主要方法和发现 ​

本研究为一项国际性、II期的关键性研究，涉及经过中心化制造的tisagenlecleucel，针对那些不适合或在自体造血干细胞移植后病情进展的成人DLBCL患者。研究的主要终点是最佳总体反应率，即由独立评审委员会判断的患者完全或部分缓解的比例。共纳入93名患者进行评估，患者从输注到数据截止的中位时间为14个月（范围0.1至26个月）。结果显示，总体反应率为52%（95%置信区间41-62），其中40%的患者达到了完全缓解，12%达到了部分缓解。反应率在不同预后亚组间保持一致。初始反应后12个月的无复发生存率估计为65%（在完全缓解患者中为79%）。常见的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28天以上的细胞减少症（32%）、感染（20%）及发热性中性粒细胞减少症（14%）。在输注后30天内有3名患者因疾病进展死亡，但未有死亡与tisagenlecleucel、细胞因子释放综合征或脑水肿直接相关。

3. 核心结论 ​

本研究显示，tisagenlecleucel在成人复发或难治性DLBCL患者中产生了高比例的持久反应，证明了其作为一种有效的治疗选择。

4. 研究意义和影响 ​

本研究提供了重要的临床证据，支持CAR T细胞疗法在复发或难治性DLBCL患者中的应用，展示了其能够有效改善患者的反应率及生存状况。考虑到传统治疗方案在这些患者中的疗效有限，tisagenlecleucel为这部分患者群体带来了新的希望。这项研究的结果不仅为临床实践提供了指导，也为未来的研究奠定了基础，促使进一步探索CAR T细胞疗法在其他类型淋巴瘤及不同癌症中的潜力。

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  2. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. - Daniel W Lee;Bianca D Santomasso;Frederick L Locke;Armin Ghobadi;Cameron J Turtle;Jennifer N Brudno;Marcela V Maus;Jae H Park;Elena Mead;Steven Pavletic;William Y Go;Lamis Eldjerou;Rebecca A Gardner;Noelle Frey;Kevin J Curran;Karl Peggs;Marcelo Pasquini;John F DiPersio;Marcel R M van den Brink;Krishna V Komanduri;Stephan A Grupp;Sattva S Neelapu - Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation (2019)
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