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Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. ​

文献信息 ​

DOI10.1056/NEJMoa1709866
PMID29385370
期刊The New England journal of medicine
影响因子78.5
JCR 分区Q1
发表年份2018
被引次数2743
关键词CAR T细胞疗法, B细胞急性淋巴细胞白血病, 完全缓解, 毒性反应
文献类型Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't
ISSN0028-4793
页码439-448
期号378(5)
作者Shannon L Maude, Theodore W Laetsch, Jochen Buechner, Susana Rives, Michael Boyer, Henrique Bittencourt, Peter Bader, Michael R Verneris, Heather E Stefanski, Gary D Myers, Muna Qayed, Barbara De Moerloose, Hidefumi Hiramatsu, Krysta Schlis, Kara L Davis, Paul L Martin, Eneida R Nemecek, Gregory A Yanik, Christina Peters, Andre Baruchel, Nicolas Boissel, Francoise Mechinaud, Adriana Balduzzi, Joerg Krueger, Carl H June, Bruce L Levine, Patricia Wood, Tetiana Taran, Mimi Leung, Karen T Mueller, Yiyun Zhang, Kapildeb Sen, David Lebwohl, Michael A Pulsipher, Stephan A Grupp

一句话小结 ​

在一项全球多中心的研究中，抗CD19 CAR T细胞疗法tisagenlecleucel对复发或难治性B细胞急性淋巴细胞白血病的儿童和年轻成年患者显示出81%的总体缓解率，且疗效持久，伴随有较高的可逆性毒性反应。此研究为该疗法在该人群中的应用提供了有力的临床证据，显示其有效性和安全性。

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CAR T细胞疗法 · B细胞急性淋巴细胞白血病 · 完全缓解 · 毒性反应

摘要 ​

背景
在一项单中心的1-2a期研究中，抗CD19嵌合抗原受体（CAR）T细胞疗法tisagenlecleucel在复发或难治性B细胞急性淋巴细胞白血病（ALL）的儿童和年轻成年人中产生了高达完全缓解的比例，并伴随有严重但主要可逆的毒性反应。

方法
我们开展了一项2期单队列、25个中心的全球研究，研究对象为CD19+复发或难治性B细胞ALL的儿童和年轻成年患者。主要终点是3个月内的总体缓解率（完全缓解或伴有不完全血液学恢复的完全缓解的比例）。

结果
在此次计划的分析中，75名患者接受了tisagenlecleucel的输注，并可评估其疗效。3个月内总体缓解率为81%，所有对治疗有反应的患者在流式细胞术评估下均为微小残留病阴性。事件无复发生存率和总生存率分别为73%（95%置信区间[CI]，60至82）和90%（95% CI，81至95），在6个月时为50%（95% CI，35至64）和76%（95% CI，63至86）在12个月时。未达到中位缓解持续时间。观察到tisagenlecleucel在血液中的持续存在时间长达20个月。疑似与tisagenlecleucel相关的3级或4级不良事件发生在73%的患者中。细胞因子释放综合症发生在77%的患者中，其中48%的患者接受了托珠单抗治疗。40%的患者发生神经系统事件，并通过支持性治疗进行管理，未报告脑水肿。

结论
在这项CAR T细胞疗法的全球研究中，单次输注tisagenlecleucel在复发或难治性B细胞ALL的儿童和年轻成年患者中提供了持久的缓解，并在体内长期持续，伴有短暂的高等级毒性反应。（由诺华制药资助；临床试验注册号，NCT02435849）。

英文摘要 ​

BACKGROUND In a single-center phase 1-2a study, the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).

METHODS We conducted a phase 2, single-cohort, 25-center, global study of tisagenlecleucel in pediatric and young adult patients with CD19+ relapsed or refractory B-cell ALL. The primary end point was the overall remission rate (the rate of complete remission or complete remission with incomplete hematologic recovery) within 3 months.

RESULTS For this planned analysis, 75 patients received an infusion of tisagenlecleucel and could be evaluated for efficacy. The overall remission rate within 3 months was 81%, with all patients who had a response to treatment found to be negative for minimal residual disease, as assessed by means of flow cytometry. The rates of event-free survival and overall survival were 73% (95% confidence interval [CI], 60 to 82) and 90% (95% CI, 81 to 95), respectively, at 6 months and 50% (95% CI, 35 to 64) and 76% (95% CI, 63 to 86) at 12 months. The median duration of remission was not reached. Persistence of tisagenlecleucel in the blood was observed for as long as 20 months. Grade 3 or 4 adverse events that were suspected to be related to tisagenlecleucel occurred in 73% of patients. The cytokine release syndrome occurred in 77% of patients, 48% of whom received tocilizumab. Neurologic events occurred in 40% of patients and were managed with supportive care, and no cerebral edema was reported.

CONCLUSIONS In this global study of CAR T-cell therapy, a single infusion of tisagenlecleucel provided durable remission with long-term persistence in pediatric and young adult patients with relapsed or refractory B-cell ALL, with transient high-grade toxic effects. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02435849 .).

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主要研究问题 ​

  1. 在儿童和年轻成人中，tisagenlecleucel治疗B细胞淋巴母细胞白血病的长期疗效如何与其他治疗方法进行比较？
  2. 对于使用tisagenlecleucel的患者，是否存在特定的基因标记或生物标志物可以预测治疗反应？
  3. 在tisagenlecleucel治疗过程中，如何有效管理与细胞因子释放综合症相关的副作用？
  4. 该研究中提到的神经事件的具体类型是什么，如何影响患者的生活质量？
  5. 在全球范围内，tisagenlecleucel的使用是否面临不同的监管挑战或政策障碍？

核心洞察 ​

研究背景和目的 ​

本研究旨在评估tisagenlecleucel（CAR T细胞疗法）在复发或难治性B细胞急性淋巴细胞白血病（ALL）儿童和年轻成人患者中的疗效和安全性。之前的单中心研究显示，该疗法可导致高达93%的完全缓解率，但相关的严重毒副作用仍需进一步评估。

主要方法/材料/实验设计 ​

本研究为一项全球多中心的II期单队列研究，涉及25个研究中心。参与者为3至21岁之间的B细胞ALL复发或难治患者，主要终点为3个月内的总体缓解率（包括完全缓解和不完全血液学恢复的完全缓解）。

Mermaid diagram

关键结果和发现 ​

  • 患者特征：共筛选107名患者，92名入组，75名接受了tisagenlecleucel输注。
  • 总体缓解率：在75名患者中，3个月内的总体缓解率为81%（95% CI: 71-89%），其中60%患者达到完全缓解，21%患者为不完全血液学恢复的完全缓解。
  • 生存率：6个月的事件无生存率为73%（95% CI: 60-82%），总体生存率为90%（95% CI: 81-95%）；12个月时，事件无生存率为50%（95% CI: 35-64%），总体生存率为76%（95% CI: 63-86%）。
  • 持久性：tisagenlecleucel在血液中的持续时间最长可达20个月。
  • 不良事件：73%的患者出现与tisagenlecleucel相关的3或4级不良事件，77%患者发生细胞因子释放综合征，40%患者出现神经系统事件。

主要结论/意义/创新性 ​

该研究表明，tisagenlecleucel在复发或难治性B细胞ALL患者中具有高效的治疗效果和可接受的安全性。大多数不良反应为短暂且可逆的，这为未来CAR T细胞疗法在该人群中的应用提供了有力支持。

研究局限性和未来方向 ​

尽管研究结果令人鼓舞，但仍存在一些局限性，包括样本量较小和多中心研究的可变性。未来的研究应关注长期随访数据的收集，以及不同治疗方案对疗效的影响。此外，需进一步探索如何优化管理细胞因子释放综合征及其他不良事件的策略。

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引用本文的文献 ​

  1. Immunotherapy: CAR T cell therapy efficacious against B-ALL across age groups. - Peter Sidaway - Nature reviews. Clinical oncology (2018)
  2. Building a CAR Garage: Preparing for the Delivery of Commercial CAR T Cell Products at Memorial Sloan Kettering Cancer Center. - Karlo Perica;Kevin J Curran;Renier J Brentjens;Sergio A Giralt - Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation (2018)
  3. CD19 CAR-T cell therapy for relapsed/refractory acute lymphoblastic leukemia: factors affecting toxicities and long-term efficacies. - Li-Na Zhang;Yongping Song;Delong Liu - Journal of hematology & oncology (2018)
  4. Current Strategies to Enhance Anti-Tumour Immunity. - Katherine W Cook;Lindy G Durrant;Victoria A Brentville - Biomedicines (2018)
  5. Insights into cytokine release syndrome and neurotoxicity after CD19-specific CAR-T cell therapy. - Jordan Gauthier;Cameron J Turtle - Current research in translational medicine (2018)
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  7. Development and Evaluation of an Optimal Human Single-Chain Variable Fragment-Derived BCMA-Targeted CAR T Cell Vector. - Eric L Smith;Mette Staehr;Reed Masakayan;Ishan J Tatake;Terence J Purdon;Xiuyan Wang;Pei Wang;Hong Liu;Yiyang Xu;Sarah C Garrett-Thomson;Steven C Almo;Isabelle Riviere;Cheng Liu;Renier J Brentjens - Molecular therapy : the journal of the American Society of Gene Therapy (2018)
  8. Defining success with cellular therapeutics: the current landscape for clinical end point and toxicity analysis. - Leslie S Kean - Blood (2018)
  9. Chimeric antigen receptor-modified T cells: CD19 and the road beyond. - Alexander I Salter;Margot J Pont;Stanley R Riddell - Blood (2018)
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