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ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. ​

文献信息 ​

DOI10.1016/j.bbmt.2018.12.758
PMID30592986
期刊Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation
影响因子4.3
JCR 分区Q1
发表年份2019
被引次数1518
关键词CAR T细胞疗法，细胞免疫治疗，一致性分级，细胞因子释放综合征，免疫效应细胞
文献类型Consensus Development Conference, Journal Article, Review
ISSN1083-8791
页码625-638
期号25(4)
作者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

一句话小结 ​

研究表明，CAR T细胞治疗在血液恶性肿瘤中展现出显著疗效，但其伴随的细胞因子释放综合征（CRS）和神经毒性等副作用的评估和分级存在显著差异，影响了安全性比较和管理策略的制定。因此，专家们提出了统一的CRS和神经毒性的定义和分级系统，以便在临床试验和后续治疗中更准确地评估这些副作用。

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CAR T细胞疗法 · 细胞免疫治疗 · 一致性分级 · 细胞因子释放综合征 · 免疫效应细胞

摘要 ​

嵌合抗原受体（CAR）T细胞治疗正在迅速成为治疗血液恶性肿瘤最有前景的疗法之一。最近，美国和欧洲批准了两种CAR T产品，用于治疗最多可达25岁、患有复发性或难治性B细胞急性淋巴细胞白血病的患者，以及成人大B细胞淋巴瘤患者。还有更多的CAR T产品以及其他免疫疗法，包括各种免疫细胞和双特异性抗体基础的方案，这些方案通过激活免疫效应细胞来发挥作用，目前正在临床开发中，旨在治疗血液和实体肿瘤恶性肿瘤。这些疗法与细胞因子释放综合征（CRS）和神经毒性等独特毒性相关。对这些毒性的评估和分级在不同的临床试验和机构之间差异显著，这使得比较不同产品的安全性变得困难，并且阻碍了制定最佳管理这些毒性的策略。此外，这些分级系统的某些方面在不同中心实施时可能面临挑战。因此，为了统一对CRS和神经毒性的定义和分级系统，来自该领域各个方面的专家于2018年6月20日至21日在美国阿灵顿举行了一次由美国移植与细胞治疗学会（ASTCT；前身为美国血液与骨髓移植学会，ASBMT）支持的会议。在此，我们报告该小组的共识建议，并提出CRS和神经毒性的新的定义和分级，这些定义和分级客观、易于应用，最终更准确地对这些毒性的严重程度进行分类。我们的目标是提供一个统一的共识分级系统，用于与免疫效应细胞疗法相关的CRS和神经毒性，以便在临床试验和批准后的临床环境中使用。

英文摘要 ​

Chimeric antigen receptor (CAR) T cell therapy is rapidly emerging as one of the most promising therapies for hematologic malignancies. Two CAR T products were recently approved in the United States and Europe for the treatment ofpatients up to age 25years with relapsed or refractory B cell acute lymphoblastic leukemia and/or adults with large B cell lymphoma. Many more CAR T products, as well as other immunotherapies, including various immune cell- and bi-specific antibody-based approaches that function by activation of immune effector cells, are in clinical development for both hematologic and solid tumor malignancies. These therapies are associated with unique toxicities of cytokine release syndrome (CRS) and neurologic toxicity. The assessment and grading of these toxicities vary considerably across clinical trials and across institutions, making it difficult to compare the safety of different products and hindering the ability to develop optimal strategies for management of these toxicities. Moreover, some aspects of these grading systems can be challenging to implement across centers. Therefore, in an effort to harmonize the definitions and grading systems for CRS and neurotoxicity, experts from all aspects of the field met on June 20 and 21, 2018, at a meeting supported by the American Society for Transplantation and Cellular Therapy (ASTCT; formerly American Society for Blood and Marrow Transplantation, ASBMT) in Arlington, VA. Here we report the consensus recommendations of that group and propose new definitions and grading for CRS and neurotoxicity that are objective, easy to apply, and ultimately more accurately categorize the severity of these toxicities. The goal is to provide a uniform consensus grading system for CRS and neurotoxicity associated with immune effector cell therapies, for use across clinical trials and in the postapproval clinical setting.

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主要研究问题 ​

  1. 在不同的临床试验中，如何确保ASTCT共识分级系统的实施一致性？
  2. 除了CRS和神经毒性，CAR T细胞疗法还有哪些常见的副作用，如何进行管理？
  3. 针对CRS和神经毒性的最新研究进展如何影响当前的分级标准？
  4. 不同类型的免疫效应细胞疗法（如双特异性抗体）在毒性表现上有何差异？
  5. 如何评估ASTCT共识分级系统在临床实践中的实际应用效果？

核心洞察 ​

研究背景和目的 ​

随着嵌合抗原受体（CAR）T细胞疗法的迅速发展，相关的细胞因子释放综合征（CRS）和神经毒性已成为重要的副作用。这些毒性反应在临床试验和不同机构间的评估和分级标准不一致，导致比较不同产品的安全性变得困难。本文旨在提出一种统一的CRS和神经毒性分级系统，以便在临床试验和上市后使用中进行标准化报告。

主要方法/材料/实验设计 ​

本研究通过组织一场由美国血液与骨髓移植学会（ASBMT）支持的专家会议，汇集了49位来自不同领域的专家，讨论并达成共识。会议内容包括对CRS和神经毒性的定义、分级及其临床应用。最终形成了一套客观、易于使用的分级系统。

Mermaid diagram

关键结果和发现 ​

  1. CRS的分级：分为五个等级，主要依据体温、低血压和低氧血症的严重程度。

    • Grade 1: 发热（≥38°C）。
    • Grade 2: 发热伴低血压不需使用血管收缩药。
    • Grade 3: 发热伴需使用一种血管收缩药。
    • Grade 4: 发热伴需多种血管收缩药或需机械通气。
    • Grade 5: 因CRS导致的死亡。

  2. 神经毒性的分级：也分为五个等级，使用免疫效应细胞相关的脑病（ICANS）评分工具进行评估。

    • Grade 1: 轻微症状，如轻度意识模糊。
    • Grade 2: 表达性失语等明显症状。
    • Grade 3: 严重失语，无法进行有效交流。
    • Grade 4: 无法唤醒或昏迷。

主要结论/意义/创新性 ​

本文提出的CRS和ICANS的分级系统具有广泛的适用性，旨在提高不同机构间的比较和沟通效率。该系统不仅能帮助临床医生快速识别和管理毒性反应，还能促进后续的临床研究和产品监管。

研究局限性和未来方向 ​

尽管本研究建立了统一的分级系统，但由于临床实践中的个体差异，实施可能面临挑战。此外，随着新的免疫疗法的出现，分级系统可能需要进一步调整。未来的研究应集中在验证该系统的有效性及其在不同人群中的适用性。

部分内容
研究背景和目的统一CRS和神经毒性的分级系统以提高安全性比较
主要方法专家会议讨论，达成共识，制定分级标准
关键结果CRS和ICANS分级系统的建立
主要结论提高临床毒性管理的标准化
研究局限性个体差异与新疗法的适应性调整需求

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引用本文的文献 ​

  1. Clinical Utilization of Chimeric Antigen Receptor T Cells in B Cell Acute Lymphoblastic Leukemia: An Expert Opinion from the European Society for Blood and Marrow Transplantation and the American Society for Blood and Marrow Transplantation. - Ankit J Kansagra;Noelle V Frey;Merav Bar;Theodore W Laetsch;Paul A Carpenter;Bipin N Savani;Helen E Heslop;Catherine M Bollard;Krishna V Komanduri;Dennis A Gastineau;Christian Chabannon;Miguel A Perales;Michael Hudecek;Mahmoud Aljurf;Leslie Andritsos;John A Barrett;Veronika Bachanova;Chiara Bonini;Armin Ghobadi;Saar I Gill;Joshua Hill;Saad Kenderian;Partow Kebriaei;Arnon Nagler;David Maloney;Hien D Liu;Nirali N Shah;Mohamed A Kharfan-Dabaja;Elizabeth J Shpall;Ghulam J Mufti;Laura Johnston;Elad Jacoby;Ali Bazarbachi;John F DiPersio;Steven Z Pavletic;David L Porter;Stephan A Grupp;Michel Sadelain;Mark R Litzow;Mohamad Mohty;Shahrukh K Hashmi - Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation (2019)
  2. Mechanisms of resistance to CAR T cell therapy. - Nirali N Shah;Terry J Fry - Nature reviews. Clinical oncology (2019)
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