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

Literature Information ​

DOI10.1016/j.bbmt.2018.12.758
PMID30592986
JournalBiology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation
Impact Factor4.3
JCR QuartileQ1
Publication Year2019
Times Cited1518
KeywordsCAR T cell therapy, Cellular immunotherapy, Consensus grading, Cytokine release syndrome, Immune effector cell
Literature TypeConsensus Development Conference, Journal Article, Review
ISSN1083-8791
Pages625-638
Issue25(4)
AuthorsDaniel 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

TL;DR ​

This study addresses the urgent need for standardized definitions and grading systems for cytokine release syndrome (CRS) and neurotoxicity associated with chimeric antigen receptor (CAR) T cell therapies, which are gaining traction in treating hematologic malignancies but present unique toxicities. The consensus recommendations aim to provide an objective and easily applicable framework to enhance safety comparisons and management strategies across clinical trials and post-approval settings.

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CAR T cell therapy · Cellular immunotherapy · Consensus grading · Cytokine release syndrome · Immune effector cell

Abstract ​

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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Primary Questions Addressed ​

  1. What are the specific challenges in implementing the proposed grading systems for CRS and neurotoxicity across different clinical centers?
  2. How do the new definitions and grading systems for CRS and neurotoxicity compare with previous standards used in clinical trials?
  3. What role do other immunotherapies play in the context of CRS and neurologic toxicity, and how are they being assessed?
  4. How might the harmonization of grading systems impact the development of future CAR T cell therapies and their safety profiles?
  5. What are the implications of these consensus recommendations for the management strategies of CRS and neurologic toxicity in clinical practice?

Key Findings ​

Research Background and Purpose ​

Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are significant toxicities associated with immune effector cell therapies, particularly chimeric antigen receptor (CAR) T cell therapies. The variation in grading and assessment of these toxicities across clinical trials has created challenges in comparing safety and developing management strategies. The primary aim of this study was to establish a consensus grading system for CRS and ICANS to facilitate standardized reporting and improve patient management.

Main Methods/Materials/Experimental Design ​

A consensus meeting was held by experts from various institutions on June 20-21, 2018, supported by the American Society for Blood and Marrow Transplantation (ASBMT). The meeting focused on harmonizing definitions and grading systems for CRS and ICANS. The proposed grading system is designed to be objective, easy to use, and applicable across different clinical settings.

Mermaid diagram

Key Results and Findings ​

  1. CRS Grading:

    • Grade 1: Fever (≥38°C) without hypotension or hypoxia.
    • Grade 2: Fever with hypotension not requiring vasopressors or hypoxia requiring low-flow oxygen.
    • Grade 3: Fever with hypotension requiring one vasopressor or hypoxia requiring high-flow oxygen.
    • Grade 4: Fever with hypotension requiring multiple vasopressors or hypoxia requiring positive pressure ventilation.
    • Grade 5: Death due to CRS.

  2. ICANS Grading:

    • Grade 1: ICE score of 7-9 (mild impairment).
    • Grade 2: ICE score of 3-6 (moderate impairment).
    • Grade 3: ICE score of 0-2 (severe impairment) or any seizure.
    • Grade 4: Unarousable patient or life-threatening seizures.

Main Conclusions/Significance/Innovation ​

The consensus grading system for CRS and ICANS provides a standardized framework for evaluating and managing toxicities associated with immune effector cell therapies. This grading system is crucial for:

  • Facilitating comparison of safety data across different CAR T products and clinical trials.
  • Improving patient management by providing clear criteria for intervention.
  • Supporting regulatory compliance and enhancing patient safety in clinical practice.

Research Limitations and Future Directions ​

  • The proposed grading system may require future revisions as new data and therapies emerge.
  • Further studies are needed to validate the grading criteria in diverse clinical settings and populations.
  • Ongoing monitoring and reporting through centralized databases like the CIBMTR will be essential for capturing long-term outcomes and safety data.

Summary Table of Grading Systems ​

ToxicityGrade 1Grade 2Grade 3Grade 4
CRSFever ≥38°CFever + Hypotension (no vasopressors)Fever + Hypotension (1 vasopressor)Fever + Hypotension (multiple vasopressors)
ICANSICE score 7-9ICE score 3-6ICE score 0-2 or any seizureUnarousable or life-threatening seizures

This structured consensus provides a comprehensive approach to managing CRS and ICANS, aiming to enhance patient safety and therapeutic outcomes in the rapidly evolving field of cellular immunotherapy.

References ​

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Literatures Citing This Work ​

  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)
  3. Current approaches in the grading and management of cytokine release syndrome after chimeric antigen receptor T-cell therapy. - Lara L Riegler;Gavin P Jones;Daniel W Lee - Therapeutics and clinical risk management (2019)
  4. Glial injury in neurotoxicity after pediatric CD19-directed chimeric antigen receptor T cell therapy. - Juliane Gust;Olivia C Finney;Daniel Li;Hannah M Brakke;Roxana M Hicks;Robert B Futrell;Danielle N Gamble;Stephanie D Rawlings-Rhea;Hedieh K Khalatbari;Gisele E Ishak;Virginia E Duncan;Robert F Hevner;Michael C Jensen;Julie R Park;Rebecca A Gardner - Annals of neurology (2019)
  5. Selecting costimulatory domains for chimeric antigen receptors: functional and clinical considerations. - Robert Weinkove;Philip George;Nathaniel Dasyam;Alexander D McLellan - Clinical & translational immunology (2019)
  6. Safety and feasibility of chimeric antigen receptor T cell therapy after allogeneic hematopoietic cell transplantation in relapsed/ refractory B cell non-Hodgkin lymphoma. - Tania Jain;Craig S Sauter;Gunjan L Shah;Molly A Maloy;Jason Chan;Michael Scordo;Scott T Avecilla;Yakup Batlevi;Parastoo B Dahi;Connie W Batlevi;M Lia Palomba;Sergio A Giralt;Miguel-Angel Perales - Leukemia (2019)
  7. Clinical chimeric antigen receptor-T cell therapy: a new and promising treatment modality for glioblastoma. - Michael P Brown;Lisa M Ebert;Tessa Gargett - Clinical & translational immunology (2019)
  8. Hematopoietic-cell transplantation for lymphoma in the era of genetically engineered cellular therapy: it's not quite time to scrap the old vehicle for the new car. - Michael Scordo;Richard J Lin;Craig S Sauter - Current opinion in hematology (2019)
  9. Chimeric Antigen Receptor T Cells: A Race to Revolutionize Cancer Therapy. - Marion Subklewe;Michael von Bergwelt-Baildon;Andreas Humpe - Transfusion medicine and hemotherapy : offizielles Organ der Deutschen Gesellschaft fur Transfusionsmedizin und Immunhamatologie (2019)
  10. Adverse Events of Oncologic Immunotherapy and Their Management. - Fedricker Diane Barber - Asia-Pacific journal of oncology nursing (2019)

... (1508 more literatures)

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