ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells
Open accessAbstract
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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Adverse events and laboratory abnormalities were graded by NCI CTCAE v5.0, and CRS and ICANS were graded according to ASTCT criteria.
“Adverse events (AEs) and laboratory abnormalities were graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0, and CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to the American Society for Transplantation and Cellular Therapy criteria18.”
From Elranatamab in relapsed or refractory multiple myeloma: phase 2 MagnetisMM-3 trial results (2023) · cites this paper as [18]
Adverse events were graded according to NCI CTCAE version 4.03, except CRS and ICANS, which were graded according to ASTCT criteria.
“Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03), except for cytokine release syndrome (Table S2) and immune effector cell–associated neurotoxicity syndrome, which were graded according to the criteria of the American Society for Transplantation and Cellular Therapy.12”
From Teclistamab in Relapsed or Refractory Multiple Myeloma (2022) · cites this paper as [12]
Cytokine release syndrome and ICANS were graded according to consensus criteria of the American Society for Transplantation and Cellular Therapy.
“Cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to consensus criteria of the American Society for Transplantation and Cellular Therapy. 20”
From Cilta-cel or Standard Care in Lenalidomide-Refractory Multiple Myeloma. (2023) · cites this paper as [20]
CRS and ICANS were recorded and graded according to ASTCT consensus guidelines.
“The development of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) were recorded and graded according to the consensus guidelines of the American Society of Transplantation and Cellular Therapy (ASTCT)44.”
From A non-antibiotic-disrupted gut microbiome is associated with clinical responses to CD19-CAR-T cell cancer immunotherapy (2023) · cites this paper as [44]
The onset and duration of cytokine storm vary depending on the cause and treatments administered.
“The onset and duration of cytokine storm vary, depending on the cause and treatments administered.”
From Cytokine storm (2020) · cites this paper as [7]
The National Cancer Institute's CTCAE-based definition of cytokine storm is too broad, since the criteria for an inflammatory syndrome can also apply to other physiological states.
“The National Cancer Institute’s definition, based on the Common Terminology Criteria for Adverse Events (CTCAE), is too broad, since the criteria for an inflammatory syndrome can also apply to other physiological states”
From Cytokine storm (2020) · cites this paper as [7]
The American Society for Transplantation and Cellular Therapy definition of cytokine storm is based on criteria that focus too specifically on iatrogenic causes of cytokine storm alone.
“the definition of the American Society for Transplantation and Cellular Therapy is based on criteria that focus too specifically on iatrogenic causes of cytokine storm alone”
From Cytokine storm (2020) · cites this paper as [7]
Neurologic toxic effects associated with T-cell immunotherapy are often delayed, developing several days after the onset of cytokine storm.
“The neurologic toxic effects are often delayed, developing several days after the onset of the cytokine storm.”
From Cytokine storm (2020) · cites this paper as [7]
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- Authors
- Lee, D. W., Santomasso, B. D., Locke, F. L., Ghobadi, A., Turtle, C. J., Brudno, J. N., Maus, M. V., Park, J. H., Mead, E., Pavletic, S., Go, W. Y., Eldjerou, L., Gardner, R. A., Frey, N., Curran, K. J., Peggs, K., Pasquini, M., DiPersio, J. F., van den Brink, M. R. M., Komanduri, K. V., Grupp, S. A., & Neelapu, S. S.
- Affiliations
- University of Virginia (US)
- Memorial Sloan Kettering Cancer Center (US)
- Moffitt Cancer Center (US)
- Washington University in St. Louis (US)
- Fred Hutch Cancer Center (US)
- National Institutes of Health (US)
- Massachusetts General Hospital (US)
- Seattle Children's Hospital (US)
- Abramson Cancer Center (US)
- University College London (GB)
- Medical College of Wisconsin (US)
- University of Miami (US)
- Children's Hospital of Philadelphia (US)
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Grupp, Stephan A.
- Neelapu, Sattva S.
- ORCID
- Venue
- Biology of Blood and Marrow Transplantation
- Publisher
- Elsevier BV
- Published
- 2019-04
- Volume
- 25
- Issue
- 4
- Pages
- 625-638
- ISSN
- 1083-8791 (ISSN-L)
- PMC
- PMC12180426
- OpenAlex
- W2905654445
- Cited by
- 3,675
- References
- 35
- Citations by year
- 2026: 671 · 2025: 676 · 2024: 570 · 2023: 503 · 2022: 410 · 2021: 406 · 2020: 315 · 2019: 112 · 2018: 1 · 2013: 2
- FWCI
- 78.20
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Transplantation and Cellular Therapy (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by-nc-nd)
- Funders
- American Society for Transplantation and Cellular Therapy
- American Society of Hematology
- National Cancer Institute
- Celgene
- Novartis
- Genentech
- ,
- Amgen
- and
- GlaxoSmithKline
- Roche
- Merck
- Topics
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- cytokine release syndrome, neurotoxicity, CAR T-cell therapy, immune effector cell therapy, toxicity grading, hematologic malignancies, B-cell acute lymphoblastic leukemia, large B-cell lymphoma, bispecific antibodies, safety assessment
- MeSH terms
- Cytokine Release Syndrome, Humans, Immunotherapy, Receptors, Antigen, T-Cell
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