Overview of CRS
CRS is characterized by elevated levels of proinflammatory cytokines and a supraphysiologic response to infection (eg, COVID-19), disorders (eg, HLH), or T-cell–engaging therapy (eg, bispecific antibodies, CAR-T). CRS is a life-threatening adverse event that can be effectively managed in the clinical setting.1-3
CAR-T, chimeric antigen receptor T cells; COVID-19, coronavirus disease 2019; CRS, cytokine release syndrome; GM-CSF, granulocyte-macrophage colony-stimulating factor; HLH, hemophagocytic lymphohistiocytosis; IFN, interferon; IL, interleukin; MCP-1, monocyte chemoattractant protein-1; TNF, tumor necrosis factor.
1. Shimabukuro-Vornhagen A, Gödel P, Subklewe M, et al. J Immunother Cancer. 2018;6:56. 2. Wang Z, Han W. Biomarker Res. 2018;6:4. 3. Fajgenbaum DC, June CH. N Engl J Med. 2020;383:2255-2273.
Symptoms1-3
Flu-like symptoms
Fever ≥100.4°F
(≥38°C)
Fatigue
Headache
Rash
Diarrhea
Arthralgia
Myalgia
Severe life-threatening manifestations
Hypotension
Hypoxia
Seizures
Multiorgan
dysfunction
Uncontrolled
systemic
inflammatory
response
Disseminated
intravascular
coagulation
Fatality
CRS, cytokine release syndrome.
1. Shimabukuro-Vornhagen A, Gödel P, Subklewe M, et al. J Immunother Cancer. 2018;6:56. 2. Wang Z, Han W. Biomarker Res. 2018;6:4. 3. Lee DW, Santomasso BD, Locke FL, et al. Biol Blood Marrow Transplant. 2019;25:625-638.
Clinical factors associated with the
severity of CRS1
Patient-related
- Age
- Comorbidities
- Preexisting inflammation
- Thrombocytopenia prior to lymphodepletion (eg, with CAR-T)
Therapy-related
- Immune therapy modality construct
- Administration dose and schedule
- Strength of T-cell activation
- Degree of T-cell expansion
Disease-related
- Disease type
- High tumor burden
Conditions associated with CRS2
CRS has clinical signs similar to those of HLH/MAS and sepsis. Appropriate dfferential diagnosis should be considered for CRS diagnosis and management.
Possible risk associated with CRS: neurotoxicity – ICANS3
Pathologic outcome involving the central nervous system with T-cell–engaging therapies. Symptoms may include tremor, encephalopathy, aphasia, seizure, cerebral edema, and others.
CAR-T, chimeric antigen receptor T cells; CRS, cytokine release syndrome; HLH, hemophagocytic lymphohistiocytosis; ICANS, immune effector cell–associated neurotoxicity syndrome; MAS, macrophage activation syndrome.
1. Acharya UH, Dhawale T, Yun S, et al. Expert Rev Hematol. 2019;12:195-205. 2. Shimabukuro-Vornhagen A, Gödel P, Subklewe M, et al. J Immunother Cancer. 2018;6:56. 3. Lee DW, Santomasso BD, Locke FL, et al. Biol Blood Marrow Transplant. 2019;25:625-638.
CRS grading systems
Multiple grading criteria have been defined, including CTCAE,1 CARTOX,2 and MSKCC3 guidelines. ASTCT (shown below) is a broadly used grading system that harmonizes other guidelines into a consensus framework.4
Figure modified from Lee DW, Santomasso BD, Locke FL, et al. Biol Blood Marrow Transplant. 2019;25:625-638.
*Fever is defined as temperature ≥100.4 °F (≥38 °C) not attributable to any other cause. In patients who have CRS and then receive antipyretic or anticytokine therapy, such as anti–IL-6R or steroids, fever is no longer required to grade subsequent CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia. †CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For example, a patient with temperature of 103.1 °F (39.5 °C), hypotension requiring 1 vasopressor, and hypoxia requiring low-flow nasal cannula is classified as having grade 3 CRS. ‡Low-flow nasal cannula is defined as oxygen delivered at ≤6 L/min. Low flow also includes blow-by oxygen delivery, sometimes used in pediatrics. High-flow nasal cannula is defined as oxygen delivered at >6 L/min.
ASTCT, American Society for Transplantation and Cellular Therapy; BiPAP, bilevel positive airway pressure; CARTOX, CAR-T cell therapy–associated toxicity; CPAP, continuous positive airway pressure; CRS, cytokine release syndrome; CTCAE, Common Terminology Criteria for Adverse Events; IL-6R, interleukin 6 receptor; MSKCC, Memorial Sloan Kettering Cancer Center.
1. National Cancer Institute. Accessed July 29, 2026. https://dctd.cancer.gov/research/ctep-trials/for-sites/adverse-events. 2. Neelapu SS, Tummala S, Kebriaei P, et al. Nat Rev Clin Oncol. 2018;15:47-62. 3. Park JH, Rivière I, Gonen M, et al. N Engl J Med. 2018;378:449-459. 4. Lee DW, Santomasso BD, Locke FL, et al. Biol Blood Marrow Transplant. 2019;25:625-638.
Operational considerations for therapy modalities1,2
1
Potential requirement of clinical interventions (eg, inpatient monitoring, anti–IL-6R availability, and ICU availability) and specific site training on CRS
2
Implementation of a dedicated clinical and safety monitoring plan for outpatient and inpatient setting
3
Logistical considerations for the transition of care: outpatient to inpatient and inpatient to outpatient
4
Patient and caregiver education on signs and symptoms of CRS
Mitigation1-8
For prevention of CRS associated with therapy, clinical trials include the following medications for consideration as per therapy modality:
- Corticosteroids
- Antipyretics
- Antihistamines
- Anti–IL-6R (ie, tocilizumab)*
Administration of bispecific therapies should be avoided during active infections as infections could precipitate severe CRS
Monitoring1,9
Monitor for early signs and symptoms indicative of CRS, including clinical assessment and laboratory testing for:
- Fever
- Disseminated intravascular coagulation
- Hematology parameters
- Pulmonary, cardiac, renal, and hepatic function
Management1,3,7-16
Shown below are select pharmacological management strategies for CRS from
established guidelines.
Established CRS management guidelines are
available for immunotherapies (ie, bispecifics, CAR-T). For more comprehensive
guidance on supportive care related to CRS management, refer to your institutional
guidelines and established guidelines (eg, ASCO,11
CARTOX,12 IMWG,8
mSMART,13 National Comprehensive Cancer Network®
[NCCN®],14 and
SITC15).
Consider administration of:
- Anti–IL-6R (ie, tocilizumab)
- Acetaminophen
- Intravenous fluids
- Corticosteroids
- Oxygen
- Antibiotics†
*The NCCN states that prophylactic tocilizumab may be considered to reduce the risk of CRS14; IMWG guidelines state that prophylactic tocilizumab use is considered investigational but note the increasing body of evidence for its use in the real-world setting.8 †In patients with neutropenia, concomitant infection, or other predisposing risk factors for infection.16
ASCO, American Society of Clinical Oncology; CAR-T, chimeric antigen receptor T cells; CARTOX, CAR-T cell therapy–associated toxicity; CRS, cytokine release syndrome; ICU, intensive care unit; IL-6R, interleukin 6 receptor; IMWG, International Myeloma Working Group; mSMART, Mayo Stratification for Myeloma and Risk-Adapted Therapy; NCCN, National Comprehensive Cancer Network; SITC, Society for Immunotherapy of Cancer.
1. Stewart MD, McCall B, Pasquini M, et al. Cytotherapy. 2022;S1465-324900023-8. 2. Using Bispecific Antibodies in Community Practice: Challenge and Opportunities. Accessed July 29, 2026. https://cdn.sanity.io/files/0vv8moc6/accc-cancer/af29a090fc6ed269a3d0d041eddc6551bf80c290.pdf. 3. Acharya UH, Dhawale T, Yun S, et al. Expert Rev Hematol. 2019;12:195-205. 4. Brudno JN, Kochenderfer JN. Blood. 2016;127:3321-3330. 5. Maude SL, Laetsch TW, Buechner J, et al. N Engl J Med. 2018;378:439-448. 6. Topp MS, Gökbuget N, Stein AS, et al. Lancet Oncol. 2015;16:57-66. 7. Moreau P, Garfall AL, van de Donk NWCJ, et al. N Engl J Med. 2022;387:495-505. 8. Rodriguez-Otero P, Usmani S, Cohen AD, et al Lancet Oncol. 2024;25:E205-E216. 9. Shimabukuro-Vornhagen A, Gödel P, Subklewe M, et al. J Immunother Cancer. 2018;6:56. 10. Park JH, Rivière I, Gonen M, et al. N Engl J Med. 2018;378:449-459. 11. Santomasso BD, Nastoupil LJ, Adkins S, et al. J Clin Oncol. 2021;39:3978-3992. 12. University of Texas MD Anderson Cancer Center. Accessed July 29, 2026. https://www.mdanderson.org/documents/for-physicians/algorithms/clinical-management/clin-management-cytokine-release-web-algorithm.pdf. 13. Mayo Clinic. mSMART. Accessed July 29, 2026. https://www.msmart.org/mm-treatment-guidelines. 14. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Management of CAR T-Cell and Lymphocyte Engager-Related Toxicities V.2.2026. © National Comprehensive Cancer Network, Inc. 2026. All rights reserved. Accessed [July 29, 2026]. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. 15. Maus MV, Alexander S, Bishop MR, et al. J Immunother Cancer. 2020;8:e001511. 16. Rodriguez-Otero P, et al. Lancet Oncol. 2024;25(5):Suppl.
The intent of this page is to provide background information regarding CRS and grading system management guidelines. This page is not intended to provide treatment guidance for patients.