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After CAR T-cell therapy, the immune cells can release a flood of chemical messengers, causing fever, low blood pressure and breathing trouble: cytokine release syndrome. Any fever after CAR T-cell therapy needs the treating centre at once. Teams grade it from 1 to 4 and treat with tocilizumab and, if needed, steroids; infection is treated at the same time because the two look alike.
CRS usually starts within 1 to 2 weeks of infusion (median 2 to 3 days for tisagenlecleucel and axicabtagene ciloleucel, sometimes within 24 hours) (SITC 2020). ASTCT 2019 grading: fever of 38 °C or more not attributable to another cause, with grade set by the worse of hypotension (grade 2 no vasopressor, grade 3 one vasopressor with or without vasopressin, grade 4 several) and hypoxia (grade 2 low-flow oxygen up to 6 L/min, grade 3 high-flow, face mask or non-rebreather, grade 4 positive pressure). Once antipyretics, tocilizumab or steroids are given, fever is no longer needed to grade.
SITC 2020: tocilizumab may be considered at grade 2 in adults (LE: 3) and earlier for older or comorbid patients; in children, at grade 3 (LE: 3). If one dose does not work, give steroids with a second dose (LE: 3); after two doses, consider anakinra, siltuximab or high-dose methylprednisolone (LE: 4). EBMT/JACIE 2019 limits tocilizumab to four doses per episode and names siltuximab as second line. Presume infection and treat it while investigating; neutropenic fever antibiotics are not delayed for a presumed CRS. Daily blood count, metabolic panel, magnesium, phosphate, CRP and ferritin while in hospital; cardiac assessment for prolonged severe CRS; hold G-CSF and avoid GM-CSF during CRS.
The ASTCT 2026 update to the grading and the 2022 EBMT/JACIE/EHA recommendations were read only as abstracts.
Why: These give a baseline to compare with when CRS starts and show whether the heart can cope.
“Prior to CAR T cell therapy, treating physicians should order CRP, ferritin, lactate dehydrogenase (LDH), complete blood counts, comprehensive metabolic panel (including Mg/Pho), and transthoracic echocardiogram (TTE) or multigated acquisition (MUGA) scan.”
Why: Severe CRS can come on within hours, and the drug that treats it must be available on site.
“However, adequate staff and supportive care resources are an absolute prerequisite for proceeding with CAR T cell therapy, and it is important to ensure that tocilizumab—which, along with other interleukin (IL)-6-modulating agents, was used as an investigational intervention for COVID-19—is available for the management of CRS.”
Why: Patients treated as outpatients, or after discharge, are the first to notice a fever.
“This should include information and education on the symptoms of CRS and serious neurological adverse reactions, the need to report any symptoms immediately to their treating physician and the need to remain in close proximity to the center in which the CAR T cells were administered for at least 4 weeks following the infusion.”
Why: CRS can worsen quickly and needs monitoring that only a ward can give.
“If patients are treated with CAR T cell products in the outpatient setting, admission should be strongly considered at the first signs of toxicity, including fever, hypotension or altered mental status.”
Why: Trends help track CRS and spot organ damage, although no blood test alone decides treatment.
“In the inpatient setting, complete blood counts, comprehensive metabolic panel (CMP), Mg, Phos, CRP, and ferritin should be ordered daily for patients treated with CAR T cell therapies.”
Why: These are the early warnings SITC names for physician review.
“Events requiring physician notification should include deviations from baseline in systolic blood pressure, heart rate of >120 or <60 beats/min, arrhythmia, respiratory rate of >25 or <12 breaths/min (or values outside the normal range in pediatric patients), arterial oxygen saturation of <92% on room air, upward trend in blood creatinine levels or liver function tests, tremors or jerky movements in extremities, altered mental status, and first occurrence of temperature greater than 38°C, as per the ASTCT definition of fever.”
Why: CRS and sepsis look alike and can happen together; many patients are also neutropenic.
“Empiric antimicrobial therapy based on symptoms and institutional protocols should not be delayed based on the presumption of CRS and clinicians should consider the prior duration of neutropenia.”
Why: One shared scale lets teams and trials compare like with like and links grade to treatment.
“CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause.”
Why: Treatment can switch off the fever while CRS continues.
“In patients who have CRS then receive antipyretics or anti-cytokine therapy such as tocilizumab or steroids, fever is no longer required to grade subsequent CRS severity.”
Why: Blocking IL-6 early can stop CRS from progressing; frailer patients tolerate low blood pressure and hypoxia less well.
“For elderly patients or patients with extensive comorbidities, tocilizumab should be considered earlier in the course of CRS. For adults who develop ASTCT grade 2 CRS, tocilizumab may be considered”
Why: SITC sets a different threshold for children based on paediatric experience.
“For pediatric patients, tocilizumab should be administered at ASTCT grade 3 CRS”
Why: Steroids add a second, broader brake on the inflammation.
“In both adults and children, if CRS does not improve after 1 dose of tocilizumab, then steroids should be administered with a second dose of tocilizumab”
Why: Refractory CRS needs drugs that act on other parts of the cytokine cascade.
“If CRS does not improve after 2 doses of tocilizumab (and steroids), third-line agents, including anakinra, siltuximab, and high-dose methylprednisolone, should be considered”
Why: Further doses add risk without evidence of benefit; EBMT names siltuximab as the second-line IL-6 drug.
“Tocilizumab should be administered no more than four times during one episode of CRS.”
Why: Prolonged CRS can strain or inflame the heart.
“In patients with prolonged severe CRS (persisting for 72 hours without response to interventions), a cardiac assessment should be considered as described in the cardiology section; this may include measurement of cardiac biomarkers such as troponin or the performance of a TTE”
Why: Growth factors may feed the inflammation while CRS is active.
“Consider holding G-CSF during CRS. GM-CSF should be avoided during CRS.”
How care is usually carried out, read from the guidelines and standards cited. Your own team's protocol and their judgement come first; this page is for understanding it, not for doing it yourself.
Grade with the ASTCT 2019 consensus scale, which all the sources read here use; ASTCT published an update in 2026 whose changes could not be read. For treatment, SITC 2020 is the most detailed graded guideline that could be read: tocilizumab may be considered at grade 2 in adults and earlier in older or comorbid patients (LE: 3), at grade 3 in children (LE: 3), steroids with a second dose if one fails (LE: 3), and anakinra, siltuximab or high-dose methylprednisolone after two doses (LE: 4). EBMT/JACIE 2019 agrees on tocilizumab with steroids for severe cases, caps tocilizumab at four doses per episode and names siltuximab as second line. ASCO 2021 (abstract) treats prolonged or severe CRS with tocilizumab with or without a corticosteroid. All rest on expert consensus and non-randomised data; no randomised comparison of thresholds for tocilizumab was read.
American Society for Transplantation and Cellular Therapy, Biology of Blood and Marrow Transplantation 2019 · American Society for Transplantation and Cellular Therapy, Transplantation and Cellular Therapy 2026 · SITC, Journal for ImmunoTherapy of Cancer 2020 · EBMT and JACIE, Haematologica 2020 · ASCO, Journal of Clinical Oncology 2021
Where it differs: SITC reports that the algorithm from the axicabtagene ciloleucel trials advised considering tocilizumab 8 mg/kg intravenously for fever lasting more than 3 days and refractory in grade 1 CRS, and anti-IL-6 therapy for all grade 2 or higher CRS.
Evidence: A trial management algorithm reported in SITC's review, not a panel recommendation.
Where it differs: Managed early CRS with tocilizumab and used corticosteroids only for refractory hypotension or severe symptoms not responding to the first dose.
Evidence: Trial practice reported by SITC.
Where it differs: Gives tocilizumab, with or without dexamethasone, before CRS develops or at its earliest signs in high-risk patients. SITC cites a Fred Hutchinson study reporting a modest decrease in severe CRS and a Children's Hospital of Philadelphia study in children with high disease burden.
Evidence: Non-randomised studies reported by SITC; not recommended routinely.
Where it differs: The FDA ended the risk-management programme for BCMA- and CD19-directed autologous CAR T-cell products, removing the requirement that dispensing hospitals be specially certified and have on-site, immediate access to tocilizumab. SITC 2020 still treats tocilizumab availability as a prerequisite, and the clinical need for it has not changed.
Evidence: Regulatory decision; FDA cites established management guidelines and stable adverse event reporting.
US Food and Drug Administration 2025 · SITC, Journal for ImmunoTherapy of Cancer 2020
| Recommendation | Grade, as printed | Source |
|---|---|---|
| Baseline CRP, ferritin, LDH, blood count, metabolic panel and echocardiogram before CAR T cells | LE: 4 | SITC, Journal for ImmunoTherapy of Cancer 2020 |
| Daily blood count, metabolic panel, magnesium, phosphate, CRP and ferritin in hospital | LE: 3 | SITC, Journal for ImmunoTherapy of Cancer 2020 |
| Tocilizumab may be considered for adult grade 2 CRS | LE: 3 | SITC, Journal for ImmunoTherapy of Cancer 2020 |
| Tocilizumab at grade 3 CRS in children | LE: 3 | SITC, Journal for ImmunoTherapy of Cancer 2020 |
| Steroids with a second tocilizumab dose if one dose fails | LE: 3 | SITC, Journal for ImmunoTherapy of Cancer 2020 |
| Anakinra, siltuximab or high-dose methylprednisolone after two tocilizumab doses | LE: 4 | SITC, Journal for ImmunoTherapy of Cancer 2020 |
| Prolonged or severe CRS treated with tocilizumab with or without a corticosteroid “Management of patients with prolonged or severe CAR T-cell-associated cytokine release syndrome includes treatment with tocilizumab with or without a corticosteroid.” | expert consensus | ASCO, Journal of Clinical Oncology 2021 |
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