Cytokine release syndrome
A systemic inflammatory reaction driven by interleukin 6 and other cytokines released after chimeric antigen receptor (CAR) T-cell therapy or other T-cell engaging immunotherapy, ranging from fever alone to shock and multiorgan failure. Diagnosis is clinical and graded by fever, hypotension, and hypoxia; first-line treatment for higher-grade disease is tocilizumab, an interleukin 6 receptor blocker, with corticosteroids added for refractory or severe cases.
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What this article covers
- Overview
Cytokine release syndrome (CRS) is a systemic inflammatory response caused by massive release of interleukin 6 (IL-6) and other inflammatory cytokines following T-cell activating immunotherapy, most…
- Epidemiology
CRS occurs in the majority of patients who receive cluster of differentiation 19 (CD19)-directed CAR T-cell therapy for relapsed or refractory ALL or aggressive B-cell lymphoma, with severe disease requiring intensive care in a minority.
- Risk factors
High pretreatment tumor burden: A larger population of antigen-expressing malignant cells drives more vigorous T-cell expansion and a larger cytokine surge.
- Pathophysiology
The inciting event is engagement of the target antigen, most often CD19 on malignant B cells, by the CAR T cell or a bispecific antibody-bridged T cell.
- Clinical features
Onset: Typically within the first 1 to 14 days after cell infusion, most often in the first week, coinciding with peak T-cell expansion.
- Differential diagnosis
Sepsis: Fever with hypotension, but CRS occurs in the expected window after cell infusion with negative blood cultures, although coexisting infection must still be excluded before attributing shock to CRS alone.
- Diagnosis
The diagnosis is made clinically: fever with hypotension and/or hypoxia in the expected window after CAR T-cell infusion or a T-cell engaging therapy, with reasonable exclusion of infection, graded…
- Management
First, for grade 1 disease, give supportive care: acetaminophen 650 mg orally every 4 to 6 hours for fever, intravenous fluids for mild hypotension, and vital sign monitoring, with blood cultures…
- Complications
Vascular leak and pulmonary edema: From endothelial activation, most prominent in grade 3 to 4 disease.
- Prognosis
Most CRS resolves within 1 to 2 weeks with supportive care and tocilizumab, and the large majority of patients recover fully without permanent organ damage.
- Prevention
Reduce tumor burden with bridging therapy before cell infusion in patients with high disease burden, since a lower burden lessens subsequent T-cell expansion and cytokine release.
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