Table 2.
Summary of the clinical features of CRS and ICANS
| CRS | ICANS | |
|---|---|---|
| Symptoms & Signs |
Onset: Fever with other constitutional symptoms (myalgias, malaise, nausea, vomiting, diarrhea, etc.) Progression: Hypotension, hypoxia, tachycardia, tachypnea, arrhythmia, pleural effusion, capillary leak, coagulopathy, pulmonary edema, DIC and multiorgan failure [7, 155, 216] Accompanied infections [217] L-CRS (in NHL): Local swelling and redness [43] |
Onset: Somnolence, disorientation, inattention, tremor, expressive aphasia, dysgraphia and apraxia [84, 218] Progression: Globe aphasia, cognitive disturbance, focal motor and sensory defects, seizures, fatal cerebral edema and intracranial hemorrhage [155, 219] |
| Timing |
Onset: 1–9 days after CAR T-cells infusion Duration: |
Onset: 2–9 days after CAR T-cells infusion Duration: |
| Cytokine profile | IL-6, IFN-γ, TNF-α, GM-CSF, IL-10, MIP-1, MCP-1 [44, 221] |
Serum: IFN-γ, IL-15, IL-6, IL-10, GM-CSF, IL-1RA, IL-2, IP-10 IL-1β, IL-8, and TNF CSF: Similar to the cytokine profile in the serum, except for higher levels of IL-8, IP-10, and MCP-1 [45, 222] |
| Risk factors |
Patient Characters: Disease type (ALL), high disease burden, preexisting thrombocytopenia and endothelial activation Characters of CAR T-cell products: Targeting CD19, CD28 costimulatory domain, receiving fludarabine and cyclophosphamide, high infusion dose, peak serum CAR T-cells levels [146, 223] |
Patient Characters: CRS, disease type (ALL), high disease burden, preexisting thrombocytopenia and endothelial activation, preexisting neurologic comorbidities Characters of CAR T-cell products: Targeting CD19, CD28 costimulatory domain, receiving fludarabine and cyclophosphamide, high infusion dose, peak serum CAR T-cells levels [146, 223] |
| Grading criteria* |
•Temperature ≥ 38.0 °C •Hypotension (based on vasopressor) •Hypoxia |
•ICE score (for adults and children> 12 years) or CAPD (for children≤12 years) •Depressed level of consciousness •Seizures •Motor findings •Elevated intracranial pressure/cerebral edema |
| Management |
•Antipyretics, IV hydration, anti-infective treatment •Tocilizumab, corticosteroids •ICU treatment, vasopressor support, supplemental O2 [224] •Symptomatic treatment for L-CRS (e.g. drainage of serous effusion, airway protection, regulation of intestinal flora) [43] |
•Supportive management •EEG, neuroimaging •Tocilizumab (only when concurrent with CRS), corticosteroids, anti-epileptics drugs •ICU treatment, airway protection, specific neurointensive treatment [224] |
CRS Cytokine release syndrome, ICANS Immune effector cell associated neurotoxicity syndrome, DIC Disseminated intravascular coagulation, L-CRS Local-Cytokine release syndrome, NHL Non-Hodgkin’s lymphoma, CAR Chimeric antigen receptor, IL Interleukin, IFN-γ Interferon-γ, TNF-α Tumor necrosis factor-α, GM-CSF Granulocyte-macrophage colony-stimulating factor, MIP Macrophage inflammatory protein, MCP Monocyte chemoattractant protein, ALL Acute lymphoblastic leukemia, IL-1RA Interleukin-1 receptor agonist, IP-10 Interferon-γ-inducible protein 10, ICE Immune effector cell–associated encephalopathy, CAPD Cornell Assessment of Pediatric Delirium, IV intravenous, ICU Intensive care unit, EEG Electroencephalogram
* Based on the ASTCT consensus, which is applicable to systemic CRS and ICANS. A grading criteria for L-CRS has recently been proposed [43]