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Table 2 Summary of the clinical features of CRS and ICANS

From: Mechanisms of cytokine release syndrome and neurotoxicity of CAR T-cell therapy and associated prevention and management strategies

 

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]

Long-term sequelae [66, 220]

Timing

Onset:

1–9 days after CAR T-cells infusion

Duration:

5–11 days [81, 89, 118, 206,207,208, 210, 211, 213]

Onset:

2–9 days after CAR T-cells infusion

Duration:

3–17 days [89, 118, 207, 208, 213]

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]

  1. 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
  2. * Based on the ASTCT consensus, which is applicable to systemic CRS and ICANS. A grading criteria for L-CRS has recently been proposed [43]