TABLE 3.
Grading of CRS.
| CRS grading system | CTCAE version 5.0 (National Cancer Institute, 2017) | Lee criteria (Lee et al., 2014) | CARTOX criteria (Neelapu et al., 2018a) | ASTCT consensus criteria (Lee et al., 2019) | ASCO guideline (Santomasso et al., 2021) |
|---|---|---|---|---|---|
| Grade 1 | • Fever (≥38.0°C) | Symptoms are not life-threatening and require symptomatic treatment only (e.g., fever, nausea, fatigue, headache, myalgias, malaise) | • Fever (≥38.0°C) | • Fever (≥38.0°C) | • Fever (≥38.0°C) not attributable to any other cause |
| • And/or constitutional symptoms | • No hypotension | • No hypotension | • No hypotension | ||
| • No hypoxia | • No hypoxia | • No hypoxia | |||
| • And/or grade 1 organ toxicities (CTCAEv4.03) | |||||
| Grade 2 | • Fever (≥38.0°C) | Symptoms require and respond to moderate intervention | • Fever (≥38.0°C) | • Fever (≥38.0°C) | • Fever (≥38.0°C) not attributable to any other cause |
| • Hypotension (responds to fluids) | • Hypotension (responds to IV fluids or low dose of one vasopressor) | • Hypotension (Responds to IV fluids or low-dose vasopressors) | • And hypotension not requiring vasopressors | • And hypotension not requiring vasopressors | |
| • hypoxia (FiO2 <40%) | • Hypoxia (FiO2 <40%) | • Or hypoxia (FiO2 <40%) | • And/or hypoxia requiring low-flow nasal cannula (≤6 L/min) | • And/or hypoxia requiring low-flow nasal cannula (≤6 L/min) or blowby | |
| • Grade 2 organ toxicity (CTCAEv4.03) | • Or grade 2 organ toxicities (CTCAEv4.03) | ||||
| Grade 3 | • Fever (≥38.0°C) | Symptoms require and respond to aggressive intervention | • Fever (≥38.0°C) | • fever (≥38.0°C) | • Fever (≥38.0°C) not attributable to any other cause |
| • Hypotension (needs one vasopressors) | • Hypotension (responds to high-dose or multiple vasopressors) | • Hypotension (needs high-dose or multiple vasopressors) | • And hypotension requiring one vasopressor ± vasopressin | • And hypotension requiring one vasopressor ± vasopressin | |
| • hypoxia (FiO2 ≥40%) | • hypoxia (FiO2 ≥40%) | • Or hypoxia (FiO2 ≥40%) | • And/or hypoxia requiring high-flow nasal cannula (>6 L/min), facemask, non-rebreather mask, or venturi mask | • And/or hypoxia requiring high-flow nasal cannula, facemask, non-rebreather mask, or venturi mask | |
| • Grade 3 organ toxicity or grade 4 transaminitis (CTCAEv4.03) | • Or grade 3 organ toxicity or grade 4 transaminitis (CTCAEv4.03) | ||||
| Grade 4 | • Fever (≥38.0°C) | Life-threatening symptoms | • Fever (≥38.0°C) | • fever (≥38.0°C) | • Fever (≥38.0°C) not attributable to any other cause |
| • Life-threatening consequences; urgent intervention needed | • Hypoxia (needing ventilator support) | • Hypotension (Life-threatening) | • And hypotension requiring multiple vasopressors (excluding vasopressin) | • And hypotension requiring multiple vasopressors (excluding vasopressin) | |
| • Grade 4 organ toxicity except grade 4 transaminitis (CTCAEv4.03) | • Or hypoxia (needing ventilator support) | • And/or hypoxia requiring positive pressure (e.g., CPAP, BiPAP, intubation and mechanical ventilation) | • And/or hypoxia requiring positive pressure (e.g., CPAP, BiPAP, intubation and mechanical ventilation) | ||
| • Or grade 4 organ toxicity except grade 4 transaminitis (CTCAEv4.03) | |||||
| Grade 5 | Death | Death | — | death due to CRS | — |
Hypotension, Systolic blood pressure <90 mmHg; Hypoxia, Needing oxygen for SaO2 >90%.
High-dose vasopressors (all doses are required for ≥3 h) (Lee et al., 2014) are defined as any of the following: noradrenaline ≥20 μg/kg/min; dopamine ≥10 μg/kg/min; phenylephrine ≥200 μg/kg/min; adrenaline ≥10 μg/kg/min; if on vasopressin, vasopressin + noradrenaline equivalent of ≥10 μg/kg/min; if on combination vasopressors (not including vasopressin), noradrenaline equivalent of ≥20 μg/kg/min. VASST Trial vasopressor equivalent equation: norepinephrine equivalent dose = [norepinephrine (μg/min)] + [dopamine (μg/kg/min) ÷ 2] + [epinephrine (μg/min)] + [phenylephrine (μg/min) ÷10].
CRS, cytokine release syndrome; CTCAE, Common Terminology Criteria for Adverse Events; FiO2, fraction of inspired oxygen; IV, intravenous; CTCAE, Common Terminology Criteria for Adverse Events; CARTOX, CAR-T cell therapy associated toxicity; ASTCT, American Society for Transplantation and Cellular Therapy; CPAP, continuous positive airway pressure; BiPAP, Bilevel positive airway pressure; ASCO, American Society of Clinical Oncology.