TABLE 4.

Management of CRS.

CRS management system	Lee criteria (Lee et al., 2014)	CARTOX criteria (Neelapu et al., 2018a)	ASTCT consensus criteria (Neelapu, 2019)	ASCO guideline (Santomasso et al., 2021)
Grade 1	• Vigilant supportive care (treat fever and neutropenia if present, antipyretics, analgesics as needed)	• Fever: Acetaminophen and hypothermia blanket; Consider tocilizumab 8 mg/kg IV or siltuximab 11 mg/kg IV for persistent (lasting >3 days) and refractory fever	•Antipyretics and IV hydration	• Supportive care with antipyretics, IV hydration, and symptomatic management of organ toxicities and constitutional symptoms
	• Assess for infection	• Organ toxicity: Symptomatic management	• Diagnostic work-up to rule out infection	• Consider empiric broad-spectrum antibiotics if neutropenic
	• Monitor fluid balance	• Empiric broad-spectrum antibiotics and filgrastim if neutropenic	• Consider growth factors and antibiotics if neutropenic	• If neutropenia, consider empiric broad-spectrum antibiotics and G-CSF (GM-CSF is not recommended)
		• Maintenance IV fluids for hydration		• In patients with persistent (>3 days) or refractory fever, consider managing as per grade 2
Grade 2	• Maintenance of adequate hydration and blood pressure	• Fever: manage fever as in grade 1 CRS	• Supportive care as in grade 1	• Supportive care as per grade 1
	• Vigilant supportive care (monitor cardiac and other organ function closely), if the patient doesn’t have extensive co-morbidities or older age	• Hypotension: IV fluid bolus of 500–1,000 ml of normal saline; Second IV fluid bolus if pressure remains <90 mmHg; Tocilizumab or siltuximab for the hypotension refractory to fluid boluses (tocilizumab can be repeated after 6 h); If hypotension persists, start vasopressors, consider transfer to ICU), dexamethasone (10 mg q6h, IV)	• IV fluid boluses and/or supplemental oxygen	• Administer tocilizumab (8 mg/kg, IV); Repeat q8h if no improvement in signs and symptoms of CRS; Limit to a maximum of three doses in a 24 h period, with a maximum of four doses total
	• Tocilizumab (adults 4 mg/kg, children 8 mg/kg) ± corticosteroids (methylprednisolone 2 mg/kg/day, dexamethasone 0.5 mg/kg maximum 10 mg/dose), if the patient has extensive co-morbidities or older age	• Hypoxia: supplemental oxygen; Tocilizumab or siltuiximab ± corticosteroids and supportive care	• Tocilizumab ± dexamethasone or its equivalent of methylprednisolone	• In patients with hypotension that persists after two fluid boluses and after one to two doses of tocilizumab, may consider dexamethasone (10 mg q12h, IV) for one to two doses and then reassess
		• Organ toxicity: symptomatic management of organ toxicities, as per standard guidelines; Tocilizumab or siltuiximab ± corticosteroids and supportive care		• Manage per grade 3 if no improvement within 24 h of starting tocilizumab
Grade 3	• Maintenance of adequate hydration and blood pressure	• Fever: manage fever as in grade 1 CRS	• Supportive care as in grade 1	• Supportive care as per grade 2 and include vasopressors as needed
	• Vigilant supportive care	• Hypotension: IV fluid bolus, tocilizumab and siltuximab as recommended for grade 2 CRS; Increase dexamethasone to 20 mg q6h IV, if refractory; Transfer to ICU, obtain echocardiogram, and perform haemodynamic monitoring	• Consider monitoring in intensive care unit	• Tocilizumab as per grade 2 if maximum dose is not reached within 24 h period plus dexamethasone (10 mg q6h, IV) and taper once symptoms improve
	• Tocilizumab (adults 4 mg/kg, children 8 mg/kg) ± corticosteroids (methylprednisolone 2 mg/kg/day, dexamethasone 0.5 mg/kg maximum 10 mg/dose)	• Hypoxia: supplemental oxygen including high-flow oxygen delivery and non-invasive positive pressure ventilation; Tocilizumab or siltuximab + corticosteroids	• Vasopressor support and/or supplemental oxygen	• If echocardiogram was not already performed, obtain ECHO to assess cardiac function and conduct hemodynamic monitoring
		• Organ toxicity: symptomatic management of organ toxicities, as per standard guidelines; Tocilizumab or siltuximab + corticosteroids	• Tocilizumab + dexamethasone (10–20 mg q6h, IV) or its equivalent of methylprednisolone	• If refractory, manage as per grade 4
				• Admit patient to ICU
Grade 4	• maintenance of adequate hydration and blood pressure	• Fever: manage fever as in grade 1 CRS	• Supportive care as in grade 1	• Supportive care as per grade 3 plus mechanical ventilation as needed
	• Vigilant supportive care	• Hypotension: manage hypotension as in grade 3 CRS; Methylprednisolone (1 g/day, IV)	• Monitoring in intensive care unit	• Tocilizumab as per grade 2 if maximum dose is not reached within 24 h period; Initiate high-dose methylprednisolone (500 mg q12h, IV) for 3 days, followed by 250 mg IV q12h for 2 days, 125 mg IV q12h for 2 days, and 60 mg IV q12h until CRS improvement to grade 1
	• Tocilizumab (adults 4 mg/kg, children 8 mg/kg) ± corticosteroids (methylprednisolone 2 mg/kg/day, dexamethasone 0.5 mg/kg maximum 10 mg/dose)	• Hypoxia: mechanical ventilation; Tocilizumab or siltuximab + corticosteroids	• Vasopressor support and/or supplemental oxygen via positive pressure ventilation	• If not improving, consider methylprednisolone (1g, IV) 2 times a day or alternate therapy
		• Organ toxicity: symptomatic management of organ toxicities, as per standard guidelines; Tocilizumab or siltuximab + corticosteroids	• Tocilizumab + methylprednisolone 1 g/day

Tocilizumab IV over 1 h, Maximum amount of tocilizumab per dose is 800 mg.

CRS, cytokine release syndrome; CARTOX, CAR-T cell therapy associated toxicity; IV, intravenous; ICU, intensive-care unit; q6h, every 6 hours; q8h, every 8 hours; q12h, every 12 hours; ASTCT, American Society for Transplantation and Cellular Therapy; ASCO, American Society of Clinical Oncology; G-CSF, granulocyte-colony stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; ECHO, echocardiography.