| Grade 1: fever (defined as ≥38°C) not attributable to any other cause | Withhold therapy until CRS resolves. Refer to package insert for restarting after dose delay Antipyretic (acetaminophen) for fever and consider cooling blanket Assess for infection and adjust antibiotics as indicated Maintenance IV fluid for hydration Symptomatic management of constitutional symptoms and organ toxicities If refractory fever at 24 hours (not responsive to antimicrobials or antipyretics within 24 hours), administer repeat anti–IL-6 therapy tocilizumab (in addition to previous single prophylactic dose) 8 mg/kg (max, 800 mg) IV once Add dexamethasone 10 mg IV once if anti–IL-6 therapy administered (excluding prophylactic dose) For recurrent grade 1 CRS may repeat above once each Administer premedications (ie, acetaminophen 650 mg × 1, diphenhydramine 50 mg × 1, and dexamethasone 16 mg × 1) before subsequent dose
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Grade 2: fever (defined as ≥38°C) not attributable to any other cause and at least 1 additional criterion:Hypotension (not requiring vasopressors) Hypoxia requiring low-flow nasal cannula (≤6 L/min) or blow-by oxygen delivery facemask, nonrebreather mask, or venturi mask
| Withhold therapy until CRS resolves. Refer to package insert for restarting after dose delay IV fluid challenge (30 mL/kg of normal saline) for hypotension Supplemental oxygen for hypoxia Symptomatic management of organ toxicities Consider, at the discretion of treating oncologist, repeat tocilizumab 8 mg/kg (max, 800 mg) IV × 1 dose (not within 8 hours of last dose) and up to 3 doses at every 8 hours if not responding (max, 3 doses per 24 hours; total 4 dose max per patient) or anakinra at 100 mg subcutaneous every 12 hours until toxicity resolves to grade ≤1: no taper necessary Add dexamethasone at 10 mg IV ×1 for each tocilizumab dose; if starting third or fourth tocilizumab dose continue dexamethasone at 10 mg IV every 6 hours × 2 doses or 1 more doses, respectively (total 4 doses); may stop earlier if hypotension resolves; no taper necessary If hypotension persists consider vasopressors, transfer to ICU, and follow grade 3 recommendations Administer premedications (ie, acetaminophen 650 mg × 1, diphenhydramine 50 mg × 1, and dexamethasone 16 mg × 1), and observe patients in the hospital with subsequent dose
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Grade 3: fever (defined as ≥38°C) not attributable to any other cause and at least 1 additional criterion:Hypotension requiring vasopressors (with or without vasopressin) Hypoxia requiring high-flow nasal cannula (>6 L/min), facemask, nonrebreather mask, or venturi mask
| First occurrence grade 3 CRS with duration <48 hours:Withhold therapy until CRS resolves. Refer to package insert for restarting after dose delay. IV fluid boluses and/or vasopressors as needed for hypotension Supplemental oxygen as needed Symptomatic management of organ toxicities Tocilizumab as recommended for grade 2 CRS (not within 8 hours of last dose) or anakinra at 100 mg subcutaneous every 12 hours until toxicity resolves to grade ≤1: no taper necessary Transfer to ICU and consider echocardiogram (if not done already) Dexamethasone 10 mg IV every 6 hours × 8 doses followed by 10 mg IV every 12 hours × 4 doses, then 5 mg IV every 12 hours × 4 doses, and then stop; if refractory initially, may increase to 20 mg IV every 6 hours × 8 doses and then follow taper >8. Administer premedications (ie, acetaminophen 650 mg ×1, diphenhydramine 50 mg × 1, and dexamethasone 16 mg ×1) and observe patients in the hospital with subsequent dose
If recurrent grade 3 CRS or duration of ≥48 hours:Permanently discontinue therapy IV fluid boluses and/or vasopressors as needed for hypotension Supplemental oxygen as needed Symptomatic management of organ toxicities Tocilizumab as recommended for grade 2 CRS (not within 8 hours of last dose) Transfer to ICU and consider echocardiogram (if not done already) Dexamethasone 10 mg IV every 6 hours × 8 doses followed by 10 mg IV evert 12 hours × 4 doses, then 5 mg IV every 12 hours × 4 doses and then stop; if refractory initially, may increase to 20 mg IV every 6 hours × 8 doses and then follow taper above 8. If refractory to all the above, consider addition of anakinra at 100 mg subcutaneous every 12 hours until toxicity resolves to grade ≥1: no taper necessary
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Grade 4: fever (defined as ≥38°C) not attributable to any other cause and at least 1 additional criterion:Hemodynamic instability requiring multiple vasopressors (excluding vasopressin) Worsening hypoxia or respiratory distress despite oxygen administration requiring positive pressure (eg, CPAP, BiPAP, intubation, and mechanical ventilation)
| Permanently discontinue therapy Mechanical ventilation for hypoxia Symptomatic management of organ toxicities IV fluids, tocilizumab, vasopressors, and hemodynamic monitoring as recommended for grade 3 CRS Methylprednisolone 500 mg IV every 12 hours; taper when able by 50% decrease every 2 days, stop once on 60 mg IV every 12 hours × 4 doses Start or escalate anakinra 100 mg subcutaneous every 8 hours until resolves to grade ≤1: no taper necessary
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