What are the diagnostic criteria, grading system, and treatment recommendations for cytokine release syndrome, including indications for tocilizumab and corticosteroids?

Cytokine Release Syndrome: Diagnostic Criteria and Management

Diagnostic Criteria and Grading System

CRS is defined by the American Society for Transplantation and Cellular Therapy (ASTCT) as a supraphysiologic immune response following immune therapy, with severity graded based on fever, hypotension, and hypoxia. 1

ASTCT Consensus Grading Criteria

• Grade 1: Temperature ≥38°C without hypotension or hypoxia 2, 1
• Grade 2: Temperature ≥38°C with hypotension not requiring vasopressors and/or hypoxia requiring low-flow oxygen (≤6 L/min) 2, 1
• Grade 3: Temperature ≥38°C with hypotension requiring one vasopressor (with or without vasopressin) and/or hypoxia requiring high-flow oxygen (>6 L/min) 2, 1
• Grade 4: Temperature ≥38°C with hypotension requiring multiple vasopressors and/or hypoxia requiring positive pressure ventilation 2, 1

Critical Grading Considerations

• CRS grade is determined by the more severe event between hypotension and hypoxia, not attributable to other causes 3
• In patients receiving antipyretics or anticytokine therapy, fever is not required for grading subsequent CRS severity; use hypotension and/or hypoxia instead 1
• A patient with fever, hypotension requiring one vasopressor, and hypoxia requiring low-flow oxygen is classified as Grade 3 CRS (based on the more severe parameter) 3

Initial Evaluation and Monitoring

Mandatory Laboratory Workup

• Complete blood count, comprehensive metabolic panel, magnesium, phosphorus, CRP, LDH, uric acid, fibrinogen, PT/PTT, and ferritin 1
• Blood and urine cultures, chest radiograph if fever present 1
• Daily monitoring of CBC, comprehensive metabolic panel, CRP, ferritin, and fibrinogen 2

Cardiovascular and Respiratory Monitoring

• Continuous cardiac telemetry and pulse oximetry for Grade 2 or higher CRS 1
• Baseline echocardiogram recommended before CAR T-cell therapy, especially for patients with cardiovascular comorbidities 3
• Consider repeat echocardiogram to assess cardiac function in severe CRS 1
• Central venous access (double or triple lumen) recommended for IV fluids and possible vasopressor use 3

Critical Differential Diagnosis

Always perform infectious workup immediately, as CRS presentation overlaps significantly with neutropenic sepsis 1

• Start empiric broad-spectrum IV antibiotics immediately in patients with severe CRS given the overlap with neutropenic sepsis 1
• Active infection should be controlled before CAR T-cell infusion when possible 1

Treatment Algorithm by CRS Grade

Grade 1 CRS Management

• Supportive care with antipyretics and IV hydration 1
• For axicabtagene ciloleucel or brexucabtagene autoleucel: consider tocilizumab if symptoms persist >24 hours 3
• For lisocabtagene maraleucel: consider tocilizumab for Grade 1 CRS developing <72 hours after infusion plus dexamethasone 10 mg × 1 3
• For CRS developing ≥72 hours after infusion: treat symptomatically 3

Grade 2 CRS Management

Administer tocilizumab 8 mg/kg IV (maximum 800 mg, or 12 mg/kg in pediatric patients <30 kg) 2, 1

• Tocilizumab can be repeated every 8 hours if no improvement, with reassessment after each dose 3, 2
• Product-specific considerations:
  • For axicabtagene ciloleucel: consider dexamethasone 10 mg IV every 24 hours after initial tocilizumab, regardless of clinical response 3
  • For lisocabtagene maraleucel: consider dexamethasone 10 mg IV every 12-24 hours if early-onset CRS 3
  • For idecabtagene vicleucel: consider dexamethasone 10 mg IV every 12-24 hours 3

Grade 3 CRS Management

Administer tocilizumab 8 mg/kg IV (maximum 800 mg) plus dexamethasone 10 mg IV every 6 hours 2, 1

• Transfer to ICU for close monitoring 2
• Provide supplemental oxygen to maintain saturation >92% 2
• Administer IV fluids for volume resuscitation; initiate vasopressors if hypotension persists 2
• Consider higher doses of corticosteroids if HLH/MAS is suspected 3

Grade 4 CRS Management

Administer tocilizumab 8 mg/kg IV (maximum 800 mg), high-dose corticosteroids, and ICU care with mechanical ventilation as needed 1

• High-dose corticosteroid regimen: methylprednisolone 1,000 mg/day (may consider twice daily) for 3 days, followed by rapid taper at 250 mg every 12 hours for 2 days, 125 mg every 12 hours for 2 days, and 60 mg every 12 hours for 2 days 3
• Alternative equivalent-dose steroids may be considered 3

Refractory CRS Management

Second-Line Therapy: Anakinra

For CRS refractory to tocilizumab and/or when steroids cannot be used, administer anakinra (IL-1 receptor antagonist) 100 mg subcutaneous or IV 2-4 times daily 2

• Consider adding anakinra to corticosteroids if no improvement within 48 hours for HLH/MAS 3

Additional Refractory Options

• Siltuximab (alternative IL-6 antagonist) 2, 1
• Ruxolitinib 3, 2
• Cyclophosphamide 3, 2
• Intravenous immunoglobulin 2
• Antithymocyte globulin 2
• Extracorporeal cytokine adsorption with continuous renal replacement therapy 3, 2
• Etoposide or intrathecal cytarabine as last resort for HLH with CNS involvement 3

Tocilizumab Conservation Strategies

Under conditions of limited tocilizumab availability 3:

• Limit tocilizumab to maximum of 2 doses per CRS episode
• Use steroids more aggressively during CRS episodes
• Consider replacing second tocilizumab dose with siltuximab or anakinra (very limited evidence)

Concurrent Neurotoxicity (ICANS) Management

Key Principles

Tocilizumab may be used for CRS in patients with concurrent neurotoxicity, but corticosteroids alone may be preferable for Grade 1 CRS (fever alone) with concurrent higher-grade neurotoxicity, as tocilizumab may exacerbate neurotoxicity 3

• Transfer to ICU if neurotoxicity is associated with Grade 2 or higher CRS 3

Neurotoxicity-Specific Treatment

• Grade 1 neurotoxicity: Supportive care alone 3
• Grade 2 neurotoxicity: Dexamethasone 10 mg IV, repeated every 6-12 hours if no improvement 3
• Grade 3 neurotoxicity: Dexamethasone 10 mg IV every 6 hours or methylprednisolone 1 mg/kg IV every 12 hours; for axicabtagene ciloleucel or brexucabtagene autoleucel, methylprednisolone 1 gram daily for 3-5 days may be preferable 3
• Grade 4 neurotoxicity: High-dose corticosteroids with rapid taper as outlined above 3

Hemophagocytic Lymphohistiocytosis/Macrophage-Activation Syndrome (HLH/MAS)

Recognition and Management

• HLH/MAS occurs in approximately 3.5% of CAR T-cell therapy patients 3
• Clinical features overlap significantly with CRS: high fevers, elevated ferritin, CRP, cytopenias, hypofibrinogenemia, coagulopathy 3
• Treat as per CRS with tocilizumab and steroids, but suspicion of HLH/MAS should prompt consideration of higher steroid doses at a given CRS grade 3
• Most cases resolve with CRS management and do not require HLH/MAS-specific treatment 3

Critical Supportive Care Measures

Infection Prophylaxis

Strongly consider antifungal prophylaxis in all patients receiving corticosteroids for CRS or neurotoxicity 3, 2, 1

Additional Supportive Measures

• Administer empiric broad-spectrum antibiotics if neutropenic 2
• Use fast steroid taper when there is improvement in ICANS 3
• GM-CSF is not recommended in the setting of CAR T-cell therapy 3, 1

Critical Pitfalls to Avoid

Treatment Delays

Do not delay appropriate treatment due to concerns about CAR T-cell efficacy, as untreated severe CRS can be life-threatening 2

• Short courses of corticosteroids do not significantly impact CAR T-cell outcomes 1

Diagnostic Pitfalls

• Always perform infectious workup; CRS can be confused with infection 1
• Do not rely solely on fever for grading CRS in patients receiving antipyretics or anticytokine therapy 1
• Be vigilant for concurrent ICANS, which requires different management strategies 1

Medication Considerations

• Do not use GM-CSF in CAR T-cell therapy setting 3, 1
• Tocilizumab may not be effective for ICANS and may potentially contribute to it 1
• Consider that tocilizumab is FDA-approved for CAR T-cell-induced severe or life-threatening CRS in adults and pediatric patients ≥2 years 1

Timing Considerations

• Earlier onset of fever (within days of infusion) is associated with more severe, progressive CRS requiring multiple doses of anti-IL-6 therapy 4
• Longer time to fever onset (>25 days), lower platelet count, and higher urea at presentation are associated with Grade 3-5 CRS 5