Management of Cytokine Release Syndrome
For moderate to severe CRS (Grade ≥2), administer tocilizumab 8 mg/kg IV (maximum 800 mg) as first-line therapy, with corticosteroids added for Grade 3-4 or refractory cases. 1, 2
CRS Grading System
The ASTCT consensus criteria define CRS severity based on fever, hypotension, and hypoxia 2:
- Grade 1: Fever ≥38°C without hypotension or hypoxia 2
- Grade 2: Fever with hypotension not requiring vasopressors and/or hypoxia requiring low-flow oxygen (≤6 L/min) 2
- Grade 3: Fever with hypotension requiring vasopressor (with/without vasopressin) and/or hypoxia requiring high-flow oxygen (>6 L/min) 2
- Grade 4: Fever with hypotension requiring multiple vasopressors and/or hypoxia requiring positive pressure ventilation 2
Important caveat: Once antipyretics are administered, fever is no longer required to grade subsequent CRS severity—grading is based solely on hypotension and/or hypoxia 2. CRS grading should be performed at least twice daily and whenever clinical status changes 1.
Initial Evaluation and Monitoring
Before initiating treatment, obtain the following laboratory workup 2:
- CBC, comprehensive metabolic panel, magnesium, phosphorus
- CRP, LDH, uric acid, ferritin
- Fibrinogen, PT/PTT
- Blood and urine cultures
- Chest radiograph if fever present 2
Continuous cardiac telemetry and pulse oximetry are mandatory for Grade ≥2 CRS 2. Consider baseline echocardiogram to assess cardiac function, particularly in severe cases 1, 2.
Treatment Algorithm by Grade
Grade 1 CRS
- Supportive care only: Acetaminophen for fever, IV hydration 1, 2
- Evaluate for infectious etiologies with cultures and imaging 1
- Consider broad-spectrum antibiotics if neutropenic 1
- Monitor closely for progression 1
Grade 2 CRS
- Administer tocilizumab 8 mg/kg IV (maximum 800 mg) 1, 2, 3
- Continue supportive care with IV fluids and oxygen as needed 2
- Product-specific considerations: For axicabtagene ciloleucel or brexucabtagene autoleucel, consider tocilizumab if symptoms persist >24 hours; for lisocabtagene maraleucel with early-onset CRS (<72 hours), consider adding dexamethasone 10 mg × 1 1
Grade 3 CRS
- Administer tocilizumab 8 mg/kg IV (maximum 800 mg) PLUS dexamethasone 10 mg IV every 6 hours 1, 2
- Transfer to ICU for closer monitoring 1, 4
- Initiate vasopressor support for persistent hypotension despite fluid resuscitation 1, 4
- Provide high-flow oxygen or non-invasive ventilation as needed 4
- Product-specific considerations: For axicabtagene ciloleucel, consider dexamethasone 10 mg IV every 24 hours after initial tocilizumab regardless of response 1
Grade 4 CRS
- Administer tocilizumab 8 mg/kg IV (maximum 800 mg) PLUS dexamethasone 10 mg IV every 6 hours 2
- ICU care with mechanical ventilation as needed 2
- Multiple vasopressor support 2
- Consider escalating to methylprednisolone 1000 mg/day for 3 days if inadequate response, followed by rapid taper 1
Management of Refractory CRS
If CRS persists or worsens despite tocilizumab and corticosteroids, consider the following 1, 2:
- Repeat tocilizumab dosing: Assess need after each dose; maximum 2 doses during a CRS episode is recommended under tocilizumab conservation strategies 1
- Anakinra (IL-1 receptor antagonist): Consider for refractory cases 1, 2
- Alternative IL-6 antagonists: Siltuximab or clazakizumab may be considered, though evidence is limited 1, 2
- Other agents with limited evidence: Ruxolitinib, cyclophosphamide, IVIG, ATG, or extracorporeal cytokine adsorption with CRRT 1
Special Considerations and Critical Pitfalls
Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS)
Suspect CAR T cell-related HLH/MAS if peak ferritin >10,000 ng/ml during CRS-risk period plus any two of: Grade ≥3 organ toxicities involving liver, kidney, or lung; or hemophagocytosis in bone marrow or other organs 1. Treat with tocilizumab AND corticosteroids simultaneously; consider higher steroid doses than typical for CRS grade 1. If no improvement within 48 hours, add anakinra 1. Etoposide or intrathecal cytarabine can be considered as last resort for HLH with CNS involvement 1.
Infection Risk
- Always perform infectious workup before attributing symptoms solely to CRS—CRS can be confused with infection 1, 2
- Delay CAR T-cell infusion in patients with active infection until controlled 2
- Strongly consider antifungal prophylaxis in patients receiving steroids for CRS treatment 1, 2
- Both tocilizumab and corticosteroids increase infection risk; monitor closely 4
Concurrent Neurotoxicity
- CRS may occur with immune effector cell-associated neurotoxicity syndrome (ICANS), which requires separate management 2
- Tocilizumab may not be effective for ICANS and may potentially contribute to it 2
- Moderate to severe ICANS should be managed with corticosteroids and supportive care 1
Impact on CAR T-Cell Efficacy
Short courses of tocilizumab and corticosteroids do not significantly impact outcomes in life-threatening situations and should not be delayed due to concerns about CAR T-cell efficacy 2, 5. However, corticosteroids may potentially reduce CAR T-cell efficacy, so use judiciously 2.
Product-Specific Timing
- CRS typically appears 1-14 days after CAR T-cell infusion and can last 1-10 days 6
- Patients with early-onset CRS (within 3 days), bulky disease, and comorbidities are at high risk for severe CRS 1
Laboratory Monitoring During Treatment
Perform daily laboratory tests including 4:
- CBC, comprehensive metabolic panel
- CRP, ferritin, fibrinogen
- Monitor for cytopenias and hepatotoxicity
Contraindications and Precautions
- For CAR T-cell therapy patients: Severe or life-threatening CRS frequently presents with cytopenias or elevated transaminases; the decision to administer tocilizumab should weigh potential benefit versus short-term treatment risks 3
- Do not use GM-CSF in the setting of CAR T-cell therapy 1
- Central venous access (preferably double or triple lumen) is recommended for IV fluid and possible vasopressor use 1