What is the management for Cytokine Release Syndrome (CRS) due to CAR (Chimeric Antigen Receptor) T cell therapy?

Management of Cytokine Release Syndrome (CRS) Due to CAR T-Cell Therapy

For CAR T-cell-induced CRS, initiate supportive care for grade 1, add tocilizumab 8 mg/kg IV for grade 2 or higher, and escalate to corticosteroids (dexamethasone 10 mg IV) for grade 3-4 or refractory cases. 1

Initial Assessment and Monitoring

All patients require baseline laboratory evaluation before treatment:

• Complete blood count (CBC), comprehensive metabolic panel (CMP), magnesium, phosphorus 1
• C-reactive protein (CRP), ferritin, LDH, uric acid, fibrinogen, PT/PTT 1, 2
• Daily CRP and ferritin monitoring specifically for CRS surveillance 1
• Assess for infection with blood and urine cultures, chest radiograph if fever present 1

Continuous monitoring parameters:

• Vital signs every 4 hours including pulse oximetry 1
• Continuous cardiac telemetry and pulse oximetry for grade ≥2 CRS 1
• CRS grading at least every 12 hours, more frequently if clinical status changes 2

Grade-Specific Management Algorithm

Grade 1 CRS (Fever ≥38°C only, no hypotension or hypoxia)

Supportive care only: 1

• Antipyretics (acetaminophen) for fever 2
• IV hydration 1
• Symptomatic management of organ toxicities 1
• Consider empiric broad-spectrum antibiotics if neutropenic 1
• May consider G-CSF per product guidelines (GM-CSF is NOT recommended) 1

Escalation criteria: If fever persists >3 days, manage as grade 2 1

Grade 2 CRS (Fever + hypotension not requiring vasopressors OR hypoxia requiring low-flow oxygen ≤6 L/min)

Tocilizumab is the primary intervention: 1, 3

• Administer tocilizumab 8 mg/kg IV over 1 hour (maximum 800 mg/dose) 1
• Repeat every 8 hours if no improvement; maximum 3 doses in 24 hours, 4 doses total 1
• Continue supportive care: IV fluid boluses and supplemental oxygen as needed 1

Add corticosteroids if inadequate response:

• If hypotension persists after two fluid boluses AND one to two doses of tocilizumab, add dexamethasone 10 mg IV every 12 hours for 1-2 doses 1
• Escalate to grade 3 management if no improvement within 24 hours of starting tocilizumab 1

Grade 3 CRS (Fever + vasopressor requirement OR high-flow oxygen/non-rebreather mask)

Immediate ICU admission required: 1

• Continue tocilizumab as per grade 2 if maximum dose not reached 1
• Add dexamethasone 10 mg IV every 6 hours immediately (or equivalent corticosteroid) 1
• Rapidly taper steroids once symptoms improve 1
• Initiate vasopressors as needed 1
• Obtain echocardiogram to assess cardiac function and conduct hemodynamic monitoring 1

Important caveat: Earlier steroid use reduces CRS severity and is recommended for certain products (axicabtagene ciloleucel, brexucabtagene autoleucel) 1

Grade 4 CRS (Fever + multiple vasopressors OR positive pressure ventilation)

Aggressive intervention required: 1

• Continue tocilizumab if maximum not reached within 24 hours 1
• High-dose methylprednisolone 500 mg IV every 12 hours for 3 days 1
• Then taper: 250 mg IV q12h × 2 days → 125 mg IV q12h × 2 days → 60 mg IV q12h until improvement to grade 1 1
• If not improving, consider methylprednisolone 1,000 mg IV twice daily or alternate therapy 1
• Mechanical ventilation as needed 1

Critical Management Principles

Fever is not required for grading subsequent CRS severity in patients receiving antipyretics or anticytokine therapy; grading is driven by hypotension and/or hypoxia 1

Do NOT routinely administer corticosteroids as pre-medication before CAR T-cell infusion 1

Strongly consider antifungal prophylaxis in patients receiving steroids for CRS and/or ICANS treatment 1

Special Considerations

Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome

Suspect when: 1

• Ferritin >10,000 ng/ml 1, 4
• Grade ≥3 organ toxicities (liver, kidney, lung) 1
• Evidence of hemophagocytosis in bone marrow 1

Management: Treat as grade 3 CRS initially; if no improvement after 48-72 hours, consider HLH-2004 protocol 1

Concurrent ICANS

In the specific setting of grade 1 CRS with concurrent grade 2 ICANS, administer steroids (NOT tocilizumab) 1

This distinction is critical because tocilizumab does not cross the blood-brain barrier effectively, while corticosteroids address both CRS and neurologic toxicity 1

Alternative Agents for Refractory Cases

With limited experience, alternate options include: 1

• Anakinra (anti-IL-1R) 1
• Siltuximab (anti-IL-6) 1
• Ruxolitinib 1
• Cyclophosphamide 1

Common Pitfalls to Avoid

Do NOT delay tocilizumab administration: Each 12-hour delay increases cardiotoxicity risk 1.7-fold 1

Do NOT use GM-CSF: It is specifically contraindicated despite G-CSF being permissible 1

Do NOT use leukapheresis filters for CAR T-cell infusion 1

Organ toxicities associated with CRS (cardiac, hepatic, renal dysfunction) may be graded by CTCAE v5.0 but do not influence CRS grading itself 1