What is the management approach for Nivolumab (nivolumab)-associated liver injury with fever?

Management of Nivolumab-Associated Liver Injury with Fever

For nivolumab-associated liver injury with fever, immediately discontinue nivolumab, initiate high-dose corticosteroids (1-2 mg/kg/day of prednisolone or methylprednisolone), and consider mycophenolate mofetil if no improvement occurs within 2-3 days. 1

Assessment and Initial Management

• Evaluate the severity of liver injury using serum ALT/AST levels, with grade 3-4 elevations (>5x ULN) requiring immediate intervention 1
• Rule out other causes of liver injury including viral hepatitis, autoimmune liver diseases, and biliary pathology 1
• For patients with fever, consider both immune-mediated hepatitis and potential infection, as fever may indicate either severe immune reaction or concomitant infection 2, 3
• Monitor liver function tests regularly regardless of baseline results 1

Treatment Algorithm Based on Severity

Grade 1-2 Liver Injury (ALT/AST <5x ULN)

• Withhold nivolumab and monitor liver function tests closely 1
• For grade 2 elevations, initiate oral corticosteroids (prednisolone 0.5-1 mg/kg/day) 1
• If improvement to grade 1 occurs, taper corticosteroids over 4-6 weeks 1
• Consider resuming nivolumab only after corticosteroid dose reaches ≤10 mg/day and liver function has significantly improved 1

Grade 3-4 Liver Injury (ALT/AST >5x ULN)

• Permanently discontinue nivolumab 1
• Start high-dose corticosteroids immediately:
  • Grade 3: Oral prednisolone/methylprednisolone 1 mg/kg/day 1
  • Grade 4: Intravenous methylprednisolone 2 mg/kg/day 1
• If no response to corticosteroids within 2-3 days, add mycophenolate mofetil 500-1000 mg twice daily 1
• Consult with a hepatologist and consider liver biopsy 1
• For fulminant cases with encephalopathy, consider plasma exchange 2, 3

Special Considerations

• Fever may indicate severe immune-related hepatitis requiring more aggressive management 2, 4
• Nivolumab-induced liver injury can occur suddenly even after long-term therapy with previously normal liver function 4
• Fulminant hepatitis can develop after a single dose of nivolumab, requiring vigilant monitoring 3
• Patients with pre-existing liver disease may require modified thresholds for intervention, using multiples of baseline ALT rather than ULN 1

Monitoring During Treatment

• Perform frequent liver function tests (every 1-2 days initially) to assess response to treatment 1
• Monitor for signs of hepatic encephalopathy which may indicate progression to fulminant hepatic failure 3
• Continue corticosteroid treatment until liver enzymes normalize, then taper slowly over at least 4-6 weeks 1
• Be aware that some patients may experience sustained liver injury despite appropriate treatment 5

Pitfalls and Caveats

• Delaying immunosuppressive therapy can lead to progression to fulminant hepatic failure and death 2, 3
• Do not use infliximab for nivolumab-induced hepatitis due to its potential hepatotoxicity 1
• Liver injury can occur even after a single dose of nivolumab or after long-term treatment with previously normal liver function 3, 4
• Combination therapy with other immune checkpoint inhibitors or chemotherapeutic agents significantly increases the risk of severe liver injury 1
• Histologically, nivolumab-induced liver injury typically shows CD8+ T-cell infiltration, which helps confirm the diagnosis 3, 6