Hepatotoxicity (immunotherapy-induced inflammation of liver tissue)

Grading Toxicity: ULN

LFTs should be checked and results reviewed prior to each dose of immunotherapy
Rule out infectious, non-infectious, and malignant causes. Consider assessing for new onset or re-activation of viral hepatitis, medications (acetaminophen, statins, and other hepatotoxic meds, or supplements/herbals), recreational substances (alcohol); consider disease progression

Immunotherapy may be withheld if LFTs are trending upward; recheck LFTs within ~ 1 week

Immunotherapy to be withheld; recheck LFTs daily x 3 days or every 3 days; to be resumed when complete/partial resolution of adverse reaction (Grade 0/1)
Immunotherapy to be discontinued for Grade 2 events lasting ≥6 (ipilimumab) or ≥12 weeks (pembrolizumab, nivolumab), or for inability to reduce steroid dose to 7.5 mg prednisone or equivalent per day
Consider starting steroids* 0.5 mg – 1 mg/kg/day prednisone or equivalent daily (IV methylprednisolone 125 mg total daily dose) + an anti-acid
Consider hospital admission for IV steroids*
If LFT normalized and symptoms resolved, steroids* to be tapered over ≥ 4 weeks when function recovers
Once patient returns to baseline or Grade 0-1, consider resuming treatment

Steroids* to be initiated at 2 mg/kg/day prednisone or equivalent daily oral
Nivolumab to be withheld for first-occurrence Grade 3 event. Ipilimumab to be discontinued for any Grade 3 event, and nivolumab or pembrolizumab for any recurrent Grade 3 event or Grade 3 event persisting ≥12 weeks
Admission for IV steroids*
R/O hepatitis infection (acute infection or reactivation)
Daily LFTs
If sustained elevation is significant and/or refractory to steroids* potential for ADDING to steroid regimen immunosuppressive agent:
- CellCept^® (mycophenolate mofetil) 500 mg – 1000 mg po q 12 hours OR
- Antithymocyte globulin infusion
Hepatology/gastroenterology consult
Consider liver biopsy
If LFTs stable/declining daily for 5 consecutive days: decrease LFT checks to q 3 days, then weekly
If LFT normalized and symptoms resolved, steroids* to be tapered over ≥4 weeks

Immunotherapy to be discontinued
Hospital admission
Steroids* to be initiated at 2 mg/kg/day prednisone or equivalent daily intravenous
R/O hepatitis infection
Daily LFTs
If sustained elevation and refractory to steroids* potential for ADDING to steroid regimen:
- CellCept^® (mycophenolate mofetil) 500 mg – 1000 mg po or IV q 12 hours OR
- Antithymocyte globulin infusion
Hepatology/gastroenterology consult
Consider liver biopsy
If LFTs stable/declining daily for 5 consecutive days: decrease LFT checks to q 3 days, then weekly
If LFTs normalized and symptoms resolved, steroids* to be tapered slowly over ≥4 weeks

Review LFT results prior to administration of immunotherapy
Early identification and evaluation of patient symptoms
Early intervention with lab work and office visit if hepatotoxicity is suspected
Grade LFTs and any other accompanying symptoms

*Steroid taper instructions/calendar as a guide but not an absolute

Taper should consider patient’s current symptom profile
Close follow-up in person or by phone, based on individual need & symptomatology
Anti-acid therapy daily as gastric ulcer prevention while on steroids
Review steroid medication side effects: mood changes (anger, reactive, hyperaware, euphoric, mania), increased appetite, interrupted sleep, oral thrush, fluid retention
Be alert to recurring symptoms as steroids taper down & report them (taper may need to be adjusted)

Long-term high-dose steroids:

Consider antimicrobial prophylaxis (sulfamethoxazole/trimethoprim double dose M/W/F; single dose if used daily) or alternative if sulfa-allergic (e.g., atovaquone [Mepron^®] 1500 mg po daily)
Consider additional antiviral and antifungal coverage
Avoid alcohol/acetaminophen or other hepatoxins