Hepatotoxicity (immunotherapy-induced inflammation of liver tissue)

Grading Toxicity: ULN

  • AST/ALT:    >ULN – 3.0× ULN
  • Bilirubin:    >ULN – 1.5× ULN
  • AST/ALT:    >3.0× – 5.0× ULN
  • Bilirubin:    >1.5× – 3.0× ULN
  • AST/ALT:    >5.0× – 20.0× ULN
  • Bilirubin:    >3.0× ULN
  • AST/ALT:    >20× ULN
  • Bilirubin:    >10× ULN

Management (including anticipatory guidance)

Overall Strategy:

  • 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

Infliximab infusions are not recommended due to potential hepatotoxic effects

  • 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

Nursing Implementation:

  • 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

RED FLAGS:

  • Severe abdominal pain, ascites, somnolence, jaundice, mental status changes