Immune-Related Adverse Events for GI Toxicity - Hepatitis

Monitor patients for abnormal liver blood tests: AST, ALT, and bilirubin prior to each infusion. 

Grade 1: Monitor patient for abnormal liver blood tests: AST, ALT, and bilirubin once or twice weekly.

Grade 2-4: Further diagnostic work-up is recommended as following: 

• Work-up for other causes of elevated liver enzymes, including viral hepatitis, alcohol history, iron studies, thromboembolic event, liver ultrasound, cross-sectional imaging for potential liver metastasis from primary malignancy. Consider antinuclear antibodies, antismooth muscle antibodies, antineutrophil cytoplasmic antibodies if suspicion for primary autoimmune hepatitis is high.
• Work-up for other etiologies: consider checking creatine kinase for isolated elevation of transaminases.

For all patients where an IRAE diagnosis is being considered, it is always recommended to involve the specialist or team prescribing the immune checkpoint therapy.

All patients

• Counsel all patients to be aware of and inform their health care provider immediately if they experience any of the following:
  • Yellowing of skin or whites of the eyes, severe nausea or vomiting, pain on the right side of the abdomen, drowsiness, dark urine (tea colored), bleeding or bruising more easily than normal, feeling less hungry than usual.

Grade 1:

1. Continue immune checkpoint inhibitor with close monitoring.

2. Consider alternate etiologies.

3. Monitor laboratories one to two times weekly.

4. Manage with supportive care for symptom control.

Grade 2: 

1. Hold immune checkpoint inhibitor temporarily and resume if recovers to grade 1 or less on prednisone ≤ 10 mg/d.

2. For patients with symptoms, consider corticosteroid 0.5–1 mg/kg/d prednisone or equivalent if the abnormal elevation persists with significant clinical symptoms in 3–5 days.

3. Increase frequency of monitoring to every 3 days.

4. Infliximab might not be the most appropriate treatment option in the situation of immune-mediated hepatitis given the potential risk of idiosyncratic liver failure (Note: No clear evidence shows the liver toxicity from infliximab from other studies).

5. In follow-up, may resume immune checkpoint inhibitor treatment followed by taper only when symptoms improve to G1 or less and corticosteroid ≤ 10 mg/d; taper over at least 1 month.

6. Patients should be advised to stop unnecessary medications and any known hepatotoxic drugs.

Grade 3: 

1. Often corticosteroid 1–2 mg/kg methylprednisolone or equivalent is recommended.

2. If corticosteroid refractory or no improvement after 3 days, consider mycophenolate mofetil or azathioprine (if using azathioprine should test for thiopurine methyltransferase deficiency).

3. Laboratories at daily or every other day; consider inpatient monitoring for patients with AST/ALT > 8 × ULN and/or elevated TB 3 × ULN Increase frequency of monitoring to every 1–2 days.

4. Infliximab might not be the most appropriate treatment option in the situation of immune-mediated hepatitis given the potential risk of liver failure (Note: No clear evidence shows that the liver toxicity from infliximab from other studies); alternatives include non–TNF-α agents as systemic immunosuppressants.

5. Corticosteroid taper can be attempted around 4–6 weeks; re-escalate if needed; optimal duration unclear.

Grade 4: 

1. Permanently discontinue immune checkpoint inhibitor.

2. Steroid 2 mg/kg/d methylprednisolone equivalents should be considered.

3. If corticosteroid refractory or no improvement after 3 days, consider mycophenolate mofetil.

4. Monitor laboratories daily; consider inpatient monitoring.

5. Avoid the use of infliximab in the situation of immune-mediated hepatitis.

6. Consult hepatology if no improvement was achieved with corticosteroid.

7. Corticosteroid taper can be attempted around 4–6 weeks when symptoms improve to G1 or less; re-escalate if needed; optimal duration unclear.

8. Consider transfer to tertiary care facility if necessary.

See Brahmer 2018 for full ASCO guidelines.

Infliximab, as an immunosuppressant, might not be the most appropriate treatment option due to potential risk of liver failure despite no clinical evidence in the literature; alternatives include non–TNF-α agents as systemic immunosuppressants.