Grade 1 hepatitis includes aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than the upper limit of normal (ULN) to 3x the ULN and/or total bilirubin greater than ULN to 1.5x ULN. Grade 1 is usually managed conservatively, with close monitoring of liver tests and continuing the immunotherapy.

Grade 2 toxicity is AST or ALT 3x to 5x ULN or total bilirubin 1.5x to 3x ULN during which the patient’s immunotherapy dose should be held, more frequent monitoring of the patient’s liver function should be initiated, and low-dose steroids should be considered (0.5 to 1 mg/kg/day of prednisone equivalent).4


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Grade 3 to 4 toxicity is AST or ALT greater than 5x ULN or total bilirubin greater than 3x ULN, at which point the medication should be permanently discontinued, liver function tests should be monitored every 24 to 48 hours, and 1 to 2 mg/kg/day of prednisone equivalent should be started and tapered over several weeks.

If the patient does not respond to steroids after 3 to 5 days, adding another immunosuppressive medication, such as mycophenolate, should be considered.

It can take several weeks to months for the liver function tests to return to normal, even in patients where the medication has been permanently discontinued.

When a patient is suspected of having immune-mediated hepatitis, it is important to consider other etiologies, including drug-induced liver injury from other non-immunotherapy based medications, occult viral infections (eg, hepatitis A, B, or C, Epstein-Barr virus, cytomegalovirus, herpes simplex virus), and/or new or worsening metastatic disease.

If a liver biopsy is performed to assist in identifying the underlying etiology of a patient’s elevated liver function tests, the pathology will typically show diffuse T cell infiltrates.

References

  1. Nivolumab (Opdivo): Immune-mediated adverse reactions management guide. http://www.opdivohcp.com/servlet/ servlet.FileDownload?file=00Pi000000ijs1vEAA. Accessed July 2017.
  2. Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30(21):2691-7.
  3. Common Terminology Criteria for Adverse Events (CTCAE; Version 4.0). US Department of Health and Human Services website. https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. Published May 28, 2009. Accessed July 2017.
  4. Nivolumab (Opdivo) package insert. Bristol-Myers Squibb website. https://packageinserts.bms.com/pi/pi_opdivo.pdf. Accessed July 2017.