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Checkpoint inhibitor induced steroid refractory drug‐induced liver injury

We describe the case of a 75-year-old man with BRAF wild-type melanoma with metastases to lymph nodes, liver, spleen and bone being enrolled in a clinical trial receiving dual checkpoint inhibitor (CPI) therapy with a CTLA-4 antagonist and PD1 inhibitor plus a RANK ligand inhibitor. The regimen consisted of 4 weeks of weekly denosumab 120 mg subcutaneously, followed by three weekly nivolumab 88 mg (1 mg/kg) intravenously and ipilimumab 264 mg (3 mg/kg) intravenously. After 4 weeks of therapy, he developed a 10-fold increase in the transaminases above the upper limit of normal, consistent with a Grade 3 toxicity. He was commenced on intravenous methylprednisolone 180 mg daily and CPI therapy was ceased. His transaminases peaked with an alanine aminotransferase (ALT) of 455 IU/L and he was started on a weaning course of prednisolone starting at 100 mg daily (Fig. 1). At Week 3, the prednisolone was tapered to 37.5 mg, a flare occurred with an ALT rise to 647 IU/L. He was re-commenced on oral prednisolone 200 mg daily. At Week 4, mycophenolate 500 mg twice daily (BD) was commenced and gradually uptitrated to 2 mg BD. At Week 5, prednisolone was weaned to 75 mg daily, then by 10 mg per week until Week 7 at 50 mg when it was switched to budesonide 9 mg daily due to concerns about the development of metabolic and immunosuppressive effects of systemic steroids. His liver function tests returned to normal at Week 11; therefore, mycophenolate was reduced to 1 g BD and budesonide to 6 mg daily with a view to reduce further. Restaging computed tomography and positron-emission tomography scans showed a good partial response to therapy. A decision was made not to pursue liver biopsy as features of drug-induced liver injury (DILI) related to CPI are non-specific and the results would unlikely change management. The prevalence of CPI-induced hepatitis is 3–9% with single-agent CTLA-4 antagonists, 5% with single-agent PD-1 inhibitors and 20% with combination CTLA-4 antagonist and PD1 inhibitor therapy. Most cases of Grade 2 toxicities improve after temporarily withholding the CPI, 88% of Grade 3 or 4 toxicities respond to