Background

Metastatic melanoma is traditionally associated with poor prognosis, with a median survival reported as 9 months with 1 year survival rate of 33%.1 Queensland has one of the highest incidences of melanoma in the world. Melanoma is sometimes labelled as Australia's national cancer. In 2009, melanoma of the skin was the fourth most commonly diagnosed cancer in Australia (after prostate, bowel and breast cancer), accounting for 10.1% of all new cancers. About 12 500 new cases of melanoma are diagnosed every year in Australia, predominantly in Queensland, accounting for 3.4% of all cancer deaths in Australia.2 Recently, new therapeutic options for metastatic melanoma have changed its outlook, in particular with immunotherapy. The programmed death 1 (PD-1) inhibitor nivolumab has shown promise when used concurrently with ipilimumab, causing more rapid and deeper clinical tumour response.3

Ipilimumab (tradename: Yervoy) is a full human monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4 (CTLA-4), a prominent negative regulator in T-cell activation. Ipilimumab was approved by the Food and Drug Administration (FDA) in March of 2011 for unresectable stage III or IV melanoma. Although ipilimumab has a manageable safety profile, treatment has been associated with potentially fatal adverse effects, most notable immune-related adverse events (irAEs). Most of the serious complications of ipilimumab treatment reported are associated with the gastrointestinal (GI) tract; these include diarrhoea, hepatotoxicity, abdominal pain and bloating. Recently, there have been reports of ipilimumab induced myasthenia gravis complicating treatment of metastatic melanoma.4 Immune-mediated hepatitis has been reported in 2–9% of patients treated with ipilimumab.5 At least one death due to liver failure has been reported, which was attributed to a delay in the initiation of treatment.6

Case presentation

A 50-year-old Caucasian woman from Far North Queensland, Australia, presented with febrile illness associated with rigours and grossly deranged liver function tests with a history of ipilimumab treatment for metastatic melanoma. She was healthy before diagnosis of melanoma and did not take any regular medications. She lived with her husband and did not drink alcohol.

She presented to the emergency department late in the afternoon of Monday 18 November 2013 (day 1) with hypotension, fevers and malaise. Her biochemistry showed grossly altered liver enzymes with an aspartate aminotransaminase (AST) of 936 units/L and alanine aminotransaminase (ALT) of 640 units/L with equally elevated lactate dehydrogenase, alkaline phosphatase and γ-glutamyl transferase . Her bilirubin, however, was normal and blood counts were also largely normal except for minor abnormalities. She did not drink alcohol and denied taking any hepatotoxic medications or herbal treatments in the recent past. Her initial diagnosis was ipilimumab induced irAEs causing hepatitis or drug-induced liver injury (DILI). She was started on 2 mg/kg of methylprednisolone to treat grade III hepatotoxicity according to ipilimumab immune toxicity guidelines. The next morning (day 2), however, her liver enzymes showed an exponential rise to AST of 7280 and ALT of 4700, and minor elevation of bilirubin. There was a concern of fulminant hepatic failure, however, she remained clinically stable without any hepatic encephalopathy. She, however, developed mild coagulopathy the next day. She was seen by gastroenterologists and alternative aetiologies were considered. According to Council for International Organizations of Medical Sciences scale (CIOMS)7 for hepatocellular injury, the final score calculated was 9. This indicated that the DILI was most probably secondary to ipilimumab, as depicted in table 1.

Investigations

The patient's work up for viral hepatitis including hepatitis A, B, C, E, rickettsia and cryptococcal antigen, and extended autoimmune work up, which included antimitochondrial antismooth muscle, antiliver-kidney microsomal, antinuclear and antineutrophil cytoplasmic antibodies, were negative. She underwent ultrasound of the liver, which was unremarkable. Her serum paracetamol level was unremarkable. Her blood cultures performed in the emergency department were negative for growth. Her serology for dengue and leptospirosis was negative. Her serum paracetamol levels were undetectable. She was positive for cytomegalovirus (CMV) and Epstein-Barr virus IgG. Liver biopsy was not considered safe in such an acutely unwell patient.

Differential diagnosis

Our main differential diagnosis was ipilimumab induced irAEs causing hepatotoxicity.

Treatment

Our patient initially presented with non-specific symptoms with transaminases up to 30 times the normal limit, which subsequently rose to 230 times the limit in a span of merely hours. This degree of hepatic enzyme elevation with ipilimumab, to the best of our knowledge, has not been reported before. Given the patient's deteriorating clinical course in such a rapid span of time, she was started on methylprednisolone, equine antithymocyte globulin (ATG) (ATGAM) and mycophenolate mofetil up front. She was considered for a liver biopsy before starting of treatment; however, it was deferred because of mild coagulopathy and the emergent life-threatening situation. She received her first dose of methylprednisolone in the emergency department. The next morning, her blood tests showed acute worsening. She was started on ATGAM with mycophenolate mofetil early in the morning of day 2. She tolerated the infusion generally well. This treatment was complicated overnight by asymptomatic sinus bradycardia. Her liver functions showed steep decline after the first dose of ATGAM, which further improved after the second dose on day 3. She was continued on methylprednisolone for a total of four doses, 120 mg each, over days 1–4.

The patient's liver functions improved within 24 h, with a drop in absolute lymphocyte count to 0.07×10⁹/L. Her liver functions touched baseline in 2-weeks of treatment. After the four doses of methylprednisolone, she was switched to prednisolone, which she was weaned off in 6 weeks. Mycophenolate was continued at 1 gm two times per day and subsequently halved, and finally stopped in 2 weeks. Table 2 below shows the level of liver enzymes, absolute lymphocyte counts and effect of treatment with triple immunosuppressant treatment on both parameters from day 0 to day 30.

Our patient was administered ATGAM with good response. We were able to keep absolute lymphocyte counts to <0.1×10⁹ by administering ATG, without any side effects. The patient's absolute lymphocyte count remained below 0.1 for at least 3 days during her treatment. She was started on prophylaxis with trimethoprim/sulfamethoxazole and valacyclovir, for pneumocystis jirovecii and CMV, respectively. In renal transplantations, rabbit ATG (thymoglobulin) is the standard of care; it has proved to be superior in acute renal allograft rejection settings. Compared with ATGAM, rabbit ATG (thymoglobulin) resulted in a higher rate of reversal of rejection (88% vs 76%) and a lower rate of recurrent rejection at 90 days after antibody therapy (17% vs 36%). Patient and graft survival and the rates of adverse events and infections were similar in both groups.8 We chose ATGAM for our patient as thymoglobulin was not available in our centre at the time.

Outcome and follow-up

The patient continues to be well with regard to liver functions; unfortunately, however, 4 months after the last dose of ipilimumab, she developed progressive disease, which involved development of new lesions in the pancreas and enlargement of her previous metastatic deposits. On further investigation, she was found to carry N-RAS mutation in a previous sample. She is currently being considered for participation in a clinical trial with MEK (mitogen-activated protein kinase) inhibitor for her N-RAS mutated metastatic melanoma. The N-RAS clinical trial is randomising patients between a MEK inhibitor versus chemotherapy with dacarbazine.