Hemophagocytic lymphohistiocytosis with advanced malignant melanoma accompanied by ipilimumab and nivolumab: A case report and literature review

Combination therapy with nivolumab + ipilimumab was recently approved for treating unresectable cases of malignant melanoma. In spite of the high response rate, it is associated with a high incidence of serious adverse events, including immune-related hemophagocytic syndrome/hemophagocytic lymphohistiocytosis (irHPS/HLH), a difficult to diagnose rare disease. This is the first report of this disease in an Asian malignant melanoma patient treated with nivolumab + ipilimumab. A 69-year-old Japanese woman with unresectable malignant melanoma was treated with nivolumab + ipilimumab. Following the combined therapy, her fever and symptoms of malaise occurred, and she visited to our hospital's emergency department. Blood tests revealed significant liver dysfunction, anemia, and thrombocytopenia. We suspected irHPS/HLH, based on tests revealing decreased fibrinogen and significantly increased ferritin. Bone marrow biopsy revealed numerous macrophages and high hemophagocytosis levels. After 50 mg prednisolone (1 mg/kg per day) was administered, fever and cytopenia markedly improved. irHPS/HLH has a high rate of coagulation abnormalities accompanied by hypertriglyceridemia and hypofibrinogenemia, which are unlikely to occur in adult HPS/HLHs. Because irHPS/HLH responds better to steroids than other secondary HPS/HLHs, we expect a complete cure with steroids. Quick diagnosis and appropriate treatment based on clinical symptoms and laboratory tests are needed in suspected cases.