Treatment-refractory immune checkpoint inhibitor-induced hemophagocytic lymphohistiocytosis in the setting of adjuvant pembrolizumab for resected stage IIC melanoma: a case report.

backgroundHemophagocytic lymphohistiocytosis is rare and does not have any distinct clinical features or laboratory abnormalities, whereby a high index of suspicion is required for diagnosis. Hemophagocytic lymphohistiocytosis can be divided into primary/genetic or secondary causes that can be immunotherapy-induced. With the increasing use of immune checkpoint inhibitors for treatment of multiple solid tumor malignancies, the incidence of rare complications such as hemophagocytic lymphohistiocytosis can be expected to rise. CASE PRESENTATION: We describe a fatal case of immunosuppression-refractory pembrolizumab-induced hemophagocytic lymphohistiocytosis complicated by secondary disseminated fungal infection. A 75-year-old white Australian man with resected stage IIC melanoma who received four cycles of adjuvant pembrolizumab presented 11 weeks after commencement with febrile neutropenia, elevated C-reactive protein, and nonspecific symptoms. He developed progressive transaminitis, acute kidney injury, pancytopenia, hyperferritinemia, and hypofibrinogenemia. In addition, a bone marrow aspiration and trephine biopsy demonstrated hemophagocytosis. Treatment was commenced with high-dose corticosteroids and mycophenolate mofetil initially for suspected immune-related side effects, followed by tocilizumab and anakinra once a diagnosis of hemophagocytic lymphohistiocytosis was made. Unfortunately, his disease was refractory to treatment with development of multiorgan failure secondary to hemophagocytic lymphohistiocytosis, complicated by disseminated candidemia from prolonged immunosuppression, leading to death 26 days after admission.

conclusionThis case underscores the diagnostic complexities of hemophagocytic lymphohistiocytosis, the importance of a multidisciplinary approach to management, and the fatal side effects of extended immunosuppression. This also highlights the importance of the discussion of risks versus benefits of treatment, particularly in the adjuvant setting, emphasizing the rare but real risk of fatal toxicities. Prolonged immunosuppression can lead to severe complications, and judicious use of corticosteroids with intensive prophylaxis is crucial. Further research into the mechanism of checkpoint inhibitor-induced toxicities is critical in the era of immunotherapy to allow personalized immunosuppressive and steroid-sparing strategies in complex cases.