Effective Multi-agent Therapy With Anakinra, Corticosteroids and Mycophenolate in Immunotherapy-Associated Haemophagocytic Lymphohistiocytosis (HLH).

Haemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening complication of immune checkpoint inhibitor (ICI) therapy. Clinical overlap with sepsis contributes to delayed diagnosis and high mortality, showing the need for prompt recognition and targeted immunosuppression. This case presents a successful treatment pathway for HLH with high-dose methylprednisolone, mycophenolate mofetil (MMF) and anakinra, as well as emphasising the importance of early detection and management of HLH. A man in his sixties with stage IV cutaneous melanoma presented six weeks after the first cycle of ipilimumab and nivolumab immunotherapy with persistent high-grade fever, rigours, myalgia, malaise, and weight loss. Initial investigations revealed no infectious source, but computed tomography (CT) scans showed splenomegaly, and laboratory findings, including high ferritin, hypertriglyceridemia, high aspartate aminotransferase (AST), and low cell counts in two lines (lymphopenia and thrombocytopenia), met the modified HLH-2009 diagnostic criteria within 72 hours. Absence of melanoma progression, infection, or genetic predisposition suggested immunotherapy as the trigger. Treatment commenced on day 1 with anakinra and high-dose intravenous methylprednisolone, with mycophenolate mofetil added on day 3 due to worsening transaminitis, indicative of concurrent immunotherapy-induced hepatitis. The patient became afebrile within 48 hours, with ferritin normalising by day 10 and haematological and biochemical markers returning to normal. Anakinra was discontinued after 14 days. Complications included steroid-induced hyperglycemia, herpes simplex infection, and insomnia, all managed medically. At one-month follow-up, the patient remained asymptomatic with no HLH recurrence during immunosuppression tapering. This case highlights that steroids remain the primary acute treatment for HLH and immune-mediated disorders, with anakinra effectively inhibiting Interleukin-1 driven cytokine overproduction and mycophenolate mofetil addressing immune-related hepatitis. The combination of anakinra, mycophenolate mofetil, and high-dose methylprednisolone achieved rapid clinical and biochemical remission within 10 days, consistent with adult HLH consensus guidelines advocating early, multi-agent immunosuppression to prevent relapse in hyperinflammatory syndromes. Close monitoring of HLH biomarkers and a low threshold for suspicion in febrile patients on immunotherapy is recommended to facilitate timely intervention.