Nivolumab-Induced Hemophagocytic Lymphohistiocytosis (HLH) in a Patient With Metastatic Melanoma: A Case Report and Literature Review

Immune checkpoint inhibitors (ICIs) have transformed cancer therapy, particularly in melanoma. However, their immune-enhancing mechanisms can lead to rare but severe immune-related adverse events (irAEs), including hemophagocytic lymphohistiocytosis (HLH), a hyperinflammatory syndrome marked by uncontrolled immune activation. HLH is challenging to diagnose due to symptom overlap with sepsis, disease progression, and other irAEs. This study presents a case of steroid-refractory HLH following nivolumab therapy and a literature review of published cases to highlight patterns in diagnosis, treatment, and outcomes. We conducted a chart review of a 79-year-old male patient with metastatic melanoma who developed HLH after nivolumab therapy at a community hospital in Park Ridge, Illinois. Additionally, a literature review (2018-2024) was performed using PubMed Central to identify HLH cases linked to ICIs. Inclusion criteria required clear reporting of the ICI used, underlying malignancy, time to HLH onset, diagnostic approach, treatment, and clinical outcomes. The patient developed HLH after his second nivolumab dose. Initial immunosuppressive therapy, including dexamethasone, tocilizumab, anakinra, and ruxolitinib, was ineffective. Improvement occurred only after initiating the HLH-2004 protocol with etoposide and adjunctive cyclosporine. His course was complicated by infections and neutropenia, but recovery was achieved after 10 weeks. The literature review included 16 publications. HLH typically develops within 1-6 weeks of ICI initiation, most often with nivolumab or pembrolizumab. While corticosteroids were first-line therapy, escalation to etoposide, intravenous immunoglobulin (IVIG), or cytokine inhibitors was common in severe cases. Approximately 70-75% of patients recovered. HLH is a rare but potentially fatal irAE of ICIs. Early recognition and aggressive treatment are essential. Oncology-specific diagnostic criteria and treatment guidelines are needed to improve outcomes as immunotherapy use expands.