Pembrolizumab-Associated Hemophagocytic Lymphohistiocytosis in Clear Cell Renal Carcinoma: Case Report and Literature Review

<b>Background and Clinical Significance:</b> Immune checkpoint inhibitors (ICIs) have transformed the management of advanced solid tumors but can trigger severe immune-related adverse events (irAEs). Among the rarest and most life-threatening is hemophagocytic lymphohistiocytosis (HLH), a hyperinflammatory syndrome driven by uncontrolled immune activation. <b>Case Presentation:</b> We report the case of an 80-year-old man with clear cell renal carcinoma with sarcomatoid features who developed secondary hemophagocytic lymphohistiocytosis (HLH) after receiving four cycles of adjuvant pembrolizumab therapy. Following four cycles of immunotherapy, he presented with persistent fever, pancytopenia, hyperferritinemia (>49,000 ng/mL), hypofibrinogenemia, and elevated soluble IL-2 receptor (>7500 U/mL), fulfilling at least five HLH-2004 diagnostic criteria. Despite treatment with high-dose corticosteroids and intravenous anakinra (100 mg every 6 h), his condition rapidly deteriorated, leading to multiorgan failure and death. <b>Discussion:</b> ICI-induced HLH is an exceptional but increasingly recognized irAE, with fewer than 30 pembrolizumab-related cases reported to date. Diagnosis is challenging due to its nonspecific presentation, which can mimic infection, hepatic toxicity, or disease progression. The pathogenesis is believed to involve excessive activation of cytotoxic T cells and cytokine storm. While established pediatric protocols (HLH-94, HLH-2004) guide management, adult cases often require individualized approaches using corticosteroids and cytokine-targeted therapies such as IL-1 or IL-6 blockade. <b>Conclusions:</b> HLH secondary to ICIs should be considered in the differential diagnosis of patients receiving immunotherapy who develop unexplained fever and cytopenia. Early recognition and prompt initiation of immunosuppressive therapy are critical to improving outcomes in this potentially fatal complication.