Successful Management of Suspected Epstein-Barr Virus-Associated Hemophagocytic Lymphohistiocytosis in BRAF-Mutant Cholangiocarcinoma Following Treatment With Immune Checkpoint Inhibitors and BRAF/MEK Inhibitors: A Case Report.

[BACKGROUND] The BRAF V600E mutation is a rare genetic alteration in cholangiocarcinoma for which sequential therapy with immune checkpoint inhibitors (ICIs) and BRAF/MEK inhibitors may be effective. However, the full spectrum of adverse events associated with the sequential use of these agents remains unclear. Hemophagocytic lymphohistiocytosis (HLH) is a fatal cytokine release syndrome that can be triggered by a cytokine storm.

[CASE] A 49-year-old man underwent left lateral hepatectomy and adjuvant chemotherapy for cholangiocarcinoma and subsequently developed lymph node recurrence. The patient initially received systemic chemotherapy with gemcitabine, cisplatin, and S-1; however, due to disease progression, the regimen was switched to gemcitabine, cisplatin, and durvalumab. After these treatments, a BRAF V600E mutation was identified through comprehensive gene panel testing, leading to the initiation of BRAF and MEK inhibitors. However, 3 months later, the patient presented to the emergency department of Steel Memorial Muroran Hospital with fever and fatigue in June 2024. He was initially diagnosed with septic shock but was unresponsive to broad-spectrum antibiotics. Laboratory tests revealed elevated ferritin levels, elevated soluble interleukin-2 receptor levels, and Epstein-Barr Virus (EBV)-DNA. HLH was diagnosed, and multidisciplinary treatment, including steroid pulse therapy, was initiated. The patient's condition improved dramatically, and he survived.

[CONCLUSION] We report a rare case of cholangiocarcinoma with suspected EBV-associated HLH that developed after sequential therapy with an ICI and BRAF/MEK inhibitors. Clinicians should consider HLH as a differential diagnosis in patients with a history of ICI therapy who present with severe unexplained inflammation or shock. Prompt diagnosis and multidisciplinary management are crucial to prevent death.