Hemophagocytic lymphohistiocytosis and posterior reversible encephalopathy syndrome during BRAF/MEK inhibitor therapy following immune checkpoint blockade in metastatic melanoma: a case report

Hemophagocytic lymphohistiocytosis (HLH) is a rare but potentially life-threatening hyperinflammatory syndrome characterized by uncontrolled immune activation and cytokine release. Secondary HLH has increasingly been reported in association with modern oncologic therapies, including immune checkpoint inhibitors and targeted therapies for malignant melanoma. Sequential treatment with checkpoint inhibitors followed by BRAF/MEK inhibitors may further increase the risk of immune dysregulation. We report the case of a 61-year-old female with BRAF V600K-mutant metastatic melanoma (stage IV) initially treated with combination immunotherapy consisting of nivolumab and ipilimumab, followed by nivolumab monotherapy. Due to progressive disease and immune-related hypophysitis, targeted therapy with dabrafenib and trametinib was initiated. Shortly thereafter, the patient was admitted with suspected sepsis, gastroenteritis, and a trunk-predominant rash. During hospitalization, she developed hemolysis, disseminated intravascular coagulation, and acute kidney injury. Further evaluation revealed reactivation of Epstein-Barr virus, absolute lymphocytosis, and marked T-cell activation on flow cytometry. An HScore of 234 indicated a 98% probability of HLH. Under supportive treatment and immunosuppressive therapy, inflammatory markers, coagulation parameters, and renal function gradually improved. During the clinical course, the patient developed transient visual disturbances. Neuroimaging excluded cerebral ischemia, and findings were compatible with posterior reversible encephalopathy syndrome, likely secondary to HLH. Visual symptoms resolved within 2 days. This case highlights HLH as a rare but severe complication in patients receiving sequential immune checkpoint inhibition and BRAF/MEK-targeted therapy for metastatic melanoma. Early recognition of hyperinflammatory syndromes and interdisciplinary management are essential to improve clinical outcomes.