Trametinib’s Transformative Role in BRAF-Mutated Multisystem Langerhans Cell Histiocytosis: A Case Report

Langerhans cell histiocytosis (LCH) is an inflammatory neoplasm, though rare, of myeloid origin, primarily driven by mutations in the MAPK pathway, most specifically BRAF. It is characterized by having a wide clinical spectrum, including lytic bone lesions, endocrinopathy, and multisystem disease. Diagnosis is difficult owing to variable presentation and often necessitates confirmation by histology. We report a complex case of a 6-month-old boy who presented with diffuse rash, fever, and pancytopenia. He was eventually diagnosed with multisystem LCH, having a BRAF mutation. Although there was some improvement after the first course of treatment, which included prednisolone and vinblastine according to the standard LCH protocol, the persistent cytopenia and fever raised the possibility of secondary hemophagocytic lymphohistiocytosis (HLH). Dexamethasone and etoposide were then used in the patient’s HLH-directed treatment, which eliminated the fever but left the cytopenias unabated. The BRAF mutation was verified by next-generation sequencing, and trametinib targeted therapy was initiated. Over the next six weeks, clinical remission, including the resolution of cytopenias, rash, and hepatosplenomegaly, was achieved. Trametinib induced rapid remission in BRAF-mutated LCH after failed conventional/HLH-directed therapy, highlighting its role as first-line targeted therapy for high-risk infants. This case highlights trametinib as a promising precision medicine option for BRAF-mutated, treatment-resistant LCH and demonstrates the diagnostic and therapeutic challenges of high-risk pediatric LCH.