Histiocytoses are clonal disorders diseases derived from the monocyte-macrophage lineage. The Erdheim–Chester disease (ECD) and Langerhans cell histiocytosis (LCH) may occur in association with overlapping clinical, histopathological and molecular features, harboring somatic MAP2K1 mutations in more than 50% of patients. BRAF and MEK inhibitors have shown to be efficacious in ECD and LCH, including responses in patients with CNS involvement. This case report describes a 59-year-old woman who presented with vemurafenib-refractory ECD/LCH overlap syndrome treated with vemurafenib/cobimetinib dual therapy, with rapidly progressing neurological involvement after its initiation. Although targeted therapy plays a crucial role in treatment of histiocytosis, only anecdotal clinical cases treated with dual therapy have been reported in ECD or LCH and collaborative trials are needed to improve outcomes.

Keywords: Mixed histiocytosis; Erdheim–Chester disease; Langerhans cell histiocytosis; Cobimetinib; Vemurafenib