COBIMETINIB FOR TREATING PATIENTS WITH BRAF WILD-TYPE ERDHEIM-CHESTER DISEASE

Miras Rodriguez I., Carrasco-García I., Sancho P., Gárcia-Grove C., Benedetti J.C.*

Erdheim-Chester disease (ECD) is a non-Langerhans histiocytosis that usually affects adults between the fourth and seventh decade of life. Its clinical presentation can vary, the main symptom being bone pain, predominantly in the diaphysis and metaphysis of the long bones; it can even compromise the patient's general condition due to massive multisystemic infiltration. The etiology is still unknown, but is associated with a TH1 type immune response. It is diagnosed using immunohistochemistry based on characteristic markers including S100(+/-), CD68(+) and CD1a (-). The 5-year survival rate is estimated to be just 68%. Mutations activating the MAPK pathway are described in 80% of patients, the most frequent being the BRAFV600E mutation (57% to 70%) of cases, followed by the MAP2K1 mutation (20%). Currently, this disease represents a challenge in terms of both diagnosis and treatment due to the scarce options available to adequately control the disease. Interferon-α is the most commonly used first-line treatment, with cladribine (2CDA), anakinra and vemurafenib recommended as second-line treatments. We present the experience of four patients in our center who were diagnosed with ECD without BRAF mutation and treated due to progression with cobimetinib, a protein kinase 1 inhibitor that inhibits the catalytic activity of MEK1, thereby inhibiting phosphorylation and activating extracellular signal-related kinase 2 (ERK2) while decreasing the proliferation of tumor cells. In our case series, the median response time to cobimetinib was 4.5 months, with all patients achieving at least a partial response. The median treatment duration was 50 months, with a median overall survival of 72.5 months. The most frequent toxicity reported was a skin rash, which occurred in 75% of patients. Cobimetinib may therefore be a viable treatment option in ECD without BRAF mutation, where therapeutic options are scarce and low response rates are achieved.