Lekárska genetika a diagnostika 1/2024
Personalised treatment of plexiform neurofibromas
Neurofibromatosis type 1 is an autosomal dominantly inherited disease. The incidence of the disease is estimated to be approximately 1:2600 to 1:3000 inhabitants. It develops on the basis of the presence of a pathogenic variants in the NF1 gene, which codes the tumor suppressor protein neurofibromin. Neurofibromin functions as a negative regulator of the RAS signaling pathway, which has an important role in the process of cell proliferation and differentiation. Thus, impaired function of this gene predisposes to the formation of benign and malignant tumors (1). Typical manifestations of the disease include café-au-lait macules, inguinal and axillary freckling, Lisch nodules, skeletal abnormalities, disorders of growth, pubertal and cognitive development impairment, and the formation of tumors of the peripheral or central nervous system. The most common types of tumors associated with neurofibromatosis type 1 are neurofibromas and low-grade optic pathway gliomas. Causal treatment for neurofibromatosis type 1 is currently not available. Patients are enrolled in regular multidisciplinary monitoring, which allows early recognition of complications and thus their therapeutic interventions. For symptomatic, inoperable plexiform neurofibromas, MEK inhibitor therapy is currently available (2). In 2021, selumetinib was approved in this indication by the European Medicines Agency (EMA) for children aged three years and older. Thus, selumetinib is so far the only medication approved for the treatment of symptomatic and inoperable neurofibromatosis-associated plexiform neurofibromas (3). We used the preparation trametinib at our workplace. It is not yet approved by the European Medicines Agency in this indication, but it is available in the Slovak Republic through the pharmaceutical company‘s Compassionate use program in both tablet and oral suspension form. The first patient treated with trametinib in 2018 was a patient with life-threatening neck plexiform neurofibroma. A total of six patients have been treated at our workplace since 2018. The median age of treatment initiation was 12,6 years. Five of them achieved stable disease. In one patient, who was also the longest treated patient, we experienced progression after five years of treatment. No radiological regression was present in either patient. Currently, four patients are undergoing treatment. The most commonly observed form of adverse event is skin toxicity.
Keywords: neurofibromatosis, plexiform neurofibroma, MEK inhibitors, trametinib, pediatrics
