Preoperative Reduction of Plexiform Neurofibromas by Trametinib

Background: Plexiform neurofibromas are congenital tumors of the peripheral nerve sheath and occur in 30–50% of NF1 patients. Due to their extensive growth they can significantly contribute to the burden of disease and may also progress to malignancy with a risk of 10–15%. To date, neither surgery nor medication has produced a breakthrough therapeutic success. Recently, a clinical phase I study reported significant shrinkage of plexiform neurofibromas following treatment with the MEK-inhibitor selumetinib in all treated patients.

Case Report: We report an 11 year old girl with genetically confirmed diagnosis of NF1 and a large plexiform neurofibroma of the neck which had led to massive deformity of the cervical vertebral column and sharp-angled kinking of the cervical spine. Spasticity of the right leg with compromised motor function was indicative of progressive myelopathy. Although surgical stabilization of the cervical vertebral column was urgently recommended the vertebral column was inaccessible due to extensive tumor growth. In this situation oral treatment with the MEK-inhibitor trametinib was started with a initial dosage of 0.5 mg/d (=0.015 mg/kgKG/d) followed by 2 × 0.5 mg/d (=0.03 mg/kgKG/d).

Results: Patient follow-up included monthly clinical, ophthalmological, laboratory and cardiac examinations. The only side effect observed was mild facial rash which could successfully be treated with topic steroids. To monitor tumor size volumetric MRIs with identical examination protocols were performed before and after 3 and 6 months of therapy. After 6 months of trametinib treatment a reduction of tumor volume by 22% was observed which finally enabled further surgical treatment.

Discussion: Basic science and clinical studies have shown that the MEK-inhibitor selumetinib can reduce the size of NF1-associated plexiform neurofibromas. However, selumetinib is not yet available as medication for neurofibromas since results of an ongoing phase II clinical trial are still pending. In contrast, the MEK-inhibitor trametinb is routinely used for the treatment of malignant melanoma in adults. Since trametinib and selumetinib aim at the same molecular pathway we started trametinib treatment in our patient to prevent imminent paralysis caused by progressive tumor growth. The observed tumor size reduction of 22% meets the criteria of a partial response as defined by Dombi et al. To date is unclear if MEK-inhibitor treatment can be terminated after a certain period of time of if this will result in tumor regrowth. Similar issues are currently on debate in the context of tuberous sclerosis complex (TSC), a neurocutaneous disorder caused by hyperactivation of the mTOR signal transduction pathway, where the mTOR inhibitor everolimus provides a therapeutic option for several aspects of the disease. Similarly, in NF1 MEK inhibition might be a therapeutic option for several disease manifestations. While much more data are necessary to answer this question, the course of our patient as well as clinical data published elsewhere demonstrate that MEK-inhibitors are likely to play an essential role in a multimodal therapeutic approach for NF1-associated plexiform neurofibromas.

No conflict of interest has been declared by the author(s).