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Chronic Unilateral Uveitis with Macular Edema Secondary to Dabrafenib for Pilocytic Astrocytoma

This report describes a unique case of chronic unilateral anterior uveitis associated with macular edema while on oral dabrafenib treatment for chronic recurrent pilocytic astrocytoma. After gradual taper of prednisolone acetate OS, the patient developed recurrent mild low-grade anterior uveitis and macular edema OS that required low dose of prednisolone acetate OS to prevent recurrences while on oral dabrafenib. When oral dabrafenib was temporarily discontinued for 3 months due to her ocular inflammation, she had no flares of her uveitis; however, her tumor increased significantly in size. The collaborative decision was made to continue her oral dabrafenib while on topical anti-inflammatory therapy for her uveitis. Clinicians should be aware of this potential unilateral sequela of uveitis secondary to dabrafenib. Further investigation should be conducted to identify factors that may place certain patients at higher risk for this complication.


Introduction
Pilocytic astrocytoma arises in the pediatric population and is typically benign. The 10-year survival rate is >90% in children but has a higher mortality in adults [1,2]. Approximately 6-10% of pilocytic astrocytomas develop activating mutations in the BRAF V600E Chang et al.: Chronic Uveitis with Macular Edema due to Dabrafenib for Pilocytic Astrocytoma www.karger.com/cop oncogene which leads to the transcription of genes that increase the proliferation of tumor cells [3].
Dabrafenib (Tafinlar) was approved in 2013 for the treatment of metastatic melanoma. It is an oral antitumor drug that selectively inhibits the BRAF V600E kinase, the product of the BRAF V600E oncogene, thereby inhibiting the growth of tumor cells. Ocular side effects of dabrafenib have been reported in patients with metastatic melanoma and may include anterior and posterior uveitis, bilateral panuveitis, papillitis, and retinal detachment [3]. We report a unique case of chronic unilateral anterior uveitis associated with macular edema while on oral dabrafenib treatment for chronic recurrent pilocytic astrocytoma.

Case Report
A woman in her late 30s with history of a pilocytic astrocytoma treated with surgical resection 8 years prior, presented with blurred vision OS, with a best-corrected visual acuity of 20/40 OD and 20/70 OS. Her intraocular pressures were normal OU. There were no remarkable findings OD except mild cataract. Slit lamp examination OS demonstrated 1+ cell/ flare with patchy posterior synechiae inferonasally and inferotemporally without pupillary block, and a mild cataract. Fundus examination OS demonstrated 1+ anterior vitreous cell and macular edema (Fig. 1). She was started on topical cyclopentolate TID and topical prednisolone acetate QID OS, with gradual resolution of her inflammation and macular edema. After gradual taper of these drops, she developed recurrent mild low-grade anterior uveitis and macular edema and has required low dose of prednisolone acetate BID OS to prevent recurrences while on oral dabrafenib.
She had been on oral dabrafenib since her surgery 8 years prior. She had no history of prior radiation or other chemotherapy. When oral dabrafenib was temporarily discontinued for 3 months due to her ocular inflammation, she had no flares of her uveitis; however, her tumor increased significantly in size. The collaborative decision was made to continue her oral dabrafenib while on topical anti-inflammatory therapy for her uveitis.

Discussion
Ophthalmic side effects of dabrafenib began after the drug was FDA-approved for metastatic melanoma in 2013 and has been associated with uveitis at a rate of 1-10% [4,5]. While symmetrical uveitis sequelae is more common, asymmetric unilateral presentations may also  be seen as in our case [6]. In this report, we highlight the first case of a patient developing chronic unilateral anterior uveitis in response to dabrafenib therapy for the treatment of pilocytic astrocytoma. Based on handful of case reports found in the literature, it appears the time from initiation of dabrafenib and presentation with uveitis ranges from week to months, although there has been a report of uveitis arising in a matter of days, as well as a report of uveitis presenting 4 years later. To our knowledge, this is the first report of uveitis arising 8 years after initiation of oral dabrafenib [7][8][9][10].
Besides dabrafenib, several other drugs that target the MAPK pathway have been associated with uveitis [6,11,12]. Due to very similar mechanisms (Fig. 2), uveitis has also been reported with vemurafenib, encorafenib plus binimetinib, and trametinib plus cobimetinib use [6,11,12]. Inhibition of epidermal growth factor receptor (EGFR), an upstream mediator of the MAPK pathway, via erlotinib or gefitinib has been associated with uveitis [5,13]. It has been hypothesized that dabrafenib induces uveitis through breakdown of the blood-retinal barrier, a possible effect of MAP kinase inhibition, eventually leading to compromise of ocular immune privilege and autoimmune uveitis [14].
Clinicians should be aware of this potential unilateral sequela of dabrafenib in treatment of primary tumors such as pilocytic astrocytomas. Further investigation should be conducted to identify factors that may place certain patients at higher risk for this complication. Patients should be monitored and maintenance topical corticosteroids may be used to prevent recurrences.