2 │ CASE PRESENTATION
We describe a now 9-year-old female patient with an optic pathway glioma diagnosed by magnetic resonance imaging at 5 months old after experiencing bilateral nystagmus (Figure 1A and B). A genetic work up ruled out the presence of neurofibromatosis-1. Because of the definitive imaging features consistent with optic pathway glioma, she was administered vincristine and carboplatin at the referring institution without biopsy.11 After 9 months of treatment, she experienced a carboplatin allergy and was subsequently switched to weekly vinblastine to complete 1 year of therapy. After 18 months, imaging findings revealed progressive disease (PD), and she was administered bevacizumab and irinotecan, with frequent treatment interruptions due to proteinuria.12 At 5 years old, she received a tumor biopsy, which confirmed pilocytic astrocytoma with a BRAFV600E mutation, and was subsequently enrolled in a clinical trial using trametinib. She was removed from the trial after 7 months because of PD. She was followed with serial imaging and eye exams for 1 year and then referred to St. Jude Children’s Research Hospital for consideration of targeted therapy for her tumor when visual worsening was noted on an ophthalmological exam (Figure 1C and D).
Upon presentation to St. Jude Children’s Research Hospital at 7 years old, she exhibited bilateral nystagmus and visual field constriction on confrontation testing but no motor or other cranial nerve deficits. Ophthalmological evaluation revealed a visual acuity of 20/200 and 20/100 bilaterally for distance and near vision, respectively (Supporting Information Table S1). A visual field examination was remarkable for bilateral superotemporal quadrantanopia. She was administered a targeted therapy regimen with single-agent vemurafenib but experienced a maculopapular rash over her face, trunk, and extremities after 2 weeks, warranting discontinuation. The rash resolved over the next 2 weeks, and vemurafenib was re-administered at a reduced dose. However, within 3 hours of administering vemurafenib, she experienced an extensive full body rash with intense itching. Because of the likelihood of an anaphylactic reaction occurring with further vemurafenib administration and after discussion with her family, vemurafenib was permanently discontinued.
Reports primarily from adult studies suggest that using either dabrafenib alone or in combination with a MEK inhibitor, such as trametinib, can reduce the risk of skin toxicity.8–10This treatment strategy was presented to the family, and they decided to proceed with dabrafenib and trametinib treatment. Because of her prior hypersensitivity reaction to vemurafenib, we formulated a desensitization plan with slow escalation and administered dabrafenib at 35% of the recommended dose concurrently with full-dose trametinib (Table 1). She was observed in the hospital daily for 6 hours after dabrafenib administration during the first week of therapy. No adverse events were observed, and the dabrafenib dose was slowly escalated over the next 3 weeks.
Apart from rare interruptions of therapy for fever symptoms, both medications were tolerated without any dose reductions for approximately 18 months. Ophthalmological examinations revealed improved near vision (20/60 OS and 20/70 OD) with stable distant vision (Supporting Information Table S1). The tumor demonstrated an immediate response, with decreased enhancement and size of the lesion within 8 weeks of starting treatment (Figure 1E and F), and continues to show slow, but steady improvement after 18 months of therapy (Figure 1G and H).