962044 case-report2020

EJO0010.1177/1120672120962044European Journal of OphthalmologyBrambati et al.

EJO

Case report

A case of Vogt-Koyanagi-Harada-like uveitis secondary to dabrafenib/trametinib therapy for advanced melanoma

European Journal of Ophthalmology

European Journal of Ophthalmology 1­–5 © The Author(s) 2020 Article reuse guidelines: sagepub.com/journals-permissions https://doi.org/10.1177/1120672120962044 DOI: 10.1177/1120672120962044 journals.sagepub.com/home/ejo

Maria Brambati, Chiara Giuffrè, Alessandro Marchese , Francesco Bandello , Giulio Maria Modorati and Elisabetta Miserocchi

Abstract We report a case of ocular drug toxicity consistent with bilateral Vogt-Koyanagi-Harada (VKH) like disease in a patient with cutaneous melanoma treated with Dabrafenib/Trametinib therapy. A 53-year-old man with a history of metastatic cutaneous melanoma, treated with Dabrafenib/Trametinib, developed a severe acute panuveitis with granulomatous anterior uveitis and multiple serous retinal detachments. The ocular inflammatory reaction was classified as a bilateral Vogt-Koyanagi-Harada disease. Intraocular inflammation resolved after discontinuation of chemotherapeutic agents and aggressive topical and systemic corticosteroid therapy. The present case outlines the importance of recognizing VKHlike syndrome as a possible consequence of therapy with dabrafenib and trametinib. Keywords Immunology, choroidal/retinal inflammation, UVEA, panuveitis, UVEITIS, systemic drug retinal toxicity, RETINA, pharmacology Date received: 14 June 2020; accepted: 6 September 2020

Introduction

Case description

Dabrafenib (BRAF inhibitor) and Trametinib (MEK inhibitor) are chemotherapeutic agents approved for the treatment of BRAF-mutant advanced or metastatic melanoma.1 In melanomas, activating mutations in the B-RAF and RAS genes cause dysregulation of the Mitogen Activated Protein Kinase (MAPK) pathway, leading to increased signaling activity and promoting cell proliferation, growth, invasion and metastasis. The combined therapy with Dabrafenib and Trametinib modulate the activity of MAPK pathway, inhibiting cell proliferation.1 Vogt-Koyanagi-Harada-like (VKH-like) uveitis has been described in a few reports as a possible side effect of the combined treatment with BRAF-inhibitors and MEK-inhibitors.2 In this paper, we present a case of ocular drug toxicity consisting of severe bilateral granulomatous panuveitis and multiple serous retinal detachments manifesting as a Vogt Koyanagi Harada disease.

A 53-year-old Caucasian man presented to our department complaining of acute bilateral visual loss two months after beginning oral chemotherapy for a metastatic cutaneous melanoma. The patient’s ocular history was unremarkable for any previous episode of ocular inflammation. However, his recent medical history revealed a diagnosis of primary cutaneous melanoma in the trunk, positive for BRAF V600E mutation on the right haunch, and involvement of right axillary lymph nodes. The patient also presented diffuse metastasis to the lung, liver, bone and central nervous system. For Department of Ophthalmology, San Raffaele Scientific Institute, University Vita-Salute, Milan, Italy Corresponding author: Elisabetta Miserocchi, Department of Ophthalmology, University VitaSalute, IRCCS Ospedale San Raffaele, Via Olgettina 60, Milan, 20132, Italy. Email: [email protected]

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Figure 1.  Spectral-domain optical coherence tomography (SD-OCT) showed the typical detachments of the neurosensory retina and bacillary detachments with fluid accumulating between photoreceptor layers (red arrows).

the extensive body involvement, the treatment consisted of both local tumor resection with nodal dissection and a combined chemotherapy with Dabrafenib and Trametinib. At the time of his first presentation, the best-corrected visual acuity (BCVA) was hand motion in the right eye and 20/400 in the left eye. Anterior segment slit-lamp examination showed granulomatous anterior uveitis with conjunctival injection, mutton-fat keratic precipitates, 3+ cells in the anterior chamber, and posterior synechiae in both eyes (BE). Intraocular pressure was within normal limits in both eyes. Bilateral fundus examination revealed 2+ vitreous cells, hyperemic disc, and multiple yellowish bullous serous retinal detachments in both eyes. Spectral-domain optical coherence tomography showed the typical detachments of the neurosensory retina and bacillary detachments with fluid accumulating between photoreceptor layers3 (Figure 1, arrows). Fundus fluorescein angiography (FA) showed bilateral hot disc as well as hyperfluorescent pin points, that increased in size in the late phases of the exam. Indocyanine green angiography (ICG-A) showed multiple hypofluorescent spots of choroiditis scattered throughout the fundus, observed throughout the entire angiographic phase (Figures 2 and 3). The patient was hospitalized for extensive systemic workup, laboratory tests including autoimmune and infectious panel. The results of infectious and autoimmune laboratory exams were all negative except for the presence of a slight lymphopenia compatible with his oncological condition. The patient was diagnosed with bilateral granulomatous panuveitis with Vogt-Koyanagi Harada like appearance presumably secondary to MEK and BRAF inhibitors therapy. In agreement with the oncologist, Dabrafenib and

Trametinib were discontinued, and the patient received corticosteroid pulse therapy (i.v. methylprednisolone 1 g/day for 3 days), followed by oral prednisolone 60 mg/day for 2 weeks, which was gradually tapered to a daily maintenance dose of 12.5 mg/day. Aggressive topical received mydriatics and corticosteroid drops were prescribed. Two weeks after BRAF and MEK inhibitors discontinuation and anti-inflammatory treatment, the patient’s BCVA recovered to 20/25 bilaterally, with no residual signs of inflammation. Furthermore, a complete resolution of the serous retinal detachments was achieved. Indeed, SD-OCT revealed disappearance of the fluid, with slight residual disruption of the interdigitation and ellipsoid zone (Figure 4, arrows). Oncological treatment was modified, and the patient received immunotherapy (Pembrolizumab). Our last ophthalmologic examination, performed after 6 months from the resolution of the ocular disease, revealed stable BCVA, with no signs of active uveitis, nor serous retinal detachments. Unfortunately, the patient died of systemic complications of metastatic melanoma, few months later. A statement of consent to publish this case and the related images were gathered from the patient.

Conclusion In this report, we describe a case of ocular drug toxicity consisting with severe VKH-like disease in a patient treated with a combination of BRAF and MEK inhibitors. MAPK pathway has an important role in regulating cellular activities such as gene expression, mitosis, differentiation, and cell survival/apoptosis. In cells harboring BRAFV600 mutations, there is a permanent

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Figure 2.  FA showed bilateral hot disc as well as subtle punctuate hyperfluorescent dots at the level of retinal pigment epithelium (RPE) which enlarged during the exam.

Figure 3.  ICG-A showed multiple hypofluorescent spots of choroiditis scattered throughout the fundus, observed throughout the entire angiographic phase.

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Figure 4.  SD-OCT after 2 weeks treatment revealed disappearance of the fluid, with slight residual disruption of the interdigitation and ellipsoid zone (red arrows).

MAPK pathway activation, which ultimately can lead to uncontrolled proliferation. Targeted therapies along with immune checkpoint blockades have been shown to prolong overall survival in BRAF mutant advanced melanoma.1,4 The systemic adverse effects of these drugs include fatigue, nausea, arthralgia and reduction of the cardiac ejection fraction. Ocular adverse events (OAE) are rare and the majority are related to MEK inhibitors treatment.5 Méndez-Martínez et al.5 reported that MEK inhibitors could lead to different degrees of retinal, uveal, and adnexal OAE, causing discomfort or visual disturbances. Among the wide spectrum of ocular side effects, they included two main retinal disorders: retinal vein occlusion (RVO) and MEK-associated retinopathy (MEKAR). MEKAR is characterized by the development of subretinal fluid blebs and serous macular detachments, often bilateral, relatively symmetric and without pigment epithelium detachments. In addition, the choroid in MEKAR is often normal and it suggests that serous retinal detachments caused by MEKinhibitor are not associated with pachychoroid.6 All these features differentiate MEKAR from central serous chorioretinopathy.

In our paper, we describe another form of retinal toxicity in patients treated with combined BRAF and MEK-inhibitors. After extensive investigations that ruled out secondary causes of uveitis, the diagnosis of Vogt-Koyanagi-Harada-like (VKH-like) ocular disease was made. VKH-like syndrome is a rare but serious complication of targeted therapy that should be considered when evaluating a patient with visual disturbances on Dabrafenib and Trametinib therapy. VKH-like retinochoroidal abnormalities associated with combined treatment with BRAF and MEK-inhibitors had already been described by other authors.4 It has been supposed that MAPK inhibition by Dabrafenib and Trametinib could lead to a reactive oxygen species production causing the breakdown of the blood retinal barrier and consequently the loss of the immune privileged ocular site.7 This event could induce an autoimmune response leading to uveitis. Another potential explanation for the origin of uveitis is related to shared antigens between melanocytes of melanoma and melanocytes of the choroid.7 With our case of VKH-like syndrome, we reinforce the hypothesis of this mechanism as origin of uveitis occurring in patients who undergo these treatments for melanomas. In addition, we perform a multimodal imaging evaluation by means of OCT, FA

Brambati et al. and ICG-A. Taken together, these techniques allow us to better diagnose VKH-like syndrome and to rule out other possible etiology of uveitis. In our patient, uveitis was treated with Dabrafenib and Trametinib discontinuation and prompt steroids administration. It is still unclear if removal of offending agents could be the treatment for this condition or if corticosteroid are also required to restore normal retinochoroidal architecture. Sober and Haynes,8 Stein9 and Aisenbrey et al.10 reported cases of patients with melanoma who developed VKH syndrome and had a favorable prognosis of underlying disease. Future studies may elucidate if cellmediated and humoral immunity, activated in VKH syndrome, are related to a favorable outcome of melanoma and if the discontinuation of the therapy has important consequences in term of mortality rate. It is important to recognize potential for sight-threating complications caused by these drugs in oncologic patients and, for this reason, cooperation between ophthalmologists and oncologists is fundamental. The reason why just few patients develop ocular adverse events is yet to be elucidated. Further research is needed to recognize patients who are most susceptible to develop VKH-like syndrome as ocular side effect. Declaration of conflicting interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MB, CG, AM, EM and GM have no disclosures. FB has the following disclosures: Allergan (S), Alimera (S), Bayer (S), Farmila-Thea (S), Schering Pharma (S), Sanofi-Aventis (S), Novagali (S), Pharma (S), Hoffmann-La Roche (S), Genetech (S), Novartis (S). EM and FB confirm they are, respectively, an associate editor and the editor in chief of this journal and were not involved in the peer review process of this paper.

Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.

5 ORCID iDs Alessandro Marchese Francesco Bandello Elisabetta Miserocchi

https://orcid.org/0000-0001-7716-7261 https://orcid.org/0000-0003-3238-9682 https://orcid.org/0000-0003-2989-6712

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