Posterior reversible encephalopathy syndrome in a melanoma patient with dabrafenib and trametinib treatment following immunotherapy

A 28-year-old woman was treated with oral vemurafenib (960 mg twice daily) and oral cobimetinib (60 mg once daily, days 1–21) for advanced melanoma with skeletal, pulmonary, hepatic, and peritoneal metastases. Four months later, brain MRI demonstrated new cerebral metastases and treatment was switched to combined immunotherapy with ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) [1]. After two cycles of immunotherapy, the patient was admitted urgently to hospital with a severe headache, nausea, vomiting, and deteriorating consciousness. Brain MRI revealed fulminant progression of the cerebral metastases with up to forty new supratentorial and two new pontine lesions. We also noted prominent leptomeningeal enhancement without obstruction of cerebrospinal fluid (CSF) flow. Microbiological and virological tests of the CSF were negative. Antiedema treatment was initiated with oral dexamethasone (2 mg three times daily) and treatment was then switched to oral dabrafenib (150 mg twice daily) and oral trametinib (2 mg once daily) as a rechallenge of BRAFand MEK-inhibition therapy [2, 3]. Whole brain radiation was discussed as a treatment option, but the patient refused it. Under corticosteroid treatment, the patient’s neurological status improved markedly and symptoms of increased intracranial pressure resolved completely. Seven weeks after cessation of immunotherapy and five weeks after initiation of dabrafenib and trametinib treatment, the patient was hospitalized urgently after suffering a generalized tonic-clonic seizure. Her symptoms were a debilitating headache and a Bálint’s syndrome, which is characterized by a triad of severe neuropsychological deficits, namely optic ataxia, oculomotor apraxia, and simultanagnosia [4]. Brain MRI showed a partial response with reduced size of the cerebral metastases, but also with intralesional hemorrhage. MRI revealed prominent bilateral cortical and subcortical edema in the parieto-occipital regions, compatible with a posterior reversible encephalopathy syndrome (PRES). PRES also explained the clinical symptoms of Bálint’s syndrome [4]. In addition to marked meningeal enhancement, prominent biparietal and left temporal cortical laminar necrosis was noted (Figure 1). CSF analysis showed an elevated cell count (15 cells/μl) with evidence of malignant cells. The long-term blood pressure measurement excluded hypertension. CT angiography and transcranial Doppler ultrasound excluded cerebral vasospasms. Electroencephalography showed no epileptic activity, but the patient had already been treated with levetiracetam. Due to the prominent meningeal gadolinium enhancement, concomitant immune-mediated meningitis was suspected and high-dose corticosteroid treatment was initiated. Therapy with dabrafenib and trametinib was discontinued. One month later, a brain MRI showed regression of PRES, but dramatic progression of the cerebral metastases was noted. Reintroduction of the targeted therapy with vemurafenib and cobimetinib was initiated. Over the following three months, PRES gradually resolved under initial treatment with oral dexamethasone 8 mg once daily, tapering off by 2 mg every two weeks. Significant regression of the cerebral metastases then followed (Figure 1). Seventeen weeks after diagnosis of PRES and during ongoing treatment with vemurafenib and cobimetinib, MRI revealed new progression of cerebral metastases and additional meningeal carcinomatosis. PRES did not recur, but unfortunately the patient died a few weeks later due to progression of the cerebral metastases that resulted in brainstem herniation. PRES was first described in 1996 [5] as a clinical syndrome presenting with headache, seizures, visual disorders, altered mentation, consciousness disturbances, and focal neurological signs. The most characteristic finding of PRES is subcortical edema, predominantly localized in the territories of the posterior circulation. The predilection for involvement of the parieto-occipital lobes has been attributed to their less extensive sympathetic innervation of the arteries of the posterior circulation [6]. The underlying pathogenetic mechanisms of PRES are only partially understood. Although hypertension is the most common cause of PRES, it occurs in up to 40 % of the cases without manifest hypertension. In these cases, PRES has been associated with autoimmune disorders, cytotoxic or immunosuppressive medication [7] (Figure 2). To the best of our knowledge, there are only four case reports on PRES under novel melanoma treatments [8–11]. However, the diagnosis of PRES in these cases was not completely reliable because an MRI was not performed [8, 10]. The possibilities that we considered regarding the pathogenesis of PRES in our patient included an adverse event due to therapy with dabrafenib plus trametinib, an overlap effect after the switch from immunotherapy to dabrafenib plus trametinib, and a late carry-over effect from the immunotherapy with ipilimumab plus nivolumab. BRAFand MEK-inhibitors can induce a decrease of angiogenic growth factors such as the VEGF and proangiogenic cytokines [12–14]. This might explain the numerous DOI: 10.1111/ddg.13991 Posterior reversible encephalopathy syndrome in a melanoma patient with dabrafenib and trametinib treatment following immunotherapy Clinical Letter