LAUSR

Dear Sirs, Immune checkpoint inhibitors (ICIs) became the new milestone of the immune-oncology therapy. This family includes three drug classes: anti-cytotoxic T lymphocyte–associated protein4 (CTLA4), anti-programmed cell death 1 (PD-1), and anti-programmed death-ligand 1 (PD-L1). Durvalumab is a monoclonal antibody that prevents the binding of PD-L1 with PD-1 and CD80, stimulating immune response against tumors [1, 2]. The phase III clinical trial PACIFIC showed that durvalumab improved the overall survival in patients with non-small cell lung cancer (NSCLC) treated with definitive chemoradiotherapy (CRT) [3]. Therefore, it was recently approved, both by the US Food and DrugAdministration and the European Medicines Agency, for patients with unresectable stage III NSCLC and unprogressed disease following CRT. However, its toxicity on central nervous system (CNS) is not well established. To date, cases of exacerbations or new diagnosis of multiple sclerosis (MS) during durvalumab are not reported in literature, nor in the main databases of pharmacovigilance (https://www.fda.gov/drugs/questionsand-answers-fdas-adverse-event-reporting-system-faers/fdaadverse-event-reporting-system-faers-public-dashboard; http://www.adrreports.eu/it/search.html). According to our knowledge, we hereby describe the first case of a patient who develops brain magnetic resonance imaging (MRI) demyelinating lesions during durvalumab therapy. In 2018, a Caucasian 46-year-old man was diagnosed with locally advanced pulmonary adenocarcinoma EGFR and KRAS wild type. The PD-L1 expression was >1%. After CRT, he started durvalumab 120 mg endovenously. After ten infusions, restaging whole-body computed tomography showed a reduction of the lung neoformation but a right peritrigonal contrast enhancing (CE+) lesion. A brain MRI revealed other multiple T2 white matter hyperintensities, with subcortical and periventricular localization diagnosed as demyelinating lesions (Fig. 1). The spinal cordMRI was normal. Durvalumab was discontinued, and the patient received a course of methylprednisolone 1 g/die ev for 4 days, with a reduction of CE+. He was admitted to our Neurology Department to rule out a demyelinating disorder, and he reported fluctuating episodes of paraesthesia of right limbs since 2013. The neurological examination was unremarkable. All clinical and laboratory tests were normal, but the cerebrospinal fluid analysis showed twenty-three oligoclonal bands. He was diagnosed with MS according to 2017 McDonald criteria. Considering the clinical features and his comorbidity, he started treatment with glatiramer acetate 40 mg three times per week subcutaneously. From the beginning of this therapy, MS remained stable. Since his malignancy did not show radiological signs of progression, durvalumab was not restarted. Our case suggests that PDL-1 is an immunological checkpoint that may trigger active demyelinating lesions in CNS. Although it is unknown if ICIs anti-PD1 and anti-PDL1 can determinate de novo demyelinating diseases, they can exacerbate or unmask them, since the PD-1/PD-L1 pathway modulates immune functions in MS patients [4]. Moreover, in experimental autoimmune encephalomyelitis (EAE), mice with aberrant T cell regulation for PD-1 deficiency show increased T lymphocytes expansion with an earlier onset or worsening of EAE compared with wild-type mice [5]. Furthermore, it is hypothesized that PDL-1 is overexpressed on astrocytes and microglia in inflammatory environments; therefore, the antiPD-1/PD-L1 antibodies could increase preexisting inflammatory conditions [6]. Considering the wide use of anti-PDL1 in cancer therapy and how other ICI agents can cause a rapid worsening of neurological status and deaths in MS patients [7], it is crucial to be aware of durvalumab’s role in neurological inflammatory disease, even if no demyelinating events has been reported during PACIFIC study. Nowadays, we are aware how post* Damiano Paolicelli [email protected]