title: Subacute CNS Demyelination after Treatment with Nivolumab for Melanoma.
abstract: Immunotherapy with monoclonal antibodies targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) or programmed cell death 1 (PD-1) has improved the survival of patients with metastatic melanoma. These agents carry a certain risk of adverse immune-related events. We present a patient with widely metastatic melanoma who was initially treated with ipilimumab and subsequently with nivolumab. After four infusions of nivolumab, he developed subacute multifocal central nervous system (CNS) demyelination. Nivolumab was discontinued and, despite immunosuppressive therapy, the largest lesion progressed significantly, whereas another lesion showed radiographic improvement. After further progression, the patient succumbed to his CNS lesions 4 months later. Autopsy revealed extensive demyelination, a mild multifocal T-cell-rich perivascular lymphoid infiltrate, abundant macrophages, and necrosis. There was no metastatic melanoma in the brain. CNS demyelination has not been described in association with nivolumab. We hypothesize that the combination therapy of ipilimumab and subsequent nivolumab accounted for the severity of the demyelinating process in this patient. This case, with comprehensive clinical, molecular, and neuropathologic characterization, illustrates the need for awareness of these potential CNS complications with the use of multiple checkpoint inhibitors.
authors.affiliation: Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. Catherine.Maurice@uhn.ca.
authors.forename: Catherine
authors.initials: C
authors.lastname: Maurice
authors.affiliation: Department of Postgraduate Medical Education, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Raphael
authors.initials: R
authors.lastname: Schneider
authors.affiliation: Department of Pathology, University Health Network Toronto, Ontario, Canada. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Tim-Rasmus
authors.initials: TR
authors.lastname: Kiehl
authors.affiliation: Department of Pathology, University Health Network Toronto, Ontario, Canada. BioSpecimen Sciences Program, University Health Network, Toronto, Ontario, Canada.
authors.forename: Prashant
authors.initials: P
authors.lastname: Bavi
authors.affiliation: Department of Pathology, University Health Network Toronto, Ontario, Canada. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. BioSpecimen Sciences Program, University Health Network, Toronto, Ontario, Canada.
authors.forename: Michael H A
authors.initials: MH
authors.lastname: Roehrl
authors.affiliation: Princess Margaret Cancer Centre, University Health Network Toronto, Ontario, Canada.
authors.forename: Warren P
authors.initials: WP
authors.lastname: Mason
authors.affiliation: Princess Margaret Cancer Centre, University Health Network Toronto, Ontario, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Hogg
mesh_terms: D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use; D060908:CTLA-4 Antigen / Q000276:immunology; D003711:Demyelinating Diseases / Q000139:chemically induced*; D018450:Disease Progression; D018572:Disease-Free Survival; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000601:surgery; D008875:Middle Aged; D000077594:Nivolumab; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000601:surgery; D000096142:Cutaneous Malignant Melanoma
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen; D000074324:Ipilimumab; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000077594:Nivolumab