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Progressive multifocal leukoencephalopathy after natalizumab discontinuation

Authors

  • Andrew J. Fine PharmD, BCPS,

    Corresponding author
    1. Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD
    • Address correspondence to Dr Fine, US Food and Drug Administration, Center for Drug Evaluation and Research, 10903 New Hampshire Avenue, Silver Spring, MD 20993. E-mail: Andrew.Fine@fda.hhs.gov

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  • Alfred Sorbello DO, MPH,

    1. Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD
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  • Cindy Kortepeter PharmD,

    1. Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD
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  • Linda Scarazzini MD, RPh

    1. Current address for Dr Scarazzini: Global Pharmacovigilance, AbbVie, Inc, North Chicago, IL
    Current affiliation:
    1. Current address for Dr Scarazzini: Global Pharmacovigilance, AbbVie, Inc, North Chicago, IL
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  • The views expressed are those of the authors and do not necessarily represent those of, nor imply endorsement from, the US Food and Drug Administration or the US government.

Abstract

Objective

To identify cases of laboratory- or biopsy-confirmed progressive multifocal leukoencephalopathy (PML) in patients with multiple sclerosis (MS) who previously discontinued natalizumab (NTZ) for reasons unrelated to suspected or proven PML and assess PML risk factors in these cases.

Methods

We searched the US Food and Drug Administration Adverse Event Reporting System and MEDLINE for reports submitted from 2006 to 2012 of laboratory-confirmed PML with symptom onset ≥30 days following NTZ withdrawal. We only analyzed cases where NTZ discontinuation was unrelated to suspected PML.

Results

Seventeen patients discontinued NTZ for reasons unrelated to PML but were subsequently diagnosed with the disease. The median NTZ duration was 47 monthly doses (range = 9–59 doses). All patients presented with compatible clinical symptoms within 6 months following withdrawal, and PML was confirmed by brain biopsy or by identifying JC virus in the cerebrospinal fluid by polymerase chain reaction. Immune reconstitution inflammatory syndrome (IRIS) was reported in 11 patients. Eleven patients (65%) received new MS treatments between NTZ discontinuation and PML confirmation. No deaths were reported. At NTZ withdrawal, 16 patients (94%) had ≥1 PML risk factor, including NTZ duration ≥2 years (n = 13), prior immunosuppressive agents (n = 8), and reported anti–JC virus seropositivity (n = 13).

Interpretation

NTZ-treated patients presenting clinically with PML within 6 months after NTZ withdrawal frequently have pre-existing PML risk factors. Clinicians need heightened awareness for new onset PML, IRIS, and MS relapse in evaluating neurological decline following NTZ discontinuation. Ann Neurol 2014;75:108–115

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