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Neurological Complications Associated With Anti–Programmed Death 1 (PD-1) Antibodies

Educational Objective
To characterize and describe the frequency of neurologic complications associated with anti–programmed death (PD-1) inhibitor use for the treatment of solid-organ tumors.
1 Credit CME
Key Points

Question  What are the frequency and characteristics of neurological complications from anti–programmed death 1 (PD-1) antibody use?

Findings  Among 347 patients treated with anti–programmed death 1 (PD-1) antibody use (pembrolizumab or nivolumab), this cohort study supports a low frequency (2.9%) of neurological complications associated with anti–PD-1 therapy. The range and severity of complications are diverse, including necrotizing myopathy, various neuropathies, cerebellar ataxia, internuclear ophthalmoplegia, retinopathy, and headache; the median modified Rankin Scale score of 2.5 indicates mild to moderate disability.

Meaning  Subacute presentation of neurological symptoms in a patient receiving anti–PD-1 therapy should prompt consideration of an association and discontinuation of anti–PD-1 antibody use and possible treatment with corticosteroids or other immune treatment depending on the severity.

Abstract

Importance  Neurological complications are an increasingly recognized consequence of the use of anti–programmed death 1 (PD-1) antibodies in the treatment of solid-organ tumors, with an estimated frequency of 4.2%. To date, the clinical spectrum and optimum treatment approach are not established.

Objective  To investigate the frequency, clinical spectrum, and optimum treatment approach to neurological complications associated with anti–PD-1 therapy.

Design, Setting, and Participants  This single-center, retrospective cohort study was conducted from either September or December 2014 (the approval dates of the study drugs by the US Food and Drug Administration) to May 19, 2016. All patients receiving anti–PD-1 monoclonal antibodies were identified using the Mayo Cancer Pharmacy Database. Patients with development of neurological symptoms within 12 months of anti–PD-1 therapy were included. Patients with neurological complications directly attributable to metastatic disease or other concurrent cancer-related treatments were excluded.

Main Outcomes and Measures  Clinical and pathological characteristics, time to development of neurological symptoms, and modified Rankin Scale (mRS) score.

Results  Among 347 patients treated with anti–PD1 monoclonal antibodies (pembrolizumab or nivolumab), 10 (2.9%) developed subacute onset of neurological complications. Seven patients were receiving pembrolizumab, and 3 patients were receiving nivolumab. The patients included 8 men and 2 women. Their median age was 71 years (age range, 31-78 years). Neurological complications occurred after a median of 5.5 (range, 1-20) cycles of anti–PD-1 inhibitors. Complications included myopathy (n = 2), varied neuropathies (n = 4), cerebellar ataxia (n = 1), autoimmune retinopathy (n = 1), bilateral internuclear ophthalmoplegia (n = 1), and headache (n = 1). Peripheral neuropathies included axonal and demyelinating polyradiculoneuropathies (n = 2), length-dependent neuropathies (n = 1), and asymmetric vasculitic neuropathy (n = 1). The time to maximum symptom severity varied from 1 day to more than 3 months. The median mRS score was 2.5 (range, 1-5), indicating mild to moderate disability. Five patients experienced other systemic immune-mediated complications, including hypothyroidism (n = 3), colitis (n = 2), and hepatitis (n = 1). Treatment with anti–PD-1 antibodies was discontinued in 7 patients. Treatment included corticosteroids (n = 7), intravenous immunoglobulin (n = 3), and plasma exchange (n = 1). Nine patients improved, with a median mRS score of 2 (range, 0-6). One patient with severe necrotizing myopathy died.

Conclusions and Relevance  Neurological adverse events associated with anti–PD-1 therapy have a diverse phenotype, with more frequent neuromuscular complications. Although rare, they will likely be encountered with increasing frequency as anti–PD-1 therapy expands to other cancers. The time of onset is unpredictable, and evolution may be rapid and life-threatening. Prompt recognition and discontinuation of anti–PD-1 therapy is recommended. In some cases, immune rescue treatment may be required.

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Article Information

Accepted for Publication: May 20, 2017.

Corresponding Author: Michelle L. Mauermann, MD, Department of Neurology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (mauermann.michelle@mayo.edu).

Correction: This article was corrected on October 9, 2017, to fix an error in the abstract.

Published Online: September 5, 2017. doi:10.1001/jamaneurol.2017.1912

Author Contributions: Dr Mauermann had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Liao, Klein, Naddaf, Staff, Mauermann.

Acquisition, analysis, or interpretation of data: Kao, Liao, Markovic, Naddaf, Staff, Liewluck, Hammack, Sandroni, Finnes, Mauermann.

Drafting of the manuscript: Kao, Staff, Finnes, Mauermann.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Kao, Mauermann.

Administrative, technical, or material support: Liao, Naddaf, Finnes.

Study supervision: Markovic, Hammack, Sandroni, Mauermann.

Conflict of Interest Disclosures: Dr Liewluck reported receiving an honorarium from the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) for a lecture. Dr Mauermann reported received honoraria from the AANEM and the American Academy of Neurology for lectures, reported receiving honoraria from the Continuum: Lifelong Learning in Neurology journal for manuscripts published, reported receiving consultant fees from Ionis Pharmaceuticals for the transthyretin amyloid clinical trials, reported receiving research support from Ionis Pharmaceuticals and Alnylam for the transthyretin amyloid clinical trials, and reported receiving royalties from the book Autonomic Failure: A Textbook of Clinical Disorders of the Autonomic Nervous System, published by Oxford University Press. No other disclosures were reported.

Additional Contributions: Janean Engelstad, HT (Peripheral Nerve Laboratory, Mayo Clinic, Rochester, Minnesota) prepared the figure. No compensation was received.

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