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Neurotoxicities associated with immune checkpoint inhibitor therapy

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Abstract

Introduction

Immune checkpoint inhibitors (ICIs) have emerged as a promising class of cancer immunotherapies. Neurotoxicities are uncommon, but often severe, and potentially fatal complications of ICIs, and clinical experience is limited. The aim of this study is to further define the clinical spectrum and outcome of ICI-mediated neurotoxicities.

Methods

Patients with ICI-associated neurotoxicities were identified from retrospective review of the quality control database at a single institution. Data regarding demographics, medical history, clinical presentation, diagnosis, management and outcome were recorded.

Results

We identified 18 patients with neurotoxicity following ICI therapy with pembrolizumab, nivolumab, atezolizumab, or ipilimumab for a diverse set of malignancies. Neurotoxicities comprised central demyelinating disorder (28%), autoimmune encephalitis predominantly affecting the grey matter (17%), aseptic meningitis (6%), myasthenia gravis (MG) (17%) with concurrent myositis (6%), sensorimotor polyneuropathy (11%) and hypophysitis (17%). Median time to onset of neurotoxicities was 5 weeks (range 1–72). All patients discontinued ICIs and received steroids with additional immunomodulation required in 9 patients, resulting in improvement for 16 of 18 patients. Grade 3–4 neurotoxicity developed in 14 patients, of whom 6 had died at database closure. Grade 3–4 severity negatively impacted overall survival (OS) (p = 0.046).

Conclusions

ICI-mediated neurotoxicities present early, are rapidly progressive and include a diverse phenotype affecting the CNS, PNS and neuroendocrine system. A high level of vigilance is warranted, as early diagnosis and targeted treatment can substantially prevent morbidity and mortality. Prospective clinical trials are warranted to assess optimized management of ICI-induced neurotoxicities.

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Data availability

Data available on request from the authors.

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Acknowledgements

The abstract was previously presented at the American Academy of Neurology 2019 Annual Meeting in Philadelphia, PA, United States of America and the American Neurology Association Meeting 2018 in Atlanta, GA, United States of America.

Funding

No funding was received for conducting this study.

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Authors and Affiliations

  1. Department of Neurology, Yale School of Medicine, New Haven, CT, USA

    Sophie L. Duong, Frank J. Barbiero & Richard J. Nowak

  2. Institute of Neurophysiology, Goethe University Frankfurt, Frankfurt, Germany

    Sophie L. Duong

  3. Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA

    Joachim M. Baehring

  4. Division of Neuro-Oncology, Department of Neurology, Yale School of Medicine, 15 York Street LLCI 912, PO Box 208028, New Haven, CT, 06520-8082, USA

    Joachim M. Baehring

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  1. Sophie L. Duong
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  2. Frank J. Barbiero
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  4. Joachim M. Baehring
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Contributions

SLD, FJB and JMB designed the study, analyzed, interpreted the data, and drafted the manuscript. SLD, FJB, JMB and RJN acquired patient records. All authors critically revised, read and approved the final manuscript.

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Correspondence to Joachim M. Baehring.

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The authors have no conflicts of interest to declare that are relevant to the content of this article.

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Study design and methods were approved by the institutional review board of Yale School of Medicine.

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Duong, S.L., Barbiero, F.J., Nowak, R.J. et al. Neurotoxicities associated with immune checkpoint inhibitor therapy. J Neurooncol 152, 265–277 (2021). https://doi.org/10.1007/s11060-021-03695-w

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