Review
Neurological adverse events associated with immune checkpoint inhibitors: Review of the literature

https://doi.org/10.1016/j.ejca.2016.12.001Get rights and content

Highlights

  • ā€¢

    Incidence of neurologicalĀ AEs is under 1% in treatment with immune checkpoint inhibitors.

  • ā€¢

    The clinical spectrum of neurological disorders is highly heterogeneous.

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    Their median time to onset is 6 weeks.

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    In most cases, drug interruption and steroids lead to neurological recovery.

Abstract

Immune checkpoint inhibitors (ICIs) targeting CTLA4 and PD1 constitute a promising class of cancer treatmentĀ but are associated with several immune-related disorders. We here review the literature reporting neurological adverse events (nAEs) associated with ICIs. A systematic search of literature, up to February 2016, mentioning nAEs in patients treated with ICIs was conducted. Eligible studies included case reports and prospective trials. One case seen in our ward was also added. Within the 59 clinical trials (totalling 9208 patients) analysed, the overall incidence of nAEs was 3.8% with anti-CTLA4 antibodies, 6.1% with anti-PD1 antibodies, and 12.0% with the combination of both. The clinical spectrum of neurological disorders was highly heterogeneous. Most of these nAEs were grade 1ā€“2 and consisted of non-specific symptoms such as headache (55%). The incidence of high grade nAEs was below 1% for all types of treatment. Headaches, encephalopathies and meningitis were the most commonly reported (21%, 19% and 15%, respectively). Among the 27 case reports, the most common nAEs were encephalopathies, meningoradiculoneuritis, Guillain-BarrĆ© like syndromes and myasthenic syndromes. The median time of nAEs onset was 6 weeks. In most cases, drug interruption and steroids led to neurological recovery, even in conditions where steroids are not usually recommended such as Guillain-BarrĆ© syndrome.

Introduction

Anti-CTLA4 (ipilimumab, tremelimumab) and anti-PD1 (nivolumab, pembrolizumab, lambrolizumab, pidilizumab) monoclonal antibodies enhance antitumour immunity by targeting T-cells inhibitory receptors. These antibodies, classified as immune checkpoint inhibitors (ICIs), have recently obtained approval for treatment in metastatic melanoma [1], [2], [3], [4], [5], non-small cell lung cancer [6], [7], [8], renal-cell carcinoma [9] and are currently under clinical trials in several other indications. Immune checkpoint inhibitors have undoubtedly been a major step forward in immunotherapy these last years, having significantly increased survival of cancer patients.

As might be expected, adverse effects (AEs) can occur through immunologic activation, that have been termed immune-related adverse events (irAEs) or, occasionally, adverse events of special interest. Grade 3 and 4 adverse events occurred in 13ā€“55% of ipilimumab-treated patients, in 9ā€“43% of nivolumab-treated patients, in 11ā€“14% of pembrolizumab-treated patientsĀ and in 54ā€“86% in ipilimumab plus nivolumab-treated patients [10]. These irAEs can potentially involve every organ system but gastrointestinal, dermatologic, hepatic, endocrine and pulmonary toxicities predominate [11], [12]. Although rare, neurological adverse effects (nAEs) require prompt recognition and treatment to avoid substantial morbidity.

This review summarises the published data on neurological toxicities reported with immune checkpoint inhibitors, trying to define their incidence, timing patterns, clinical and paraclinical presentation.

Section snippets

Patients and methods

A systematic literature search, up to February 2016, mentioning treatment with immune checkpoint inhibitors on adult human beings and published in English was conducted in PubMed database, using the keywords: ā€˜ipilimumab or tremelimumab or nivolumab or pembrolizumab or lambrolizumab or pidilizumab or anti-CTLA4 or anti-CTLA-4 or anti-PD1 or anti-PD-1ā€™ and ā€˜clinical trialsā€™. Observational studies were excluded. For the case reports search, the keywords used were ā€˜safety or toxicity or sides

Literature search

The Pubmed search identified 82 relevant publications for the present study: 59 clinical trials (totalling 9208 patients exposed to anti-CTLA4 or anti-PD1 antibodies) and 23 case reports reporting 26 cases. One case seen in our ward was added to the case reports. Among the 59 clinical trials, 37 were investigating anti-CTLA4 antibodies (7 phase I, 24 phase II, 6 phase III), 22 anti-PD1 antibodies (9 phase I, 6 phase II, 7 phase III)Ā and 4 a combination of both (1 phase I, 1 phase II, 2 phase

Discussion

Immune checkpoint inhibitors have shown promising results in cancersĀ but can possibly induce auto-immune disorders. In this study, we reviewed the neurological adverse events occurring under immune checkpoint inhibitors in oncologic patients to more clearly define their incidence and characteristics.

The most striking feature of this literature review is the extremely broad spectrum of possible syndromes, potentially involving all areas of the central and peripheral nervous system. An

Conflict of interest statement

None declared.

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