Neurologic toxicity associated with immune checkpoint inhibitors: a pharmacovigilance study

Journal for ImmunoTherapy of Cancer

Andrew Mammen¹  Ali Manouchehri²  Javid J. Moslehi²  Douglas B. Johnson²  Justin M. Balko²  Alexandra M. Haugh²  Henry T. Quach²  Joe-Elie Salem³  Benedicte Lebrun-Vignes⁴ 

[1] 0000 0001 2237 2479, grid.420086.8, Muscle Disease Unit, Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA;0000 0004 1936 9916, grid.412807.8, Department of Medicine, Vanderbilt University Medical Center, 777 PRB, 2220 Pierce Ave, 37232, Nashville, TN, USA;0000 0004 1936 9916, grid.412807.8, Department of Medicine, Vanderbilt University Medical Center, 777 PRB, 2220 Pierce Ave, 37232, Nashville, TN, USA;Department of Pharmacology, Sorbonne Université, INSERM CIC Paris-Est, AP-HP, ICAN, Regional Pharmacovigilance Centre, Pitié-Salpêtrière Hospital, Paris, France;Department of Pharmacology, Sorbonne Université, INSERM CIC Paris-Est, AP-HP, ICAN, Regional Pharmacovigilance Centre, Pitié-Salpêtrière Hospital, Paris, France;

关键词: Neurotoxicity;    PD-1;    CTLA-4;    PD-L1;    Neuropathy;    Encephalitis;    Myasthenia gravis;    Guillain-Barre syndrome;   

DOI  :  10.1186/s40425-019-0617-x

来源: publisher

【 摘 要 】

BackgroundImmune checkpoint inhibitors (ICI) produce durable antitumor responses but provoke autoimmune toxicities, including uncommon but potentially devastating neurologic toxicities. The clinical features, including the spectrum, timing, and outcomes, of ICI-induced neurologic toxicities are not well characterized.MethodsWe performed disproportionality analysis using Vigibase, the World Health Organization pharmacovigilance database, comparing neurologic adverse event (AE) reporting in patients receiving ICIs vs. the full database. Neurologic AEs were classified by group queries using Medical Dictionary for Regulatory Activities, between database inception to September 28, 2018. Associations between ICIs and neurologic AEs were assessed using reporting odds ratios (ROR) and information component (IC). IC compares observed and expected values to find associations between drugs and AEs using disproportionate Bayesian reporting; IC025 (lower end of the IC 95% credibility interval) > 0 is considered statistically significant.ResultsAmong the full database, 18,518,994 AEs were reported, including 48,653 with ICIs. ICIs were associated with higher incidence of myasthenia gravis (0.47% of ICI reports vs. 0.04% of the full database, ROR 16.5 [95% CI 14.5–18.9]; IC025 3.31), encephalitis (0.51% vs. 0.05%, ROR 10.4 [95% CI 9.2–11.8]; IC025 3.15), peripheral neuropathy (1.16% vs. 0.67%, IC025 0.68), and meningitis (0.15% vs. 0.06%, ROR 3.1 [95% CI 2.5–3.9]; IC025 1.01). Myasthenia gravis and encephalitis were associated with anti-PD-1 whereas other neurologic AEs were associated with anti-CTLA-4. Myasthenia gravis was characterized by high fatality rates (~ 20%), early onset (median 29 days), and frequent concurrent myocarditis and myositis; whereas other neurologic AEs had lower fatality rates (6–12%), later onset (median 61–80 days), and were non-overlapping.ConclusionsICIs produce a spectrum of distinct classes of neurologic AEs that can cause significant morbidity and mortality and tend to occur early and with class-specific associations.

【 授权许可】

CC BY