Neurologic toxicity associated with immune checkpoint inhibitors: a pharmacovigilance study

Abstract

Background: Immune 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. Methods: We 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; IC 025 (lower end of the IC 95% credibility interval) > 0 is considered statistically significant. Results: Among 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]; IC 025 3.31), encephalitis (0.51% vs. 0.05%, ROR 10.4 [95% CI 9.2-11.8]; IC 025 3.15), peripheral neuropathy (1. 16% vs. 0.67%, IC 025 0.68), and meningitis (0.15% vs. 0.06%, ROR 3.1 [95% CI 2.5-3.9]; IC 025 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. Conclusions: ICIs 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.

Severe Neurological Toxicity of Immune Checkpoint Inhibitors: Growing Spectrum

“…We suspect that this concurrent myositis and myocarditis accounts for the increased mortality due to “MG” in patients with ocular, bulbar, limb, and respiratory weakness. This has also been demonstrated by analysis of the World Health Organization pharmacovigilance database . Prospective evaluation with uniform clinical and immunologic testing is needed to understand the pathophysiology of these associations.…”

A review of cancer immunotherapy toxicity

“…Thirty‐two of 43 observed neurologic events were grade 3 or 4, and 1 case of encephalitis was fatal. Another analysis of a pharmacovigilance database identified different patterns of neurologic toxicity, depending on class of immunotherapy . For instance, myasthenia gravis was associated with anti–PD‐1/anti–PD‐L1 therapy.…”

“…Another analysis of a pharmacovigilance database identified different patterns of neurologic toxicity, depending on class of immunotherapy. 82 For instance, myasthenia gravis was associated with anti-PD-1/anti-PD-L1 therapy. Noninfectious encephalitis/myelitis was more common with anti-PD-1/anti-PD-L1 therapy than with anti-CTLA-4 therapy and with combination therapy versus monotherapy.…”

New Approaches to Targeting B Cells for Myasthenia Gravis Therapy

“…It is important to be vigilant for occurrence of adverse effects of immunotherapy for cancer in patients with MG or underlying mild or latent MG (81)(82)(83). For example, treatment of patients with MG with ipilimumab (anti-CTLA4 mAb) for melanoma and lung cancer had fatal consequences (84).…”