Neurological complications induced by immune checkpoint inhibitors: a comprehensive descriptive case-series unravelling high risk of long-term sequelae

Abstract

Neurological immune-related adverse events (n-irAEs) are complications of programmed-cell death 1 (anti-PD-1) or programmed-cell death 1 ligand (anti-PD-L1) immunotherapies that can be life threatening and often lead to anticancer immunotherapy withdrawal. Scant clinical data are available that integrate the clinical presentation, therapeutic management, and long-term outcome. All consecutive adult patients treated by programmed-cell death 1 or programmed-cell death 1 ligand immunotherapies, given alone or in combination with other treatment, who experienced a neurological immune-related adverse event with a severity grade ≥ 2 in Paris Saclay-University hospitals were investigated from June 2014 to February 2019. The frequency of neurological immune-related adverse events was calculated from the prospective Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie (REISAMIC) cohort. Forty patients presenting with 51 distinct neurological immune-related adverse events were included. The prevalence of grade ≥ 2 neurological immune-related adverse events was estimated to be 1.22% in the Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie cohort. Among 40 patients with neurological immune-related adverse events, 65% received programmed-cell death 1 or programmed-cell death 1 ligand monotherapy and 35% received a combination of programmed-cell death 1 plus anti-CTLA4 (Common Terminology Criteria for Adverse Events). Clinical neurological presentations were peripheral (48%), central (35%), or mixed (18%). The severity of neurological immune-related adverse events were grade 2 for 14 (35%) and ≥ grade 3 for 26 patients (65%). The mortality rate related to neurological immune-related adverse events was 8%. Corticosteroid treatment led to neurological recovery in 74%. Long-term follow-up highlighted that 53% of patients experienced long-term neurological sequelae. Five patients were rechallenged by programmed-cell death 1 monotherapy without recurrence of their neurological immune-related adverse event(s). Neurological immune-related adverse events induced by programmed-cell death 1 or programmed-cell death 1 ligand are rare but are severe with a mortality rate of 8% and long-term sequelae for 53% of patients. Corticosteroids should be started when neurological immunological complications are identified to avoid long-term sequelae.

Anti-Hu Antibodies in Patients With Neurologic Side Effects of Immune Checkpoint Inhibitors

“…As opposed to other n-irAEs, 38 most of the Hu-Ab–positive patients did not improve after ICI discontinuation and immunosuppressive treatment. This almost universal lack of treatment response in such patients parallels the experience of those with Hu-Ab–associated PNS outside the ICI context.…”

Metabolic and Toxic Myelopathies

“…89 ICI-associated myelitis is relatively uncommon, accounting for 2% to 4.8% of ICI-associated neurologic complications. 90,91 CLINICAL PRESENTATION. ICI-associated myelitis is typically acute and transverse, affecting motor and all sensory modalities as well as sphincter function.…”

“…90,92 The decision to rechallenge a patient with an ICI after an ICI-associated neurologic toxicity must balance the potential oncologic benefit with the risk of triggering further neurologic autoimmunity. 89,91,93 Data on rechallenging KEY POINTS…”

Neurologic Complications of Immune Checkpoint Inhibitors

“…The clinical manifestations of immune checkpoint inhibition neurotoxicity may affect both the central nervous system (CNS) and the peripheral nervous system (PNS) (Table 2). [13][14][15][16]20,21,22 Neurologic irAE after ICI may occur at any time, but neuromuscular complications generally manifest earlier (median: 70 days) than CNS complications (median: 119 days). 20 Immune response associated with neurologic irAEs involves T cell activation, cytokine release and autoantibody production, both with previously described and novel autoantibodies.…”

“…12 It has been estimated that neurologic complications may affect up to 2.0-4.0% of patients treated with ICI, with clinically relevant and severe neurotoxicity affecting fewer than 1.0% of patients. [13][14][15] Neurologic irAEs may present de novo or manifest as exacerbations of pre-existing neurologic disorders. Multisystemic irAEs, including gastrointestinal, skin, pulmonary, endocrine or neurologic irAEs, are fairly common after ICI treatment.…”