Immune checkpoint inhibitor-related neurotoxicity: Incidence and management. A systematic review and meta-analysis
Dorte Lisbet Nielsen1, Carsten Bogh Juhl2, Inna Markovna Chen1
1Department of Oncology, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
Background:
Immune checkpoint inhibitors (ICIs) have improved outcomes for various malignancies. However, serious immune-related adverse events (irAEs), including neurologic complications (NAEs), may occur. The aim of this study was to examine the incidence and spectrum of NAEs and evaluate management strategies for reducing their impact.
Methods:
Two studies were conducted: 1) A meta-analysis of phase I-IV clinical trials involving adults with malignancies treated with ICIs, either as monotherapy, in combination with other ICIs, or with chemotherapy. The primary outcome was the incidence of (ir)NAEs, summarized using a meta-analysis with a random-effects model. 2) A systematic review of the literature addressing the clinical manifestations and treatment of irNAEs.
Results:
The meta-analysis included 657 unique trials with 91,340 participants. For all ICIs, the incidence of all-grade NAEs was 0.24% (95% CI, 0.15-0.32%). Cerebral events, cerebrovascular accidents, were increased post-treatment and accounted for 54% of all grade-5 events in clinical trials. Among 991 reported irNAE cases, 77% of patients improved with treatment; however, 42% experienced unresolved sequelae and the overall mortality rate was 17.1%. Among patients with overlapping myasthenia gravis, myositis, and myocarditis ("Triple M"), the mortality reached 38%; primarily due respiratory failure (50%) or cardiotoxicity (41%).
Conclusions:
Although the incidence of ICI-related NAEs is low such side effects may lead to severe morbidity and mortality. In patients with Triple M syndrome intensive respiratory function monitoring and support are essential parameters to improve the outcome. PROSPERO Protocol # CRD42023463750.
Insights
Immune checkpoint inhibitors (ICIs) can cause rare but severe neurologic adverse events (NAEs). While most patients improve, some experience lasting effects or mortality, especially with "Triple M" syndrome, necessitating careful monitoring.
Area of Science:
- Oncology
- Neurology
- Immunology
Background:
- Immune checkpoint inhibitors (ICIs) are vital cancer treatments.
- Immune-related adverse events (irAEs), including neurologic complications (NAEs), are potential serious side effects.
- Understanding NAEs is crucial for patient safety and treatment optimization.
Purpose of the Study:
- To determine the incidence and spectrum of NAEs associated with ICIs.
- To evaluate management strategies for mitigating the impact of NAEs.
- To analyze outcomes and mortality in patients experiencing NAEs.
Main Methods:
- A meta-analysis of 657 clinical trials (91,340 participants) was conducted to assess NAE incidence.
- A systematic review of literature examined clinical manifestations and treatments of irNAEs.
- Random-effects models were used for incidence summarization.
Main Results:
- The overall incidence of all-grade NAEs was 0.24%.
- Cerebral events were increased post-treatment, accounting for 54% of fatal events.
- 77% of patients with irNAEs improved, but 42% had sequelae; overall mortality was 17.1%.
Conclusions:
- ICI-related NAEs, though infrequent, can cause significant morbidity and mortality.
- The "Triple M" syndrome (myasthenia gravis, myositis, myocarditis) has a high mortality rate (38%).
- Intensive respiratory monitoring and support are critical for improving outcomes in "Triple M" patients.
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