Atypical immune-related adverse events of immune checkpoint inhibitors: A narrative review

Immune checkpoint inhibitors (ICIs) have transformed the management of multiple solid tumors. Beyond common immune-related adverse events (irAEs), atypical toxicities – most often neurological, cardiac, or hematologic – are rare but frequently severe and underrepresented in pivotal trials, leading to diagnostic delays and suboptimal outcomes. To synthesize contemporary evidence on atypical irAEs, emphasizing their clinical spectrum, diagnostic pitfalls, and management strategies, with a focus on high-risk presentations. Narrative review of PubMed-indexed studies, pharmacovigilance signals, and major oncology meeting abstracts (2016–2025) reporting atypical irAEs under anti-PD-1/PD-L1 and anti-CTLA-4 therapies. Neurological irAEs include autoimmune encephalitis, myelitis, peripheral neuropathies, and myasthenia-myositis-myocarditis overlap; cardiac irAEs comprise myocarditis and malignant arrhythmias with high early mortality; hematologic irAEs encompass aplastic anemia, immune thrombocytopenia, and autoimmune hemolytic anemia. Atypical irAEs often mimic infection or tumor progression, delaying corticosteroid initiation. The first-line management relies on prompt high-dose corticosteroids and supportive care; steroid-refractory cases may require mycophenolate, intravenous immunoglobulin or plasmapheresis (neuro), rituximab (hematologic), or abatacept (myocarditis). Rechallenge is generally discouraged after life-threatening events. Atypical irAEs are uncommon yet high-impact toxicities that demand heightened vigilance, early multidisciplinary assessment, and protocolized escalation to second-line immunosuppression when indicated. Prospective registries, biomarker-driven risk stratification, and integration into clinical guidelines are priorities to improve recognition and outcomes.