By Alexandra Gewirtz, MD
Clinical Fellow in Neuro-Oncology, Memorial Sloan Kettering Cancer Center
SYNOPSIS: Immune checkpoint inhibitors have transformed the natural history of many metastatic cancers and now are widely used. However, the activation of killer T-cells also has caused serious, often fatal complications from the treatment. The central nervous system is a common victim of these complications.
SOURCE: Fonseca E, Cabrera-Maqueda JM, Ruiz-García R, et al. Neurological adverse events related to immune-checkpoint inhibitors in Spain: A retrospective cohort study. Lancet Neurol 2023;22:1150-1159.
Immune checkpoint inhibitors (ICI) have revolutionized oncologic care in multiple cancer types. These drugs inhibit multiple targets, including cytotoxic T-lymphocyte-associated protein 4, programmed cell death 1, and programmed death ligand 1, thereby unleashing the T-cell response. This immune system activation can lead to toxicity in multiple organs, including the central nervous system (CNS). To date, the specific characteristics of ICI-related encephalopathy and predictive factors of CNS toxicity have not been well defined.
This retrospective study grouped the clinical features of patients with ICI-related neurologic toxicity and assessed prognosticators of improved response to therapy and survival. Sixty-four patients with suspected neurological toxicity after immunotherapy treated at 20 hospitals in Spain were included. All patients had extensive testing for other causes of neurologic dysfunction as well as a lumbar puncture to rule out leptomeningeal disease. Patients with evidence of other causes of neurologic impairment or preexisting paraneoplastic neurologic syndromes were excluded. Included patients had available serum and/or cerebrospinal fluid (CSF) samples that were analyzed for antibodies at Hospital Clínico de Barcelona.
Patients were categorized by type of neurologic toxicity, including encephalopathy, myelopathy, cerebellar ataxia, myasthenia and myositis, meningitis, optic neuropathy, peripheral neuropathy, and enteric neuropathy. Patients with encephalopathy were further subdivided into three subgroups: definite autoimmune or paraneoplastic encephalitis with or without associated antibodies; encephalitis with CSF pleocytosis, brain biopsy with evidence of inflammation, and/or suggestive magnetic resonance imaging (MRI) brain changes without a definite syndrome or antibodies; and encephalopathy without evidence of inflammation and no alternative reason. Severity of events, neurologic disability, and CNS toxicity were characterized and rated according to standard scales.
Fifty-nine (92%) patients had grade 3 or higher ICI toxicity. Fifty-two (81%) patients had CNS involvement. Symptoms developed at a median of 5.2 weeks post-treatment initiation. Encephalopathy was the most common toxicity reported in 45 (70%) patients. Of the patients with encephalopathy, 12 (27%) had definite autoimmune or paraneoplastic encephalitis, with antibodies present in 10/12 cases.
Most patients with encephalopathy (n = 24, 53%) had encephalitis without a definite syndrome or antibodies. Of these patients, 83% had CSF pleocytosis and 29% had characteristic MRI findings. Nine patients (20%) with encephalopathy had no corresponding inflammation on biopsy, CSF, or MRI. Twelve patients had peripheral nervous system toxicity. Nine (14%) patients had myasthenia with myositis, with five of the nine patients also exhibiting myocarditis. Only 14 (22%) patients overall had neural antibodies identified, with 12 of the 14 cases with CNS-associated antibodies. A high percentage of patients (91%) received steroids, with an additional 48% receiving stronger immunosuppression.
At one-month follow-up, 72% of patients had improvement in symptoms and 18 (28%) patients had no improvement. Of these 18 patients, 11 died, with death attributed to immunotherapy-related CNS toxicity in all cases. At a median follow-up of six months, of the 53 remaining patients, 62% had a good outcome and 38% had a poor outcome. Sixteen (30%) patients with poor outcomes died, one because of complications from immunotherapy after rechallenging. Four additional patients were rechallenged successfully with no return of neurologic symptoms. On multivariate analysis, a higher mortality risk was associated with lung cancer, encephalopathy with no inflammatory changes, and the triad of myocarditis, myasthenia, and myositis.
COMMENTARY
Immunotherapy has changed oncologic care in multiple cancer types but can be associated with clinically significant and severe toxicity, notably in the CNS. Early recognition of ICI-related neurologic toxicity is paramount in leading to prompt treatment. In this retrospective study, more than 90% of patients had grade 3 or higher CNS toxicity and approximately 17% of patients died within the first month after treatment from reasons related to ICI. These findings raise the importance of identifying these patients early for aggressive monitoring and management. In addition, lung cancer and the triad of myocarditis, myasthenia, and myositis were identified as independent poor prognostic factors that carried a high mortality risk.
Encephalopathy without defined associated syndrome, inflammation, or antibodies was shown to be increasingly associated with mortality. Only a minority of patients with CNS-related adverse events after ICI had positive antibodies and clearly defined encephalitis. Therefore, clinicians should have a heightened awareness of patients with encephalopathy after ICI without clearly defined syndromes, antibodies, or alternative diagnoses and consider early management or referral of these patients. A future direction would be to identify underlying biomarkers associated with this subgroup of encephalopathic patients with no clear evidence of inflammation.
Limitations of the study included that it was retrospective, there was variability in follow-up assessments, and there was a lack of routine studies for all patients. In addition, there was a referral bias, because the investigating institution is a center for patients with ICI-related toxicity.
