Incidence of immune-related adverse events in U.S. veterans treated with immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are associated with potentially severe immune-related adverse events (irAEs). Emerging clinical practice reports have suggested higher incidence of irAEs in real-world settings than initially observed in phase III clinical trials. Objectives were to determine the incidence of irAEs associated with ICIs in a clinical population, the Veterans Health Administration, characterize their time to onset, and explore potential risk factors. METHODS: This retrospective observational study included patients from eight Midwest VA medical centers who initiated an ICI between January 1, 2014, and June 30, 2022. Courses of incident prednisone therapy lasting at least seven days at a dose ≥ 20 mg/day were used to identify irAEs, within two years following ICI initiation. A multivariate Cox proportional hazards regression model was used to explore potential irAE risk factors. RESULTS: Of 1314 patients, the incidence of irAEs was 19.8%, with most (86.5%) occurring within one year of ICI initiation. Monthly incidence rates peaked three months following ICI initiation at 3.0% and decreased thereafter. Female gender (hazard ratio [HR] = 2.01, 95% confidence interval [CI]: 1.01-4.00) and combination therapy with ipilimumab and nivolumab (HR = 2.46, 95% CI: 1.44-4.21) were significantly associated with irAE incidence. CONCLUSIONS: These findings are consistent with recent studies in clinical populations that demonstrate higher irAE incidence rates than originally reported in clinical trials. Our findings may enhance prompt recognition and treatment of irAEs for VA patients.

Association Between Clozapine Exposure and Risk of Hematologic Malignancies in Veterans With Schizophrenia.

Objective: The objective of this study was to examine the relationship between clozapine use and hematologic malignancies, using national administrative data from the United States Veterans Health Administration (VHA).Methods: This case-control study of veterans with schizophrenia matched cases with incident hematologic malignancy to 10 controls without hematologic malignancy by gender, age, and time since first schizophrenia diagnosis from October 1999, the beginning of VHA data archives, to June 2022. Schizophrenia diagnoses were identified using International Classification of Diseases, Ninth Revision, code 295.x and International Statistical Classification of Diseases, Tenth Revision, codes F20.x and F25.x from inpatient hospitalization and outpatient encounter data. Additional inclusion criteria were age 18-85 years, no prior history of malignancy, and at least 1 year of antipsychotic exposure. Clozapine exposure was assessed using 3 metrics: any exposure, years of exposure, and cumulative defined daily doses (DDD). Conditional multivariable logistic regression was used to adjust for nonmatched confounding variables.Results: A total of 2,306 veterans with schizophrenia were identified with an incident diagnosis of hematologic malignancy and matched to 23,043 controls. Any prior clozapine exposure was more commonly observed among cases (5.3%) than controls (4.1%) and was significantly different after adjustment (odds ratio [OR], 1.31; 95% CI, 1.08-1.60). Risk was dose-dependent, where cumulative clozapine exposures from 3,000 to 4,999 DDD (OR, 1.78; 95% CI, 1.13-2.79) and ≥5,000 DDD (OR, 1.81; 95% CI, 1.24-2.64) were significantly associated with malignancy risk. Similarly, clozapine exposure of 5 or more years was associated with malignancy risk (OR, 1.88; 95% CI, 1.43-2.47).Conclusion: Consistent with prior report, this study observed an increased risk of hematologic malignancy associated with clozapine exposure. These findings suggest patients receiving clozapine use, particularly those with long-term use, should be closely monitored for hematologic malignancy.