Triplet Immunosuppression for Immune Checkpoint Inhibitor–Related Adverse Events is Associated With High Infection Risk

BACKGROUND: The use of multiagent immunosuppressive therapy (IST) to treat immune-related adverse events (irAEs) from immune checkpoint inhibitors (ICIs) increases the risk of infection. Time-normalized infection rates in a large cohort have not been previously reported. Predictors of opportunistic and nonopportunistic infections (OIs and non-OIs, respectively) and infection severity are poorly understood. METHODS: We conducted a retrospective chart review of patients treated with ICIs and identified those who received simultaneous multiagent IST for irAE treatment, defined as at least 1 supraphysiologic-dose corticosteroid (steroid) and 2 steroid-sparing ISTs administered within 90 days of one another. Patients who received ≤2 ISTs were not included in the analysis. Total exposure duration and the number of OIs and non-OIs occurring during ICI alone, 1 IST, 2 ISTs, and ≥3 ISTs were used to calculate infection rates per 1,000 exposure-days. Significance was assessed using the Poisson test. The cumulative incidence function and Fine-Gray test were applied to identify clinical features associated with infection risk. RESULTS: Between June 2011 and February 2024, 20,930 patients received ICI therapy. A total of 142 (0.68%) patients received 3 ISTs and were included in the analysis. Among the 142 patients, 74 experienced a total of 152 infections, including 132 non-OIs in 68 patients and 20 OIs in 17 patients. Cytomegalovirus reactivation accounted for 10 of 20 OIs. Per 1,000 patient-days, the OI density was 0 during ICI alone, 0.06 with 1 IST, 0.57 with 2 ISTs, and 0.42 with ≥3 ISTs (P<.0001). The corresponding non-OI densities were 0.85, 0.90, 2.04, and 4.14, respectively (P<.0001). When mild and moderate infections were omitted, the same trend was observed. In subgroup analyses, age >65 years was a predictor of OIs (P=.046) but not non-OIs, whereas cardiac irAEs were a predictor of non-OIs (P=.018) but not OIs. CONCLUSIONS: These data support the development of improved strategies for infection screening, prophylaxis, and monitoring in patients receiving multiagent IST for irAE treatment.