Risk of invasive fungal infections in patients with chronic lymphocytic leukemia treated with Bruton tyrosine kinase inhibitors: A TriNetX-based retrospective cohort study from 2000-2025.

7035 Background: Chronic lymphocytic leukemia (CLL) is associated with immunosuppression, and Bruton tyrosine kinase inhibitors (BTKis) may further increase the risk of invasive fungal infections (IFIs). This retrospective study evaluates the trends in BTKi use and the associated risk of IFIs among CLL patients in a real-world setting. Methods: We conducted a retrospective cohort study using the TriNetX database, analyzing U.S. CLL patients diagnosed between January 2000 and January 2025. Propensity score matching (1:1) by age, comorbidities, and immunosuppressive therapy was performed. Outcomes included invasive fungal infections (candidiasis, aspergillosis, cryptococcosis, and pneumocystis jirovecii pneumonia), assessed using Kaplan-Meier survival analysis and risk measures. Results: Among 10,736 patients treated with BTK inhibitors and 80,446 controls, the median follow-up was 881 and 868 days, respectively. Patients in the BTK cohort had a mean age of 75±10 years, predominantly male (62.21%) and primarily White (76.24%). In contrast, the control cohort had a mean age of 76±12 years, with 55.87% male patients and 73.12% identified as White. On the other hand, the risk of invasive candidiasis was significantly lower in the BTK cohort (RR: 0.364, 95% CI: 0.193–0.686), as was the risk of invasive aspergillosis (RR: 0.532, 95% CI: 0.289–0.98). Pneumocystis jirovecii pneumonia (PJP) rates were comparable between the cohorts (RR: 0.961, 95% CI: 0.497–1.855). Cryptococcosis was detected in 0.001% of the BTKi group but did not occur in the control cohort; this variation, however, did not reach statistical significance (P = 0.823). Conclusions: This retrospective study reveals the complex infection profile associated with BTK inhibitor use in CLL patients. Treatment with BTK inhibitors was linked to a significant decrease in the occurrence of invasive candidiasis and aspergillosis in the BTK cohort, and rates of Pneumocystis jirovecii pneumonia (PJP) and Cryptococcus were similar between groups. Although the absolute rates of fungal infections remain low, these findings underscore the importance of identifying at-risk patients to guide preventive and cost-effective interventions. Further research is needed to differentiate infection risks across specific BTK inhibitors and develop tailored management strategies to optimize patient outcomes.