Rethinking infection prevention after modern CLL and NHL therapy: A real-world study.

e19029 Background: Infections are a major source of morbidity in patients with hematologic malignancies, particularly those who develop secondary hypogammaglobulinemia during systemic therapy. Evidence supporting intravenous immunoglobulin (IVIG) use for infection prevention is derived from trials predating modern targeted therapies. Current guidelines allow for IVIG or prophylactic antibiotics in high-risk patients, yet real-world practice varies and contemporary comparative effectiveness data remain limited. Methods: We conducted a retrospective cohort study using the TriNetX Network. Patients with chronic lymphocytic leukemia or non-Hodgkin lymphoma initiating systemic therapy were identified, with therapy start defining the index date. Systemic therapies included Bruton tyrosine kinase inhibitors, venetoclax-based regimens and anti-CD20 monoclonal antibodies. Exposure groups were defined by receipt of IVIG, prophylactic antibiotics, or neither within 0–90 days after index. Outcomes were assessed beginning at a 90-day landmark to reduce immortal time bias. The primary outcome was a composite serious infection endpoint. Relative risk was assessed from days 90–270, and time-to-event analyses from days 90–455. Propensity score matching included demographics, systemic steroid exposure, respiratory comorbidities, baseline infection-related diagnoses, medication classes, and albumin as a proxy for baseline nutritional and functional status. Results: After matching, the antibiotics versus IVIG comparison included 257 patients per cohort, with 67 versus 79 events (RR 0.83, 95% CI 0.60–1.14; HR 0.80, 95% CI 0.58–1.10). Antibiotics versus neither included 263 patients per cohort, with 69 versus 53 events (RR 1.41, 95% CI 0.97–2.05; HR 1.39, 95% CI 0.97–1.98). IVIG versus neither included 538 patients per cohort, with 153 versus 104 events (RR 1.54, 95% CI 1.19–1.98; HR 1.72, 95% CI 1.34–2.21). Conclusions: In this large contemporary real-world analysis, neither IVIG nor prophylactic antibiotics demonstrated superiority over the other for prevention of serious infections in patients with hypogammaglobulinemia receiving modern systemic therapy. Neither strategy was associated with improved outcomes compared with no prophylaxis. The higher incidence of infections observed among patients receiving IVIG likely reflects preferential use of IVIG in patients perceived by clinicians to be at higher baseline risk, rather than a causal adverse effect of IVIG itself. These findings highlight the absence of clear comparative benefit among commonly used prophylactic approaches and underscore the need for prospective studies to better define patient selection and optimize infection prevention strategies. Residual confounding remains possible due to the inability to directly match baseline immunoglobulin levels, prior infection burden, and other granular measures of disease severity.