Higher Infection Risk With Venetoclax-Obinutuzumab vs Zanubrutinib in CLL/SLL

Patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) treated with venetoclax plus obinutuzumab (VO) experienced significantly higher rates of serious infections compared with zanubrutinib, particularly over extended follow-up periods, accordig to an extensive real-world analysis of over 4700 patients. The findings were presented at the 2025 American Society of Clinical Oncology (ASCO) annual meeting in Chicago, IL.1

“Given the compromised immune systems of patients with CLL/SLL, there has always been concern about the association between CLL/SLL-directed therapies and serious infection risks, prompting the need for treatments with lower risks,” the authors noted in the abstract.

The findings have potential implications for treatment selection in CLL/SLL, particularly in patients at elevated risk for infectious complications. | Image credit: Eleni - stock.adobe.com

Over the past decade, targeted therapies, including Bruton tyrosine kinase (BTK) inhibitors such as acalabrutinib, zanubrutinib, and ibrutinib, as well as the BCL2 inhibitor venetoclax, have significantly transformed the treatment landscape, replacing chemoimmunotherapy due to their superior efficacy in patients across all age groups and various treatment settings. However, these agents still vary in their safety profiles, particularly concerning the risk of infection, which remains a common concern.2 Understanding how different regimens compare in real-world clinical practice can help in treatment selection, particularly for patients at a higher risk of infection.

To explore these risks, the investigators conducted a retrospective cohort study using the Symphony Health Solutions database.1 Patients included in the study had a diagnosis of CLL/SLL and initiated treatment with either VO between April 2016 and August 2022 or zanubrutinib between November 2019 and August 2023. For inclusion in the VO cohort, obinutuzumab had to be initiated within 90 days of starting venetoclax. Serious infections were defined as those requiring intravenous antibiotic or antiviral therapy within 15 days of hospitalization.

A total of 2104 patients received VO, while 2650 received zanubrutinib. The index date was defined as the start of venetoclax (for VO) or zanubrutinib, with outcomes assessed at both 12 and 18 months post treatment initiation. To reduce baseline confounding, the authors applied inverse probability of treatment weighting using a Cox proportional hazards model adjusting for age, sex, race and ethnicity, Charlson Comorbidity Index, and geographic region.

At the 12-month follow-up, 167 patients treated with VO (7.9%) developed serious infections, compared with 128 (4.8%) of those treated with zanubrutinib. This translates to an event rate of 0.70 per 100 patient-months for VO (95% CI, 0.60-0.81) and 0.42 per 100 patient-months for zanubrutinib (95% CI, 0.35-0.49). The weighted hazard ratio indicated a 57% increased risk of serious infections in the VO group (HR, 1.57; 95% CI, 1.23-1.99).

At 18 months, infection rates remained higher in the VO group, with 212 patients (10.1%) affected, compared to 149 patients (5.6%) in the zanubrutinib group. Event rates were 0.60 (95% CI, 0.52-0.69) for VO and 0.34 (95% CI, 0.28-0.40) per 100 patient-months for zanubrutinib. The results translated to a 72% higher risk of serious infections for those treated with VO (HR, 1.72; 95% CI, 1.38-2.13).

Kaplan-Meier survival curves showed a consistently higher cumulative incidence of serious infections among VO-treated patients across both time points. Notably, the increasing gap between groups from 12 to 18 months suggests that the risk of infection with VO may extend beyond the active treatment phase.

These findings have potential implications for treatment selection in CLL/SLL, particularly in patients at elevated risk for infectious complications. While VO remains a guideline-supported, time-limited regimen with proven efficacy, the increased risk of infections observed here may prompt clinicians to more carefully consider continuous BTK inhibition with zanubrutinib in select populations.

As newer therapies continue to reshape the CLL/SLL treatment landscape, longitudinal safety data, particularly from diverse patient cohorts outside of controlled clinical trials, will remain essential in guiding optimal, individualized care.

References

1. Colasurdo J, Zhou L, Ali, A, et al. Serious infections in patients with CLL/SLL treated with combination venetoclax and obinutuzumab compared with those treated with zanubrutinib: A real-world study. J Clin Oncol. 2025;43(suppl 16):e19026. doi:10.1200/JCO.2025.43.16_suppl.e19026
2. Mauro FR, Frustaci AM, Visentin A, et al. Severe infections in patients with chronic lymphocytic leukemia included in trials investigating BTK and BCL2 inhibitors. Crit Rev Oncol Hematol. 2024;201:104408. doi: 10.1016/j.critrevonc.2024.104408