Practical Considerations for Integrating Zanubrutinib Plus Venetoclax in CLL Therapy

In this segment, Drs. Brander and Flinn discuss the potential integration of the zanubrutinib and venetoclax combination into clinical practice and the role of treatment duration in guiding therapy. Although venetoclax is currently the only approved BCL2 inhibitor, there are multiple BTK and BCL2 combination regimens in trials, raising the question of how the results of this study may influence practice. Dr. Flinn would consider using this combination, given his confidence in both zanubrutinib and venetoclax. However, he highlights the logistical challenges of MRD-guided therapy in routine practice, such as the need for sequencing, banking samples, and repeated testing, which could make implementation cumbersome for many community physicians.

As a result, Dr. Flinn suggests that many clinicians may default to a fixed-duration approach rather than MRD-driven therapy, choosing a pre-set treatment period for practicality while still achieving effective disease control. He emphasizes that second-generation BTK inhibitors like zanubrutinib are generally interchangeable, and clinicians may select the agent they are most comfortable with for combination therapy.

The discussion also addresses optimal therapy duration. Dr. Flinn notes that higher-risk patients, such as those with del(17p), may benefit from a longer course, potentially around 2 years or more, whereas lower-risk patients, including those with del(13q) or mutated IGHV, may achieve sufficient response with a shorter duration of therapy. Dr. Brander underscores the importance of tailoring treatment duration based on risk and patient characteristics to maximize benefit while minimizing unnecessary exposure. The conversation reinforces the need for further research to identify biomarkers that can guide both the selection and length of combination therapy in CLL, balancing efficacy, safety, and practicality in real-world settings.