Phase 2 venetoclax (BCL-2 inhibitor) + zanubrutinib (BTK inhibitor) in CLL/SLL

This Phase 2 study evaluates a time-staggered oral doublet—zanubrutinib first, then venetoclax added starting cycle 4—to deepen responses and reduce measurable residual disease in chronic lymphocytic leukemia/small lymphocytic lymphoma. Zanubrutinib (BeiGene) inhibits Bruton tyrosine kinase (BTK) to block B-cell receptor signaling, while venetoclax (AbbVie/Genentech-Roche) inhibits BCL-2 to trigger apoptosis in CLL cells. The trial includes two cohorts: treatment-naïve CLL/SLL, and a “second-line” cohort for patients previously treated with a front-line, time-limited venetoclax-based regimen who relapse/progress on therapy or within ~2 years of completion. It is open-label with serial blood testing, marrow exams, and CT/MRI to track depth/durability of response and safety (including tumor lysis risk during venetoclax ramp-up). Today’s frontline CLL options include continuous BTK inhibition, time-limited venetoclax-based therapy, and now the approved fixed-duration combination of acalabrutinib + venetoclax. This study asks whether pairing zanubrutinib with venetoclax can deepen remissions in untreated patients and, importantly, whether the combination can work again after relapse following an earlier time-limited venetoclax regimen.