Combination therapy with zanubrutinib and venetoclax (ZV) is showing promise in patients with relapsed or refractory chronic lymphocytic leukemia (R/R CLL), according to recent data presented at a medical conference. The combination demonstrates notable activity and a manageable safety profile, even in patients who have previously been treated with targeted agents.
Efficacy of Zanubrutinib and Venetoclax in R/R CLL
A multicenter trial evaluated the efficacy of a fixed-duration regimen of zanubrutinib, a Bruton tyrosine kinase inhibitor (BTKi), and venetoclax, a B-cell lymphoma 2 (BCL2) inhibitor, in patients with R/R CLL. The study enrolled patients into three cohorts based on prior treatment history: BTKi- and BCL2i-naïve (Cohort A), exposed to BTKis and/or BCL2is but stopped therapy for reasons other than disease progression (Cohort B), and progressed on a covalent BTKi without BTK C481 mutation (Cohort C).
The overall response rate (ORR) at best response in 22 evaluable patients was 95%, with 18% achieving complete remission (CR). There was no significant difference in clinical response across the cohorts. Partial responses were observed in patients with double-exposed disease and those who had progressed on acalabrutinib.
Safety and Tolerability
The most common treatment-emergent adverse event was bruising (57%, all Grade 1), followed by diarrhea (42%, all Grade 1-2) and thrombocytopenia (38%, all Grade 1-2). Neutropenia occurred in 35% of patients, including 19% with Grade 3-4. Two patients (8%) developed atrial fibrillation. No tumor lysis syndrome events were reported.
BOVen Regimen in Treatment-Naïve CLL
Five-year follow-up data from a phase 2 trial of zanubrutinib, obinutuzumab, and venetoclax (BOVen) in treatment-naïve CLL patients demonstrated frequent undetectable minimal residual disease (uMRD4) in peripheral blood (96%) and bone marrow (92%). The median MRD4-free survival was 34 months (95% CI 23-NR).
Retreatment with Zanubrutinib and Venetoclax
Sixteen patients received zanubrutinib-venetoclax retreatment for MRD ≥1% alone or with progressive disease (PD) after a median treatment-free interval of 29 months. The overall response rate was 92% (11/12) in patients retreated after PD. Of 13 retreatment patients with repeat MRD-FC testing, 6 (46%) achieved uMRD4 in PB.
Implications for CLL Treatment
These findings suggest that the combination of zanubrutinib and venetoclax is a promising treatment option for patients with R/R CLL, including those who have previously been exposed to targeted agents. The BOVen regimen also demonstrates durable efficacy in treatment-naïve CLL, with a high rate of uMRD and prolonged MRD4-free survival. Retreatment with zanubrutinib and venetoclax is also well-tolerated and effective.
