ALPINE Lont-Term Follow-Up: Zanubrutinib, Venetoclax Combinations, and Long-Term Outcomes

In this discussion, Drs. Flinn and Brander review recent advances in CLL therapy, focusing on BTK inhibitors, venetoclax, and combination regimens. They explore the benefits and considerations of combining zanubrutinib with venetoclax, highlighting the balance between efficacy and safety. Dr. Flinn notes that venetoclax increases neutropenia and infection risk, but its fixed-duration therapy allows patients to discontinue treatment with minimal long-term adverse events. Zanubrutinib, as a second-generation BTK inhibitor, demonstrates low rates of atrial fibrillation and hypertension even with prolonged use, making it an attractive partner for venetoclax in combination regimens, especially for patients with bulky disease or high tumor burden.

The discussion emphasizes individualizing therapy based on disease characteristics, patient comorbidities, and risk factors, noting that some patients may benefit from shorter courses, whereas high-risk populations might require extended therapy beyond 1 year. The practical challenges of MRD-guided therapy are addressed, with Dr. Flinn suggesting that fixed-duration approaches may be more feasible in community practice.

The conversation transitions to the ALPINE study, a head-to-head comparison of zanubrutinib versus ibrutinib in relapsed/refractory CLL and SLL. Long-term follow-up confirms durable remissions, with median PFS of 52.5 months and COVID-adjusted PFS of 60 months. Complete remission rates remain modest (~12–13%), but the safety profile remains favorable, with low and stable rates of atrial fibrillation, hypertension, and infections. Dr. Brander notes that these results reflect the expected outcomes for continuous therapy in relapsed patients and reinforce zanubrutinib’s tolerability.

Overall, the experts highlight that these studies provide guidance for sequencing therapies, selecting combination regimens, and anticipating long-term safety, while recognizing the evolving landscape of CLL management and the importance of tailoring therapy to individual patient needs.