Reassessing the Continuous-vs-Fixed-Duration Debate in Frontline Chronic Lymphocytic Leukemia

KEY TAKEAWAYS

• Long-term efficacy, not treatment convenience, should be the primary factor in choosing frontline therapy for chronic lymphocytic leukemia (CLL). Durability of disease control shapes immediate outcomes and the number and quality of options available later in a patient’s disease course.
• Continuous use of Bruton tyrosine kinase inhibitors (BTKis) has the longest track record of durable first-line disease control, with a median progression-free survival (PFS) of 8.9 years for ibrutinib in the RESONATE-2 trial, a 72-month PFS of 78% for acalabrutinib-obinutuzumab and of 61.5% for acalabrutinib monotherapy in the ELEVATE-TN trial, and a 72-month PFS rate of 74% for zanubrutinib in the SEQUOIA trial.
• Fixed-duration venetoclax-based regimens offer a meaningful treatment free interval and are an appropriate option for many patients, but follow-up remains comparatively short. Outcomes are less consistent in patients with unmutated IGHV or TP53 aberrations, and robust prospective retreatment data are still lacking.
• Next-generation combinations (eg, zanubrutinib plus sonrotoclax) and noncovalent BTK-targeting approaches (eg, BTK degraders) are being developed to preserve efficacy across genomic risk groups while minimizing cumulative toxicity.
• Current long-term safety data do not provide evidence that continued BTKi therapy leads to increased toxicity. Most treatment-related adverse events emerge early, and their incidence declines—rather than accumulates—with continued exposure.