What do the clinical data tell us about fixed-duration ibrutinib + venetoclax for patients with CLL?

The Lymphoma Hub was pleased to speak to Susan O’Brien, Chao Family Comprehensive Cancer Center, University of California, Irvine, US. We asked, What do the clinical data tell us about fixed-duration ibrutinib + venetoclax for patients with chronic lymphocytic leukemia (CLL)? 

Key points¹ 

• Final results, with up to 7 years of follow-up, from the phase II CAPTIVATE trial (NCT02910583), evaluating fixed-duration ibrutinib + venetoclax in 202 patients with CLL, were presented at the European Hematology Association (EHA) 2025 Congress, June 12–15, 2025, Milan, IT.
• Patients received ibrutinib, a Bruton tyrosine kinase inhibitor (BTKi), for 3 cycles followed by ibrutinib + venetoclax, a B-cell lymphoma-2 inhibitor (BCL-2i), for 12 cycles.
  • The ibrutinib lead-in phase reduces the risk of tumor lysis syndrome.
• The study was originally designed to have two cohorts; in the fixed-duration cohort (n = 153) patients received no further treatment, while patients in the measurable residual disease (MRD) cohort with undetectable MRD (uMRD; <10⁻⁴) were randomized to receive MRD-guided ibrutinib or placebo after the initial 12 cycles.
  • Patients with uMRD who were randomized to the placebo arm (n = 43) were included in the fixed-duration analysis.
• High-risk genomic features were present, including unmutated IGHV (59%), del(17p)/mutated TP53 (14%), and complex karyotype (17%).
• The median age was 60 years (range, 33–71).
• Median progression-free survival (PFS) was not reached, and MRD status at the end of treatment was highly predictive of PFS.
• Patients with progressive disease could be retreated with single-agent ibrutinib or, if they had been in remission for over 2 years, with ibrutinib + venetoclax.
  • No known resistance-associated mutations were observed in patients with progressive disease.
  • 36 patients were retreated with either ibrutinib (n = 25) or fixed-duration ibrutinib + venetoclax (n = 11); the overall response rates were 78% and 82% in the ibrutinib and fixed-duration ibrutinib + venetoclax arms, respectively. 

O’Brien concludes by highlighting that this all-oral, once-daily, chemotherapy-free, fixed-duration regimen is associated with durable responses in first-line patients with CLL. These long-term results demonstrate that ibrutinib + venetoclax is well-tolerated and effective, with the median PFS and overall survival not reached. Results suggest that MRD has a strong prognostic value, and re-treatment is possible in patients with progressive disease. 

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