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Ibrutinib vs Placebo Following Achievement of Undetectable MRD With First-Line Ibrutinib/Venetoclax in CLL


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As reported in the Journal of Clinical Oncology by William G. Wierda, MD, PhD, and colleagues, findings in the measurable residual disease (MRD) cohort of the phase II CAPTIVATE study indicated a high disease-free survival rate with placebo and no significant benefit of continued ibrutinib in patients with chronic lymphocytic leukemia (CLL) who achieved undetectable MRD on first-line ibrutinib/venetoclax.

William G. Wierda, MD, PhD

William G. Wierda, MD, PhD

Study Details

In the MRD cohort of the international trial evaluating MRD-guided treatment discontinuation, 164 patients aged < 70 years received three cycles of ibrutinib at 420 mg once daily followed by 12 cycles of ibrutinib plus venetoclax at a target dose of 400 mg once daily after a 5-week ramp-up. Patients with confirmed undetectable MRD (confirmed uMRD population; best uMRD response of 100% in both peripheral blood and marrow) were randomly assigned to double-blind treatment with ibrutinib vs placebo until confirmed MRD relapse or disease progression. Patients without confirmed uMRD (not-confirmed uMRD population) were randomly assigned to open-label ibrutinib vs ibrutinib plus venetoclax for a maximum of 2 years for venetoclax or until disease progression or unacceptable toxicity. The primary endpoint was 1-year disease-free survival with ibrutinib vs placebo in the confirmed uMRD population.

Key Findings

A total of 86 patients had confirmed uMRD and were randomly assigned to receive ibrutinib (n = 43) vs placebo (n = 43). Disease-free survival at 1 year was 100% in the ibrutinib group vs 95% in the placebo group (difference = 4.7%, 95% confidence interval [CI] = –1.6 to 10.9, P = .15).

KEY POINTS

  • Disease-free survival at 1 year was 100% in the ibrutinib group vs 95% in the placebo group.
  • In the confirmed uMRD population, with a median follow-up of 31.3 months including 16.6 months after random assignment, disease-free survival events occurred in three patients (7%) in the placebo group vs no patients in the ibrutinib group.

In the confirmed uMRD population, with a median follow-up of 31.3 months including 16.6 months after random assignment, disease-free survival events occurred in three patients (7%) in the placebo group (disease progression in 2, MRD relapse in 1) vs no patients in the ibrutinib group. Estimated 30-month progression-free survival was 100% (95% CI = 100%–100%) in the ibrutinib group vs 95% (95% CI = 83%–99%) in the placebo group.

A total of 63 patients in the not-confirmed uMRD population were randomly assigned to receive ibrutinib (n = 31) or ibrutinib plus venetoclax (n = 32). Estimated 30-month progression-free survival was 95% (95% CI = 71%­–99%) in the ibrutinib group vs 97% (95% CI = 79%–100%) in the ibrutinib/venetoclax group.

Among all patients, after ibrutinib lead-in tumor debulking, 36 (90%) of 40 patients with high tumor-lysis syndrome (TLS) risk at baseline shifted to medium or low TLS risk categories. Overall, 4 (2%) of 164 patients remained at high TLS risk.

Among all patients, adverse events were most common during the first 6 months of treatment with ibrutinib/venetoclax and generally decreased over time. In the confirmed uMRD population, diarrhea and neutropenia were more common with ibrutinib vs placebo. Grade ≥ 3 adverse events were more common with ibrutinib/venetoclax vs ibrutinib in the not-confirmed uMRD population.

The investigators concluded, “The 1-year disease-free survival rate of 95% in [patients] randomly assigned [to placebo] with confirmed uMRD suggests the potential for fixed-duration treatment with this all-oral, once-daily, chemotherapy-free regimen in first-line CLL.”

Dr. Wierda, of the Department of Leukemia, The University of Texas MD Anderson Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Pharmacyclics LLC, an AbbVie Company. For full disclosures of the study authors, visit ascopubs.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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