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

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).

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.