In a phase II trial (HOVON141/VISION) reported in The Lancet Oncology, Arnon P. Kater, MD, PhD, and colleagues found a high rate of 12-month progression-free survival among patients with relapsed or refractory chronic lymphocytic leukemia (CLL) who stopped venetoclax/ibrutinib after achieving undetectable measurable residual disease (MRD).

Arnon P. Kater, MD, PhD

Study Details

The study included 225 patients enrolled from sites in Belgium, Denmark, Finland, the Netherlands, Norway, and Sweden between July 2017 and January 2019. They received 28-day cycles of ibrutinib at 420 mg once daily and venetoclax with a weekly ramp-up of 20 mg, 50 mg, 100 mg, 200 mg, up to 400 mg once daily.

Patients with undetectable MRD (< 10^–4) in peripheral blood and bone marrow after 15 cycles were randomly assigned 1:2 to ibrutinib maintenance or treatment cessation and observation. Patients with detectable MRD after 15 cycles continued to receive ibrutinib monotherapy.

The primary endpoint was progression-free survival at 12 months after random assignment (ie, at 27 months after the start of treatment) in the treatment cessation group. A 12-month rate of 75% was predefined as the threshold for success of the strategy.

Progression-Free Survival

Among 188 patients (84%) who completed ibrutinib/venetoclax treatment and were tested for MRD at cycle 15, 78 (35%) had undetectable MRD; of these, 72 (32%) were randomly assigned to ibrutinib maintenance (n = 24) or treatment cessation (n = 48). The remaining patients continued treatment with ibrutinib monotherapy. Median follow-up among surviving patients at data cutoff in June 2021 was 34.4 months (interquartile range = 30.6–37.9 months).

Progression-free survival after 12 months (measured at month 27) in the treatment cessation group was 98% (95% confidence interval [CI] = 89%–100%), exceeding the predefined threshold for success. Among patients in the randomly assigned ibrutinib maintenance group, 12-month progression-free survival (at month 27) was 96% (95% CI = 79%–100%). Among 116 patients continuing ibrutinib after cycle 15 because they did not have undetectable MRD, progression-free survival at 27 months was 97% (95% CI = 93%–99%).

Estimated overall survival at month 27 was 100% (95% CI = 86%–100%) in the randomly assigned ibrutinib maintenance group, 98% (95% CI = 89%–100%) in the treatment cessation group, and 92% (95% CI = 86%–95%) in the non–randomly assigned group receiving ibrutinib.  

Adverse Events

Among all 225 patients, the most common adverse events of any grade were infections (58%), neutropenia (40%), and gastrointestinal adverse events (24%). After cycle 15, grade ≥ 3 adverse events occurred in 37% of patients in the randomly assigned ibrutinib group, 15% of the treatment cessation group, and 41% of the non–randomly assigned ibrutinib group; serious adverse events occurred in 33%, 8%, and 40% of patients, respectively. One non–randomly assigned patient had a fatal adverse event (bleeding) considered possibly related to ibrutinib.

The investigators concluded, “These data point to a favorable benefit-risk profile of MRD-guided, time-limited treatment with ibrutinib plus venetoclax for patients with relapsed or refractory CLL, suggesting that MRD-guided cessation and reinitiation is feasible in this patient population.”

Dr. Kater, of Amsterdam University Medical Center, and Carsten U. Niemann, MD, of Copenhagen University Hospital, are the corresponding authors for The Lancet Oncology article.

Disclosure: The study was funded by AbbVie and Janssen. For full disclosures of the study authors, visit thelancet.com.