Treatment of chronic lymphocytic leukemia (CLL) currently consists of two main approaches — continuous therapy with Bruton’s tyrosine kinase inhibitors and fixed-duration regimens combining venetoclax with either CD20 antibodies or Bruton’s tyrosine kinase inhibitors. Comparisons of these two therapeutic approaches are lacking.

We conducted an investigator-initiated, phase 3, randomized trial involving patients with previously untreated CLL. Patients were randomly assigned to receive continuous ibrutinib or fixed-duration venetoclax–obinutuzumab or venetoclax–ibrutinib. The primary end point was investigator-assessed progression-free survival (noninferiority margin for the hazard ratio, 1.608, corresponding to a noninferiority margin of 8 percentage points at 3 years). Secondary end points included minimal residual disease (MRD), response, overall survival, and safety.

A total of 909 patients were assigned to venetoclax–obinutuzumab (303 patients), venetoclax–ibrutinib (305 patients), or ibrutinib (301 patients). The median follow-up was 34.2 months. In this prespecified interim analysis, 3-year progression-free survival was 81.1% in the venetoclax–obinutuzumab group, 79.4% in the venetoclax–ibrutinib group, and 81.0% in the ibrutinib group (hazard ratio for venetoclax–obinutuzumab vs. ibrutinib, 0.87 [98.3% confidence interval {CI}, 0.54 to 1.41]; hazard ratio for venetoclax–ibrutinib vs. ibrutinib, 0.84 [98.0% CI, 0.53 to 1.32]); the results for each comparison met the criterion for noninferiority. After the end of treatment, MRD in peripheral blood was undetectable in 73.3% of the patients in the venetoclax–obinutuzumab group, 47.2% in the venetoclax–ibrutinib group, and 0% in the ibrutinib group. Three-year overall survival was 91.5%, 96.0%, and 95.7%, respectively. The most common adverse events were infections, gastrointestinal disorders, and cytopenias.

In patients with previously untreated CLL, fixed-duration treatment with venetoclax–obinutuzumab or venetoclax–ibrutinib was noninferior to continuous ibrutinib with regard to investigator-assessed progression-free survival. (Funded by the University of Cologne and others; CLL17 ClinicalTrials.gov number, NCT04608318; EudraCT number, 2019-003854-99.)