Fixed-Duration Venetoclax Combinations Are Non-Inferior to Continuous Ibrutinib in Untreated CLL
The CLL17 phase 3 trial randomised 909 treatment-naive CLL patients to venetoclax-obinutuzumab, venetoclax-ibrutinib, or continuous ibrutinib. Both fixed-duration regimens were non-inferior, with 3-year PFS around 80% across all arms. Undetectable MRD in peripheral blood was 73.3% with venetoclax-obinutuzumab, 47.2% with venetoclax-ibrutinib, and 0% with ibrutinib, confirming MRD as the key differentiator between treatment strategies and a potential tool for therapy selection.
The original study
Fixed-Duration versus Continuous Treatment for Chronic Lymphocytic Leukemia.
- Authors
- Al-Sawaf O, Stumpf J, Zhang C, Simon F, Bosch F, Feyzi E, et al.
- Journal
- The New England journal of medicine
- Type
- Clinical Trial, Phase III, Equivalence Trial, Journal Article, Multicenter Study, Randomized Controlled Trial
- PMID
- 41358601
Original abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.).