In an update from the UK phase III FLAIR trial reported in The New England Journal of Medicine, Munir et al compared the survival benefit of measurable residual disease (MRD)–guided therapy with ibrutinib/venetoclax vs ibrutinib alone in chronic lymphocytic leukemia.
An interim analysis showed improved progression-free survival with MRD-guided ibrutinib/venetoclax vs fludarabine/cyclophosphamide/rituximab (FCR). The current report includes findings on MRD-negative status with ibrutinib alone and updated progression-free survival comparisons among treatment groups.
Study Details
In the open-label multicenter trial, 786 patients were randomly assigned 1:1:1 between July 2017 and March 2021 to receive ibrutinib/venetoclax (n = 260), ibrutinib alone (n = 263), or FCR (n = 263). FCR was given every 28 days for 6 cycles. Ibrutinib/venetoclax and ibrutinib alone were given for up to 6 years unless MRD-based stopping criteria were met. In the current analyses, the primary outcome measures were undetectable MRD in bone marrow within 2 years in the ibrutinib/venetoclax group vs the ibrutinib-alone group and updated progression-free survival in the ibrutinib/venetoclax group vs the FCR group.
Key Findings
Undetectable MRD at 2 years was found in 172 patients (66.2%) in the ibrutinib/venetoclax group vs 0 patients (0%) in the ibrutinib-alone group (P < .001); 127 patients (48.3%) in the FCR group had undetectable MRD at 2 years.
At a median follow-up of 62.2 months, disease progression or death had occurred in 18 patients (6.9%) in the ibrutinib/venetoclax group vs 59 (22.4%) in the ibrutinib-alone group (hazard ratio [HR] = 0.29, 95% confidence interval [CI] = 0.17–0.49, P < .001) and 112 (42.6%) in the FCR group (HR = 0.13, 95% CI = 0.08–0.21, P < .001). Progression-free survival at 5 years was 93.9%, 79.0%, and 58.1%, respectively.
Death occurred in 11 patients (4.2%) in the ibrutinib/venetoclax group vs 26 (9.9%) in the ibrutinib-alone group (HR = 0.41, 95% CI = 0.20–0.83) and 39 (14.8%) in the FCR group (HR = 0.26, 95% CI = 0.13–0.50). Sudden death occurred in three, eight, and four patients, respectively.
The investigators concluded: “With extended follow-up and increased enrollment, our trial showed that undetectable MRD and extended progression-free survival were more common with [ibrutinib/venetoclax] than with ibrutinib alone or FCR. The results for overall survival were also consistent with a benefit of [ibrutinib/venetoclax].”
Talha Munir, PhD, of St. James’s University Hospital, Leeds, is the corresponding author for the New England Journal of Medicine article.
Disclosure: The study was funded by Cancer Research UK and others. For full disclosures of all study authors, visit the nejm.org.
