As reported in The New England Journal of Medicine by Talha Munir, MBBS, and colleagues, an analysis from the UK phase III FLAIR trial showed improved progression-free survival with measurable residual disease (MRD)-guided ibrutinib/venetoclax vs fludarabine/cyclophosphamide/rituximab (FCR) in patients with untreated chronic lymphocytic leukemia (CLL).
Talha Munir, MBBS
Study Details
In the open-label trial, 523 patients were randomly assigned to receive ibrutinib/venetoclax (n = 260) or FCR (n = 263). FCR was repeated every 28 days for six cycles. Ibrutinib was given at 420 mg/d for 8 weeks, followed by initiation of venetoclax up to 400 mg/d for a total of 6 years, unless MRD stopping rules were reached. The duration of ibrutinib/venetoclax therapy was defined by MRD assessed in peripheral blood and bone marrow and was double the time taken to achieve undetectable MRD. The primary endpoint of the trial was progression-free survival.
Key Findings
In accordance with MRD stopping rules, 146 of 260 patients in the ibrutinib/venetoclax group stopped therapy between 24 and 60 months of treatment. Proportions of patients stopping treatment by 24, 36, and 60 months were 28.9%, 58.0%, and 78.4%, respectively; at 60 months, 65.9% of patients had undetectable MRD in the bone marrow and 92.7% had undetectable MRD in the peripheral blood. Ibrutinib/venetoclax was restarted in five patients, who remained alive and progression-free at last follow-up.
Undetectable MRD in peripheral blood at any time was reported in 85.8% of those in the ibrutinib/venetoclax group vs 60.8% of the FCR group; undetectable MRD in bone marrow at any time was reported in 61.9% vs 40.3%. The adjusted odds ratios for undetectable MRD were 2.03 (95% confidence interval [CI] =1.43–2.89) in bone marrow and 3.91 (95% CI = 2.55–6.00) in peripheral blood.
At a median of 43.7 months (interquartile range = 35.1–51.5 months), disease progression or death had occurred in 12 patients in the ibrutinib/venetoclax group and in 75 patients in the FCR group (hazard ratio = 0.13, 95% CI = 0.07–0.24, P < .001). Death occurred in 9 patients vs 25 patients (HR = 0.31, 95% CI = 0.15–0.67).
Risk of infection was similar in the two groups. The rate of severe cardiac adverse events was higher in the ibrutinib/venetoclax group (10.7% vs 0.4%).
The investigators concluded, “MRD-directed ibrutinib/venetoclax improved progression-free survival as compared with FCR, and results for overall survival also favored ibrutinib/venetoclax.”
Peter Hillmen, MB ChB, PhD, of the Clinical Trials Research Unit, University of 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 the study authors, visit nejm.org.
