Adding Venetoclax to ibrutinib improves MRD negativity rate in previously untreated CLL

Patients with previously untreated chronic lymphocytic leukemia showed minimal residual disease negativity after treatment with venetoclax and ibrutinib.

Results from the NCRI FLAIR Phase 3 trial (ISRCTN01844152) indicated that the combination of venetoclax (Venclexta) and ibrutinib (Imbruvica) produced a promising rate of minimal residual disease (MRD) negativity in treatment-naïve chronic lymphocytic leukemia patients compared to ibrutinib alone.1

The findings of the trial, which were presented at the European Hematology Association Congress 2022, reported that treatment with ibrutinib and venetoclax resulted in a 2-year MRD negativity rate of 65.4% (95% CI, 56.81%-73.38%) in peripheral blood and 71.3% (95% CI, 62.95%-78.75%) in marrow compared to 0% for both measures in the ibrutinib alone arm (95% CI, 0% to 2.64% in each arm, respectively). Data from a penalized logic regression model showed a 454-fold probability of achieving MRD negativity in the combination arm compared to the single-agent arm. In the combined arm, the median time to MRM negativity was 12 months in peripheral blood and 19 months in bone marrow.

Initially, the FLAIR trial compared the use of ibrutinib and rituximab (Rituxan) with a chemotherapy regimen consisting of fludarabine (Fludara), cyclophosphamide (Cytoxan) and rituximab in a population of 771 patients with previously untreated disease.2 At a median follow-up of 52.7 months, study results demonstrated that median progression-free survival was not achieved in the experimental arm versus 66.53 months in the control arm (HR, 0 .44, 95% CI, 0.32-0.60; P <.001 from there additional study arms were added to evaluate ibrutinib alone and in combination with venetoclax.>

Venetoclax was administered daily at a dose of 400 mg and the daily dose of ibrutinib was 420 mg. A total of 274 patients were included in the analysis.

Other study outcomes included responses by iwCLL criteria 9 months after randomization. The overall response rate in the monotherapy arm was 86.2%, including a complete response (CR) rate of 8.0%, compared to 88.2% in the combination arm with a CR rate of 59.6 %.

Adverse reactions (AEs) of all grades reported in the ibrutinib and ibrutinib/venetoclax arms included diarrhea (52.6% vs 29.4%), nausea (40.7% vs 14%), anemia (28 .9% versus 16.9%) and the number of white blood cells. decrease (36.3% versus 8.8%), respectively. Additionally, the most common grade 3 or higher adverse reactions included decreased white blood cell count (27.4% vs. 5.1%), anemia (7.4% vs. 2.9%), decreased platelet count (5.9% versus 1.5%) and rash (2.2% versus 4.4%).


  1. Hillmen P, Pitchford A, Bloor A, et al. The combination of ibrutinib and venetoclax results in a high rate of negative MRD in previously untreated CLL: results from the planned interim analysis of the phase III NCRI FLAIR trial. Presented at: European Hematology Association Congress 2022; June 9-12, 2022; Vienna, Austria. Summary S145.
  2. Hillmen P, Pitchford A, Bloor A, et al. Ibrutinib plus rituximab is superior to FCR in previously untreated CLL: results from the phase III NCRI FLAIR trial. Blood. 2021;138(supplement 1):642. doi:10.1182/sang-2021-152319