Adding Venetoclax to Ibrutinib Improves Rate of MRD Negativity in Previously Untreated CLL

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

Findings from the phase 3 NCRI FLAIR trial (ISRCTN01844152) indicated that the combination of venetoclax (Venclexta) plus ibrutinib (Imbruvica) yielded a promising rate of minimal residual disease (MRD) negativity in patients with treatment-naïve chronic lymphocytic leukemia vs ibrutinib alone.1

Findings from the trial, which were presented at the 2022 European Hematology Association Congress, indicated that treatment with ibrutinib and venetoclax resulted in a 2-year MRD negativity rate of 65.4% (95% CI, 56.81%-73.38%) in the peripheral blood and 71.3% (95% CI, 62.95%-78.75%) in the marrow compared with 0% for both measures in the ibrutinib alone arm (95% CI, 0%-2.64% in each arm, respectively). Data from a penalized logic regression model highlighted a 454-fold odds of obtaining MRD negativity in the combination arm compared with the single-agent arm. In the combination arm, the median time to MRD negativity was 12 months in the peripheral blood and 19 months in the 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, findings from the study highlighted that the median progression-free survival had not been reached in the experimental arm vs 66.53 months in the control arm (HR, 0.44; 95% CI, 0.32-0.60; P <.001). From there, 2 additional study arms were added assessing 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 findings from the study included responses by iwCLL criteria 9 months after randomization. The overall response rate in single-agent arm was 86.2%, including a complete response (CR) rate of 8.0%, compared with 88.2% in the combination arm with a CR rate of 59.6%.

Any-grade adverse effects (AEs) reported in the ibrutinib and ibrutinib/venetoclax arms included diarrhea (52.6% vs 29.4%), nausea (40.7% vs 14%), anemia (28.9% vs 16.9%), and white blood cell count decrease (36.3% vs 8.8%), respectively. Moreover, the most common grade 3 or higher AEs included white blood cell count decrease (27.4% vs 5.1%), anemia (7.4% vs 2.9%), platelet count decrease (5.9% vs 1.5%), and rash (2.2% vs 4.4%).


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