MRD-Directed Ibrutinib/Venetoclax Results in PFS Benefit in CLL

“MRD-guided ibrutinib/venetoclax, including individualized treatment duration beyond undetectable MRD, resulted in significant improvement in progression-free survival and an apparent benefit with respect to overall survival among patients with previously untreated CLL,” according to the authors of the phase 3 FLARE study.

Patients with chronic lymphocytic leukemia (CLL) who underwent treatment with ibrutinib (Imbruvica) and venetoclax (Venclexta) guided by minimal residual disease (MRD) status had an improved progression-free survival (PFS) benefit over fludarabine, cyclophosphamide, and rituximab (Rituxan; FCR), according to data from the phase 3 FLARE study published in the New England Journal of Medicine.

With a median follow-up of 43.7 months, 12 patients in the ibrutinib/venetoclax group and 75 in the FCR group experienced disease progression or death of a total population of 523 (HR, 0.13; 95% CI, 0.07-0.24; P <.001). A total of 58% of patients in the experimental arm at the 3-year time point were able to stop therapy due to undetectable MRD. Additionally, 65.9% (95% CI, 59.5%-72.3%) and 92.7% (95% CI, 88.1%-97.3%) of patients in the ibrutinib/venetoclax cohort had undetectable MRD in the bone marrow and peripheral blood, respectively.

Investigators reported an estimated 3-year PFS rate of 97.2% (95% CI, 94.1%-98.6%) in the experimental arm compared with 76.8% (95% CI, 70.8%-81.7%) in the FCR arm. Investigators also reported favorable PFS findings for those in the IGHV-unmutated cohort treated with ibrutinib/venetoclax (HR, 0.07; 95% CI, 0.02-0.19). However, the same was not observed among those with IGHV mutations (HR, 0.54; 95% CI, 0.21-1.38).

“MRD-guided ibrutinib/venetoclax, including individualized treatment duration beyond undetectable MRD, resulted in significant improvement in [PFS] and an apparent benefit with respect to overall survival [OS] among patients with previously untreated CLL,” the study’s authors wrote. “Benefits appeared to be particularly marked in patients who tend to have poorer outcomes with standard treatments.”

In the open-label, multi-center, parallel group, controlled FLARE trial, investigators recruited patients from 96 hospitals across the United Kingdom. To be included in the study, patients were required to have previously untreated CLL or small lymphocytic lymphoma and be eligible to receive treatment with FCR. Those with Richter’s transformation, central nervous system involvement, and symptomatic cardiac disease were not eligible to enroll on the study.

Patients were randomly assigned 1:1:1 to either the FCR, ibrutinib monotherapy, or ibrutinib/venetoclax cohort. FCR was repeated every 28 days for 6 cycles provided that there was no disease progression or unacceptable toxicities. Additionally, patients were treated with 420 mg of ibrutinib daily for 8 weeks prior to beginning treatment with oral venetoclax at a dose of 400 mg per day. Treatment with the experimental regimen went on for 6 years until the MRD stopping rules were reached or disease progression or unacceptable toxicities were observed.

The study’s primary end point was PFS, with secondary end points including OS, rate of undetectable MRD at 9 months following randomization, pattern of MRD relapse and retreatment, response to therapy at 9 months, safety, toxicities, health-related quality of life, and cost effectiveness.

Patients were randomly assigned from July 20, 2017 to March 24, 2021, with 260 patients assigned to the ibrutinib/venetoclax arm and 263 to the FCR group. The median patient age was 62 years (IQR, 56-67), with 31.2% of patients being more than 65 years old. Additionally, 71.3% of patients were male.

In the FCR cohort, 42 patients received treatment following progression or withdrawal, including targeted therapies (n = 35), chemoimmunotherapy (n = 6), and allogeneic bone marrow transplant (n = 1).

Investigators reported 9 and 25 deaths in the experimental and comparator arms, respectively. The OS rate at 3 years was 98.0% (95% CI, 95.2%-99.2%) vs 93.0% (95% CI, 88.9%-95.6%), respectively (HR, 0.31; 95% CI, 0.15-0.67). Additionally, OS appeared favorable in the experimental arm for those with IGHV-unmutated disease (HR, 0.23; 95% CI, 0.06-0.81); conversely, OS did not favor the ibrutinib/venetoclax arm in those with IGHV-mutant disease (HR, 0.61; 95% CI, 0.20-1.82).

At the 2-year time point, MRD was undetectable in the bone marrow in 52.4% (95% CI, 45.9%-58.9%) of those in the experimental arm vs 49.8% (95% CI, 43.2%-56.5%) of those in the control arm. The rates at 5 years were 65.9% (95% CI, 59.5%-72.3%) compared with 49.8% (95% CI, 43.2%-56.5%), respectively.

A total of 91.6% of patients reported experiencing at least 1 adverse effect (AE). The most frequent high-grade AEs in the experimental and comparator arms, respectively, were neutropenia (10.3% vs 47.3%), anemia (0.8% vs 15.5%), and thrombocytopenia (2.0% vs 10.0%). Additionally, common any-grade AEs in each respective arm included fatigue (15.5% vs 49.0%) and neutropenia (19.4% vs 58.6%).

Reference

Munir T, Cairns DA, Bloor A, et al. Chronic lymphocytic leukemia therapy guided by measurable residual disease. N Engl J Med. Published online December 10, 2023. doi:10.1056/NEJMoa2310063