San Diego—Ibrutinib plus venetoclax significantly improved progression-free (PFS) and overall survival (OS) compared with a standard fludarabine, cyclophosphamide, and rituximab (FCR) regimen in patients with untreated chronic lymphocytic leukemia (CLL) and now represents a new standard for treatment of the disease. The finding comes from the randomized phase 3 FLAIR study of 523 patients with newly diagnosed CLL presented by lead investigator Peter Hillmen, MB ChB, PhD, from the University of Leeds, St. James's University Hospital, United Kingdom, at the 65th ASH Annual Meeting and Exposition, December 9-12, 2023, San Diego, California.
A novel feature of FLAIR was its use of measurable residual disease (MRD) to determine the duration of treatment, which ranged from 2 to 6 years depending on how quickly patients achieved MRD negativity.
At a median follow-up of 43.7 months, more patients treated with FCR had disease progression compared with patients who received ibrutinib plus venetoclax (75 vs 12, respectively). This finding was consistent regardless of patient gender, age, or disease stage. Moreover, patients with a worse prognosis appeared to do particularly well.
FLAIR is an ongoing randomized trial in the United Kingdom that is comparing novel treatments for newly diagnosed CLL against FCR. In the current study, 523 patients with untreated CLL (71.3% men, median age 62) were randomly assigned to receive FCR or the doublet of ibrutinib and venetoclax. Patients assigned to ibrutinib and venetoclax underwent blood testing for MRD at 1 year and then every 6 months. If these tests found no evidence of remaining leukemia cells, testing was repeated in both the blood and the bone marrow after another 3 months, and again 3 months later. If all tests were MRD negative, the patient was treated for twice the duration of time from the start of ibrutinib plus venetoclax treatment to the first MRD-negative test.
At 2 years, 42.7% of patients stopped treatment according to the MRD stopping rules, and at 3 years, 58.1% were able to stop treatment. At a median 43.7 months, 75 assigned to FCR progressed compared with only 12 patients receiving ibrutinib plus venetoclax (hazard ratio [HR], 0.13; P<.0001).
At 3 years, 2.8% of patients progressed on ibrutinib plus venetoclax compared with 23.2% on FCR. In all, 25 patients (7%) in the FCR arm and 9 (2%) in the ibrutinib plus venetoclax arm died, resulting in improved OS for ibrutinib plus venetoclax (HR, 0.31; P=.0029). “This is the first time that the combination of these drugs has shown an OS advantage against chemotherapy,” said Prof Hillmen.
At 9 months (3 months post-FCR), 48.3% of patients randomized to FCR become MRD negative in the bone marrow compared with 41.5% of those in the ibrutinib plus venetoclax arm. With continued treatment, however, more patients assigned to ibrutinib plus venetoclax became MRD negative, resulting in a doubling of the odds of MRD negativity in bone marrow at any time for ibrutinib plus venetoclax versus FCR (HR, 2.03; P<.001) and nearly 4 times the odds of achieving MRD negativity in the peripheral blood (HR, 3.91; P<.001). In addition, 90.6% of patients had MRD negativity in peripheral blood at up to 5 years with ibrutinib plus venetoclax, whereas 88% of these patients were MRD negative in bone marrow at 6 months after reaching MRD negativity in their peripheral blood for the first time.
Patients with disease features associated with a worse prognosis (ie, unmutated IGHV or deletion of chromosome 11q) had even better outcomes when treated with ibrutinib plus venetoclax than the favorable-risk, IGHV-mutated patients, he indicated. At 3-year follow up, patients with unmutated IGHV were less likely to have progressed if treated with ibrutinib plus venetoclax than with FCR. “At the latest follow-up, not a single patient with the 11q chromosome deletion who was treated with ibrutinib plus venetoclax had progressed or died, compared with 31.2% of patients with this deletion who were treated with FCR,” he said.