Among patients newly diagnosed with chronic lymphocytic leukemia (CLL) who were treated with two targeted agents and whose duration of treatment was determined by high-sensitivity testing for residual cancer cells in the blood, 97.2% were free of cancer progression and 2% had died at 3 years. By comparison, progression-free survival for patients receiving the standard of care was 76.8%, with a death rate of 7%. Results of a planned interim analysis of the UK-based FLAIR study were presented at the 2023 ASH Annual Meeting & Exposition (Abstract 631), with a simultaneous publication in The New England Journal of Medicine.

“These results appear better than those seen in any previous phase III trial in CLL,” said presenting author Peter Hillmen, MB ChB, PhD, of the University of Leeds in the United Kingdom, and principal investigator for the study. “They show that targeted therapy with high-sensitivity testing used to individualize the duration of treatment is a more effective approach than current standard therapy and represents a new gold standard for previously untreated CLL.”  

Peter Hillmen, MB ChB, PhD

FLAIR Study: Background and Methodology

In the United States, about 19,000 new cases of CLL are diagnosed every year. The median age at diagnosis is 70 years. Roughly half of patients with CLL have mutated immunoglobulin genes, also known as IGHV. Patients with mutated IGHV generally have a better outlook and longer survival compared with those who have unmutated IGHV.

The FLAIR study is a large, ongoing randomized trial in the UK that is comparing novel treatments for newly diagnosed CLL against what has been considered standard of care, a regimen consisting of the drugs fludarabine, cyclophosphamide, and rituximab (FCR). In the current study, 523 patients with untreated CLL (71.3% male, median age = 62) were randomly assigned to receive FCR or two newer agents, ibrutinib and venetoclax (I+V). Ibrutinib is an orally bioavailable, irreversible Bruton’s tyrosine kinase inhibitor, which blocks B-cell receptor signaling, thus preventing CLL cell proliferation, migration, and adhesion; venetoclax is an orally bioavailable small-molecule inhibitor of BCL2, which results in CLL cell apoptosis.

A novel feature of the FLAIR trial is its use of measurable residual disease, or MRD, to determine how long patients should continue treatment. Previous studies in leukemia and other cancers have shown that patients who are MRD-negative have better outcomes than patients who are MRD-positive.

In FLAIR, patients in the I+V group underwent blood tests for MRD at 1 year and then every 6 months. If these tests found no evidence of remaining leukemia cells, the testing was repeated in both the blood and the bone marrow after another 3 months, and again 3 months later. If all these tests were MRD-negative, the patient was treated for twice the duration of time from the start of I+V treatment to the first MRD-negative test.  

“Patients’ duration of treatment was determined by how quickly they responded,” said Dr. Hillmen. Duration of treatment ranged from 2 to 6 years. The trial’s primary endpoint was progression-free survival, while overall survival was one of several secondary endpoints. 

Outcomes

At a median follow-up of 43.7 months, patients treated with FCR were approximately eight times as likely to have disease progression compared with patients who received I+V. This finding was consistent regardless of patient sex, age, or disease stage. Moreover, patients with a worse prognosis appeared to do particularly well.

“We found that the patients with disease features associated with a worse prognosis—such as those with unmutated IGHV or deletion of chromosome 11q—had even better outcomes when treated with I+V than the favorable-risk, IGHV-mutated patients,” said Dr. Hillmen. “At 3 years’ follow-up, patients with unmutated IGHV were about 14 times less likely to have progressed if treated with I+V than with FCR. At the latest follow-up, not a single patient with the 11q chromosome deletion who was treated with I+V had progressed or died, compared with 31.2% of patients with this deletion who were treated with FCR. This indicates that the combination of I+V overcomes previously reported risk factors for a poor outcome in patients with CLL.”  

A limitation of the study, Dr. Hillmen said, is that patients were eligible to enroll in the trial only if they were deemed fit enough to undergo intensive chemotherapy with FCR. As a result, the median age of patients enrolled in the trial was 62 years, whereas the median age at which CLL is diagnosed is 70; nevertheless, 31.2% of the patients enrolled were over age 65. 

Disclosure: The study was funded by Cancer Research UK with additional support from Janssen and AbbVie. For full disclosures of the study authors, visit ash.confex.com.