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ASH: Hematology
SAN DIEGO — A time-limited, targeted combination significantly improved survival compared with chemoimmunotherapy in fit chronic lymphocytic leukemia (CLL) patients who met criteria for starting treatment, findings from the randomized FLAIR trial indicated.
At 3 years, progression-free survival (PFS) rates reached 97% for patients randomized to venetoclax (Venclexta) plus ibrutinib (Imbruvica), as compared with 77% for those assigned to the standard chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab (FCR), reported Peter Hillmen, MBChB, PhD, of St. James’s University Hospital in Leeds, England.
The venetoclax-ibrutinib regimen also significantly improved overall survival (OS) — with deaths occurring in 2% of patients treated with the targeted combination at this time point versus 7% of those assigned to chemoimmunotherapy — improved responses, and was associated with half as many secondary cancers, according to findings detailed during a press briefing here at the American Society of Hematology annual meeting.
In a statement, Hillmen said the time-limited approach represents “a new gold standard for previously untreated CLL.”
This research “unequivocally shows the superiority of targeted therapy over traditional cytotoxic chemotherapy,” said press briefing moderator Mikkael Sekeres, MD, of the University of Miami Miller School of Medicine. “As someone who specializes in leukemia/myelodysplastic syndromes, I have the feeling I won’t be seeing these CLL patients in my clinic years after being treated for their CLL much longer.”
Sekeres pointed out that FCR has largely fallen out of favor in the U.S. with the approval of targeted alternatives.
In the trial, the venetoclax-ibrutinib regimen was given for 2 to 6 years depending on patients’ speed of response, as determined by measurable residual disease (MRD). Ibrutinib is conventionally given as monotherapy until disease progression in CLL, while venetoclax is given in combination with a monoclonal antibody for an arbitrary fixed duration of time, Hillmen explained.
“The big issue for targeted treatment in CLL is the duration of therapy, which can be very long in frontline,” he said, noting the risk for drug resistance and toxicities.
As some patients will relapse if only treated to MRD negativity (less than one CLL cell per 10,000 cells on flow cytometry), participants on venetoclax-ibrutinib were treated for twice as long as it took to attain MRD negativity, in the theory that the rate of MRD decline would continue at the same rate and that the additional therapy would have a “major impact” on outcomes, he said.
For example, if a patient attained MRD negativity at 1 year, they would receive 2 years of therapy. By 3 years in the study, 58% of the patients on venetoclax-ibrutinib had ceased treatment in accordance with these MRD stopping rules.
“This is the first trial to show that an MRD-guided approach, with treatment beyond negativity,