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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.

Results of the multicenter trial, which was conducted entirely in the United Kingdom, were also published in the .

In a , Hillmen called the time-limited venetoclax-ibrutinib approach "a new gold standard for previously untreated CLL." Patients in the study received the BCL2 inhibitor and Bruton's kinase (BTK) inhibitor combination for 2 to 6 years based on their measurable residual disease (MRD) status.

However, while both agents are FDA-approved in previously untreated CLL, the combination is not, and FLAIR is not a registrational trial, making the applicability of the findings for U.S. practice uncertain.

In Europe, fixed-duration venetoclax-ibrutinib gained approval based on findings from the GLOW trial, which involved an older population. Early cardiac deaths in that study may have played a role in the lack of U.S. approval, speculated Jennifer Brown, MD, PhD, of Dana-Farber Cancer Institute in Boston.

As to the FLAIR trial, "the data look really good, but it's not nearly as time-limited a therapy as we've been trying to study," she told 番茄社区app.

In fact, a good share of patients have remained on treatment for years, Brown noted, and while the PFS "is really good," the trial didn't enroll any of the highest-risk subgroups -- including patients with TP53 mutations and 17p deletions.

Brown, who was not involved in the research, said she feels comfortable sticking with a approach until there's randomized data comparing that combination with venetoclax plus ibrutinib.

"I'm also not completely comfortable with the ibrutinib cardiac safety," she said, and suggested that many clinicians in the U.S. are waiting on randomized data involving a next-generation BTK inhibitor with venetoclax in previously untreated CLL. The first such trial to read out will likely be , said Brown, which is testing acalabrutinib (Calquence) in combination with venetoclax (with and without obinutuzumab) versus chemoimmunotherapy.

Still, FLAIR "unequivocally shows the superiority of targeted therapy over traditional cytotoxic chemotherapy," said press briefing moderator Mikkael Sekeres, MD, of the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine.

Sekeres pointed out that FCR has largely fallen out of favor in the U.S. with the approval of targeted alternatives.

MRD-Guided Approach in FLAIR

"The big issue for targeted treatment in CLL is the duration of therapy, which can be very long in frontline," said Hillmen, 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, has a significant advantage over chemoimmunotherapy, both in terms of PFS and overall survival," said Hillmen. He added that roughly 90% of patients achieved MRD-negative remission with venetoclax-ibrutinib, and that the PFS benefit was observed in all subgroups apart from IGHV-mutated patients.

Study Details

The phase III enrolled fit patients with previously untreated CLL at 96 centers in the United Kingdom from July 2017 to March 2021. Investigators from the U.K. National Cancer Research Institute group randomly assigned 523 participants to either six cycles of FCR chemoimmunotherapy or to daily venetoclax (400 mg) plus ibrutinib (420 mg), with treatment duration based on MRD response. Investigators routinely assessed MRD status via peripheral blood and bone marrow.

Patients needed to have untreated CLL that required treatment per International Workshop on Chronic Lymphocytic Leukemia criteria. About 80% of patients screened for the trial presented with an isolated lymphocytosis and no symptoms, and therefore did not require treatment and were not enrolled, said Hillmen.

"This research does not alter that dynamic, we should not be treating patients earlier because probably half of those patients will never go on to need treatment," he said. Hillmen noted that patients in that phase of their disease have an inferior quality of life: "'wait and watch' in CLL is a really difficult place for patients, and it's been replaced by 'watch and worry.'"

"Now that we have therapies that really do probably stop people dying from the disease, and even potentially cure them -- that should reassure patients," he added.

To enroll in the trial, patients also had to be sufficiently fit for FCR, and age 75 or younger. They were excluded if they had a history of Richter's transformation, >20% TP53 deletion on fluorescence in situ hybridization, were taking warfarin (or an equivalent), and if they had symptomatic cardiac failure or angina.

This resulted in a study population that was 71% male, with a median age of 62 years. One-third had good-risk IGHV-mutated disease while about half had IGHV-unmutated disease; other genetic abnormalities included ATM deletions in 18%, a poor prognosticator for chemotherapy response; trisomy 12 abnormalities in 16%; and 13q deletions in 36%.

The study's primary endpoint was PFS; secondary endpoints included OS, response, and safety.

Hazard ratios (HRs) for PFS and OS at 3 years showed an 87% reduction in the risk for disease progression or death (HR 0.13, 95% CI 0.07-0.24, P<0.0001) and a 69% reduction in the risk for death (HR 0.31, 95% CI 0.15-0.67, P<0.005).

Venetoclax-ibrutinib's improvement in PFS at 3 years versus FCR proved consistent across most biological subgroups:

• IGHV unmutated: 98% vs 71% (P<0.001)
• IGHV mutated: 94% vs 89% (P=0.199)
• ATM deletion: 100% vs 68% (P<0.001)
• Trisomy 13: 95% vs 74% (P=0.002)
• 13q deletion: 95% vs 75% (P<0.001)

There was also an OS advantage for IGHV-unmutated patients, said Hillmen. In the IGHV-mutated population, investigators observed no PFS or OS benefit, though there was a trend favoring the targeted combination.

Looking at all the clinical trials in totality, "I think we're going to start stratifying patients by IGHV," Hillmen told 番茄社区app. He noted that patients with IGHV-mutant CLL achieve "very good, prolonged remissions" with 1 year of venetoclax plus obinutuzumab.

"We may not be curing many patients with that approach, but those patients tend not to evolve with disease-resistance mutations" given the time-limited duration of that treatment, he added.

Adverse events (AEs) less common with venetoclax-ibrutinib in FLAIR included blood and lymphatic systems disorders (5.2% vs 31% with FCR) and general disorders or administration site reactions (1.6% vs 5%). More common with the targeted drugs were cardiac abnormalities, such as atrial fibrillation or hypertension (10.7% vs 0.4% with FCR); metabolism and nutrition disorders (4% vs none); and eye disorders (2.4% vs none).

"In a previous part of this trial, we showed sudden deaths and cardiac deaths in the ibrutinib arm," Hillmen said. "This was not seen in this part of the trial and may be because we modified the trial -- during the trial -- to be much more aware of cardiac abnormalities and hypertension."

About twice as many secondary malignancies occurred with FCR compared with venetoclax-ibrutinib (5.4 vs 2.6 per 100,000 person-years). Significant differences included cases of myelodysplastic syndromes/acute myeloid leukemia, a known and often "fatal complication of treatment" with fludarabine-based regimens, said Hillmen.

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