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ATLANTA -- A chemotherapy-free regimen significantly improved progression-free survival (PFS) versus chemoimmunotherapy as initial treatment for chronic lymphocytic leukemia (CLL), a randomized trial showed.

Median PFS had yet to be reached with the combination of ibrutinib (Imbruvica) and rituximab as compared with a median of 66.53 months with fludarabine, cyclophosphamide, and rituximab (FCR). The chemo-free regimen improved PFS in IGHV-mutated and unmutated subgroups, but the difference reached statistical significance only for unmutated disease.

After a median follow-up exceeding 4 years, median overall survival did not differ between treatment groups, but almost all patients in the control arm received ibrutinib or venetoclax (Venclexta) plus rituximab at progression, reported Peter Hillmen, MD, of the University of Leeds in England, during the American Society of Hematology annual meeting.

"Ibrutinib-rituximab leads to superior progression-free survival, with a hazard ratio of 0.44 compared to FCR," said Hillmen. "This was clear in patients with IGHV-unmutated disease. There was no significant improvement in patients with abnormal karyotype."

"More unexplained and sudden cardiac deaths were observed with ibrutinib, particularly in patients with preceding hypertension or other cardiac conditions requiring therapy. Deaths due to secondary AML/MDS [acute myeloid leukemia/myelodysplastic syndromes] and infections were more common with FCR," he added

The results are not entirely surprising, as several cooperative group studies have produced similar results, said Alexey Danilov, MD, PhD, of City of Hope in Duarte, California.

"Over the past several years, ibrutinib has been gaining an increased market share in the community practices over chemoimmunotherapy," he told 番茄社区app. "I think this study will continue to convince physicians to choose novel therapy over standard chemoimmunotherapy for the treatment of de novo CLL, even though there is not overall survival benefit, and that's likely because patients are able to get novel agents after they progress following FCR."

The data on sudden cardiac deaths are noteworthy but not a new finding, as previous trials have shown these deaths or unexplained deaths among patients treated with ibrutinib, Danilov added.

"This is very significant and concerning for sure," he said. "How do we address that? Second-generation BTK [Bruton tyrosine kinase] inhibitors have shown superior safety compared to ibrutinib in three large randomized studies ... so I believe that with time, second-generation BTK inhibitors will take the place of ibrutinib in CLL and I hope that we will be able to circumvent some of the cardiovascular adverse events."

Hillmen reported findings from the primary analysis of the phase III FLAIR trial comparing the novel combination of ibrutinib and rituximab versus standard chemoimmunotherapy with FCR in newly diagnosed CLL. The primary objective was to determine whether ibrutinib-rituximab resulted in superior PFS versus standard therapy.

The trial involved 771 patients who had a median age of 62. A majority of patients (55%) had Binet stage A or B disease and a median disease duration of 24 months prior to randomization. B symptoms were present in 47% of patients, and 50% had beta-2 microglobulin levels ≥4 mg/L.

Half the patients had nonmutated disease, and 38% had IGHV-mutant CLL. Other baseline prognostic markers included 17p deletion in 0.4% of patients, 11q deletion in 15.4%, trisomy 12 in 12%, normal karyotype in 30%, and 13q deletion in 35%.

After a median follow-up of 52.7 months, analysis of PFS yielded a significant overall advantage in favor of ibrutinib-rituximab (95% CI 0.32-0.60, P<0.001). Three times as many patients in the ibrutinib-rituximab arm had complete responses at the 3-month assessment (60.5% vs 21.0%), although substantially more patients in the FCR arm had minimal residual disease-negative status in bone marrow at 3 months (55.3% vs 3.9%).

Analysis by IGHV mutation status showed a 60% reduction in the hazard ratio favoring ibrutinib-rituximab in patients with nonmutated disease (95% CI 0.27-0.59, P<0.001) and a 32% reduction in patients with mutated disease (95% CI 0.38-1.22, P=0.197). Median overall survival had yet to be reached in either treatment group (HR 1.01).

Hillmen reported 29 deaths in the FCR arm and 30 in the ibrutinib-rituximab group. Predominant causes of death in the FCR group were secondary hematologic malignancies, Richter's transformation, and infections (n=13 combined), whereas seven patients in the ibrutinib-rituximab arm died of nonhematologic malignancies and nine of cardiac causes.

"FLAIR is not an outlier for sudden unexplained or cardiac deaths in ibrutinib-containing arms and is consistent with other phase III CLL ibrutinib-containing trials," said Hillmen.

Twice as many patients in the FCR arm developed secondary malignancies compared with the ibrutinib-rituximab arm (57 vs 29 cases), with the primary difference being nonmelanoma skin cancer (23 vs 7, respectively).

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