Ibrutinib/Rituximab Combo Demonstrates PFS Superiority Over FCR in Previously Untreated CLL


Patients with previously untreated chronic lymphocytic leukemia derived a better progression-free survival benefit from treatment with ibrutinib and rituximab vs fludarabine, cyclophosphamide, and rituximab.

Treatment with ibrutinib (Imbruvica) and rituximab (Rituxan) resulted in a superior progression-free survival (PFS) benefit vs fludarabine, cyclophosphamide, and rituximab (FCR) in previously untreated chronic lymphocytic leukemia (CLL), according to findings from a study presented at the 2021 American Society of Hematology Annual Meeting and Exposition.

At a median follow up of 52.7 months, a median PFS was not yet reached in the ibrutinib and rituximab arm vs 66.53 months in the FCR arm (HR, 0.44; 95% CI; 0.32-0.60; P < .001).

PFS was also significantly better with ibrutinib and rituximab in patients with IGHV unmutated CLL (HR, 0.4; P < .001), 11q deletion (HR, 0.29; P = .001), and normal karyotype (HR, 0.37; P = .001) but not for patients with IGHV mutated CLL at follow up (HR, 0.68; P = .179).

The FLAIR trial (ISRCTN0844152) is an ongoing, phase III, multicenter, randomized, controlled, open, parallel group trial and includes a total of 771 patients (73.3% are male, median age, 62 years) from 113 United Kingdom-based centers who were enrolled onto trial between Sept. 19, 2014, and July 19, 2018. The data was locked on May 24, 2021. Patients who were aged over 75 years and had >20% 17p-deleted cells were excluded. Secondary endpoints included overall survival (OS), attainment of undetectable MRD, response to therapy, safety and toxicity, health-related quality of life (HRQoL), and cost-effectiveness.

Patients were randomized on a 1:1 basis to receive either 6 cycles of FCR (oral fludarabine at 24 mg/m2 / day for 5 days, oral cyclophosphamide 150 mg/ m2/ day for 5 days with IV rituximab [375 mg/m2 on day 1/ 2 of cycle 1; 500 mg/m2 on day 1 of cycles 2-6]; n= 385) every 28 days or ibrutinib at 420 mg/day plus rituximab (6 doses as of FCR) given for up to 6 years with stratification by disease stages, age, gender, and center.

A total of 59 and 21 patients received second-line treatment after FCR and ibrutinib plus rituximab, respectively, and 88.1% of patients received targeted therapies for CLL progression after FCR.

At a median follow-up of 50.2 months, OS was not different between the 2 arms (HR, 1.01; P = .956) with 29 deaths in the FCR arm (4 from CLL, 3 from Richter’s [RT], 3 AML/MDS, 3 COVID-19 and 2 cardiac/sudden) and 30 in the ibrutinib arm (3 from CLL, 1 from RT, 3 COVID-19 and 8 cardiac/sudden).

“There is no difference in overall survival, but almost all patients relapsing after FCR received either ibrutinib or venetoclax plus rituximab,” the researchers wrote in the presentation.

Notably, 4-year OS significantly improved with FCR in the FLAIR trial at 94.5%, compared with 84.2% in other trials between 2009 and 2012.

The researchers highlighted results from the ADMIRE and ARCTIC trials, both of which had the same inclusion criteria, centers, and an identical FCR schedule, however those were conducted prior to the availability of targeted therapies in the relapse setting.

At 3 months post treatment, 60.5% of patients (n = 233) in the FCR arm and 21.0% (n = 81) in the ibrutinib plus rituximab arm achieved a IWCLL complete response, 27.6% (n = 106) and 70.2% (n = 271) achieved a partial response, respectively, and 11.9% (n = 46) and 8.8% (n = 34) had either stable disease, progressive disease or no response.

Overall, a greater percentage of patients in the FCR arm (55.3%) became MRD negative via the bone morrow at 3 months post-treatment compared with the ibrutinib and rituximab arm (3.9%).

Serious adverse events (SAEs) occurred in 53.7% and 53.4% of patients in FCR and ibrutinib arms, respectively. Differences in SAEs by organ class for FCR vs ibrutinib plus rituximab were 33.6% vs 27.1%; blood and lymphatic in 19.8% vs 10.7%; and cardiac in 1.1% vs 8.3%, respectively.

Ten deaths, 8 of which occurred in the ibrutinib and rituximab arm, were attributed to sudden or cardiac events. Further analysis, according to the authors, identified that 7 of the deaths that occurred in the ibrutinib and rituximab arm were in patients who had a history of hypertension or cardiac disease, whereas the patients who accounted for the two deaths in the FCR arm did not have a history of either condition.

Additionally, there were 6 cases of secondary MDS/AML in the FCR arm and 1 in the ibrutinib and rituximab arm.


Hillmen, P, Pitchford, A, Bloor, A, et al. Ibrutinib Plus Rituximab Is Superior to FCR in Previously Untreated CLL: Results of the Phase III NCRI FLAIR Trial. Presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Virtual. Abstract: 642.

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