Results of the phase 3, ongoing FLAIR trial were presented at the 2021 American Society of Hematology (ASH) Annual Meeting to share the superiority of ibrutinib plus rituximab to standard chemoimmunotherapy (CIT) in patients with previously untreated chronic lymphocytic leukemia (CLL).

“The most effective CIT in untreated CLL is the combination of fludrarabine, cyclophosphamide, and rituximab. Ibrutinib, the first irreversible inhibitor of Bruton’s tyrosine kinase approved for CLL, has improved outcomes in numerous clinical trials compared to different CIT,” explained Peter Hillmen, MBChB, PhD, St James’s University Hospital, United Kingdom, and co-investigators.

A total of 771 patients were enrolled under the age of 75 and randomized 1 to 1 to receive either 6 cycles of fludrarabine, cyclophosphamide, and rituximab (oral fludarabine 24 mg/m²/day for 5 days, oral cyclophosphamide 150 mg/m²/day for 5 days with intravenous [IV] rituximab 375 mg/m² on day 1/2 of cycle 1; 500 mg/m² on day 1 of cycles 2-6) every 28 days, or ibrutinib plus rituximab (ibrutinib 420 mg/day plus rituximab 6 doses) given up to 6 years with stratification by disease stage, age, gender, and treatment center.

The primary endpoint of the study was to assess whether ibrutinib plus rituximab was superior to fludrarabine, cyclophosphamide, and rituximab in terms of investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), attainment of undetectable minimal residual disease (MRD), response to therapy, safety, and toxicity.

Baseline characteristics were identified in both groups as follows: 73.3% were male, the median age was 62 years (33.6 > 65yo), and 45.1% were Binet Stage C. Immunoglobulin heavy chain gene (IGHV) mutation data was available for 94.4% of patients with 53.2% IGHV unmutated and 40.5% IGHV mutated.

“The arms were well-balanced for disease variables with no significant differences. The median follow-up time was 52.7 months. Ibrutinib plus rituximab had superior PFS compared to fludrarabine, cyclophosphamide, and rituximab (median PFS not reached for ibrutinib plus rituximab vs 67 months for fludrarabine, cyclophosphamide, and rituximab,” continued Dr Hillmen and co-authors.

PFS was shown to be significantly improved for ibrutinib plus rituximab in patients with IGHV unmutated CLL (HR 0.41; P<0.001) but not in patients with IGHV mutated CLL (HR 0.66; P=0.179). There was no difference in OS between the two arms (HR 1.01; P=0.956) with 29 deaths in the fludrarabine, cyclophosphamide, and rituximab arm and 30 in the ibrutinib plus rituximab arm, respectively.

“Overall, 88.1 percent of patients have received targeted therapies for CLL progression after fludrarabine, cyclophosphamide, and rituximab. The OS with fludrarabine, cyclophosphamide, and rituximab in FLAIR is significantly improved compared to fludrarabine, cyclophosphamide, and rituximab in previous NCRI trials (ADMIRE and ARCTIC) which had the same inclusion criteria, centers, and an identical FDR schedule,” elaborated Dr Hillmen and co-investigators.

Notably, the 4-year OS for fludrarabine, cyclophosphamide, and rituximab in the FLAIR trial was 94.5 percent compared to 84.2 percent for fludrarabine, cyclophosphamide, and rituximab between 2009 and 2012.

Severe adverse events (AEs) were reported in 53.7 percent of patients on fludrarabine, cyclophosphamide, and rituximab, and 53.4% on ibrutinib plus rituximab. Differences for severe AEs by organ class for fludrarabine, cyclophosphamide, and rituximab vs ibrutinib plus rituximab include infections in 33.6 percent vs 27.1 percent, blood and lymphatic in 19.8 percent vs 10.7 percent, and cardiac in 1.1 percent vs 8.3 percent, respectively. With current follow-up, there were 10 sudden or cardiac deaths: 8 from the ibrutinib plus rituximab arm and 2 from the fludrarabine, cyclophosphamide, and rituximab arm.

“Ibrutinib plus rituximab resulted in a superior PFS compared to fludrarabine, cyclophosphamide, and rituximab. There was no difference in OS, most likely due to effective second-line targeted therapy in patients progressing after fludrarabine, cyclophosphamide, and rituximab,” concluded Dr Hillmen, et al.—Alexa Stoia

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: the 2021 ASH Annual Meeting; Dec. 11-14; 2021; Abstract 642.