Hillmen P, Pitchford A, Bloor A, Broom A, Young M, Kennedy B, Walewska R, Furtado M, Preston G, Neilson JR, Pemberton N, Sidra G, Morley N, Cwynarski K, Schuh A, Forconi F, Elmusharaf N, Paneesha S, Fox CP, Howard DR, Hockaday A, Brown JM, Cairns DA, Jackson S, Greatorex N, Webster N, Shingles J, Dalal S, Patten PEM, Allsup D, Rawstron A, and Munir T
Background: The approval of Bruton tyrosine kinase (BTK) inhibitors in patients with previously untreated chronic lymphocytic leukaemia (CLL) was based on trials which compared ibrutinib with alkylating agents in patients considered unfit for fludarabine, cyclophosphamide, and rituximab, the most effective chemoimmunotherapy in CLL. We aimed to assess whether ibrutinib and rituximab is superior to fludarabine, cyclophosphamide, and rituximab in terms of progression-free survival., Methods: This study is an interim analysis of FLAIR, which is an open-label, randomised, controlled, phase 3 trial in patients with previously untreated CLL done at 101 UK National Health Service hospitals. Eligible patients were between 18 and 75 years of age with a WHO performance status of 2 or less and disease status requiring treatment according to International Workshop on CLL criteria. Patients with greater than 20% of their CLL cells having the chromosome 17p deletion were excluded. Patients were randomly assigned (1:1) by means of minimisation (Binet stage, age, sex, and centre) with a random element in a web-based system to ibrutinib and rituximab (ibrutinib administered orally at 420 mg/day for up to 6 years; rituximab administered intravenously at 375 mg/m 2 on day 1 of cycle 1 and at 500 mg/m 2 on day 1 of cycles 2-6 of a 28-day cycle) or fludarabine, cyclophosphamide, and rituximab (fludarabine 24 mg/m 2 per day orally on day 1-5, cyclophosphamide 150 mg/m 2 per day orally on days 1-5; rituximab as above for up to 6 cycles). The primary endpoint was progression-free survival, analysed by intention to treat. Safety analysis was per protocol. This study is registered with ISRCTN, ISRCTN01844152, and EudraCT, 2013-001944-76, and recruiting is complete., Findings: Between Sept 19, 2014, and July 19, 2018, of 1924 patients assessed for eligibility, 771 were randomly assigned with median age 62 years (IQR 56-67), 565 (73%) were male, 206 (27%) were female and 507 (66%) had a WHO performance status of 0. 385 patients were assigned to fludarabine, cyclophosphamide, and rituximab and 386 patients to ibrutinib and rituximab. After a median follow-up of 53 months (IQR 41-61) and at prespecified interim analysis, median progression-free survival was not reached (NR) with ibrutinib and rituximab and was 67 months (95% CI 63-NR) with fludarabine, cyclophosphamide, and rituximab (hazard ratio 0·44 [95% CI 0·32-0·60]; p<0·0001). The most common grade 3 or 4 adverse event was leukopenia (203 [54%] patients in the fludarabine, cyclophosphamide, and rituximab group and 55 [14%] patients in the ibrutinib and rituximab group. Serious adverse events were reported in 205 (53%) of 384 patients receiving ibrutinib and rituximab compared with 203 (54%) of 378 patients receiving fludarabine, cyclophosphamide, and rituximab. Two deaths in the fludarabine, cyclophosphamide, and rituximab group and three deaths in the ibrutinib and rituximab group were deemed to be probably related to treatment. There were eight sudden unexplained or cardiac deaths in the ibrutinib and rituximab group and two in the fludarabine, cyclophosphamide, and rituximab group., Interpretation: Front line treatment with ibrutinib and rituximab significantly improved progression-free survival compared with fludarabine, cyclophosphamide, and rituximab but did not improve overall survival. A small number of sudden unexplained or cardiac deaths in the ibrutinib and rituximab group were observed largely among patients with existing hypertension or history of cardiac disorder., Funding: Cancer Research UK and Janssen., Competing Interests: Declaration of interests PH reports funding for the study and provision of investigational medicinal products from Janssen and AbbVie; personal consulting fees from Janssen, AbbVie, and AstraZeneca; personal speaker fees from Janssen, AbbVie, AstraZeneca, and BeiGene; institutional support of clinical trials from Janssen, AbbVie, Gilead Sciences, and F Hoffman-La Roche. AP reports unrestricted educational grants to her institution from Janssen, Pharmacyclics, and AbbVie. ABl reports speaker fees from Janssen and AbbVie and support for conference attendance from AbbVie. ABr reports personal payment for presentations from Janssen-Cilag and AstraZeneca and personal payment for attending meetings from AbbVie. BK reports personal payment or honoraria for lectures from AbbVie and AstraZeneca and a voluntary unpaid role as CLL Support Associate Trustee. RW reports payment for lectures from AbbVie, AstraZeneca, Janssen, and BeiGene; support for attending meetings from AbbVie and Janssen; and participation on a data safety monitoring board or advisory board for AstraZeneca, Janssen, SecuraBio, and AbbVie. MF reports travel support for conference attendance from AbbVie and remunerated participation on an advisory board for AstraZeneca. GP reports honoraria for delivering educational sessions from Janssen-Cilag and Roche. NM reports payment or honoraria for presentations from Amgen and Kite Gilead; support for attending meetings or travel from Takeda; and participation on a data safety monitoring board or advisory board for Kite Gilead, Amgen, and AbbVie. KC reports personal speakers fees from Roche, Takeda, Kite, Gilead, and Incyte; support for travel and registration for meetings from Roche, Takeda, Kite, and BMS; and participation on a data safety monitoring board or advisory board for Roche, Takeda, Celgene, Atara, Gilead, Kite, Janssen, and Incyte. AS reports receipt of part of her salary from the Oxford Biomedical Research Centre; grants from Janssen and AstraZeneca; honoraria for presentations from Roche, AbbVie, Janssen, BeiGene, and AstraZeneca; and receipt of equipment, materials, drugs, medical writing, gifts, or other services from Illumina, Oxford Nanopore Technology, and Adaptive Biotechnology. FF reports grants from Cancer Research UK and AbbVie; consulting fees from BC Platform; payment or honoraria for presentations from AbbVie, Janssen-Cilag, Acerta, and BeiGene; support for attending meetings or travel from AbbVie; and participation on a data safety monitoring board or advisory board for BeiGene. NE reports personal speaker payments from AstraZeneca and Roche and support for attending meetings and travel from AbbVie. SP reports personal honoraria for presentations from Gilead, AstraZeneca, AbbVie, BeiGene, and Takeda. CPF reports personal consultancy fees from AbbVie, AstraZeneca, Atarabio, BMS, GenMab, Gilead–Kite, Incyte, Lilly, Morphosys, Ono, Roche, and Takeda; payment for educational events from Janssen, Incyte, and Roche; institution research funding from BeiGene; support for attending meetings or travel from Roche; and participation on trial steering committees for GenMab, Morphosys, and Roche. DRH is employed by Roche and holds stock or stock options from Roche. AH reports unrestricted educational grants to her institution from Janssen, Pharmacyclics, and AbbVie and receipt of a speaker fee from AbbVie. JMB reports unrestricted educational grants to her institution from Janssen, Pharmacyclics, and AbbVie. DAC reports unrestricted educational grants to his institution from Janssen, Pharmacyclics, and AbbVie; payment to institution for educational lectures from Janssen; participation on a data safety monitoring board for an academically led investigator-initiated CLL study and personal payment for meeting attendance and report preparation from University Hospital Cologne. SJ reports receipt of unrestricted educational grants to her institution from Janssen, Pharmacyclics and AbbVie. NG reports unrestricted educational grants to her institution from Janssen, Pharmacyclics, and AbbVie and participation on an advisory board for AbbVie. PEMP reports grants from Roche and Gilead; payment or honoraria for presentations from AbbVie, AstraZeneca, BeiGene, Gilead, and Janssen; support for attending meetings or travel from AbbVie; and participation on a data safety monitoring board or advisory board for AbbVie, BeiGene, and Novartis. DA reports receipt of part of his salary from the National Institute for Health and Care Research and Medical Research Council and support to attend meetings from CSL Behring. AR reports grants to his institution from AbbVie, Janssen, Pharmacyclics, and Roche; consulting fees from BeiGene and Pharmacyclics paid to a company of which AR is a director; payment or honoraria for presentations from AbbVie, Beckman Coulter, BD Biosciences, BeiGene, and Janssen paid to a company of which AR is a director; support for attending meetings or travel from Janssen; participation on a data safety monitoring board or advisory board from AbbVie and Janssen; and receipt of equipment from Beckman Coulter. TM reports payment for lectures and presentations from Janssen, AbbVie, and AstraZeneca; support for attending conferences from Janssen, AbbVie, and AstraZeneca; and participation on advisory boards for Janssen, AbbVie, AstraZeneca, Lilly, BeiGene, and Morphosys. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)