Peter Hillmen
Ibrutinib and rituximab versus fludarabine, cyclophosphamide, and rituximab for patients with previously untreated chronic lymphocytic leukaemia (FLAIR): interim analysis of a multicentre, open-label, randomised, phase 3 trial.
Hillmen, Peter; Pitchford, Alexandra; Bloor, Adrian; Broom, Angus; Young, Moya; Kennedy, Ben; Walewska, Renata; Furtado, Michelle; Preston, Gavin; Neilson, Jeffrey R; Pemberton, Nicholas; Sidra, Gamal; Morley, Nicholas; Cwynarski, Kate; Schuh, Anna; Forconi, Francesco; Elmusharaf, Nagah; Paneesha, Shankara; Fox, Christopher P.; Howard, Dena R.; Hockaday, Anna; Brown, Julia M.; Cairns, David A.; Jackson, Sharon; Greatorex, Natasha; Webster, Nichola; Shingles, Jane; Dalal, Surita; Patten, Piers E. M.; Allsup, David; Rawstron, Andrew; Munir, Talha
Authors
Alexandra Pitchford
Adrian Bloor
Angus Broom
Moya Young
Ben Kennedy
Renata Walewska
Michelle Furtado
Gavin Preston
Jeffrey R Neilson
Nicholas Pemberton
Gamal Sidra
Nicholas Morley
Kate Cwynarski
Anna Schuh
Francesco Forconi
Nagah Elmusharaf
Shankara Paneesha
Professor CHRIS FOX Christopher.Fox@nottingham.ac.uk
Clinical Professor in Haematology
Dena R. Howard
Anna Hockaday
Julia M. Brown
David A. Cairns
Sharon Jackson
Natasha Greatorex
Nichola Webster
Jane Shingles
Surita Dalal
Piers E. M. Patten
David Allsup
Andrew Rawstron
Talha Munir
Abstract
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. 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 on day 1 of cycle 1 and at 500 mg/m on day 1 of cycles 2-6 of a 28-day cycle) or fludarabine, cyclophosphamide, and rituximab (fludarabine 24 mg/m per day orally on day 1-5, cyclophosphamide 150 mg/m 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. 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. 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. Cancer Research UK and Janssen. [Abstract copyright: 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.]
Citation
Hillmen, P., Pitchford, A., Bloor, A., Broom, A., Young, M., Kennedy, B., …Munir, T. (2023). Ibrutinib and rituximab versus fludarabine, cyclophosphamide, and rituximab for patients with previously untreated chronic lymphocytic leukaemia (FLAIR): interim analysis of a multicentre, open-label, randomised, phase 3 trial. Lancet Oncology, 24(5), 535-552. https://doi.org/10.1016/S1470-2045%2823%2900144-4
Journal Article Type | Article |
---|---|
Acceptance Date | Mar 21, 2023 |
Online Publication Date | May 22, 2023 |
Publication Date | May 22, 2023 |
Deposit Date | Sep 20, 2023 |
Publicly Available Date | Sep 20, 2023 |
Journal | The Lancet Oncology |
Print ISSN | 1470-2045 |
Electronic ISSN | 1474-5488 |
Publisher | Elsevier |
Peer Reviewed | Peer Reviewed |
Volume | 24 |
Issue | 5 |
Pages | 535-552 |
DOI | https://doi.org/10.1016/S1470-2045%2823%2900144-4 |
Keywords | Cyclophosphamide, Female, Male, State Medicine, Middle Aged, Antineoplastic Combined Chemotherapy Protocols - adverse effects, Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy, Rituximab, Humans |
Public URL | https://nottingham-repository.worktribe.com/output/21097706 |
Publisher URL | https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(23)00144-4/fulltext |
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Ibrutinib and rituximab versus fludarabine, cyclophosphamide, and rituximab for patients with previously untreated chronic lymphocytic leukaemia (FLAIR
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