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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

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
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

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.

1470-2045
535-552
Hillier, Peter R
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Pitchford, Alexandra
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Bloor, Adrian
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Broom, Angus
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Young, Moya
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Walewska, Renata
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Preston, Gavin
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Cwynarski, Kate
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Forconi, Francesco
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Elmusharaf, Nagah
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Fox, Christopher
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Webster, Nichola
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Dalal, Surita
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Patten, Piers E.M.
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Allsup, David
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Rawson, Andrew David
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Munir, Talha
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Hillier, Peter R
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Pitchford, Alexandra
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Bloor, Adrian
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Broom, Angus
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Young, Moya
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Kennedy, Ben M.
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Furtado, Michelle
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Preston, Gavin
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Cwynarski, Kate
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Schuh, Anna H.
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Forconi, Francesco
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Elmusharaf, Nagah
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Paneesha, Shankara
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Fox, Christopher
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Howard, Dena R.
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Hockaday, Anna
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Brown, Julia
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Cairns, David A.
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Jackson, Sharon (Shae) Margaret
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Webster, Nichola
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Shingles, Jane
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Dalal, Surita
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Patten, Piers E.M.
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Allsup, David
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Rawson, Andrew David
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Hillier, Peter R, Pitchford, Alexandra, Bloor, Adrian, Broom, Angus, Young, Moya, Kennedy, Ben M., Walewska, Renata, Furtado, Michelle, Preston, Gavin, Nelson, Jeffrey R, Pemberton, Nicholas, Sidra, Gamal, Morley, Nicholas H., Cwynarski, Kate, Schuh, Anna H., Forconi, Francesco, Elmusharaf, Nagah, Paneesha, Shankara, Fox, Christopher, Howard, Dena R., Hockaday, Anna, Brown, Julia, Cairns, David A., Jackson, Sharon (Shae) Margaret, Greatorex, Natasha, Webster, Nichola, Shingles, Jane, Dalal, Surita, Patten, Piers E.M., Allsup, David, Rawson, Andrew David and Munir, Talha (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. (doi:10.1016/S1470-2045(23)00144-4).

Record type: Article

Abstract

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.

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e-pub ahead of print date: 2 May 2023
Published date: 2 May 2023
Additional Information: Funding Information: Primary financial support was from Cancer Research UK (C18027/A15790). Unrestricted educational grants from Janssen, Pharmacyclics, and AbbVie supported trial coordination and laboratory studies. Study drug (ibrutinib) was provided by Janssen. This work was also supported by Core Clinical Trials Unit Infrastructure from CRUK (C7852–A25447). We thank all the patients at centres throughout the UK whose willingness to participate made this study possible. We are grateful to the UK NCRI Haematological Oncology Study Group; the NCRI CLL Subgroup; and all principal investigators, sub-investigators, and local centre staff for their dedication and commitment to recruiting patients to the study. We thank members of the FLAIR trial steering committee and data monitoring and ethics committee. We thank Lelia Duley for her valuable input from a patient perspective. The support of the Clinical Trials Research Unit at the University of Leeds (UK) was essential to the successful running of the study; we thank all their staff who have contributed, past and present. Central laboratory analysis was done at the Haematological Malignancy Diagnostic Service, St James's University Hospital, Leeds. We are very grateful to the laboratory team for their contribution to the study. Funding Information: Primary financial support was from Cancer Research UK (C18027/A15790). Unrestricted educational grants from Janssen, Pharmacyclics, and AbbVie supported trial coordination and laboratory studies. Study drug (ibrutinib) was provided by Janssen. This work was also supported by Core Clinical Trials Unit Infrastructure from CRUK (C7852–A25447). We thank all the patients at centres throughout the UK whose willingness to participate made this study possible. We are grateful to the UK NCRI Haematological Oncology Study Group; the NCRI CLL Subgroup; and all principal investigators, sub-investigators, and local centre staff for their dedication and commitment to recruiting patients to the study. We thank members of the FLAIR trial steering committee and data monitoring and ethics committee. We thank Lelia Duley for her valuable input from a patient perspective. The support of the Clinical Trials Research Unit at the University of Leeds (UK) was essential to the successful running of the study; we thank all their staff who have contributed, past and present. Central laboratory analysis was done at the Haematological Malignancy Diagnostic Service, St James's University Hospital, Leeds. We are very grateful to the laboratory team for their contribution to the study. Publisher Copyright: © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license

Identifiers

Local EPrints ID: 477713
URI: http://eprints.soton.ac.uk/id/eprint/477713
ISSN: 1470-2045
PURE UUID: 2e7ce965-b6dd-4636-918c-26a946ab02aa
ORCID for Francesco Forconi: ORCID iD orcid.org/0000-0002-2211-1831

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Date deposited: 13 Jun 2023 17:12
Last modified: 17 Mar 2024 03:27

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Contributors

Author: Peter R Hillier
Author: Alexandra Pitchford
Author: Adrian Bloor
Author: Angus Broom
Author: Moya Young
Author: Ben M. Kennedy
Author: Renata Walewska
Author: Michelle Furtado
Author: Gavin Preston
Author: Jeffrey R Nelson
Author: Nicholas Pemberton
Author: Gamal Sidra
Author: Nicholas H. Morley
Author: Kate Cwynarski
Author: Anna H. Schuh
Author: Nagah Elmusharaf
Author: Shankara Paneesha
Author: Christopher Fox
Author: Dena R. Howard
Author: Anna Hockaday
Author: Julia Brown
Author: David A. Cairns
Author: Sharon (Shae) Margaret Jackson
Author: Natasha Greatorex
Author: Nichola Webster
Author: Jane Shingles
Author: Surita Dalal
Author: Piers E.M. Patten
Author: David Allsup
Author: Andrew David Rawson
Author: Talha Munir

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