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Randomized phase III trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in non-germinal center B-cell diffuse large B-cell lymphoma

Randomized phase III trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in non-germinal center B-cell diffuse large B-cell lymphoma
Randomized phase III trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in non-germinal center B-cell diffuse large B-cell lymphoma

PURPOSE: Ibrutinib has shown activity in non-germinal center B-cell diffuse large B-cell lymphoma (DLBCL). This double-blind phase III study evaluated ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in untreated non-germinal center B-cell DLBCL.

PATIENTS AND METHODS: Patients were randomly assigned at a one-to-one ratio to ibrutinib (560 mg per day orally) plus R-CHOP or placebo plus R-CHOP. The primary end point was event-free survival (EFS) in the intent-to-treat (ITT) population and the activated B-cell (ABC) DLBCL subgroup. Secondary end points included progression-free survival (PFS), overall survival (OS), and safety.

RESULTS: A total of 838 patients were randomly assigned to ibrutinib plus R-CHOP (n = 419) or placebo plus R-CHOP (n = 419). Median age was 62.0 years; 75.9% of evaluable patients had ABC subtype disease, and baseline characteristics were balanced. Ibrutinib plus R-CHOP did not improve EFS in the ITT (hazard ratio [HR], 0.934) or ABC (HR, 0.949) population. A preplanned analysis showed a significant interaction between treatment and age. In patients age younger than 60 years, ibrutinib plus R-CHOP improved EFS (HR, 0.579), PFS (HR, 0.556), and OS (HR, 0.330) and slightly increased serious adverse events (35.7% v 28.6%), but the proportion of patients receiving at least six cycles of R-CHOP was similar between treatment arms (92.9% v 93.0%). In patients age 60 years or older, ibrutinib plus R-CHOP worsened EFS, PFS, and OS, increased serious adverse events (63.4% v 38.2%), and decreased the proportion of patients receiving at least six cycles of R-CHOP (73.7% v 88.8%).

CONCLUSION: The study did not meet its primary end point in the ITT or ABC population. However, in patients age younger than 60 years, ibrutinib plus R-CHOP improved EFS, PFS, and OS with manageable safety. In patients age 60 years or older, ibrutinib plus R-CHOP was associated with increased toxicity, leading to compromised R-CHOP administration and worse outcomes. Further investigation is warranted.

1527-7755
JCO1802403
Younes, Anas
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Sehn, Laurie H
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Johnson, Peter
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Zinzani, Pier Luigi
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Hong, Xiaonan
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Zhu, Jun
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Patti, Caterina
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Belada, David
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Samoilova, Olga
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Suh, Cheolwon
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Leppä, Sirpa
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Rai, Shinya
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Turgut, Mehmet
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Jurczak, Wojciech
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Cheung, Matthew C
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Gurion, Ronit
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Yeh, Su-Peng
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Lopez-Hernandez, Andres
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Dührsen, Ulrich
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Thieblemont, Catherine
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Chiattone, Carlos Sergio
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Balasubramanian, Sriram
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Carey, Jodi
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Liu, Grace
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Shreeve, S Martin
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Sun, Steven
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Zhuang, Sen Hong
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Vermeulen, Jessica
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Staudt, Louis M
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Wilson, Wyndham
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PHOENIX investigators
Younes, Anas
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Sehn, Laurie H
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Johnson, Peter
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Zinzani, Pier Luigi
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Hong, Xiaonan
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Zhu, Jun
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Patti, Caterina
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Belada, David
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Samoilova, Olga
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Suh, Cheolwon
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Leppä, Sirpa
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Rai, Shinya
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Turgut, Mehmet
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Jurczak, Wojciech
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Cheung, Matthew C
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Gurion, Ronit
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Yeh, Su-Peng
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Lopez-Hernandez, Andres
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Dührsen, Ulrich
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Thieblemont, Catherine
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Chiattone, Carlos Sergio
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Balasubramanian, Sriram
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Carey, Jodi
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Liu, Grace
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Shreeve, S Martin
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Sun, Steven
8d1aa8e3-43a6-4922-95ad-d83da4631968
Zhuang, Sen Hong
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Vermeulen, Jessica
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Staudt, Louis M
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Wilson, Wyndham
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Younes, Anas, Sehn, Laurie H, Johnson, Peter, Zinzani, Pier Luigi, Hong, Xiaonan, Zhu, Jun, Patti, Caterina, Belada, David, Samoilova, Olga, Suh, Cheolwon, Leppä, Sirpa, Rai, Shinya, Turgut, Mehmet, Jurczak, Wojciech, Cheung, Matthew C, Gurion, Ronit, Yeh, Su-Peng, Lopez-Hernandez, Andres, Dührsen, Ulrich, Thieblemont, Catherine, Chiattone, Carlos Sergio, Balasubramanian, Sriram, Carey, Jodi, Liu, Grace, Shreeve, S Martin, Sun, Steven, Zhuang, Sen Hong, Vermeulen, Jessica, Staudt, Louis M and Wilson, Wyndham , PHOENIX investigators (2019) Randomized phase III trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in non-germinal center B-cell diffuse large B-cell lymphoma. Journal of Clinical Oncology, JCO1802403. (doi:10.1200/JCO.18.02403).

Record type: Article

Abstract

PURPOSE: Ibrutinib has shown activity in non-germinal center B-cell diffuse large B-cell lymphoma (DLBCL). This double-blind phase III study evaluated ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in untreated non-germinal center B-cell DLBCL.

PATIENTS AND METHODS: Patients were randomly assigned at a one-to-one ratio to ibrutinib (560 mg per day orally) plus R-CHOP or placebo plus R-CHOP. The primary end point was event-free survival (EFS) in the intent-to-treat (ITT) population and the activated B-cell (ABC) DLBCL subgroup. Secondary end points included progression-free survival (PFS), overall survival (OS), and safety.

RESULTS: A total of 838 patients were randomly assigned to ibrutinib plus R-CHOP (n = 419) or placebo plus R-CHOP (n = 419). Median age was 62.0 years; 75.9% of evaluable patients had ABC subtype disease, and baseline characteristics were balanced. Ibrutinib plus R-CHOP did not improve EFS in the ITT (hazard ratio [HR], 0.934) or ABC (HR, 0.949) population. A preplanned analysis showed a significant interaction between treatment and age. In patients age younger than 60 years, ibrutinib plus R-CHOP improved EFS (HR, 0.579), PFS (HR, 0.556), and OS (HR, 0.330) and slightly increased serious adverse events (35.7% v 28.6%), but the proportion of patients receiving at least six cycles of R-CHOP was similar between treatment arms (92.9% v 93.0%). In patients age 60 years or older, ibrutinib plus R-CHOP worsened EFS, PFS, and OS, increased serious adverse events (63.4% v 38.2%), and decreased the proportion of patients receiving at least six cycles of R-CHOP (73.7% v 88.8%).

CONCLUSION: The study did not meet its primary end point in the ITT or ABC population. However, in patients age younger than 60 years, ibrutinib plus R-CHOP improved EFS, PFS, and OS with manageable safety. In patients age 60 years or older, ibrutinib plus R-CHOP was associated with increased toxicity, leading to compromised R-CHOP administration and worse outcomes. Further investigation is warranted.

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Accepted/In Press date: 11 February 2019
e-pub ahead of print date: 22 March 2019

Identifiers

Local EPrints ID: 430268
URI: http://eprints.soton.ac.uk/id/eprint/430268
ISSN: 1527-7755
PURE UUID: 0e048b36-0435-4269-8e4e-c5e68a1dcbf5
ORCID for Peter Johnson: ORCID iD orcid.org/0000-0003-2306-4974

Catalogue record

Date deposited: 23 Apr 2019 16:30
Last modified: 10 Jan 2022 02:41

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Contributors

Author: Anas Younes
Author: Laurie H Sehn
Author: Peter Johnson ORCID iD
Author: Pier Luigi Zinzani
Author: Xiaonan Hong
Author: Jun Zhu
Author: Caterina Patti
Author: David Belada
Author: Olga Samoilova
Author: Cheolwon Suh
Author: Sirpa Leppä
Author: Shinya Rai
Author: Mehmet Turgut
Author: Wojciech Jurczak
Author: Matthew C Cheung
Author: Ronit Gurion
Author: Su-Peng Yeh
Author: Andres Lopez-Hernandez
Author: Ulrich Dührsen
Author: Catherine Thieblemont
Author: Carlos Sergio Chiattone
Author: Sriram Balasubramanian
Author: Jodi Carey
Author: Grace Liu
Author: S Martin Shreeve
Author: Steven Sun
Author: Sen Hong Zhuang
Author: Jessica Vermeulen
Author: Louis M Staudt
Author: Wyndham Wilson
Corporate Author: PHOENIX investigators

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