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Title (en)
Patient-derived xenograft models of ALK+ ALCL reveal preclinical promise for therapy with brigatinib
Language
English
Description (en)
Anaplastic large-cell lymphoma (ALCL) is a T-cell malignancy predominantly driven by the oncogenic anaplastic lymphoma kinase (ALK), accounting for approximately 15% of all paediatric non-Hodgkin lymphoma. Patients with central nervous system (CNS) relapse are particularly difficult to treat with a 3-year overall survival of 49% and a median survival of 23.5 months. The second-generation ALK inhibitor brigatinib shows superior penetration of the blood-brain barrier unlike the first-generation drug crizotinib and has shown promising results in ALK+ non-small-cell lung cancer. However, the benefits of brigatinib in treating aggressive paediatric ALK+ ALCL are largely unknown. We established a patient-derived xenograft (PDX) resource from ALK+ ALCL patients at or before CNS relapse serving as models to facilitate the development of future therapies. We show in vivo that brigatinib is effective in inducing the remission of PDX models of crizotinib-resistant (ALK C1156Y, TP53 loss) ALCL and furthermore that it is superior to crizotinib as a second-line approach to the treatment of a standard chemotherapy relapsed/refractory ALCL PDX pointing to brigatinib as a future therapeutic option.
Keywords (en)
Large-Cell Lymphoma; Lung-Cancer; Solid Tumors; Open-Label; Crizotinib; Mutations; Resistance; Alectinib; Children; Stat3
DOI
10.1111/bjh.18953
Author of the digital object
Nina Prokoph  (University of Cambridge)
Suzanne D. Turner  (University of Cambridge / Masaryk University)
Laurence Brugières  (Institut Gustave Roussy)
Charlotte Riguad  (Institut Gustave Roussy)
Matthew J. Murray  (University of Cambridge / Cambridge University Hospitals NHS Foundation Trust)
Robert Johnston  (Royal Belfast Hospital for Sick Children)
Birgit Geoerger  (Université Paris-Saclay / Institut Gustave Roussy)
Lukas Kenner  (University of Veterinary Medicine Vienna / Medical University of Vienna)
Olaf Merkel  (Medical University of Vienna)
Falko Fend  (University of Tübingen)
G. A. Amos Burke  (Cambridge University Hospitals NHS Foundation Trust)
Ivonne A. Montes-Mojarro  (University of Tübingen)
Jamie D. Matthews  (University of Cambridge)
Ricky M. Trigg  (University of Cambridge)
Format
application/pdf
Size
21.6 MB
Licence Selected
CC BY 4.0 International
Type of publication
Article
Name of Publication (en)
British Journal of Haematology
Pages or Volume
14
Volume
202
Number
5
From Page
985
To Page
994
Publisher
Wiley
Publication Date
2023