Patient-derived xenograft models of ALK plus ALCL reveal preclinical promise for therapy with brigatinib

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Authors

PROKOPH Nina MATTHEWS Jamie D TRIGG Ricky M MONTES-MOJARRO Ivonne A BURKE G A Amos FEND Falko MERKEL Olaf KENNER Lukas GEOERGER Birgit JOHNSTON Robert MURRAY Matthew J RIGUAD Charlotte BRUGIERES Laurence TURNER Suzanne Dawn

Year of publication 2023
Type Article in Periodical
Magazine / Source British journal of haematology
MU Faculty or unit

Faculty of Medicine

Citation
Web https://onlinelibrary.wiley.com/doi/10.1111/bjh.18953
Doi http://dx.doi.org/10.1111/bjh.18953
Keywords ALCL; brigatinib; crizotinib; PDX; tyrosine kinase inhibitors
Attached files
Description 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.
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