o:3428 Patient-derived xenograft models of ALK+ ALCL reveal preclinical promise for therapy with brigatinib 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. Large-Cell Lymphoma; Lung-Cancer; Solid Tumors; Open-Label; Crizotinib; Mutations; Resistance; Alectinib; Children; Stat3 1552099 10.1111/bjh.18953 2024-08-26T08:27:02.754Z 44 yes 46 Nina Prokoph University of Cambridge Jamie D. Matthews University of Cambridge person Ricky M. Trigg University of Cambridge person Ivonne A. Montes-Mojarro University of Tübingen person G. A. Amos Burke Cambridge University Hospitals NHS Foundation Trust person 0000-0003-2671-9972 Falko Fend University of Tübingen person Olaf Merkel Medical University of Vienna person Lukas Kenner University of Veterinary Medicine Vienna / Medical University of Vienna person 0000-0003-2184-1338 Birgit Geoerger Université Paris-Saclay / Institut Gustave Roussy person Robert Johnston Royal Belfast Hospital for Sick Children person Matthew J. Murray University of Cambridge / Cambridge University Hospitals NHS Foundation Trust person 0000-0002-4480-1147 Charlotte Riguad Institut Gustave Roussy person Laurence Brugières Institut Gustave Roussy person Suzanne D. Turner University of Cambridge / Masaryk University person 0000-0002-8439-450 application/pdf 22600330 https://phaidra.vetmeduni.ac.at/o:3428 no yes 16 70 1552253 British Journal of Haematology 14 202 5 985 994 Wiley 2023