Large-Cell Lymphoma; Lung-Cancer; Solid Tumors; Open-Label; Crizotinib; Mutations; Resistance; Alectinib; Children; Stat3 eng Patient-derived xenograft models of ALK+ ALCL reveal preclinical promise for therapy with brigatinib application/pdf 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. Prokoph, Nina (University of Cambridge) Turner, Suzanne D. (University of Cambridge / Masaryk University) Burke, G. A. Amos (Cambridge University Hospitals NHS Foundation Trust) Montes-Mojarro, Ivonne A. (University of Tübingen) Matthews, Jamie D. (University of Cambridge) Trigg, Ricky M. (University of Cambridge) Brugières, Laurence (Institut Gustave Roussy) Riguad, Charlotte (Institut Gustave Roussy) Murray, Matthew J. (University of Cambridge / Cambridge University Hospitals NHS Foundation Trust) Johnston, Robert (Royal Belfast Hospital for Sick Children) Geoerger, Birgit (Université Paris-Saclay / Institut Gustave Roussy) Kenner, Lukas (University of Veterinary Medicine Vienna / Medical University of Vienna) Merkel, Olaf (Medical University of Vienna) Fend, Falko (University of Tübingen) article CC BY 4.0 International http://creativecommons.org/licenses/by/4.0/ British Journal of Haematology 202(5), 985-994 (2023) 2023 Wiley doi:10.1111/bjh.18953 https://phaidra.vetmeduni.ac.at/o:3428