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.

Center for Biomarker Research in Medicine Vienna Core Lab2 Medical University of Vienna Vienna Austria

Christian Doppler Laboratory for Applied Metabolomics Medical University of Vienna Vienna Austria

Department of Experimental Pathology and Laboratory Animal Pathology Institute of Clinical Pathology Medical University of Vienna Vienna Austria

Department of Paediatric Haematology and Oncology Cambridge University Hospitals NHS Foundation Trust Cambridge UK

Department of Paediatric Oncology Haematology Royal Belfast Hospital for Sick Children Belfast UK

Department of Pediatric and Adolescent Oncology Gustave Roussy Cancer Center Villejuif France

Division of Cellular and Molecular Pathology Department of Pathology University of Cambridge Addenbrooke's Hospital Cambridge UK

INSERM U1015 Gustave Roussy Cancer Center Université Paris Saclay Villejuif France

Institute of Medical Genetics and Genomics Faculty of Medicine Masaryk University Brno Czech Republic

Institute of Pathology and Neuropathology and Comprehensive Cancer Center Tübingen University Hospital Tübingen Eberhard Karls University Tübingen Germany

Unit of Laboratory Animal Pathology University of Veterinary Medicine Vienna Vienna Austria

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