Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 985-994 |
| Number of pages | 10 |
| Journal | British Journal of Haematology |
| Volume | 202 |
| Issue number | 5 |
| Early online date | 25 Jun 2023 |
| DOIs | |
| Publication status | Published - Sept 2023 |
Bibliographical note
Funding Information:This work was supported by the Cancer Research UK Cambridge Centre [C9685/A25117]. N.P., I.A.M.M, L.K. and S.D.T. were supported by a European Union Horizon 2020 Marie Skłodowska‐Curie Innovative Training Network Grant, grant no. 675712; J.D.M. by the Alex Hulme Foundation; S.D.T. was supported by the project National Institute for Cancer Research (Programme EXCELES, ID Project No. LX22NPO5102)—Funded by the European Union—Next Generation EU; L.K. was supported by the COMET Competence Center CBmed—Center for Biomarker Research in Medicine (n. FA791A0906.FFG), and the module project microOne as well as the Christian‐Doppler Lab for Applied Metabolomics, and by the Austrian Science Fund (grants FWF: P26011, P29251 and P 34781); the MAPPYACTS trial was supported by the Institut National du Cancer grant PHRC‐K14‐175, the Foundation ARC grant MAPY201501241 and the Association Imagine for Margo; MAPPYACTS PDX development was supported by Fédération Enfants Cancers et Santé, Société Française de lutte contre les Cancers et les leucémies de l'Enfant et l'adolescent (SFCE), Association AREMIG and Thibault BRIET; Parrainage médecin‐chercheur of Gustave Roussy. This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC‐1215‐20 014); the views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.
We are grateful to the patients, their families and caregivers for participation in this study. We thank Deirdre Kelly and Rowena Guermech for patient care; Harriet Kendrick-Thomas, Fallon Miller, Laura O'Reilly, Holly Bloy for mouse handling support; Wanfeng Zhao and the Human Research Tissue Bank team at Addenbrooke's Hospital for immunohistochemistry; Lakshmi Venkatraman, Liz Hook and Olivier Giger for pathological assessment; Elisabeth Gurnhofer, Maria Eugenia Marques da Costa, Liew Jun Mun and Stephen Ducray for technical support; and Tiphaine Adam de Beaumais for logistical support.
Publisher Copyright:
© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.
Keywords
- ALCL
- brigatinib
- crizotinib
- PDX
- tyrosine kinase inhibitors
ASJC Scopus subject areas
- Hematology
