Resistance, rebound, and recurrence regrowth patterns in pediatric low-grade glioma treated by MAPK inhibition: A modified Delphi approach to build international consensus-based definitions—International Pediatric Low-Grade Glioma Coalition

Author:

O’Hare Patricia1,Cooney Tabitha234,de Blank Peter235,Gutmann David H6,Kieran Mark4,Milde Till789,Fangusaro Jason10,Fisher Michael11,Avula Shivaram12,Packer Roger13,Fukuoka Kohei14ORCID,Mankad Kshitij15,Mueller Sabine16,Waanders Angela J17,Opocher Enrico18,Bouffet Eric19ORCID,Raabe Eric2021,Werle Natacha Entz22,Azizi Amedeo A23,Robison Nathan J24,Hernáiz Driever Pablo25,Russo Mark26,Schouten Netteke27,van Tilburg Cornelis M789,Sehested Astrid28,Grill Jacques29ORCID,Bandopadhayay Pratiti23,Kilday John-Paul30ORCID,Witt Olaf789,Ashley David M31,Ertl-Wagner Birgit Betina32,Tabori Uri19ORCID,Hargrave Darren R33ORCID

Affiliation:

1. Department of Paediatric Oncology, Royal Belfast Hospital for Sick Children , Northern Ireland , UK

2. Dana-Farber/Boston Children’s Cancer and Blood Disorders Center , Boston, Massachusetts ,  USA

3. Department of Pediatrics, Harvard Medical School, Broad Institute , Cambridge, Massachusetts ,  USA

4. Day One Biopharmaceuticals , Boston, Massachusetts , USA

5. University of Cincinnati College of Medicine and Cincinnati Children’s Hospital Medical Center , Cincinnati, Ohio , USA

6. Department of Neurology, Washington University School of Medicine , St. Louis, Missouri , USA

7. Clinical Pediatric Oncology, Hopp Children’s Cancer Center (KiTZ) , Heidelberg , Germany

8. Heidelberg University Hospital, Heidelberg , Germany

9. German Cancer Research Center, National Center for Tumor Diseases (NCT) , Heidelberg , Germany

10. Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta and Emory University School of Medicine , Atlanta, Georgia , USA

11. Division of Oncology, The Children’s Hospital of Philadelphia , Philadelphia, Pennsylvania , USA

12. Department of Radiology, Alder Hey Children’s NHS Foundation Trust , Liverpool , UK

13. Brain Tumor Institute, Center for Neuroscience and Behavioral Medicine, Children’s National Hospital , Washington, District of Columbia, USA

14. Department of Hematology/Oncology, Saitama Children’s Medical Center , Saitama , Japan

15. Department of Radiology, Great Ormond Street Hospital for Children NHS Foundation Trust, Department of Radiology , London , UK

16. Department of Neurology, Neurosurgery and Pediatrics, University of California, San Francisco , San Francisco, California , USA

17. Department of Pediatrics, Northwestern University Feinberg School of Medicine , Chicago, Illinois , USA

18. Paediatric Haematology, Oncology and Stem Cell Transplant Division, Padua University Hospital , Padua , Italy

19. The Hospital for Sick Children and Department of Paediatrics, University of Toronto , Toronto, Ontario , Canada

20. Division of Pediatric Oncology, Department of Oncology, Johns Hopkins University School of Medicine , Baltimore, Maryland , USA

21. Department of Pathology, Johns Hopkins University School of Medicine , Baltimore, Maryland , USA

22. Pediatric Onco-Hematology Department, University Hospital of Strasbourg. UMR CNRS 7021, University of Strasbourg , Strasbourg ,  France

23. Department of Pediatrics and Adolescent Medicine and Comprehensive Centre of Pediatrics, Medical University of Vienna , Vienna , Austria

24. Division of Hematology & Oncology, Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine , Los Angeles, California , USA

25. Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, German HIT-LOGGIC-Registry for LGG in children and adolescents, Department of Pediatric Oncology/Hematology , Berlin , Germany

26. Novartis Pharmaceuticals Corporation, East Hanover , New Jersey , USA

27. Princess Maxima Center for Pediatric Oncology , Utrecht , Netherlands

28. Department of Paediatrics and Adolescent Medicine, The University Hospital Rigshospitalet , Copenhagen , Denmark

29. Department of Pediatric and Adolescent Oncology , Villejuif , France

30. The Centre for Paediatric, Teenage and Young Adult Cancer, Institute of Cancer Sciences, University of Manchester, and Royal Manchester Children’s Hospital , Manchester , UK

31. Department of Neurosurgery, The Preston Robert Tisch Brain Tumor Center. Pediatric Neuro-Oncology, Preuss Laboratory for Brain Tumor Research, Durham , North Carolina , USA

32. Department of Diagnostic Imaging, The Hospital for Sick Children , Toronto, Ontario , Canada

33. UCL Great Ormond Street Institute of Child Health, Great Ormond Street Hospital for Children , London , UK

Abstract

Abstract Pediatric low-grade glioma (pLGG) is the most common childhood brain tumor group. The natural history, when curative resection is not possible, is one of a chronic disease with periods of tumor stability and episodes of tumor progression. While there is a high overall survival rate, many patients experience significant and potentially lifelong morbidities. The majority of pLGGs have an underlying activation of the RAS/MAPK pathway due to mutational events, leading to the use of molecularly targeted therapies in clinical trials, with recent regulatory approval for the combination of BRAF and MEK inhibition for BRAFV600E mutated pLGG. Despite encouraging activity, tumor regrowth can occur during therapy due to drug resistance, off treatment as tumor recurrence, or as reported in some patients as a rapid rebound growth within 3 months of discontinuing targeted therapy. Definitions of these patterns of regrowth have not been well described in pLGG. For this reason, the International Pediatric Low-Grade Glioma Coalition, a global group of physicians and scientists, formed the Resistance, Rebound, and Recurrence (R3) working group to study resistance, rebound, and recurrence. A modified Delphi approach was undertaken to produce consensus-based definitions and recommendations for regrowth patterns in pLGG with specific reference to targeted therapies.

Funder

National Institute for Health Research/Biomedical Research Center at Great Ormond Street Hospital for Children

NHS Foundation Trust

University College London

Publisher

Oxford University Press (OUP)

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