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

Patricia O'Hare¹, Tabitha Cooney^{2

3

4}, Peter de Blank^{2

3

5}, David H Gutmann⁶, Mark Kieran⁴, Till Milde^{7

8

9}, Jason Fangusaro¹⁰, Michael Fisher¹¹, Shivaram Avula¹², Roger Packer¹³, Kohei Fukuoka¹⁴, Kshitij Mankad¹⁵, Sabine Mueller¹⁶, Angela J Waanders¹⁷, Enrico Opocher¹⁸, Eric Bouffet¹⁹, Eric Raabe^{20

21}, Natacha Entz Werle²², Amedeo A Azizi²³, Nathan J Robison²⁴, Pablo Hernáiz Driever²⁵, Mark Russo²⁶, Netteke Schouten²⁷, Cornelis M van Tilburg^{7

8

9}, Astrid Sehested²⁸, Jacques Grill²⁹, Pratiti Bandopadhayay^{2

3}, John-Paul Kilday³⁰, Olaf Witt^{7

8

9}, David M Ashley³¹, Birgit Betina Ertl-Wagner³², Uri Tabori¹⁹, Darren R Hargrave³³

Affiliations

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.

PMID: 38743009
PMCID: PMC11300023
DOI: 10.1093/neuonc/noae074

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

Patricia O'Hare et al. Neuro Oncol. 2024.

. 2024 Aug 5;26(8):1357-1366.

doi: 10.1093/neuonc/noae074.

Authors

Affiliations

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.

PMID: 38743009
PMCID: PMC11300023
DOI: 10.1093/neuonc/noae074

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.

Keywords: MAPK; child; low-grade glioma; pediatric brain tumor; rebound; recurrence; resistance.

PubMed Disclaimer

Conflict of interest statement

DH has acted as a consultant/ advisory board member for Alexion, AstraZeneca, Day One Biopharmaceuticals, Novartis and Ipsen plus received clinical trial research funding from Alexion/AstraZeneca. AS has acted as a consultant/ advisory board member for Alexion, AstraZeneca and Day One Biopharmaceuticals. NR has received clinical trial research funding from Pfizer. EB has received clinical trial research funding from Roche and advisory board member for Alexion and Novartis. MK is an employee of Day One Biopharmaceuticals. MF has acted as a consultant/ advisory board member for Alexion, AstraZeneca, Day One Biopharmaceuticals and SpringWorks. JPK has acted as a consultant/ advisory board member for Alexion. PdB has acted as a consultant/ advisory board member for Alexion. MR is an employee of Novartis. TM has received research grants from Biomed Valley Discoveries and Day One Biopharmaceuticals. PB has received grant funding from Novartis and from Deerfield Therapeutics. EO has received travel support/ honoraria from Alexion. SM has received research grants from Beigene, Blueprint, Bristol Myers Squibb, Chimerix, Curis, Day One Biopharmaceuticals, Novartis, Pfizer and Regeneron. JS has acted as a consultant/ advisory board member for Alexion. AA has acted as a consultant/ advisory board member for Alexion and Novartis. CvT has acted as a consultant/ advisory board member for Alexion, Bayer and Novartis. PHD has acted as a consultant/ advisory board member for Ipsen. TC is an employee of Day One Biopharmaceuticals. OW has acted as a consultant/ advisory board member for Biomed Valley Discoveries, Day One Biopharmaceuticals and Novartis.

Figures

**Figure 1.**
Summary of Modified Delphi Process

See this image and copyright information in PMC

References

1. Bandopadhayay P, Bergthold G, London WB, et al.. Long-term outcome of 4,040 children diagnosed with pediatric low-grade gliomas: An analysis of the Surveillance Epidemiology and End Results (SEER) database. Pediatr Blood Cancer. 2014;61(7):1173–1179. - PMC - PubMed
1. Jones DTW, Kieran MW, Bouffet E, et al.. Pediatric low-grade gliomas: Next biologically driven steps. Neuro Oncol. 2018;20(2):160–173. - PMC - PubMed
1. Manoharan N, Liu KX, Mueller S, Haas-Kogan DA, Bandopadhayay P.. Pediatric low-grade glioma: Targeted therapeutics and clinical trials in the molecular era. Neoplasia. 2023;36:100857. - PMC - PubMed
1. Bouffet E, Hansford J, Garré ML, et al.. Primary analysis of a phase II trial of dabrafenib plus trametinib (dab + tram) in BRAF V600–mutant pediatric low-grade glioma (pLGG). J Clin Oncol. 2022;40(17_suppl):LBA2002–LBA2002.
1. Administration UFaD. FDA approves dabrafenib with trametinib for pediatric patients with low-grade glioma with a BRAF V600E mutation. 2023; https://www.fda.gov/drugs/resources-information-approved-drugs/fda-appro.... Accessed April 16, 2024.

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials