Multi-institutional study of the frequency, genomic landscape, and outcome of IDH-mutant glioma in pediatrics

Author:

Yeo Kee Kiat12ORCID,Alexandrescu Sanda3ORCID,Cotter Jennifer A4,Vogelzang Jayne1,Bhave Varun2,Li Marilyn M5,Ji Jianling4ORCID,Benhamida Jamal K6,Rosenblum Marc K6,Bale Tejus A6,Bouvier Nancy7,Kaneva Kristiyana89,Rosenberg Tom12ORCID,Lim-Fat Mary Jane10,Ghosh Hia11,Martinez Migdalia12,Aguilera Dolly13,Smith Amy12,Goldman Stewart14,Diamond Eli L15ORCID,Gavrilovic Igor15,MacDonald Tobey J13,Wood Matthew D16,Nazemi Kellie J17,Truong AiLien17,Cluster Andrew18,Ligon Keith L19,Cole Kristina20,Bi Wenya Linda2,Margol Ashley S21,Karajannis Matthias A7,Wright Karen D12

Affiliation:

1. Department of Pediatric Oncology, Dana-Farber/Boston Children’s Cancer and Blood Disorder Center , Boston, MA , USA

2. Harvard Medical School , Boston, MA , USA

3. Department of Pathology, Boston Children’s Hospital , Boston, MA , USA

4. Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles , Los Angeles, CA, USA

5. Division of Genomic Diagnostics, Children’s Hospital of Philadelphia , Philadelphia, PA , USA

6. Department of Pathology, Memorial Sloan Kettering Cancer Center , New York, NY , USA

7. Department of Pediatrics, Memorial Sloan Kettering Cancer Center , New York, NY , USA

8. Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago , USA

9. Tempus Labs, Inc. , Chicago, IL , USA

10. Department of Medical Oncology, Dana-Farber/Brigham and Women’s Hospital Cancer Center , Boston, MA , USA

11. Department of Neurosurgery, Brigham and Women’s Hospital , Boston, MA , USA

12. Department of Pediatrics, Arnold Palmer Hospital for Children , Orlando, FL , USA

13. Department of Pediatrics, Children’s Healthcare of Atlanta, Emory University School of Medicine , Atlanta, GA , USA

14. Department of Child Health, Phoenix Children’s Hospital, University of Arizona College of Medicine , Phoenix, AZ , USA

15. Department of Neurology, Memorial Sloan Kettering Cancer Center , New York, NY , USA

16. Department of Pathology and Laboratory Medicine, Oregon Health & Science University , Portland, OR , USA

17. Department of Pediatrics, Doernbecher Children’s Hospital , Portland, OR , USA

18. Department of Pediatrics, St. Louis Children’s Hospital , St. Louis, MO , USA

19. Department of Pathology, Dana-Farber/Brigham and Women’s Hospital Cancer Center , Boston, MA , USA

20. Department of Pediatrics, Children’s Hospital of Philadelphia , Philadelphia, PA , USA

21. Department of Pediatrics, Children’s Hospital Los Angeles , Los Angeles, CA , USA

Abstract

Abstract Background The incidence and biology of IDH1/2 mutations in pediatric gliomas are unclear. Notably, current treatment approaches by pediatric and adult providers vary significantly. We describe the frequency and clinical outcomes of IDH1/2-mutant gliomas in pediatrics. Methods We performed a multi-institutional analysis of the frequency of pediatric IDH1/2-mutant gliomas, identified by next-generation sequencing (NGS). In parallel, we retrospectively reviewed pediatric IDH1/2-mutant gliomas, analyzing clinico-genomic features, treatment approaches, and outcomes. Results Incidence: Among 851 patients with pediatric glioma who underwent NGS, we identified 78 with IDH1/2 mutations. Among patients 0–9 and 10–21 years old, 2/378 (0.5%) and 76/473 (16.1%) had IDH1/2-mutant tumors, respectively. Frequency of IDH mutations was similar between low-grade glioma (52/570, 9.1%) and high-grade glioma (25/277, 9.0%). Four tumors were graded as intermediate histologically, with one IDH1 mutation. Outcome: Seventy-six patients with IDH1/2-mutant glioma had outcome data available. Eighty-four percent of patients with low-grade glioma (LGG) were managed observantly without additional therapy. For low-grade astrocytoma, 5-year progression-free survival (PFS) was 42.9% (95%CI:20.3–63.8) and, despite excellent short-term overall survival (OS), numerous disease-related deaths after year 10 were reported. Patients with high-grade astrocytoma had a 5-year PFS/OS of 36.8% (95%CI:8.8–66.4) and 84% (95%CI:50.1–95.6), respectively. Patients with oligodendroglioma had excellent OS. Conclusions A subset of pediatric gliomas is driven by IDH1/2 mutations, with a higher rate among adolescents. The majority of patients underwent upfront observant management without adjuvant therapy. Findings suggest that the natural history of pediatric IDH1/2-mutant glioma may be similar to that of adults, though additional studies are needed.

Funder

Marie-Josée and Henry R. Kravis Center for Molecular Oncology

Pediatric Brain Tumor Foundation

PLGA Fund

David Andrysiak CRA

Publisher

Oxford University Press (OUP)

Subject

Cancer Research,Neurology (clinical),Oncology

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