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Children with DIPG and high-grade glioma treated with temozolomide, irinotecan, and bevacizumab: the Seattle Children’s Hospital experience

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Abstract

Introduction

Beyond focal radiation, there is no consensus standard therapy for pediatric high-grade glioma (pHGG) and outcomes remain dismal. We describe the largest molecularly-characterized cohort of children with pHGG treated with a 3-drug maintenance regimen of temozolomide, irinotecan, and bevacizumab (TIB) following radiation.

Methods

We retrospectively reviewed 36 pediatric patients treated with TIB at Seattle Children’s Hospital from 2009 to 2018 and analyzed survival using the Kaplan–Meier method. Molecular profiling was performed by targeted DNA sequencing and toxicities, steroid use, and palliative care utilization were evaluated.

Results

Median age at diagnosis was 10.9 years (18 months–18 years). Genetic alterations were detected in 26 genes and aligned with recognized molecular subgroups including H3 K27M-mutant (12), H3F3A G34-mutant (2), IDH-mutant (4), and hypermutator profiles (4). Fifteen patients (42%) completed 12 planned cycles of maintenance. Side effects associated with chemotherapy delays or modifications included thrombocytopenia (28%) and nausea/vomiting (19%), with temozolomide dosing most frequently modified. Median event-free survival (EFS) and overall survival (OS) was 16.2 and 20.1 months, with shorter survival seen in DIPG (9.3 and 13.3 months, respectively). Survival at 1, 2, and 5 years was 80%, 10% and 0% for DIPG and 85%, 38%, and 16% for other pHGG.

Conclusion

Our single-center experience demonstrates tolerability of this 3-drug regimen, with prolonged survival in DIPG compared to historical single-agent temozolomide. pHGG survival was comparable to analogous 3-drug regimens and superior to historical agents; however, cure was rare. Children with pHGG remain excellent candidates for the study of novel therapeutics combined with standard therapy.

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Data availability

All data generated or analysed during this study are included in this published article [and its supplementary information files].

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Acknowledgements

We thank the many children and families who struggled through these impossibly difficult diseases and entrusted us with their care. We thank our entire pediatric neuro-oncology team, especially C. Hoeppner, S. Holtzclaw, I. Lam, M. Field, S. Chaffee, A. Laurine, S. Stasi, R. Miller, E. Stowe, G. Mun, and W. Iwata for their dedication and compassion. We thank our child life specialists, especially A. Sevilla and Erin Behem. We thank the radiation oncology and palliative care teams, especially R. Hays and A. Towbridge, who work tirelessly to improve the lives of our patients. We thank J. Stevens, as well as the Seattle Children’s Hospital’s Department of Anatomic Pathology and TTS Brain Tumor Committee, for assistance in tissue collection and research coordination.

Funding

We are grateful for generous funding from the Seattle Run of Hope (S.E.S.L., J.M.O., N.A.V), the Pediatric Brain Tumor Research Fund Guild of Seattle Children’s Hospital (S.E.S.L., J.M.O, N.A.V.), the McKenna Claire Foundation (N.A.V.), Unravel Pediatric Cancer (N.A.V., J.M.O.), Team Cozzi Foundation (N.A.V.), the Julianna Sayler Foundation (N.A.V.), the Grousemont Foundation (N.A.V.), the Michael Mosier Defeat DIPG Foundation (N.A.V.), and the ChadTough Foundation (N.A.V.).

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Authors and Affiliations

  1. Division of Hematology/Oncology, Department of Pediatrics, Seattle Children’s Hospital, University of Washington, 4800 Sand Point Way NE, M/S MB.8.501, PO Box 5371, Seattle, WA, 98105, USA

    Erin E. Crotty, Sarah E. S. Leary, J. Russell Geyer, James M. Olson, Nathan E. Millard & Nicholas A. Vitanza

  2. Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Erin E. Crotty, Sarah E. S. Leary, James M. Olson & Nicholas A. Vitanza

  3. Division of Pediatric Neurology, Department of Neurology, University of Washington, Seattle, WA, USA

    Aimee A. Sato

  4. Department of Radiation Oncology, University of Washington, Seattle, WA, USA

    Ralph P. Ermoian

  5. Department of Laboratories, Seattle Children’s Hospital, University of Washington, Seattle, WA, USA

    Bonnie L. Cole

  6. Department of Anatomic Pathology, University of Washington School of Medicine, Seattle, WA, USA

    Bonnie L. Cole

  7. Department of Laboratory Medicine, Genetics and Solid Tumor Diagnostics Laboratory, University of Washington and Seattle Children’s Hospital, Seattle, WA, USA

    Christina M. Lockwood & Vera A. Paulson

  8. Division of Neurosurgery, Department of Neurological Surgery, Seattle Children’s Hospital, University of Washington, Seattle, WA, USA

    Samuel R. Browd, Richard G. Ellenbogen, Jason S. Hauptman, Amy Lee & Jeffrey G. Ojemann

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  1. Erin E. Crotty
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Contributions

Conception and design: EC, SL, and NV. Data collection and assembly: EC, BC, CL, and VP. Data analyses and interpretation: all authors with survival analyses by SL, molecular analyses by CL and VP, and pathologic analyses by BC. Manuscript writing and editing: EC and NV with critical feedback from all authors. Final approval of manuscript: All authors. Accountable for all aspects of the work: All authors.

Corresponding author

Correspondence to Nicholas A. Vitanza.

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The authors declare that they have no competing interests.

Ethical approval

This retrospective chart review study involving human participants was in accordance with the ethical standards of our institutional and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The Institutional Review Board of Seattle Children’s Hospital approved this study (IRB#14449).

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Crotty, E.E., Leary, S.E.S., Geyer, J.R. et al. Children with DIPG and high-grade glioma treated with temozolomide, irinotecan, and bevacizumab: the Seattle Children’s Hospital experience. J Neurooncol 148, 607–617 (2020). https://doi.org/10.1007/s11060-020-03558-w

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