Erin E Crotty1,2, Sarah E S Leary1,2, J Russell Geyer1, James M Olson1,2, Nathan E Millard1, Aimee A Sato3, Ralph P Ermoian4, Bonnie L Cole5,6, Christina M Lockwood7, Vera A Paulson7, Samuel R Browd8, Richard G Ellenbogen8, Jason S Hauptman8, Amy Lee8, Jeffrey G Ojemann8, Nicholas A Vitanza9,10. 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. 2. Fred Hutchinson Cancer Research Center, Seattle, WA, USA. 3. Division of Pediatric Neurology, Department of Neurology, University of Washington, Seattle, WA, USA. 4. Department of Radiation Oncology, University of Washington, Seattle, WA, USA. 5. Department of Laboratories, Seattle Children's Hospital, University of Washington, Seattle, WA, USA. 6. Department of Anatomic Pathology, University of Washington School of Medicine, Seattle, WA, USA. 7. Department of Laboratory Medicine, Genetics and Solid Tumor Diagnostics Laboratory, University of Washington and Seattle Children's Hospital, Seattle, WA, USA. 8. Division of Neurosurgery, Department of Neurological Surgery, Seattle Children's Hospital, University of Washington, Seattle, WA, USA. 9. 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. Nicholas.Vitanza@seattlechildrens.org. 10. Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Nicholas.Vitanza@seattlechildrens.org.
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.
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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