Vorinostat, temozolomide or bevacizumab with irradiation and maintenance BEV/TMZ in pediatric high-grade glioma: A Children's Oncology Group Study

Rishi R Lulla; Allen Buxton; Mark D Krailo; Margot A Lazow; Daniel R Boue; James L Leach; Tong Lin; James I Geller; Shiva Senthil Kumar; Marina N Nikiforova; Uma Chandran; Sachin S Jogal; Marvin D Nelson Jr; Arzu Onar-Thomas; Daphne A Haas-Kogan; Kenneth J Cohen; Mark W Kieran; Amar Gajjar; Rachid Drissi; Ian F Pollack; Maryam Fouladi

doi:10.1093/noajnl/vdae035

Vorinostat, temozolomide or bevacizumab with irradiation and maintenance BEV/TMZ in pediatric high-grade glioma: A Children's Oncology Group Study

Neurooncol Adv. 2024 Mar 14;6(1):vdae035. doi: 10.1093/noajnl/vdae035. eCollection 2024 Jan-Dec.

Authors

Rishi R Lulla¹, Allen Buxton², Mark D Krailo², Margot A Lazow³, Daniel R Boue⁴, James L Leach⁵, Tong Lin⁶, James I Geller⁷, Shiva Senthil Kumar⁸, Marina N Nikiforova⁹, Uma Chandran¹⁰, Sachin S Jogal¹¹, Marvin D Nelson Jr¹², Arzu Onar-Thomas⁶, Daphne A Haas-Kogan¹³, Kenneth J Cohen¹⁴, Mark W Kieran¹⁵, Amar Gajjar¹⁶, Rachid Drissi¹⁷, Ian F Pollack¹⁸, Maryam Fouladi³

Affiliations

¹ Department of Pediatrics, Hasbro Children's Hospital, The Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.
² Department of Biostatistics, Children's Oncology Group, Monrovia, California, USA.
³ Pediatric Neuro‑Oncology Program, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, Ohio, USA.
⁴ Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, Ohio, USA.
⁵ Department of Radiology and Medical Imaging, Cincinnati Children's Hospital Medical Center, Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
⁶ Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
⁷ Division of Oncology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA.
⁸ Center for Childhood Cancer Research, Nationwide Children's Hospital, Columbus, Ohio, USA.
⁹ Division of Molecular & Genomic Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
¹⁰ Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
¹¹ Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
¹² Department of Radiology, Children's Hospital Los Angeles, Keck University of Southern California School of Medicine, Los Angeles, California, USA.
¹³ Department of Radiation Oncology, Brigham and Women's Hospital, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
¹⁴ Division of Pediatric Oncology, Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
¹⁵ Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, Massachusetts, USA.
¹⁶ Department of Pediatric Medicine, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
¹⁷ Center for Childhood Cancer Research, Nationwide Children's Hospital, Columbus, OH, The Ohio State University College of Medicine, Columbus, Ohio, USA.
¹⁸ Department of Neurosurgery, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Abstract

Background: Outcomes for children with high-grade gliomas (HGG) remain poor. This multicenter phase II trial evaluated whether concurrent use of vorinostat or bevacizumab with focal radiotherapy (RT) improved 1-year event-free survival (EFS) compared to temozolomide in children with newly diagnosed HGG who received maintenance temozolomide and bevacizumab.

Methods: Patients ≥ 3 and < 22 years with localized, non-brainstem HGG were randomized to receive RT (dose 54-59.4Gy) with vorinostat, temozolomide, or bevacizumab followed by 12 cycles of bevacizumab and temozolomide maintenance therapy.

Results: Among 90 patients randomized, the 1-year EFS for concurrent bevacizumab, vorinostat, or temozolomide with RT was 43.8% (±8.8%), 41.4% (±9.2%), and 59.3% (±9.5%), respectively, with no significant difference among treatment arms. Three- and five-year EFS for the entire cohort was 14.8% and 13.4%, respectively, with no significant EFS difference among the chemoradiotherapy arms. IDH mutations were associated with more favorable EFS (P = .03), whereas H3.3 K27M mutations (P = .0045) and alterations in PIK3CA or PTEN (P = .025) were associated with worse outcomes. Patients with telomerase- and alternative lengthening of telomeres (ALT)-negative tumors (n = 4) had an EFS of 100%, significantly greater than those with ALT or telomerase, or both (P = .002). While there was no difference in outcomes based on TERT expression, high TERC expression was associated with inferior survival independent of the telomere maintenance mechanism (P = .0012).

Conclusions: Chemoradiotherapy with vorinostat or bevacizumab is not superior to temozolomide in children with newly diagnosed HGG. Patients with telomerase- and ALT-negative tumors had higher EFS suggesting that, if reproduced, mechanism of telomere maintenance should be considered in molecular-risk stratification in future studies.

Keywords: bevacizumab; high-grade glioma; pediatric; radiation; telomerase.

Grants and funding

U10 CA180899/CA/NCI NIH HHS/United States