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

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

Rishi R Lulla  1 , Allen Buxton  2 , Mark D Krailo  2 , Margot A Lazow  3 , Daniel R Boue  4 , James L Leach  5 , Tong Lin  6 , James I Geller  7 , Shiva Senthil Kumar  8 , Marina N Nikiforova  9 , Uma Chandran  10 , Sachin S Jogal  11 , Marvin D Nelson Jr  12 , Arzu Onar-Thomas  6 , Daphne A Haas-Kogan  13 , Kenneth J Cohen  14 , Mark W Kieran  15 , Amar Gajjar  16 , Rachid Drissi  17 , Ian F Pollack  18 , Maryam Fouladi  3
Affiliations

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

Rishi R Lulla et al. Neurooncol Adv. .

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.

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Conflict of interest statement

None.

Figures

Figure 1.
Figure 1.
Overall and event-free survival for all patients in the phase II portion of ACNS0822 (A). Event-free survival by chemoradiotherapy treatment arm (B). Event-free survival (C) and overall survival (D) by simplified disease classification. The number of patients at risk over time is shown below the curves.
Figure 2.
Figure 2.
Biological variables impact survival on ACNS0822. Event-free survival by PIK3CA/PTEN mutation status (A) and H3-3A and IDH mutation status (B). Overall survival by telomere maintenance mechanism (C), TERC expression (D), and TERT Promoter status (E). The number of patients at risk over time is shown below the curves.
See this image and copyright information in PMC

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