A comparative analysis of IDH-mutant glioma in pediatric, young adult, and older adult patients

Abstract

Background: The frequency and significance of IDH mutations in glioma across age groups are incompletely understood. We performed a multi-center retrospective age-stratified comparison of patients with IDH-mutant gliomas to identify age-specific differences in clinico-genomic features, treatments, and outcomes.

Methods: Clinical, histologic, and sequencing data from patients with IDH-mutant, grades 2-4 gliomas, were collected from collaborating institutions between 2013 and 2019. Patients were categorized as pediatric (<19 years), young adult (YA; 19-39 years), or older adult (≥40 years). Clinical presentation, treatment, histologic, and molecular features were compared across age categories using Fisher's exact test or analysis-of-variance. Cox proportional-hazards regression was used to determine the association of age and other covariates with overall (OS) and progression-free survival (PFS).

Results: We identified a cohort of 379 patients (204 YA) with IDH-mutant glioma with clinical data. There were 155 (41%) oligodendrogliomas and 224 (59%) astrocytomas. YA showed significantly shorter PFS and shorter median time-to-malignant transformation (MT) compared to pediatric and adult groups, but no significant OS difference. Adjusting for pathology type, extent of resection, and upfront therapy in multivariable analysis, the YA group was independently prognostic of shorter PFS than pediatric and adult groups. Among astrocytomas, CDK4/6 copy number amplifications were associated with both shorter PFS and shorter OS. Among oligodendrogliomas, PIK3CA and CDKN2A/2B alterations were associated with shorter OS.

Conclusions: IDH-mutant glioma YA patients had significantly shorter PFS and time to MT but did not differ in OS compared to pediatric and adult groups. Treatment approaches varied significantly by patient age and warrant further study as addressable age-associated outcome drivers.

Keywords: AYA; IDH-mutation; clinical outcome; glioma; survivorship.

Figure 1.

Screening and enrollment of 331 adult and 48 pediatric patients with IDH1/2 mutant glioma. Clinical, pathology, and genomic data were captured for 379 total patients across the 3 age cohorts.

Figure 2.

Distribution by age category of grade and diagnosis (A), extent of resection (B), and upfront treatment modality (C). (GTR, gross total resection, STR, subtotal resection).

Figure 3.

(A) Progression-free survival, by pathologic subtype (astrocytoma [n = 224] vs. oligodendroglioma [n = 155]); (B) Overall survival, by pathologic subtype (astrocytoma [n = 224] vs. oligodendroglioma [n = 155]); (C) Progression-free survival, by age group (pediatric [n = 48] vs. young adult [n = 204] vs. older adult [n = 127]); (D) Overall survival by age group (pediatric [n = 48] vs. young adult [n = 204] vs. older adult [n = 127]).

Figure 4.

Oncoprint showing key genomic alterations in the molecular cohort, stratified by histology, grade, MGMT status and age.

Figure 5.

Volcano plots for overall survival (OS), progression-free survival (PFS), and malignant transformation-free survival (MTFS) for (A) astrocytoma and (B) oligodendroglioma. Horizontal dotted lines represent P < .05, and all labeled genes are significant at a false discovery rate (FDR) < 0.05.