Multi-institutional study of the frequency, genomic landscape, and outcome of IDH-mutant glioma in pediatrics

Abstract

Background The incidence and biology of IDH1/2 mutations in pediatric gliomas are unclear. Notably, current treatment approaches by pediatric and adult providers vary significantly. We describe the frequency and clinical outcomes of IDH1/2-mutant gliomas in pediatrics. Methods We performed a multi-institutional analysis of the frequency of pediatric IDH1/2-mutant gliomas, identified by next-generation sequencing (NGS). In parallel, we retrospectively reviewed pediatric IDH1/2-mutant gliomas, analyzing clinico-genomic features, treatment approaches, and outcomes. Results Incidence Among 851 patients with pediatric glioma who underwent NGS, we identified 78 with IDH1/2 mutations. Among patients 0-9 and 10-21 years old, 2/378 (0.5%) and 76/473 (16.1%) had IDH1/2-mutant tumors, respectively. Frequency of IDH mutations was similar between low- (52/570, 9.1%) and high-grade glioma (25/277, 9.0%). Four tumors were graded as intermediate histologically, with one IDH1 mutation. Outcome Seventy-six patients with IDH1/2-mutant glioma had outcome data available. Eighty-four percent of patients with low-grade glioma were managed observantly without additional therapy. For low-grade astrocytoma, 5-year progression-free survival (PFS) was 42.9% (95%CI:20.3-63.8) and, despite excellent short-term overall survival (OS), numerous disease-related deaths after year 10 were reported. Patients with high-grade astrocytoma had a 5-year PFS/OS of 36.8% (95%CI:8.8-66.4) and 84% (95%CI:50.1-95.6), respectively. Patients with oligodendroglioma had excellent OS. Conclusions A subset of pediatric gliomas are driven by IDH1/2 mutations, with a higher rate among adolescents. The majority of patients underwent upfront observant management without adjuvant therapy. Findings suggest that the natural history of pediatric IDH1/2-mutant glioma may be similar to that of adults, though additional studies are needed.

Immunohistochemical Approach to Mismatch Repair Deficiency in Pediatric High-Grade Glioma

“…They also tend to be tumors seen in older children or early adulthood, which is not a characteristic of our group. 23 According to Yeo et al, 24 there could be 9% IDH mutant adult-type gliomas in our study, but that does not affect the importance of the MMR status of the tumors. Suwala et al 25 have suggested that primary dMMR IDH mutant astrocytoma have the worst clinical outcome.…”

Review of the Recent Changes in the WHO Classification for Pediatric Brain and Spinal Cord Tumors

“…While category (1) is beyond the scope of this review, it is understood that there are no firm age cutoffs for either the adult-type or pediatric-type tumors. For example, isocitrate dehydrogenase (IDH) mutant diffuse gliomas are not exclusive to adult patients, and conversely, some diffuse gliomas in adults can have pediatric-type molecular features [12, 13].…”

Pediatric low-grade glioma: Targeted therapeutics and clinical trials in the molecular era

“…The role of IDH1 mutations in the natural history of pLGGs remains unclear. A recent case series found that patients with IDH1-mutant pLGGs had excellent short-term survival, but 5-year progression-free survival (PFS) was 42.9%, with glioma-related mortality after 10 years [31] .…”