Abstract
BACKGROUND AND AIMS: IDH-mutant gliomas comprise <10% of HGG in children. RRD-HGG comprise 5-10% of childhood HGG, demonstrate high mutation burden (TMB) and respond to immune-checkpoint inhibition (ICI). The impact of RRD within childhood IDH-mutant gliomas, and effective therapeutic options for these patients are not well-established. METHODS: Clinical and multi-omic analyses were performed on IDH( mut) -RRD-HGG registered to the IRRDC and the Toronto glioma taskforce. Tumor development and genomic data were studied from a novel IDH( mut) -RRD-HGG immunocompetent mouse model. Outcome following ICI and targeted therapy were evaluated. RESULTS: RRD was detected in >60% of childhood IDH( mut) -HGG. IDH1-mutations were detected in 20% of RRD-HGG. All patients with IDH mut -RRD-HGG (n=49) harboured germline variants in MMR genes (CMMRD: 65%, Lynch: 35%). Contrary to sporadic IDH( mut) -gliomas, >91% were WHO-grades 3/4. Diffuse/multifocal disease involving the frontal lobe was frequent. TMB (median: 28 mutations/Mb) was lower than IDH-wildtype RRD-HGG (p<0.05). POLE/POLD1 mutations were absent. TP53 and ATRX were frequent somatic hits. Copy number changes, particularly CDKN2A/2B loss, were common. IDH-mutation contributed to an immune-suppressed microenvironment, with lower CD8-T-cell infiltration (immunohistochemistry) and tumor-inflammation scores (transcriptome; p<0.05). A novel mouse model (Olig2-Cre(+)/Msh2(LoxP/)LoxP/LSL-Idh1(R132H/+)) demonstrated similar TMB, diffuse cerebral involvement, slower growth, and lesser immune infiltrates as compared with IDH-wildtype RRD-HGG models, and provided opportunity for therapeutic testing. RRD contributed to poor survival in IDH(mut)-gliomas (p<0.001). Despite hypermutation, ICI monotherapy resulted in inferior survival in IDH( mut) -RRD-HGG vs IDH-wildtype RRD-HGG (p<0.05). Five patients developed metachronous IDH( mut) -RRD-HGG while on anti-PD1 treatment for IDH-wildtype RRD-HGG, suggesting intrinsic ICI-resistance. Ivosidenib (IDH-inhibitor) demonstrated objective response in 4/8 IDH mut -RRD-HGG. Furthermore, for IDH( mut) -RRD-HGG on ICI treatment, the addition of ivosidenib prolonged survival at 12-months in comparison to those without IDH-inhibition (p=0.01) CONCLUSIONS: Hypermutant RRD-HGG with IDH1;p.R132H harbour unique immuno-biology and do not respond to anti-PD1 monotherapy. The addition of IDH-inhibition demonstrated favourable responses, supporting need for evaluation of the combination in clinical trials.