Abstract Background Pediatric high-grade gliomas (pHGG) are the most common intracranial tumors in children with replication repair deficiency (RRD) syndromes. The hypermutant phenotype constitutes a vulnerability to immune checkpoint inhibitors (ICI). However, responses are variable, and resistance mechanisms are not fully understood. Methods Single-institution retrospective review from children and adolescents diagnosed with HGG and molecularly confirmed RRD treated at the South London Paediatric and TYA Neuro-Oncology Network between January 2000 and December 2023. Clinical, histopathological, molecular, genetic, therapeutic and survival data were collected. Descriptive statistics, Kaplan-Meier and univariable Cox proportional hazard models were used. Results Six cases were identified (3 females). Median age was 9.6 years (range 2.74-11.02). Five supratentorial and one spinal HGG. Germline genetic testing confirmed heterozygous MMR gene variants (Lynch Syndrome) in 4 cases (67%) and homozygous (CMMRD syndrome) in 2 (33%). Tumour Mutational Burden was available for 3 patients, of whom two presented additional mutations in POLE/POLD2 and ultrahypermutant phenotype. Two children were treated with ICI upfront, two at relapse and two upfront and at relapse. One presented a synchronous Burkitt Lymphoma and received sequential rituximab and ICI after initial surgery; another developed a metachronous lymphoblastic lymphoma whilst on ICI for pHGG. Two cases developed hypothyroidism grade 2. Grade 3 toxicities included (n = 1 each): elevated AST/ALT and new onset of insulin-dependent diabetes. No grade 4 toxicities. Five cases (83%) died of disease: median OS 11.4 months (range 10.0-35.8). One patient remains in complete remission 26.5 months after initial diagnosis. The two patients with ultrahypermutant phenotype presented the longest survival. Conclusions Although ICI have a molecularly-driven rationale to treat RRD-HGG, the best agent, optimal drug combinations, and best predictive biomarkers yet remain to be elucidated. Collaboration with expert initiatives such as the International Replication Repair Deficiency Consortium (IRRDC) is essential to continue developing better tailored treatments for these children.
Perez-Somarriba et al. (Fri,) studied this question.