NFS-08. Upfront Nivolumab and Trametinib Therapy for a Diffuse Pediatric High-Grade Glioma in the Setting of Constitutional Mismatch Repair Deficiency Syndrome, A Case Report

Abstract Brain tumors are the second most common malignancy in children, with high-grade gliomas (HGG) being the deadliest. Constitutional mismatch repair deficiency syndrome (CMMRD) is a rare cancer predisposition syndrome associated with increased risk of developing a variety of malignancies, including brain tumors. We report a case of a 9-year-old female with headaches, vomiting and photophobia. Imaging revealed a right temporoparietal tumor. Pathologic diagnosis of diffuse pediatric HGG, WHO grade 4 with NF1 somatic mutations and two pathologic variants in PMS2. The patient presented with a two-week history of intermittent headaches, emesis, photophobia, and auditory/visual hallucinations. Examination revealed café au lait macules and axillary freckling. Head CT showed a brain mass, and she was transferred to our institution where MRI brain confirmed a hemorrhagic lesion with surrounding vasogenic edema measuring 3.8 x 3.7 x 3.6 cm with cystic and solid components within the right temporoparietal lobe, with midline shift, and abnormal FLAIR in the left frontal region. Patient underwent a right temporoparietal craniotomy achieving a gross total resection. Pathology and methylation from the temporoparietal lesion was consistent with diffuse pediatric HGG, NOS, H3-wildtype, IDH-wildtype, WHO grade 4 and a left frontal biopsy was consistent with HGG. Genetic evaluation identified two pathogenic PMS2 variants and NF1 somatic mutations leading to CMMRD diagnosis. Patient completed radiotherapy and began Nivolumab, 3 mg/kg every 2 weeks and subsequently 6 mg/kg every 4 weeks. Upfront oral targeted therapy was started with trametinib due evidence of immune synergism in replication-repair-deficient HGG and NF1 mutations. The upfront combination of immunotherapy with targeted therapy to treat patients in this setting is a promising novel therapeutic intervention. Bringing trametinib upfront rather waiting for relapse/progression can truly be beneficial. This case highlights the importance of obtaining comprehensive tumor profiling to identify additional upfront therapeutic agents that improve patients’ overall survival.