Upfront immunotherapy for synchronous high-grade glioma and B-lymphoma in a pediatric patient with CMMRD syndrome.De Vanssay T1, El Riachy N2, Donze C1,3, Appay R2,4, Scavarda D5,6, Testud B7, Andre N1,3, Revon-Rivière G1,31. Department of Pediatric Hematology, Immunology and Oncology, APHM, La Timone Children's Hospital, Marseille, France. 2. Aix-Marseille Univ, CNRS, INP, Inst Neurophysiopathol, GlioME Team, Marseille, France3. REMAP4KIDS, CNRS, INSERM, CRCM, Aix Marseille University, Marseille, France.4. APHM, CHU Timone, Service d'Anatomie Pathologique et de Neuropathologie, Marseille, France5. Department of Pediatric Neurosurgery. APHM Timone Children’s hospital. Marseille France6. Aix Marseille Univ, INSERM, INS, Inst Neurosci Syst, Marseille, France7. Department of Neuroradiology, APHM, La Timone, Marseille INTRODUCTIONConstitutional Mismatch Repair Deficiency (CMMRD)1, is a rare pediatric cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors.2 It results from bi-allelic inactivation of mismatch repair (MMR) genes, predominantly PMS2 followed by MSH6, MLH1 and MSH2.3 CMMRD predisposes individuals to various malignancies including CNS glioma, gastrointestinal cancer, and hematologic malignancy.4 With an incidence of 1 per million5,6, diagnosing CMMRD is challenging, but early detection is crucial as surveillance significantly impact overall survival (OS). Durno et al. reported a five-year overall survival rate of 90% with systematic surveillance versus 50% without it for asymptomatic cancer.7 Diagnosing CMMRD leads to the use of immunotherapy to treat ultra-hypermutated CMMRD-derived tumors with a Tumor Mutation Burden (TMB) ≥100 mutations/megabase.8 Immune checkpoints inhibitors (ICIs) have shown durable responses in paediatric high-grade glioma arising in CMMRD patients,9, 9 contrasting with their limited efficacy in most other types of pediatric cancers.10 A 2024 international cohort highlighted better outcomes for patients treated with immunotherapy,  regardless of cancer type.3 Consequently, ICIs were approved for advanced paediatric solid tumors in the context of CMMRD, irrespective of histology.9 We report a case of a twelve-year-old CMMRD patient with synchronous high-grade glioma (HGG) and B-cell lymphoma, treated with upfront ICIs alongside with conventional treatment.