ID #1106 Clinical outcomes of pediatric patients with NTRK, ALK, and ROS1 fusion-positive pleomorphic xanthoastrocytomas

Background Pleomorphic xanthoastrocytoma (PXA) is a rare circumscribed glioma representing <1% of all primary brain tumors in children and young adults. Receptor tyrosine kinase (RTK) fusions involving NTRK1/2/3, ALK, and ROS1 genes are exceptionally uncommon in PXA. Methods A retrospective analysis of 7 pediatric patients with RTK fusion-positive PXA (2015–2025) was performed. Molecular characterization of the tumor included transcriptomic RNA sequencing and DNA methylation analysis. Results Median age at diagnosis was 10 years 5 months (range: 1 year 10 months–13 years 11 months). Initial histological diagnosis included: PXA Grade 2 (n = 2), PXA Grade 3 (n = 3), high-grade glioma (HGG) (n = 1), and desmoplastic infantile astrocytoma/ganglioglioma (DIG/DIA) (n = 1). DNA methylation profiling was performed in all cases, reclassifying two cases initially diagnosed as HGG and DIG/DIA to PXA, while confirming the diagnosis in five histologically diagnosed PXA cases. Molecular profiles identified NTRK1 (n = 2), NTRK2 (n = 1), ALK (n = 3), and ROS1 (n = 1) fusions. All patients underwent initial surgical resection (gross total resection n = 2, subtotal resection n = 2, partial resection n = 3). All patients received radiation therapy. Disease progression occurred in 6/7 patients, with metastatic dissemination in 3 cases. Upon disease progression, three patients received targeted therapy: entrectinib (n = 3), with sequential administration of larotrectinib in 1 patient and addition of cabozantinib in 2 patients upon further progression. Initial partial responses were observed in all treated patients; however, all developed resistance (median time to progression on first-line targeted therapy: 10 months, range: 4–18 months). Two patients died (median overall survival was not reached). Five patients remain alive (median follow-up: 4 years 10 months). Conclusions RTK fusion-positive PXAs demonstrate aggressive behavior with rapid disease progression despite multimodal therapy. Targeted therapies induce initial responses but acquired resistance develops within one year, highlighting the need for combination strategies and novel resistance-modifying approaches in this rare molecular subgroup.