ID #974 Diencephalic syndrome in an infant with low grade glioma refractory to chemotherapy a dramatic and sustained response to tovorafenib

Background

Diencephalic syndrome is a rare but severe presentation of pediatric low-grade glioma (LGG), often associated with hypothalamic and optic pathway tumors in infancy and early childhood[1]. It is characterized by profound failure to thrive despite adequate caloric intake, with relative preservation of linear growth. Management is challenging, and responses to conventional chemotherapy are variable[2]. Despite low-grade histology, infant LGG with diencephalic syndrome is associated with poorer outcomes, with 5-year PFS of approximately 20%[3].

Methods

We report the case of an infant diagnosed at three months of age with a large hypothalamic/optic pathway tumor with solid and cystic components, presenting with profound failure to thrive consistent with diencephalic syndrome. He underwent resection of large cystic components of the tumor and biopsy, which confirmed the diagnosis of pilomyxoid astrocytoma with a KIAA1549-BRAF fusion.

Results

The patient was treated with carboplatin for two months but showed early radiographic progression and leptomeningeal dissemination. Despite enteral nutritional support, he continued to show poor weight gain. Subsequent switch to vinblastine therapy failed to halt clinical or radiographic progression. In the setting of chemotherapy refractory disease, tovorafenib was initiated at six months of age. This resulted in rapid radiographic response after six weeks of treatment, associated with significant improvement in weight. Radiographic response was sustained, with improvement in both solid and cystic components of the tumor. While the patient tolerated treatment well without significant side effects, he experienced significant decrease in growth velocity while on therapy, a known side effect of tovorafenib.

Conclusions

This case highlights the potential for tovorafenib to induce rapid and meaningful clinical and radiographic responses in infants with diencephalic syndrome and refractory BRAF-altered low-grade glioma. Targeted therapy may represent an important treatment option for this high-risk population and is currently being evaluated in a phase 3 clinical trial.

1. Poussaint, T. Y., Barnes, P. D., Nichols, K., Anthony, D. C., Cohen, L., Tarbell, N. J., & Goumnerova, L. (1997). Diencephalic syndrome: clinical features and imaging findings. AJNR. American journal of neuroradiology, 18(8), 1499–1505.

2. Mirow, C., Pietsch, T., Berkefeld, S., Kwiecien, R., Warmuth-Metz, M., Falkenstein, F., Diehl, B., von Hornstein, S., & Gnekow, A. K. (2014). Children <1 year show an inferior outcome when treated according to the traditional LGG treatment strategy: a report from the German multicenter trial HIT-LGG 1996 for children with low grade glioma (LGG). Pediatric blood & cancer, 61(3), 457–463. https://doi.org/10.1002/pbc.24729

3. Kilday, J. P., Bartels, U., Huang, A., Barron, M., Shago, M., Mistry, M., Zhukova, N., Laperriere, N., Dirks, P., Hawkins, C., Bouffet, E., & Tabori, U. (2014). Favorable survival and metabolic outcome for children with diencephalic syndrome using a radiation-sparing approach. Journal of neuro-oncology, 116(1), 195–204. https://doi.org/10.1007/s11060-013-1284-2