Abstract
INTRODUCTION: Diffuse midline glioma is a fatal CNS tumor that chiefly occurs in children. To date, standard of care has been limited to local field radiation. A histone mutation in H3K27M is seen in 80% of diffuse midline gliomas of the brainstem, also called diffuse intrinsic pontine glioma (DIPG). Panobinostat, a potent inhibitor of histone deacetylases, has shown moderate efficacy in DIPG/DMGs in preclinical models, and a dose-finding clinical trial (PBTC-047) is ongoing. We report on a case of a child with biopsy-proven H3K27M-mutated DMG of the brainstem treated off-trial with panobinostat monotherapy after radiation. METHODS: This is a case report of a 12-year-old female with H3K27M-mutated DMG of the medulla and cerebellum that exhibited gadolinium-enhancement on MRI. The patient was treated with 54 Gy focal photon radiation to the tumor field over six weeks after biopsy demonstrating the H3.3K27M mutation (H3F3A), as well as mutations in TP53, PIK3R1 and AXSL1 genes. She was not eligible for PBTC-047 due to uncontrolled hypertension. She received panobinostat as per the ongoing PBTC protocol at a dose of 28 mg/m2 given on Monday, Wednesday, and Friday on alternating weeks. She received three 28-day cycles over three months. RESULTS: The patient tolerated the therapy well, with minimal adverse reactions of low-grade abdominal pain and constipation. MRI imaging after three cycles revealed an 80% reduction in tumor volume. Together with this radiographic response, she exhibited improvement in left-sided motor strength and improved left facial sensation. Due to an unrelated need for oral surgery, panobinostat was held. MRI imaging six weeks after cessation of panobinostat revealed extensive relapse with supratentorial and spinal disease. CONCLUSION: Systemic panobinostat may demonstrate anti-tumor efficacy in some cases of H3K27M-mutated DMG. Future work is required to determine factors predictive of favorable response.
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