P14.03.B ADDITIONAL METRONOMIC CYCLOPHOSPHAMIDE SURMOUNTS VISMODEGIB RESISTANCE IN ADULT SHH-MUTATED MEDULLOBLASTOMA WITH BONE METASTASIS: A CASE REPORT
F Bouille, E Jouglar, L Rozenblum, L Nichelli, B Mathon, L Morardet, F Bielle, P Leblond, F LAIGLE-DONADEYAbstract
BACKGROUND
Only 20% of medulloblastomas occur in adults, a rarity that limits the availability of large-scale therapeutic trials in this population. Vismodegib has shown some signs of efficacy in patients with SHH-medulloblastoma, especially in those with bone metastases. However, its combination with metronomic treatments such as cyclophosphamide has not been reported yet. Material and methods: We report the case of a 40-year-old man diagnosed in 01/2022 with a desmoplastic SHH-activated medulloblastoma with SMO mutation. A T6 bone metastasis was identified at disease onset and histologically confirmed. Given the early progression of the bone lesion despite stable brain imaging, systemic chemotherapy — two cycles of carboplatin-etoposide (03-04/2022), followed by Temozolomide-Topotecan (06-07/2022) — was prioritized over immediate craniospinal irradiation. Then, the brain MRI showed a leptomeningeal infratentorial enhancement, and the patient was treated by radiation therapy (RT) on the craniospinal axis, including all adjacent bone metastases, followed by boosts to a large skull metastasis, and to the posterior fossa (54 Gy, terminated in 09/2022). Unfortunately, in 12/2022, despite the patient’s excellent general condition (KPS 90), the 18F-FDG-PET showed a bone progression outside of the field of RT (femur, hips...). A “compassionate” regimen with vismodegib (150 mg/d) was initiated in 01/2023. The patient achieved a complete metabolic cerebral response and a partial bone response in 04/2023, maintained until 11/2023. However, a slow progression of bone lesions was observed by the end of 2023. Given the unusual sustained response to vismodegib, our national board decided on 01/2024 to add a metronomic regimen of cyclophosphamide (50 mg/d) to vismodegib.
RESULTS
The clinical tolerance of the vismodegib + cyclophosphamide combination was excellent, only with grade 2 alopecia, grade 1 myalgia, and grade 3 lymphopenia. In 06/2024, a slow progression of three bone lesions was observed which were treated by hypofractionated RT (30 Gy in 10 fractions). A good metabolic response was noted on PET-scan in 08/2024. Due to perfect control of brain and bone lesions, it was decided to continue the association of vismodegib and cyclophosphamide. As local bone progression occurred on 02/2025, new targets were treated by focal radiotherapy. Twenty-seven months after the initiation of vismodegib, and seventeen months after the initiation of the combined therapy of vismodegib/cyclophosphamide, the patient maintained a KPS of 90%, with a good quality of life, and no bone pain.
CONCLUSION
We report the first case of vismodegib combined with cyclophosphamide for the treatment of bone metastatic SHH-medulloblastoma in an adult. The favorable therapeutic outcome in this patient supports the need for dedicated prospective trials to further evaluate the potential benefits of this strategy.