Thomsen, Anna

Abstract BACKGROUND Von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome characterized by development of multiple neoplasms, including central nervous system (CNS) hemangioblastomas, renal cell carcinoma (RCC), pancreatic neuroendocrine tumors (pNETs), and retinal hemangioblastomas. Belzutifan, a hypoxia-inducible factor 2-alpha (HIF-2α) inhibitor, has demonstrated efficacy in treating VHL-associated tumors. This study evaluates our institutional experience with belzutifan in patients with VHL-related tumors. MATERIAL AND METHODS We conducted a retrospective cohort study across three Mayo Clinic sites, including patients aged ≥18 years with genetically confirmed VHL disease who received belzutifan between October 2021 and March 2025. Clinical/radiological data, and adverse events (AEs) were extracted from electronic health records. Tumor responses were assessed using RECIST v1.1 criteria for RCC, pNET, CNS hemangioblastoma. Retinal hemangioblastoma responses were evaluated through ophthalmologic assessments. RESULTS Forty-five patients were included (median age 44 58% female). Sixty-seven percent had RCC, 91% had CNS hemangioblastomas, 53% had pNETs, and 62% had retinal hemangioblastomas. The median duration of belzutifan therapy was 22.6 months (range 1.0-41.4 months). Among patients with RCC (n=26), overall response rate (ORR) was 19% and median time to best response (MTBR) was 7.4 months. Five patients had partial response (PR), 15 had stable disease (SD), and 1 had progressive disease (PD). For CNS hemangioblastomas (n=41), ORR was 12%, MTBR was 6.2 months. 5 patients had PR, 30 had SD, and none had PD. For pNET (n=17), ORR was 41%, MTBR was 8.2 months. One patient had CR, 6 patients had PR, 6 had SD, none had PD. For retinal hemangioblastomas (n=28), 6 (21%) showed improvement, 9 (32%) remained stable, and 3 (11%) showed progression. MTBR was 6.7 months. Treatment-related AEs occurred in 98% of patients. Common AEs included anemia (89%), fatigue (80%), hypoxia (18%), and headache (13%). Grade 3 AEs were observed in 20% of patients, including anemia (7%), hypoxia (9%), fatigue (4%), pneumonitis (2%), loss of consciousness (2%). One patient experienced a grade 4 event (status epilepticus). Anemia management involved iron supplementation (n=11), RBC transfusion (n=3), dose reduction (n=2), treatment holiday (n=8), permanent discontinuation (n=1). Hypoxia management included dose reduction (n=1), treatment holiday (n=3), discontinuation (n=1). CONCLUSION Belzutifan shows clinical activity across various VHL-associated neoplasms in real-world practice, with a manageable safety profile. The lower ORR compared to the phase III trial may reflect differences in baseline disease, including lower tumor burden in our cohort. These findings support its continued use in VHL disease, with attention to monitoring and managing treatment-related AEs.

Abstract BACKGROUND Pineocytoma is a rare pineal parenchymal WHO grade 1 tumor, typically well-managed with surgical resection alone. With gross total resection (GTR), 91% 1-year and 84% 5-year survival rates have been reported. Recurrent pineocytoma is rare and optimal management in that setting is unknown, in part owing to the rarity of the condition. METHODS We report an atypical course of pineocytoma in a 58-year-old male involving metastatic disease. RESULTS A pineal mass was identified upon MRI of the brain obtained for vision changes. Patient underwent GTR, pathology was consistent with pineocytoma, WHO grade 1. Ki-67 labeling index was low at 1-2%. Despite low-grade pathology, two years later, surveillance imaging demonstrated recurrence in the pineal region and a second lesion in the right thalamus. The patient underwent gamma knife surgery (GKRS) to both lesions. Three years later, he developed three new lesions in the right cerebellum and again underwent GKRS. Subsequent surveillance imaging identified new lesions in the right cerebellum and along ventricular walls, treated with further GKRS. Nine years after initial diagnosis, focal nodular leptomeningeal metastases were discovered, along with progression at the primary tumor site. Patient was treated with GKRS to the nodular deposits followed by pembrolizumab. Further disease progression as noted despite immunotherapy. Patient was treated with 6 cycles of temozolomide chemotherapy and at further progression 3 cycles of lomustine. Upon additional progression, further radiation therapy was administered with bevacizumab to reduce risk of radiation necrosis. Patient remains on surveillance 13 years after initial diagnosis with visual changes and mild headache representing only clinical issues. CONCLUSIONS Although exceedingly rare, pineocytoma is capable of metastasizing to brain parenchyma and the leptomeninges, as demonstrated in our patient. However, our case demonstrates prolonged survival is possible even in the setting of relentlessly progressive metastatic disease with utilization of multimodality treatment.

Abstract Von Hippel-Lindau (VHL) disease is caused by pathogenic variants in the VHL gene. Abnormal function of VHL protein leads to accumulation of HIF-α and the engagement of hypoxia-sensitive genes with oncogenic effects. VHL is associated with tumors in multiple organs. Belzutifan is an oral selective inhibitor of hypoxia-inducible factor 2 alpha. Belzutifan was approved in 2021 as a targeted therapy for VHL-associated CNS hemangioblastomas, renal cell carcinomas, and pancreatic neuroendocrine tumors. Here, we report on our institutional clinical experience with belzutifan for VHL-associated CNS hemangioblastomas. From October 2021 to May 2024, thirteen adults (9 female, 4 male, median age 40) were treated. Median duration of therapy was 24 months. Seven had a partial radiographic response after median of 3 months; one patient had a partial response; 1 patient had progressive disease on belzutifan. Four patients have been taking belzutifan for less than 3 months, and do not have follow-up imaging to assess response. The most common adverse effect was fatigue (7 patients). Four patients experienced anemia and 2 experienced hypoxia. Three patients discontinued belzutifan due to adverse effects. One patient had to take multiple medication pauses, due to seizure and kidney injury, but resumed treatment with dose reduction. Nine patients remain on therapy. Based on this data, belzutifan is often well-tolerated and associated with durable radiographic responses. Toxicity profile among our patients was similar to that encountered in the clinical trial leading to approval of the agent. These findings provide real-world data supporting continued use of belzutifan in this patient population, with an awareness of potential adverse reactions. Future studies should assess continued radiographic response, sex differences, and effects after long-term use.

Abstract BACKGROUND Myxopapillary ependymomas (MPE) are slow-growing tumors of the spine typically involving the medullary conus and cauda equina. MPE is regularly managed with surgical resection with radiation therapy reserved for cases where gross total resection cannot be achieved. Management of inoperable cases represents a clinical challenge. No systemic therapy is approved for treatment of MPE. Addition of chemotherapy may improve outcomes for cases not amenable to resection. MATERIAL AND METHODS We report feasibility and preliminary efficacy of combination treatment with proton beam radiation therapy and temozolomide chemotherapy for a patient with large, unresectable MPE. RESULTS A 19-year-old female presented with one year of gradually worsening hip and back pain despite treatment with physical therapy. MRI Lumbar spine identified a destructive and expansile T2-heterogenous and hyperintense intraosseous mass (14 x 12 x 13 cm) with extraosseous expansion involving the sacrum, coccyx, and left SI joint with abnormal soft tissue enhancement extending along the posterior spine. No additional lesions were identified on neuro-axis imaging. Biopsy of the mass was consistent with a WHO grade 2 myxopapillary ependymoma. Standard treatment of care would include complete surgical resection. Unfortunately, this would require a morbid procedure in an en block fashion with immediate and permanent loss of bowel, bladder, sexual, and ambulatory function in a young patient whose primary symptom was pain and mild weakness. It was therefore elected to treat the patient in an unconventional approach and begin with proton beam radiation therapy (59.4 Gy in 33 fractions) with concurrent temozolomide followed by 6 cycles of adjuvant temozolomide. Mild clinical improvement and significant radiographic response were achieved (size reduced to 8 x 7 x 11 cm). CONCLUSION This case suggests a potential role for use of proton radiation therapy with concurrent and adjuvant temozolomide for management of myxopapillary ependymoma not amenable to surgical resection.

Abstract BACKGROUND Von Hippel-Lindau (VHL) disease is a rare autosomal-dominant hereditary disease associated with tumors in multiple organs. VHL is characterized by mutation of the VHL gene which leads to accumulation of HIF-α and the engagement of hypoxia-sensitive genes with oncogenic effects. Conventional management of VHL-associated tumors involves surgical resection and radiation therapy. Belzutifan is an oral selective inhibitor of hypoxia-inducible factor 2 alpha (HIF-2a). Belzutifan was approved by the United States Food and Drug Administration (FDA) in August 2021 as a targeted therapy option for VHL-associated CNS hemangioblastomas, renal cell carcinomas, and pancreatic neuroendocrine tumors. Our objective here is to report on our clinical experience with use of belzutifan for VHL-associated CNS hemangioblastomas. MATERIAL AND METHODS We retrospectively chart reviewed our institutional (Mayo Clinic Rochester) experience of belzutifan in adults (18 years or older) with VHL and craniospinal hemangioblastomas not amenable to surgery. The study period was October 2021 to March 2024. RESULTS Nine adults (5 female, 4 male) were included in the study. Of those able to continue the therapy without interruption (6 patients), the median duration of therapy at last follow-up was 11.5 months (range 3-22 months). Seven had radiographic response to therapy after a median of 3 months (1-5 months), with a maximal response to therapy after a median of 13 months (3-29 months). One patient had a mixed radiographic response, and 1 patient had tumor progression while on belzutifan noted at 5 months. The most common adverse effect was fatigue. Seven patients reported fatigue, 4 patients experienced anemia, and 2 experienced hypoxia. Three patients discontinued belzutifan due to adverse effects, specifically fatigue and hypoxia. One patient had to take multiple medication pauses, once due to seizure and once due to kidney injury, but resumed treatment with dose reduction. CONCLUSION Among patients with VHL-associated CNS hemangioblastomas, belzutifan is often well-tolerated and associated with durable radiographic responses. Toxicity profile among our patients was similar to that encountered in the clinical trial leading to FDA approval of the agent. These findings provide real-world data supporting continued use of belzutifan in this patient population, with an awareness of potential adverse reactions. Future studies should assess continued radiographic response, sex differences, duration of treatment, and effects of cessation after long-term use.

Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Despite an established standard of care including surgical resection, radiation therapy, and chemotherapy, GBM unfortunately is associated with a dismal prognosis. Therefore, researchers are extensively evaluating avenues to expand GBM therapy and improve outcomes in patients with GBM. In this review, we provide a broad overview of novel GBM therapies that have recently completed or are actively undergoing study in clinical trials. These therapies expand across medical, surgical, and radiation clinical trials. We additionally review methods for improving clinical trial design in GBM.

Isocitrate dehydrogenase (IDH) mutant gliomas are a primary malignancy of the central nervous system (CNS) malignancies, most commonly affecting adults under the age of 55. Standard of care therapy for IDH-mutant gliomas involves maximal safe resection, radiotherapy, and chemotherapy. However, despite good initial responses to multimodality treatment, recurrence is virtually universal. IDH-mutant gliomas represent a life-limiting prognosis. For this reason, there is a great need for novel treatments that can prolong survival. Uniquely for IDH-mutant gliomas, the IDH mutation is the direct driver of oncogenesis through its oncometabolite 2-hydroxygluterate. Inhibition of this mutated IDH with a corresponding reduction in 2-hydroxygluterate offers an attractive treatment target. Researchers have tested several IDH inhibitors in glioma through preclinical and early clinical trials. A phase III clinical trial of an IDH1 and IDH2 inhibitor vorasidenib yielded promising results among patients with low-grade IDH-mutant gliomas who had undergone initial surgery and no radiation or chemotherapy. However, many questions remain regarding optimal use of IDH inhibitors in clinical practice. In this review, we discuss the importance of IDH mutations in oncogenesis of adult-type diffuse gliomas and current evidence supporting the use of IDH inhibitors as therapeutic agents for glioma treatment. We also examine unresolved questions and propose potential directions for future research.