Anaplastic pleomorphic xanthoastrocytoma with leptomeningeal dissemination responsive to BRAF inhibition and bevacizumab

Abstract

Our experience suggests that targeted therapy with dabrafenib and trametinib can be safely combined with antiangiogenic therapy and may improve quality of life and survival in patients with leptomeningeal disease associated with aPXA. To our knowledge, this is the first time dabrafenib, trametinib, and bevacizumab have been combined to treat a pediatric high-grade glioma.Anaplastic PXAs pose a therapeutic challenge because of their rarity and lack of consensus guidelines for treatment. The natural history of these tumors is poorly described, but a recent review of 37 patients with PXA reclassified by the 2016 WHO classification and found that 20% fulfilled criteria for aPXA. 7 All patients were treated with maximal safe resection and those with a MIB-1 of greater than 5% or with residual disease were treated with adjuvant RT. The 3-year progression-free survival (PFS) was 32% for aPXAs compared with 80% for grade II PXAs. Another retrospective series of eight patients with aPXA demonstrated a 1-year PFS of 57%. 8 In this cohort, six patients had subtotal resections and all progressed despite adjuvant radiation and chemotherapy. Among them, four patients developed disseminated disease. Few treatments have been shown to be effective in leptomeningeal carcinomatosis from gliomas, but bevacizumab can improve symptom control through its antiangiogenic effects and normalization of the blood-brain barrier. 9Mutations in the oncogene BRAF have been reported in 40-60% of PXAs. 2 A basket study of vemurafenib for nonmelanoma cancers with BRAF V600E mutations included four patients with recurrent aPXAs, three of whom had a partial response. 3 Our case report and others 4,10 suggest that BRAF-mutant aPXAs may be sensitive to targeted therapy, even if disseminated or refractory to other treatments. The growing experience with targeted therapy in rare pediatric gliomas justifies a need for a larger clinical trial. Multicenter national clinical trials for recurrent/refractory BRAF-mutant pediatric glioma are ongoing (NCT01748149) and will lead to better understanding of how to manage these challenging tumors. CONFLICT OF INTERESTThe authors declare that there is no conflict of interest. ORCID Alissa A. Thomas

Rapid Diffuse Leptomeningeal Dissemination of an Anaplastic Pleomorphic Xanthoastrocytoma in an Adult Patient

“…Anaplastic pleomorphic xanthoastrocytoma (APXA) is a rare neoplasm whose characteristics are still being delineated. The APXA was recognized as a unique entity by the WHO in 2016 as a WHO Grade III neoplasm possessing the characteristics of PXA (i.e., cellular pleomorphism, foam cells, and eosinophilic granular bodies with an abundance of reticulin) with a mitotic index of >5/10 per high-powered frame [ 1 , 2 ]. This case demonstrates a remarkably rapid progression from initial diagnosis of APXA to re-presentation with LMD.…”

An anaplastic pleomorphic xanthoastrocytoma with periventricular extension: An autopsy case report and review of the literature

“…PXAs and APXAs typically spread to the leptomeninges. [14][15][16][17][18] In gliomas, the exact incidence of leptomeningeal metastasis is unknown because postmortem examinations of the spine are not routinely performed. Previous studies suggest that subarachnoid spreading occurs in approximately 25% of patients with intracranial glioblastomas, including EGBMs.…”

“…PXAs and APXAs typically spread to the leptomeninges . In gliomas, the exact incidence of leptomeningeal metastasis is unknown because postmortem examinations of the spine are not routinely performed.…”

Pleomorphic xanthoastrocytoma: a brief review

“…There have been a number of reports utilizing BRAF inhibitor monotherapy or BRAF+MEK inhibitors. Favorable responses have ranged from stable disease to complete responses [58][59][60][61][62][63][64]. In the largest published nonrandomized trial over 40% of patients with PXA treated with BRAF-inhibiting monotherapy exhibited radiographic response.…”

“…More than half were noted to have a confirmed clinical benefit [63]. The addition of bevacizumab to this regimen at time of progression may prolong survival [64]. The utilization of BRAF inhibitor in conjunction with tumor-treating fields (TTFields) has also been reported [65].…”