In Reply: Brainstem Gliomas With Isocitrate Dehydrogenase Mutation: Natural History, Clinical-Radiological Features, Management Strategy, and Long-Term Outcome

To the Editor: We sincerely appreciate the authors1 for their insightful letter in response to our article, “Brainstem Gliomas with Isocitrate Dehydrogenase Mutation: Natural History, Clinical-Radiological Features, Management Strategy, and Long-Term Outcome.”2 The authors provide constructive points regarding the promising potential of treating isocitrate dehydrogenase-mutated brainstem gliomas (BSG-IDHmut) with IDH inhibitors. Based on the results of the global, randomized, double-blinded, phase 3 study of vorasidenib versus placebo in patients with residual or recurrent grade 2 glioma with an IDH1/2 mutation (INDIGO) trial,3 the United States Food and Drug Administration approved vorasidenib on August 6, 2024, for adult and pediatric patients aged 12 years and older with Grade 2 astrocytoma or oligodendroglioma harboring a susceptible IDH1 or IDH2 mutation, after surgery including biopsy, subtotal resection, or gross total resection. According to a Society for Neuro-Oncology consensus on isocitrate dehydrogenase (IDH) mutant gliomas, patients younger than 40 years with gross total resection may be observed.4 However, as Dr Claus and Dr Verhaak highlighted in their commentary on the INDIGO study, the tumor location often determines the extent of resection. For brainstem gliomas, the likelihood of achieving gross total resection is much lower than for supratentorial tumors. Furthermore, even with the same extent of resection, the surgical risks for brainstem gliomas are significantly higher than those for supratentorial tumors. As an orphan disease, BSG-IDHmut warrants particular attention. Unfortunately, patients with brainstem involvement were excluded from the INDIGO study. Recently, China has initiated a bridging study of vorasidenib (CTR20242581). We hope that this study will include patients with BSG-IDHmut. There are several concerns need to be considered in conducting IDH inhibitor study on BSG-IDHmut. Apart from the higher surgical risks, there are significant molecular and pathological differences between BSG-IDHmut and supratentorial IDH-mutant gliomas, including: Differences in mutation variants, for example, noncanonical IDH1-R132H mutations are more prevalent (59.1%-76%) in IDH-mutated infratentorial gliomas.2,5 Near absence of 1p/19q codeletions in BSG-IDHmut (only one case was identified in our cohort), Differences in the frequency of comutations. In our study, the prevalence of o6-methylguanine-DNA methyltransferase promoter methylation and ATRX loss in BSG-IDHmut were 55.6% and 47%, respectively, which were notably lower than the rates reported for supratentorial IDH-mutant gliomas (95% and over 90%, respectively). These differences warrant further investigation into their potential impact on the efficacy of IDH inhibitors. The INDIGO study focused on tumors that were either residual or recurrent after surgery. We postulated that surgery may play a role in opening the blood-brain barrier and facilitating drug delivery into the tumor. However, some BSG-IDHmut patients are unsuitable for radical surgery, and even open or stereotactic biopsies carry a risk of respiratory complications, as seen in cases 4, 7, and 20 in our cohort. For such patients, we recommend using liquid biopsy to confirm the presence of an IDH mutation and initiating IDH inhibitor therapy as the first-line treatment.6,7 Besides, incorporating liquid biopsy techniques based on cerebrospinal fluid could be valuable for assessing tumor response and dynamic disease monitoring.8 For some patients, the natural history of the disease may be relatively protracted. Even in cases with radiological progression, clinical symptoms can remain stable. Considering the financial burden, studies are needed to determine the optimal timing for initiating IDH inhibitors, as well as their treatment duration. Regarding the authors' concerns about the relationship between comorbidities and prognosis, this is indeed a critical issue. In our cohort, the median perioperative Karnofsky Performance Status before was 70, and no patients had severe comorbidities. This is partially attributable to the fact that IDH-mutant gliomas are more common in young and middle-aged adults.