Karbhari, Nishika

Abstract Circumscribed meningeal melanocytic neoplasms (CMMNs) represent a spectrum of rare central nervous system (CNS) tumors. Knowledge of their clinical behavior and molecular correlates remains limited. In this single‐institution retrospective study, we analyzed 31 patients (14 male, 17 female; median age, 59 years) diagnosed with CMMN between 2004 and 2025. In this patient cohort, based on the current World Health Organization Central Nervous System Tumor Classification (WHO CNS5) criteria, the majority of cases (18, 58.1%) fell into the intermediate‐grade melanocytic tumor (IMT) category based on histology, with either increased mitotic activity, CNS invasion, or both; 7 (22.6%) were melanocytomas, 5 (16.1%) melanomas, and 1 (3.2%) indeterminate case because of limited tissue. By next‐generation sequencing, mutations were identified in GNAQ/GNA11 in 21/24 cases, BAP1 in 5/23 (2 IMT, 3 melanoma), EIF1AX in 9/21 (1 melanocytoma, 8 IMT), and SF3B1 in 3/23 (2 IMT, 1 melanoma). Primary sites were spinal (20), posterior fossa (6), and supratentorial (5). During follow‐up, progression was observed in 5/6 melanocytomas, 9/13 IMTs, and 4/5 melanomas, suggesting a high frequency of progression across all groups. Two‐year progression‐free survival was 83.3% (95% confidence interval [CI], 53.5%–100.0%) for melanocytoma, 55.9% (95% CI, 26.7%–85.2%) for IMT, and 25.0% (95% CI, 0.0%–67.4%) for melanoma. Five‐year overall survival (OS) was 80.0% (95% CI, 44.9%–100.0%) for melanocytoma, 65.3% (95% CI, 37.0%–93.6%) for IMT, and 0.0% for melanoma. OS was significantly worse in melanoma compared with melanocytoma ( p = 0.002). BAP1 mutation correlated with worse OS (hazard ratio 8.73, p = 0.006). Upfront maximal safe resection appeared to be associated with improved outcomes in selected patients, whereas radiotherapy and systemic therapy did not demonstrate clear additional benefit in this cohort. In summary, our study shows that all CMMNs, irrespective of grade, have a high propensity to recur and melanoma histology and BAP1 mutation are associated with significantly worse OS.

Abstract Purpose Bevacizumab is an effective treatment for radiation necrosis; dose dependent radiographic and edema response data are lacking. Methods Multicenter, retrospective cohort study of adult patients with primary central nervous system tumors or brain metastases who received bevacizumab for radiation necrosis between June 2021 and July 2024. Patients were grouped by bevacizumab dose (7.5 mg/kg vs 10 mg/kg administered every three weeks). Primary outcome was edema response, assessed by a blinded neuro-oncologist. Secondary outcomes included contrast enhancing disease response, clinical response, adverse events, treatment discontinuation, and re-dosing for recurrent radiation necrosis. Analyses were performed with and without adjustment for tumor type. Results 104 patients were included (7.5 mg/kg, n = 53; 10 mg/kg, n = 51). Edema response differed between dosing groups in unadjusted analyses (p = 0.032), favoring the 7.5 mg/kg cohort; however, this association was attenuated after adjustment for tumor type. Contrast enhancing disease response did not differ between groups in either unadjusted or adjusted analyses (p = 0.43). Clinical response was higher in the 7.5 mg/kg group (65.2% vs 37.8%, p = 0.013). Tumor type differed significantly between cohorts (p < 0.001), with more primary CNS tumors in the 10 mg/kg group. Rates of adverse events, treatment discontinuation, and re-dosing were similar. Conclusions While lower-dose bevacizumab was associated with greater edema reduction in unadjusted analyses, this effect was attenuated after accounting for tumor type. Importantly, 7.5 mg/kg dosing appeared sufficient for achieving edema control and contrast enhancing disease response. These findings support an individualized approach to bevacizumab dosing in radiation necrosis and highlight the need for prospective, tumor-stratified studies.

Abstract Background Isocitrate dehydrogenase-1 (IDH-1) inhibitor ivosidenib and dual-IDH1/2 inhibitor vorasidenib have demonstrated clinical activity in the treatment of IDH-mutant gliomas. We evaluated the efficacy of vorasidenib in patients with prior exposure to ivosidenib. Methods Retrospective review of patients with IDH-mutant glioma treated with vorasidenib who had prior treatment with ivosidenib. Previous treatments, radiographic response, and adverse events were collected and analyzed descriptively. Results Twenty-nine patients (median age 42, 34% female) were evaluated. Tumor types included IDH-mutant astrocytoma (grade 2 n = 9, 31%; grade 3 n = 3, 10%; grade 4 n = 3, 10%) and oligodendroglioma (grade 2 n = 10, 34%; grade 3 n = 4, 14%). Treatments received prior to ivosidenib included surgical resection (n = 23, 79%), radiation (n = 16, 55%), temozolomide (n = 15, 52%), procarbazine, lomustine, vincristine (PCV, n = 2, 7%), bevacizumab (n = 3, 10%), lomustine (n = 2, 7%), and pembrolizumab (n = 1, 3%). Four patients received additional treatment in between ivosidenib and vorasidenib treatment. Ten of 16 (63%) patients who experienced disease progression on ivosidenib achieved stable disease and remain on vorasidenib, while 6 (37%) had continued progression. Eleven patients with stable disease on ivosidenib transitioned to vorasidenib following FDA approval and remained without progression. Two patients who transitioned to vorasidenib due to ivosidenib-related adverse effects (diarrhea and fatigue) experienced symptom resolution and maintained disease stability. Conclusions Vorasidenib demonstrated clinical efficacy in patients with IDH-mutant gliomas previously treated with ivosidenib. Notably, stable patients who transitioned maintained disease stability, while some of those with progressive disease achieved stabilization with vorasidenib. These findings support vorasidenib as a viable therapeutic option following ivosidenib exposure.

Abstract Background Murine double minute 2 (MDM2) inhibitors reactivate wild-type p53 and are a promising therapy for glioblastoma, IDH-wildtype (GBM). Brigimadlin is a highly potent MDM2 inhibitor being tested in a phase 0/1 clinical trial in combination with radiation in GBM. Methods Brigimadlin pharmacokinetics, pharmacodynamics, and efficacy were evaluated in GBM patient-derived xenografts (PDXs). Results In vitro, brigimadlin impaired viability in TP53 wild-type GBM with an IC50 of 0.8-6.6 nmol/L, but sensitivity did not correlate with MDM2 amplification. In vivo, MDM2 amplification was highly correlated with efficacy. In subcutaneous PDXs, 1 or 2 mg/kg brigimadlin dosed weekly was highly effective in 2 MDM2-amplified PDXs. At 2 mg/kg, brigimadlin delayed tumor regrowth by &gt;5-fold in the MDM2-amplified PDXs compared to 1.5-fold in a non-amplified PDX. In orthotopic PDXs, efficacy was more limited, but 2 mg/kg brigimadlin enhanced the response to fractionated radiation in MDM2-amplified PDXs. Consistent with blood-brain barrier efflux limiting drug distribution, 2 mg/kg brigimadlin extended survival by &gt;5-fold in an MDM2-amplified orthotopic PDX established in Rag1−/−Abcb1a−/− Abcg2−/− mice. In pharmacodynamic studies, p53 target genes were upregulated at both subtherapeutic and therapeutic dose levels, and the extent of activation did not correlate with MDM2 status. Concentrations of brigimadlin in tumor tissue were approximately 10-fold higher in MDM2-amplified tumors, and intracellular drug levels directly correlated with drug-dependent MDM2 upregulation, suggesting target binding affects drug accumulation. Conclusions Brigimadlin is highly effective in MDM2-amplified GBM when adequate drug levels are achieved in tumor tissue. MDM2 amplification impacts both treatment efficacy and intratumoral drug accumulation.

Abstract BACKGROUND Poly(ADP-ribose) polymerase inhibitors (PARPi), initially developed for BRCA-mutant tumors, are now being explored in gliomas to target DNA repair defects. In this retrospective analysis, we report our institutional experience using PARPi with temozolomide for glioma treatment. METHODS The medical record was retrospectively reviewed at our institution for neuro-oncology patients treated with off-label PARPi combined with temozolomide for &gt; 1 month between 1/1/2010 and 5/1/2025. RESULTS Nineteen patients (median age 45, 47% female) were included. PARPi included olaparib (n = 18) and niraparib (n = 1). Tumor types were glioblastoma (GBM, n = 7), Grade 4 IDH-mutant astrocytoma (G4A, n = 4), Grade 3 astrocytoma (G3A, n = 2), Grade 3 oligodendroglioma (G3O, n = 3), Grade 2 oligodendroglioma (G2O, n = 2), and IDH1-mutant brainstem glioma (BG, n = 1; IDH status determined per CSF 2-hydroxyglutarate without surgically confirmed histologic subtyping). Patients were heavily pre-treated. One patient lost to follow-up was censored at last contact. Patients had KPS ≥ 70 in all but one case (KPS 60) and multiple prior progressions (treatment was initiated at 4th recurrence or higher in 16/19 patients). Median time from drug initiation to progression, drug initiation to death, and overall survival were as follows (months): GBM (3.0, 6.5, 34.9), G4A (1.4, 3.9, 80.3), G3A (3.4, 4.2, 83.3), G3O (3.8, 17.2, 121.2), G2O (3.0, 3.5, 159.9), BG (4, 5.5, 164.8). CONCLUSIONS This retrospective analysis supports the tolerability of combining PARPi with temozolomide in a real-world, heavily pretreated glioma population. Despite limited evidence of durable tumor control, the regimen provided transient disease stability in patients with few remaining options. These findings may inform treatment in compassionate or salvage settings particularly when alkylator treatment is considered, and highlight the need for prospective trials to identify response biomarkers and assess clinical utility.

Abstract BACKGROUND The IDH inhibitor vorasidenib was FDA-approved for treatment of IDH-mutant grade 2 gliomas in August 2024. We evaluated vorasidenib in patients with grade 3 and 4 IDH-mutant gliomas who would not have been eligible for the INDIGO trial. METHODS Retrospective review of patients with grade 3 or 4 IDH-mutant gliomas treated with vorasidenib between 9/1/24 and 5/31/25. Prior treatments, radiographic response, adverse events and seizure control were collected for each patient. RESULTS Thirty-two patients (median age 39.5, 46.9% female) met inclusion criteria. Tumor types included grade 3 oligodendroglioma (11, 34.4%), grade 3 astrocytoma (13, 40.6%) and grade 4 astrocytoma (8, 25%). Thirty patients had contrast-enhancement; 2 patients had non-enhancing tumor. Prior treatments included surgical resection (30, 93.8%), radiation (27, 84.4%), cytotoxic chemotherapy (25, 78.1%), bevacizumab (5, 15.6%), pembrolizumab (3, 9.4%), and ivosidenib (8, 25%). Four patients (12.5%) were naïve to systemic treatment at the time of vorasidenib initiation. Median duration of vorasidenib was 101.5 days (range 18-255) with 19 patients still on vorasidenib at the time of last follow-up. Seventeen patients (53.1%) had stable disease, 11 (34.4%) had progressive disease, 2 (6.3%) did not yet have response assessment, and 2 (6.3%) died. Grade 1 transaminitis occurred in 12 patients with no high grade transaminitis. Two patients developed lymphopenia; both were heavily pre-treated with multiple alkylating agents; no other hematologic toxicity was noted. One patient developed myalgias leading to vorasidenib discontinuation. Nine patients had fatigue, 4 headaches, 2 nausea, 2 decreased appetite. In patients with a history of epilepsy, there were no reported seizures. CONCLUSIONS Vorasidenib was well-tolerated in this heavily pre-treated cohort of grade 3–4 IDH-mutant gliomas, with low-grade transaminitis and fatigue being the most common toxicities. Preliminary results show disease stability in 53.1% of patients after a median of 3.5 months. Conclusions are limited by short-interval follow-up.

Abstract Despite intensive research over the past two decades, all glioblastoma (GBM) Phase 3 drug trials have been negative. The utility of the preclinical studies used to inform development for 10 Phase 3 trials was evaluated by four criteria: 1) drug distribution to the brain, 2) tumor location (flank vs. intracranial), 3) GBM xenograft source (patient-derived (PD) vs. cell line-derived (CD)), and 4) magnitude of survival extension. For the trials evaluated, no preclinical brain:plasma (B/P) data were reported for enzastaurin, cilengitide, nimotuzumab, Depatux-M, or bevacizumab, although IgG typically has a B/P ≈1%. B/P for imatinib was 1-3% and the other four drugs ranged from 25% to 51%. Except for enzastaurin, all drugs were studied in orthotopic tumor survival studies. The best response for each drug compared to relevant control (relative increase in median survival) was 22% (nimotuzumab), 31% (marizomib), 36% (sunitinib CD) / 5% (sunitinib PD), 63% (bevacizumab/temozolomide), 140% (imatinib), 157% (Depatux-M), 220% (veliparib/temozolomide), 300% (cediranib); median survival was not reached for cilengitide. However, only veliparib and sunitinib were studied in orthotopic PD models, and a single CD model (U87 or D54) was used exclusively for four drugs (enzastaurin, nimotuzumab, sunitinib, marizomib). In summary, 6 of 10 drugs had unknown or very poor brain distribution, 8 of 10 drugs were tested exclusively in CD models, which have questionable translational value, and 3 of 10 drugs had nominal activity (&lt;50% survival prolongation) in preclinical survival studies. The stunning lack of clinical progress in GBM is deeply discouraging, but is consistent with underwhelming preclinical testing and the contextual interpretation of those results. Acknowledging multifaceted reasons for failed clinical trials, a more rigorous and critical approach should be used in preclinical studies, coupled with follow-up surgical window of opportunity studies, to identify and promote only the most promising therapies into advanced clinical testing.

Abstract BACKGROUND Access to in-person evaluations is challenging for patients with glioma due to disease-related disability and distance from specialized neuro-oncology centers. Telehealth is an alternative to in-person evaluations, but acceptability of and therapy compliance with this model has not been prospectively evaluated. METHODS In this single-arm non-randomized pragmatic clinical trial, we compared patient satisfaction with telehealth and in-person assessments among patients with glioma undergoing chemotherapy with temozolomide. Participants acted as their own controls, alternating between telehealth and in-person visits. Patient satisfaction with care delivered was evaluated by Press-Ganey surveys with Likert response scales (1-5, 1=very poor, 5=very good). A digital pill diary (DPD) was implemented to track chemotherapy compliance. RESULTS We accrued 30 patients (median age 59, 38% female) between October 2024 and May 2025. Half of the patients (n=15) reported a primary residence greater than 150 miles from our institution. Surveys from 25 participants were reviewed, with 17/25 completing one or more surveys following an in-person visit, and 21/25 completing one or more surveys following a telehealth visit. Overall average Press-Ganey scores were similar between the two visit modalities with high scores (telehealth=4.8; in-person=4.7). Median scores for specific modalities were similarly highly rated: likelihood of recommending practice to others (telehealth=5.0; in-person=5.0), concern the care provider showed (telehealth=5.0, in-person=4.7), provider’s discussion of treatment options (telehealth=5.0, in-person=5.0), provider effort to include patients in decision-making (telehealth=5.0, in-person=5.0). DPDs used to monitor treatment compliance indicated adherence to all prescribed doses of temozolomide in 75/79 cycles; the other 4 (of 79) treatment cycles were halted per provider instructions. CONCLUSION This interim assessment demonstrates feasibility of treating patients with similar patient satisfaction of care delivered between telehealth and in-person visits. The DPD was effective in tracking chemotherapy administration. Additional results including visit type preference and acute care utilization data are maturing.

Abstract BACKGROUND Pembrolizumab elicits durable responses in many solid tumors, yet activity in gliomas has been limited. Lymphopenia has been reported in association with reduced survival and a shorter time to progression on checkpoint inhibition in other solid tumors. We evaluated whether low absolute lymphocyte count (ALC) is related to worse outcomes in pembrolizumab-treated patients with gliomas. METHODS In this single-center retrospective study, we identified adults with gliomas who received ≥1 dose of pembrolizumab and had available lymphocyte counts at our center between 05/01/2018 and 1/31/2025. Patients’ demographics, dexamethasone use, baseline ALC (before initiation of pembrolizumab), and clinical outcomes were collected. Overall Survival (OS) was estimated using Kaplan–Meier analysis from the date of starting pembrolizumab to the date of death. RESULTS Ninety patients met eligibility criteria (glioblastoma [GBM] n = 44, astrocytoma n = 20, oligodendroglioma n = 13, meningioma n = 8, other n = 5); 62% were male and 31% (n = 28) harbored IDH-mutant tumors. Across all histological subtypes, baseline ALC&lt;750 cells/mm³ was associated with significantly shorter OS compared to baseline ALC≥750 cells/mm³ (3.7 vs 7.7 months, P = 0.0063) with similar dexamethasone exposure (63% vs 52%). In the recurrent GBM subgroup (n = 43; MGMT-methylated 26%), ALC≥750 cells/mm³ correlated with longer OS (8.5 vs 3.4 months, P = 0.0065) with a slightly lower proportion of patients on dexamethasone in high ALC group (52% vs 75%). Conversely, among patients with IDH-mutant gliomas (n = 28), no significant difference in OS was observed based on ALC levels (7.8 vs. 7.3 months, P = 0.58) with similar dexamethasone use (57% and 43% in high and low ALC groups, respectively). CONCLUSION Baseline lymphopenia preceding pembrolizumab treatment is associated with shorter OS in patients with GBM, but not in IDH-mutant gliomas. These associations require further validation in additional patient cohorts.