Influence of socioeconomic status on clinical outcomes of diffuse midline glioma and diffuse intrinsic pontine glioma.

OBJECTIVE: Given the lack of a definitive treatment and the poor prognosis of patients with diffuse midline glioma (DMG) and diffuse intrinsic pontine glioma (DIPG), socioeconomic status (SES) may affect treatment access and therefore survival. Therefore, this study aimed to examine the relationship between SES and treatment modalities, progression-free survival (PFS), and overall survival (OS) in children with DMG/DIPG. METHODS: A retrospective, single-institution review was conducted of medical records of patients ≤ 18 years of age who had DMG or DIPG that was diagnosed between 2000 and 2022. Patient demographics, surgical interventions, chemotherapy, radiation therapy, clinical trial enrollment, and medical care-related travel were extracted. SES variables (education and mean income) for associated patient census tracts were collected and stratified. Statistical analysis using unpaired t-tests, chi-square analysis, and log-rank tests was conducted. RESULTS: Of the 96 patients who met the inclusion criteria, the majority were female (59%) and non-Hispanic White (57%). The median PFS, median OS, and time from diagnosis to treatment did not differ between races/ethnicities or sex. Ninety-one of 96 patients had census tract data available. Patients from higher-income census tracts (> 50% of families with annual household income greater than $50,000) had a longer median OS (480 vs 235 days, p < 0.001) and traveled significantly longer distances for medical care (1550 vs 1114 miles, p = 0.048) than families from lower-income census tracts. Patients from the highest education quartile traveled significantly farther for treatment than the lowest education quartile (mean 2964 vs 478 miles, p = 0.047). Patients who received both oral and intravenous chemotherapy were more likely to be from higher-income census tracts than those who received intravenous or no chemotherapy. Duration of PFS, rates of clinical trial enrollment, biopsy rates, H3K27 mutation status, ventriculoperitoneal shunt placement rates, and radiotherapy rates were not associated with SES variables. CONCLUSIONS: Patients from families from higher-income census tracts experienced longer OS and traveled farther for treatment. Patients from families from higher-education-level census tracts traveled more often for treatment. The authors' findings suggest that SES influences DMG and DIPG OS. More studies should be done to understand the role of SES in the outcomes of children with DMG/DIPG.

Phase 1 study of high-dose DFMO, celecoxib, cyclophosphamide and topotecan for patients with relapsed neuroblastoma: a New Approaches to Neuroblastoma Therapy trial.

BACKGROUND: MYC genes regulate ornithine decarboxylase (Odc) to increase intratumoral polyamines. We conducted a Phase I trial [NCT02030964] to determine the maximum tolerated dose (MTD) of DFMO, an Odc inhibitor, with celecoxib, cyclophosphamide and topotecan. METHODS: Patients 2-30 years of age with relapsed/refractory high-risk neuroblastoma received oral DFMO at doses up to 9000 mg/m2/day, with celecoxib (500 mg/m2 daily), cyclophosphamide (250 mg/m2/day) and topotecan (0.75 mg/m2/day) IV for 5 days, for up to one year with G-CSF support. RESULTS: Twenty-four patients (median age, 6.8 years) received 136 courses. Slow platelet recovery with 21-day courses (dose-levels 1 and 2) led to subsequent dose-levels using 28-day courses (dose-levels 2a-4a). There were three course-1 dose-limiting toxicities (DLTs; hematologic; anorexia; transaminases), and 23 serious adverse events (78% fever-related). Five patients (21%) completed 1-year of therapy. Nine stopped for PD, 2 for DLT, 8 by choice. Best overall response included two PR and four MR. Median time-to-progression was 19.8 months, and 3 patients remained progression-free at >4 years without receiving additional therapy. The MTD of DFMO with this regimen was 6750 mg/m2/day. CONCLUSION: High-dose DFMO is tolerable when added to chemotherapy in heavily pre-treated patients. A randomized Phase 2 trial of DFMO added to chemoimmunotherapy is ongoing [NCT03794349].

A road map for the treatment of pediatric diffuse midline glioma.

Recent clinical trials for H3K27-altered diffuse midline gliomas (DMGs) have shown much promise. We present a consensus roadmap and identify three major barriers: (1) refinement of experimental models to include immune and brain-specific components; (2) collaboration among researchers, clinicians, and industry to integrate patient-derived data through sharing, transparency, and regulatory considerations; and (3) streamlining clinical efforts including biopsy, CNS-drug delivery, endpoint determination, and response monitoring. We highlight the importance of comprehensive collaboration to advance the understanding, diagnostics, and therapeutics for DMGs.

The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial.

BRAF genomic alterations are the most common oncogenic drivers in pediatric low-grade glioma (pLGG). Arm 1 (n = 77) of the ongoing phase 2 FIREFLY-1 (PNOC026) trial investigated the efficacy of the oral, selective, central nervous system-penetrant, type II RAF inhibitor tovorafenib (420 mg m-2 once weekly; 600 mg maximum) in patients with BRAF-altered, relapsed/refractory pLGG. Arm 2 (n = 60) is an extension cohort, which provided treatment access for patients with RAF-altered pLGG after arm 1 closure. Based on independent review, according to Response Assessment in Neuro-Oncology High-Grade Glioma (RANO-HGG) criteria, the overall response rate (ORR) of 67% met the arm 1 prespecified primary endpoint; median duration of response (DOR) was 16.6 months; and median time to response (TTR) was 3.0 months (secondary endpoints). Other select arm 1 secondary endpoints included ORR, DOR and TTR as assessed by Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO) criteria and safety (assessed in all treated patients and the primary endpoint for arm 2, n = 137). The ORR according to RAPNO criteria (including minor responses) was 51%; median DOR was 13.8 months; and median TTR was 5.3 months. The most common treatment-related adverse events (TRAEs) were hair color changes (76%), elevated creatine phosphokinase (56%) and anemia (49%). Grade ≥3 TRAEs occurred in 42% of patients. Nine (7%) patients had TRAEs leading to discontinuation of tovorafenib. These data indicate that tovorafenib could be an effective therapy for BRAF-altered, relapsed/refractory pLGG. ClinicalTrials.gov registration: NCT04775485 .

Rational combination platform trial design for children and young adults with diffuse midline glioma: A report from PNOC.

Background Diffuse midline glioma (DMG) is a devastating pediatric brain tumor unresponsive to hundreds of clinical trials. Approximately 80% of DMGs harbor H3K27M oncohistones, which reprogram the epigenome to increase the metabolic profile of the tumor cells. Methods We have previously shown preclinical efficacy of targeting both oxidative phosphorylation and glycolysis through treatment with ONC201, which activates the mitochondrial protease ClpP, and paxalisib, which inhibits PI3K/mTOR, respectively. Results ONC201 and paxalisib combination treatment aimed at inducing metabolic distress led to the design of the first DMG-specific platform trial PNOC022 (NCT05009992). Conclusions Here, we expand on the PNOC022 rationale and discuss various considerations, including liquid biome, microbiome, and genomic biomarkers, quality-of-life endpoints, and novel imaging modalities, such that we offer direction on future clinical trials in DMG.

Liquid Biopsy in H3K27M Diffuse Midline Glioma.

Diffuse midline glioma (DMG) with H3K27M mutation is an aggressive and difficult to treat pediatric brain tumor. Recurrent gain of function mutations in H3.3 (H3.3A) and H3.1 (H3C2) at the 27th lysine to methionine (H3K27M) are seen in over 2/3 of DMGs, and are associated with a worse prognosis. Due to the anatomical location of DMG, traditional biopsy carries risk for neurologic injury as it requires penetration of vital midline structures. Further, radiographic (MRI) monitoring of DMG often shows non-specific changes, which makes therapeutic monitoring difficult. This indicates a critical need for more minimally invasive methods, such as liquid biopsy, to understand, diagnose, and monitor H3K27M DMG. Here we review the use of all modalities to date to detect biomarkers of H3K27M in CSF, blood, and urine, and compare their effectiveness in detection, diagnosis, and monitoring treatment response. We provide specific detail of recent efforts to monitor CSF and plasma H3K27M cell-free DNA in patients undergoing therapy with the imipridone ONC201. Lastly, we discuss the future of therapeutic monitoring of H3K27M-DMG, including biomarkers such as mitochondrial DNA, mutant and modified histones, and novel sequencing-based approaches for improved detection methods.

Single-molecule systems for detection and monitoring of plasma circulating nucleosomes and oncoproteins in Diffuse Midline Glioma.

The analysis of cell-free tumor DNA (ctDNA) and proteins in the blood of cancer patients potentiates a new generation of non-invasive diagnostics and treatment monitoring approaches. However, confident detection of these tumor-originating markers is challenging, especially in the context of brain tumors, in which extremely low amounts of these analytes circulate in the patient's plasma. Here, we applied a sensitive single-molecule technology to profile multiple histone modifications on millions of individual nucleosomes from the plasma of Diffuse Midline Glioma (DMG) patients. The system reveals epigenetic patterns that are unique to DMG, significantly differentiating this group of patients from healthy subjects or individuals diagnosed with other cancer types. We further develop a method to directly capture and quantify the tumor-originating oncoproteins, H3-K27M and mutant p53, from the plasma of children diagnosed with DMG. This single-molecule system allows for accurate molecular classification of patients, utilizing less than 1ml of liquid-biopsy material. Furthermore, we show that our simple and rapid detection strategy correlates with MRI measurements and droplet-digital PCR (ddPCR) measurements of ctDNA, highlighting the utility of this approach for non-invasive treatment monitoring of DMG patients. This work underscores the clinical potential of single-molecule-based, multi-parametric assays for DMG diagnosis and treatment monitoring.

Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways.

Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multisite clinical studies. Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, whereas those treated after recurrence had a median overall survival of 9.3 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle-related genes in baseline tumor sequencing. ONC201 treatment increased 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient CSF samples. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuroglial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction. SIGNIFICANCE: The clinical, radiographic, and molecular analyses included in this study demonstrate the efficacy of ONC201 in H3K27M-mutant DMG and support ONC201 as the first monotherapy to improve outcomes in H3K27M-mutant DMG beyond radiation. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction. This article is featured in Selected Articles from This Issue, p. 2293.

Neuroimaging features of FOXR2-activated CNS neuroblastoma: A case series and systematic review.

BACKGROUND AND PURPOSE: CNS neuroblastoma, FOXR2-activated (CNS NB-FOXR2) is a newly recognized tumor type in the 2021 World Health Organization classification of central nervous system (CNS) tumors. We aimed to investigate the clinical and neuroimaging findings of CNS NB-FOXR2 and systematically review previous publications and three new cases. METHODS: We searched PubMed, SCOPUS, and Embase databases for patients with pathologically proven CNS NB-FOXR2 with sufficient information for preoperative CT and MRI findings. Two board-certified radiologists reviewed the studies and imaging data. RESULTS: Thirty-one patients from six previous publications and 3 patients from our hospital comprised the study population (median age, 4.2 [range: 1.4-16] years; 19 girls). Clinically, CNS NB-FOXR2 mainly affected children between 2 and 6 years (24/34, 67.6%). Nausea/vomiting and seizures were reported as the main presenting symptoms (100% in total). The tumors frequently showed hyperdensity compared to the cortex on nonenhanced CT (4/5, 80%) with calcification along the inner rim of the tumor (4/5, 80%). More than half of patients showed susceptibility artifacts indicating intratumoral hemorrhage and/or calcification (15/28, 53.6%) on T2*- and/or susceptibility-weighted imaging. Elevated relative cerebral blood volume and flow and percentile signal recovery were observed in one case with dynamic susceptibility contrast MRI. CONCLUSIONS: Characteristic imaging features including hyperdense attenuation of the solid components and calcification along the inner rim on CT and susceptibility-weighted imaging may assist with preoperative diagnosis of CNS NB-FOXR2 in pediatric patients.

Gene Therapy for High Grade Glioma: The Clinical Experience.

INTRODUCTION: High-grade gliomas (HGG) are the most common malignant primary brain tumors in adults, with a median survival of ~18 months. The standard of care (SOC) is maximal safe surgical resection, and radiation therapy with concurrent and adjuvant temozolomide. This protocol remains unchanged since 2005, even though HGG median survival has marginally improved. AREAS COVERED: Gene therapy was developed as a promising approach to treat HGG. Here, we review completed and ongoing clinical trials employing viral and non-viral vectors for adult and pediatric HGG, as well as the key supporting preclinical data. EXPERT OPINION: These therapies have proven safe, and pre- and post-treatment tissue analyses demonstrated tumor cell lysis, increased immune cell infiltration, and increased systemic immune function. Although viral therapy in clinical trials has not yet significantly extended the survival of HGG, promising strategies are being tested. Oncolytic HSV vectors have shown promising results for both adult and pediatric HGG. A recently published study demonstrated that HG47Δ improved survival in recurrent HGG. Likewise, PVSRIPO has shown survival improvement compared to historical controls. It is likely that further analysis of these trials will stimulate the development of new administration protocols, and new therapeutic combinations that will improve HGG prognosis.

The impact of clinical trial enrollment on specialty palliative care utilization in pediatric patients with high-grade gliomas.

BACKGROUND: Palliative care (PC) provides numerous benefits for children with cancer. Pediatric patients with high-grade glioma (HGG) are particularly well suited for early PC involvement given their high symptom burden and poor prognosis. However, studies continue to reveal that children with cancer, including HGG, have delayed PC involvement. We hypothesized that clinical trial enrollment may lead to a lack of or delay in PC involvement in this population. PROCEDURE: For each patient in our cohort of 43 pediatric patients with HGG, demographic, diagnostic, therapeutic, clinical trial enrollment, and PC information were collected. Statistical analysis was performed comparing PC characteristics between patients who did and did not enroll in a clinical trial. RESULTS: Seventy-two percent of patients had at least one visit with a PC provider. Fifty-six percent of patients enrolled in a clinical trial with HGG-directed therapy. Seventy-one percent of patients who enrolled in a clinical trial received specialty PC compared to 74% of non-trial participants (p = 1.000). Patients who enrolled in clinical trials received PC earlier in their disease course measured in days before death (mean = 177 days) compared to those who did not enroll (mean = 113 days, p = .180), though not statistically significant. CONCLUSIONS: The prevalence of clinical trial enrollment is high in patients with HGG and will likely increase as the genomic/epigenomic landscape of these tumors is better understood. As such, our data reassuringly suggest that trial participation does not interfere with the receipt of specialty PC in this population.

Pediatric Central Nervous System Cancers, Version 2.2023, NCCN Clinical Practice Guidelines in Oncology.

Central nervous system (CNS) cancers account for approximately one quarter of all pediatric tumors and are the leading cause of cancer-related death in children. More than 4,000 brain and CNS tumors are diagnosed each year in children and teens, and the incidence rate has remained stagnant in recent years. The most common malignant pediatric CNS tumors are gliomas, embryonal tumors consisting of predominately medulloblastomas, and germ cell tumors. The inaugural version of the NCCN Guidelines for Pediatric Central Nervous System Cancers focuses on the diagnosis and management of patients with pediatric diffuse high-grade gliomas. The information contained in the NCCN Guidelines is designed to help clinicians navigate the complex management of pediatric patients with diffuse high-grade gliomas. The prognosis for these highly aggressive tumors is generally poor, with 5-year survival rates of <20% despite the use of combined modality therapies of surgery, radiation therapy and systemic therapy. Recent advances in molecular profiling has expanded the use of targeted therapies in patients whose tumors harbor certain alterations. However, enrollment in a clinical trial is the preferred treatment for eligible patients.

Development of immunotherapy for high-grade gliomas: Overcoming the immunosuppressive tumor microenvironment.

The preclinical and clinical development of novel immunotherapies for the treatment of central nervous system (CNS) tumors is advancing at a rapid pace. High-grade gliomas (HGG) are aggressive tumors with poor prognoses in both adult and pediatric patients, and innovative and effective therapies are greatly needed. The use of cytotoxic chemotherapies has marginally improved survival in some HGG patient populations. Although several challenges exist for the successful development of immunotherapies for CNS tumors, recent insights into the genetic alterations that define the pathogenesis of HGG and their direct effects on the tumor microenvironment (TME) may allow for a more refined and targeted therapeutic approach. This review will focus on the TME in HGG, the genetic drivers frequently found in these tumors and their effect on the TME, the development of immunotherapy for HGG, and the practical challenges in clinical trials employing immunotherapy for HGG. Herein, we will discuss broadly the TME and immunotherapy development in HGG, with a specific focus on glioblastoma multiforme (GBM) as well as additional discussion in the context of the pediatric HGG diagnoses of diffuse midline glioma (DMG) and diffuse hemispheric glioma (DHG).

Expanding Access to CNS-TAP: Design, Development, and Initial Use of a Complex Precision Health Specialty Web App for Neuro-Oncology.

This paper offers a case study to demonstrate how a complex scoring model tool called CNS-TAP, originally created by a neuro-oncology team at one institution, was upgraded and made accessible to a wider audience. In the Results and Discussion, many issues of web app design, development, and sustainability are covered. Overall, we chart a path to expand access to many unique software tools created and needed by today's medical specialists.

Serial H3K27M cell-free tumor DNA (cf-tDNA) tracking predicts ONC201 treatment response and progression in diffuse midline glioma.

BACKGROUND: Diffuse Midline Glioma (DMG) with the H3K27M mutation is a lethal childhood brain cancer, with patients rarely surviving 2 years from diagnosis. METHODS: We conducted a multi-site Phase 1 trial of the imipridone ONC201 for children with H3K27M-mutant glioma (NCT03416530). Patients enrolled on Arm D of the trial (n = 24) underwent serial lumbar puncture for cell-free tumor DNA (cf-tDNA) analysis and patients on all arms at the University of Michigan underwent serial plasma collection. We performed digital droplet polymerase chain reaction (ddPCR) analysis of cf-tDNA samples and compared variant allele fraction (VAF) to radiographic change (maximal 2D tumor area on MRI). RESULTS: Change in H3.3K27M VAF over time ("VAF delta") correlated with prolonged PFS in both CSF and plasma samples. Nonrecurrent patients that had a decrease in CSF VAF displayed a longer progression free survival (P = .0042). Decrease in plasma VAF displayed a similar trend (P = .085). VAF "spikes" (increase of at least 25%) preceded tumor progression in 8/16 cases (50%) in plasma and 5/11 cases (45.4%) in CSF. In individual cases, early reduction in H3K27M VAF predicted long-term clinical response (>1 year) to ONC201, and did not increase in cases of later-defined pseudo-progression. CONCLUSION: Our work demonstrates the feasibility and potential utility of serial cf-tDNA in both plasma and CSF of DMG patients to supplement radiographic monitoring. Patterns of change in H3K27M VAF over time demonstrate clinical utility in terms of predicting progression and sustained response and possible differentiation of pseudo-progression and pseudo-response.

Panobinostat penetrates the blood-brain barrier and achieves effective brain concentrations in a murine model.

PURPOSE: Panobinostat, an orally bioavailable pan-HDAC inhibitor, has demonstrated potent activity in multiple malignancies, including pediatric brain tumors such as DIPG, with increased activity against H3K27M mutant cell lines. Given limited evidence regarding the CNS penetration of panobinostat, we sought to characterize its BBB penetration in a murine model. METHODS: Panobinostat 15 mg/kg was administered IV to 12 CD-1 female mice. At specified time points, mice were euthanized, blood samples were collected, and brains were removed. LC-MS was performed to quantify panobinostat concentrations. Cmax and AUC were estimated and correlated with previously published pharmacokinetic analyses and reports of IC-50 values in DIPG cell lines. RESULTS: Mean panobinostat plasma concentrations (ng/mL) were 27.3 ± 2.5 at 1 h, 7.56 ± 1.8 at 2 h, 1.48 ± 0.56 at 4 h, and 2.33 ± 1.18 at 7 h. Mean panobinostat brain concentrations (ng/g) were 60.5 ± 6.1 at 1 h, 42.9 ± 5.4 at 2 h, 33.2 ± 6.1 at 4 h, and 28.1 ± 4.3 at 7 h. Brain-to-plasma ratio at 1 h was 2.22 and the brain to plasma AUC ratio was 2.63. Based on the published human pharmacokinetic data, the anticipated Cmax in humans is expected to be significantly higher than the IC-50 identified in DIPG models. CONCLUSION: It is expected that panobinostat would be effective in CNS tumors where the IC-50 is in the low nanomolar range. Thus, our data demonstrate panobinostat crosses the BBB and achieves concentrations above the IC-50 for DIPG and other brain tumors and should be explored further for clinical efficacy.