Upfront molecular targeted therapy for the treatment of BRAF-mutant pediatric high-grade glioma.

BACKGROUND: The prognosis for patients with pediatric high-grade glioma (pHGG) is poor despite aggressive multimodal therapy. Objective responses to targeted therapy with BRAF inhibitors have been reported in some patients with recurrent BRAF-mutant pHGG but are rarely sustained. METHODS: We performed a retrospective, multi-institutional review of patients with BRAF-mutant pHGG treated with off-label BRAF +/- MEK inhibitors as part of their initial therapy. RESULTS: Nineteen patients were identified, with a median age of 11.7 years (range, 2.3-21.4). Histologic diagnoses included HGG (n = 6), glioblastoma (n = 3), anaplastic ganglioglioma (n = 4), diffuse midline glioma (n = 3), high-grade neuroepithelial tumor (n = 1), anaplastic astrocytoma (n = 1), and anaplastic astroblastoma (n = 1). Recurrent concomitant oncogenic alterations included CDKN2A/B loss, H3 K27M, as well as mutations in ATRX, EGFR, and TERT. Eight patients received BRAF inhibitor monotherapy. Eleven patients received combination therapy with BRAF and MEK inhibitors. Most patients tolerated long-term treatment well with no grade 4-5 toxicities. Objective and durable imaging responses were seen in the majority of patients with measurable disease. At a median follow-up of 2.3 years (range, 0.3-6.5), three-year progression-free and overall survival for the cohort were 65% and 82%, respectively, and superior to a historical control cohort of BRAF-mutant pHGG patients treated with conventional therapies. CONCLUSIONS: Upfront targeted therapy for patients with BRAF-mutant pHGG is feasible and effective, with superior clinical outcomes compared to historical data. This promising treatment paradigm is currently being evaluated prospectively in the Children's Oncology Group ACNS1723 clinical trial.

Arterial stiffness in childhood cancer survivors.

BACKGROUND: Cardiovascular disease is prevalent among childhood cancer survivors (CCS). Arterial stiffness measured by pulse wave velocity (PWV) may be predictive of cardiovascular morbidity. Increased PWV has been seen in adults following chemotherapy. PURPOSE: To evaluate PWV in a cohort of CCS and healthy controls. PATIENTS AND METHODS: All participants were >6 years old. CCS were >12 months off-therapy and free of cardiac disease, diabetes, and kidney dysfunction. Height, weight, blood pressure (BP), medications, cancer diagnosis, age at diagnosis, time off therapy, chemotherapy, and radiation exposures were recorded. PWV was measured on all participants. RESULTS: Sixty-eight CCS (mean 17.3 ± 6 years, 52.9% male), and 51 controls (mean 18.4 ± 5.5 years, 37.3% male) were evaluated. Among CCS, 34% had lymphoma, 44% leukemia, and 22% solid tumors, and 49% were exposed to radiation. CCS were off therapy 7 ± 4.2 years. Both groups were statistically similar in age, BMI, and BP. CCS ≥ 18 years old had significantly higher PWV compared to controls ≥ 18 years old (6.37 ± 0.89 vs. 5.76 ± 0.88 m/sec, P = 0.012). The relationship persisted in a regression model adjusted for age, sex, and BMI z-score (ß = 0.52, 95%CI 0.051-0.979, P = 0.03). Seventy percent of CCS ≥ 18 had elevated PWV compared to established norms. Radiation therapy, anthracycline dose, and chemotherapy exposures were not predictive of increased PWV in CCS. CONCLUSIONS: CCS ≥ 18 demonstrated prematurely elevated PVW. Further studies are needed to determine the predictive value of PWV in this population and its utility as a screening modality.