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.

Implementation and outcomes of a pharmacist-led collaborative drug therapy management program for oncology symptom management.

INTRODUCTION: Nausea, vomiting, constipation, and diarrhea are common cancer and cancer therapy adverse effects. Pharmacists are uniquely positioned to optimize patient symptom control and minimize excess use of hospital resources, such as emergency department visits. METHODS: Michigan Medicine oncology clinical pharmacists have been independently providing patient symptom management through a collaborative drug therapy management (CDTM) program which established guidelines for management of gastrointestinal toxicities (nausea, vomiting, diarrhea, and/or constipation) secondary to a patient's cancer diagnosis or treatment of the cancer. Patients were referred to the pharmacist by the treating oncologist or hematologist. RESULTS: From June 2019 to May 2020, there were a total of 62 patient referrals. Ten of the 62 referrals did not meet the CDTM inclusion criteria, resulting in 52 patients who were managed by the pharmacists. The total number of individual pharmacist visits was 136, with a median of 2.2 (range, 0-11) visits per patient referred. A total of 169 categorized pharmacist interventions were captured. Most interventions (100/169, 59.2%) were related to nausea/vomiting. Diarrhea-related and constipation-related interventions accounted for 10 (5.9%) and 13 (7.7%) of the total interventions, respectively. Most patients (36/52, 69.2%) had a reduction in the severity of their referral diagnosis symptom(s) based on Common Terminology Criteria for Adverse Events grading. CONCLUSION: The Michigan Medicine Pharmacist CDTM program allowed pharmacists to independently manage gastrointestinal toxicities of patients with cancer and improved patient symptom severity. The CDTM program has the opportunity to improve quality of care.

Correction to: Targeting and Therapeutic Monitoring of H3K27M-Mutant Glioma.

The original version of this review article unfortunately contained a mistake in the author group section.

Targeting and Therapeutic Monitoring of H3K27M-Mutant Glioma.

PURPOSE OF REVIEW: H3K27M is a frequent histone mutation within diffuse midline gliomas and is associated with a dismal prognosis, so much so that the 2016 CNS WHO classification system created a specific category of "Diffuse Midline Glioma, H3K27M-mutant". Here we outline the latest pre-clinical data and ongoing current clinical trials that target H3K27M, as well as explore diagnosis and treatment monitoring by serial liquid biopsy. RECENT FINDINGS: Multiple epigenetic compounds have demonstrated efficacy and on-target effects in pre-clinical models. The imipridone ONC201 and the IDO1 inhibitor indoximod have demonstrated early clinical activity against H3K27M-mutant gliomas. Liquid biopsy of cerebrospinal fluid has shown promise for clinical use in H3K27M-mutant tumors for diagnosis and monitoring treatment response. While H3K27M has elicited a widespread platform of pre-clinical therapies with promise, much progress still needs to be made to improve outcomes for diffuse midline glioma patients. We present current treatment and monitoring techniques as well as novel approaches in identifying and targeting H3K27M-mutant gliomas.