Response Rate and Molecular Correlates to Encorafenib and Binimetinib in BRAF-V600E Mutant High-Grade Glioma.

PURPOSE: Although fewer than 5% of high-grade gliomas (HGG) are BRAF-V600E mutated, these tumors are notable as BRAF-targeted therapy shows efficacy for some populations. The purpose of this study was to evaluate response to the combination of encorafenib with binimetinib in adults with recurrent BRAF-V600-mutated HGG. PATIENTS AND METHODS: In this phase 2, open-label, Adult Brain Tumor Consortium (ABTC) trial (NCT03973918), encorafenib and binimetinib were administered at their FDA-approved doses continuously in 28-day cycles. Eligible patients were required to have HGG or glioblastoma with a BRAF-V600E alteration that was recurrent following at least one line of therapy, including radiotherapy. RESULTS: Five patients enrolled between January 2020 and administrative termination in November 2021 (due to closure of the ABTC). Enrolled patients received treatment for 2 to 40 months; currently one patient remains on treatment. Centrally determined radiographic response rate was 60%, with one complete response and two partial responses. Methylation profiling revealed that all tumors cluster most closely with anaplastic pleomorphic xanthoastrocytoma (PXA). Transcriptional profile for MAPK-response signature was similar across all tumors at baseline and did not correlate with response in this small population. Circulating tumor DNA measured in plasma samples before treatment, during response, and upon progression showed feasibility of detection for the BRAF-V600E alteration. No new safety signal was detected. CONCLUSIONS: Encorafenib and binimetinib exhibit positive tumor responses in patients with recurrent BRAF-V600E mutant HGG in this small series, warranting therapeutic consideration. Although toxicity remains a concern for BRAF-targeted therapies, no new safety signal was observed in these patients.

Risk factors and prognosis of ovarian vein thrombosis.

: Ovarian vein thrombosis (OVT) remains poorly understood with no consensus regarding its importance or treatment. In this retrospective study, we investigated the clinical features, risk factors, treatment patterns, and prognosis of patients with OVT, including venous thromboembolism (VTE) recurrences. Adult patients who presented to our medical center with an identifiable diagnosis of OVT over a 10-year period were included in this retrospective observational study. Individual patient charts were reviewed to collect baseline and outcomes data. We identified 223 women with OVT. Median follow-up was 857 days. Only 36.6% presented with abdominal pain and 61.4% reported a history of gynecologic surgery. Overall, right or left OVT incidence was similar (44.6 and 41.4%, respectively) but peripartum patients were more likely to have right OVT (60.0%, P = 0.03). VTE recurred in 22 (9.9%) women, all of which were remote from the OVT and there were no recurrences in peripartum patients. Mean (±â€ŠSD) time to recurrence was 409 (±â€Š421) days. Only 7.6% of OVT patients were anticoagulated for OVT; these women had a 38% reduction in VTE recurrence but because of low numbers, this was not statistically significant. VTE recurrence after OVT was associated with greater mortality in all patients, including patients with cancer. OVT is associated with an increased rate of non-OVT recurrence. Peripartum OVT patients appear to constitute a different patient population as they were younger, exhibited different risk factors, and had no increased incidence of recurrence. Although only a minority of patients with OVT was anticoagulated, this group had a reduction in VTE recurrence. A prospective study is needed to determine the utility of anticoagulation for women with OVT.

Longitudinal Analysis of Patient Specific Predictors for Mortality in Sickle Cell Disease.

INTRODUCTION: White Blood Cell (WBC) count, %HbF, and serum creatinine (Cr), have been identified as markers for increased mortality in sickle cell anemia (SCA) but no studies have examined the significance of longitudinal rate of change in these or other biomarkers for SCA individuals. METHODS: Clinical, demographic and laboratory data from SCA patients seen in 2002 by our hospital system were obtained. Those who were still followed in 2012 (survival cohort) were compared to those who had died in the interim (mortality cohort). Patients lost to follow-up were excluded. Age adjusted multivariable Cox proportional hazards models were constructed to assess hazard ratios of mortality risk associated with the direction and degree of change for each variable. RESULTS: 359 SCA patients were identified. Baseline higher levels of WBC, serum creatinine and hospital admissions were associated with increased mortality, as were alkaline phosphatase and aspartate aminotransaminase levels. Lower baseline levels of %HbF were also associated with increased mortality. When longitudinal rates of change for individuals were assessed, increases in Hb or WBC over patient baseline values were associated with greater mortality risk (HR 1.54, p = 0.02 and HR 1.16, p = 0.01 with negative predictive values of 87.8 and 94.4 respectively), while increasing ED use was associated with decreased mortality (HR 0.84, p = 0.01). We did not detect any increased mortality risk for longitudinal changes in annual clinic visits or admissions, creatinine or %HbF. CONCLUSIONS: Although initial steady state observations can help predict survival in SCA, the longitudinal course of a patient may give additional prognostic information.

Elevated Steady State WBC and Platelet Counts Are Associated with Frequent Emergency Room Use in Adults with Sickle Cell Anemia.

INTRODUCTION: Sickle cell anemia has many sequelae that result in emergency department (ED) use, but a minority of patients with sickle cell disease are frequent utilizers and make up the majority of ED visits. If patients who are likely to be frequent ED can be identified in steady state, they can be treated with disease modifying agents in an attempt to reduce ED use frequency. We sought to identify steady state markers for frequent ED use. METHODS: We identified all patients with SS/Sß0 seen at our facilities in 2012. Health care utilization over the entire year was calculated and ED visit numbers categorized as either 0-1, 2-5, or 6 or more visits a year. Steady state and acutely active laboratory parameters were collected and analyzed using analysis of variance models and odds ratios. RESULTS: 432 adult sickle cell patients were identified, ages 18-87, 54% female, and 38% had been prescribed hydroxyurea. Of the 432 patients,192 had 0-1 visits in the year, 144 had 2-5 visits in the year, and 96 had >6 visits for a total of 2259 visits. Those who had >6 visits accounted for 1750 (77%) of the total visits for the year. When steady state laboratory markers were examined, each additional 50x10(9)/L platelets was associated with 22% greater risk (p < .001); each 1x10(9)/L of WBC was associated with 11% greater risk (p = .003), and each 1g/dL Hb was associated with 23% lower risk (p = .007) of >6 ED visits/year. We did not observe a relationship between baseline HbF, LDH or reticulocyte count with >6 ED visits. CONCLUSION: Patients with elevated white blood cell counts, elevated platelet counts, and low hemoglobin levels exhibited higher risk for frequent ED utilization and could be candidates for early and aggressive therapy with disease modifying agents.