Health-related quality-of-life in treatment-naive CLL/SLL patients treated with zanubrutinib versus bendamustine plus rituximab.

OBJECTIVE: Zanubrutinib is a highly selective, next-generation Bruton's tyrosine kinase inhibitor. In the phase 3 SEQUOIA trial (NCT03336333), treatment with zanubrutinib resulted in significantly improved progression-free survival compared to bendamustine plus rituximab (BR) in adult patients with treatment-naïve chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) without del(17p). The current analysis compared the effects of zanubrutinib versus BR on patients' health-related quality-of-life (HRQoL). METHODS: In the SEQUOIA trial, patient-reported outcomes (PROs) were assessed at baseline and every 12 weeks (3 cycles) using the EORTC QLQ-C30 and EQ-5D-5L. Descriptive analyses were performed on all the questionnaires' scales and a mixed model for repeated measures was performed using the key QLQ-C30 endpoints of global health status/QoL (GHS/QoL), physical and role functioning, and symptoms of fatigue, pain, diarrhea, and nausea/vomiting at weeks 12 and 24. RESULTS: Compared with BR-treated patients, those in the zanubrutinib arm experienced greater improvements in HRQoL outcomes at both weeks 12 and 24. By week 24, mean change differences (95% confidence interval) between the arms were significant for GHS/QoL (4.9 [0.9, 9.0]), physical functioning (3.8 [0.8, 6.7]), diarrhea (-6.2 [-10.0, -2.5]), fatigue (-4.5 [-8.9, -0.1]), and nausea/vomiting (-4.5 [-8.9, -0.1]); role functioning (4.8 [-0.2, 9.7]) was marginally better in the zanubrutinib arm and there were no differences in pain symptoms (-0.4 [-4.3, 5.1]) between the arms. CONCLUSIONS: During the first 24 weeks of treatment, zanubrutinib was associated with better HRQoL outcomes in patients with treatment-naive CLL/SLL without del(17p) compared to BR. TRIAL REGISTRATION: The SEQUOIA trial is registered on clinicaltrials.gov as SEQUOIA trial (NCT03336333).

The Pharmacogenetics of Opiates and Its Impact on Delirium in Mechanically Ventilated Adults: A Pilot Study.

Background: Pharmacogenetics may explain a substantial proportion of the variation seen in the efficacy and risk profile of analgesosedative drugs and the incidence of delirium in critically ill adults. Objectives: Conduct a feasibility study to demonstrate the reliability of collecting and analyzing pharmacogenetic information from critically ill patients and to assess the impact of pharmacogenetics on intensive care unit (ICU) outcomes. Methods: We prospectively enrolled subjects from the Medical ICU at the University of North Carolina (UNC). DNA was obtained via a buccal swab and evaluated using the DNA2Rx assay. We collected data on demographics, daily cumulative psychoactive medication exposure, and severity of illness. We performed daily delirium assessments via the CAM-ICU. We analyzed associations between select single nucleotide polymorphisms (SNPs) and delirium. Results: From June, 2018 through January, 2019, we screened 244 patients and enrolled 50. The median age was 62.0 years old (range: 28-82 years old), and 27 (54%) of the subjects were female. In all, 49 (98%) samples were both high quality and sufficient quantity. In secondary analyses, we found that 80% (12/15) of patients with two 2 copies of a G allele at rs4680 on COMT experienced delirium, whereas 44% (4/9) of patients with 2 copies of an A allele at this location had delirium. In all, 44% (4/9) of patients with 2 T allele copies at rs7439366 on UGT2B7 experienced delirium compared to 73% (11/15) of patients with 2 C allele copies at this location. Conclusions: We can feasibly collect genetic information from critically ill adults. We were able to efficiently collect high quality DNA of sufficient quantity to conduct pharmacogenetic analysis in this critically ill population. Although the sample size of our current study is too small to conduct robust inferential analyses, it suggests potential SNP targets for a future larger study.

Response to Tyrosine Kinase Inhibitors in Real-World Patients With Chronic Myeloid Leukemia.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) are the front-line therapy for chronic myeloid leukemia (CML), where phase 3 clinical trials have demonstrated their safety and efficacy. However, trial patients may not be representative of real-world patients (RWPs). OBJECTIVE: To evaluate RWP clinical factors associated with effectiveness and safety in CML patients treated with TKIs. METHODS: Patients with CML treated with at least 30 days of imatinib, dasatinib, nilotinib, or bosutinib between 2014 and 2018 were included. Patients were stratified into categories based on the number of factors that would have precluded enrollment into pivotal TKI phase 3 trials (0, 1, ≥2). End points included complete hematologic response (CHR), early molecular response (EMR), major molecular response (MMR), adverse event (AE)-induced dose decreases, treatment interruptions, and treatment discontinuations. RESULTS: Final analyses included 174 patients. Patients with ≥2 factors had a higher risk of dose decreases (relative risk = 1.54; 95% CI = 1.02-2.34; P = 0.02) and a shorter time to dose decrease (hazard ratio = 2.43; 95% CI = 1.23-4.97; P = 0.006) compared with patients with 0 factors. Significant differences were observed in CHR at 1 month and MMR at 3 months between patients with 0 and ≥2 factors (P = 0.03 and P = 0.04, respectively). CONCLUSION AND RELEVANCE: Approximately 60% of our RWPs would have been excluded from the pivotal phase 3 TKI trials. These data suggest that RWPs require more precise dosing to achieve CML clinical milestones and to mitigate AEs, but findings should be validated prospectively.

Correction: A real-world evaluation of radium-223 in combination with abiraterone or enzalutamide for the treatment of metastatic castration-resistant prostate cancer.

[This corrects the article DOI: 10.1371/journal.pone.0253021.].

A real-world evaluation of radium-223 in combination with abiraterone or enzalutamide for the treatment of metastatic castration-resistant prostate cancer.

INTRODUCTION: Radium-223, abiraterone, and enzalutamide have each been shown to significantly improve survival as monotherapy in patients with metastatic castration-resistant prostate cancer. However, effects of combination radium-223 plus abiraterone or enzalutamide on survival and safety remain unclear. PATIENTS AND METHODS: This single-center retrospective cohort study used electronic health record data of patients with metastatic castration-resistant prostate cancer and bone metastases who were treated with radium-223 between April 1, 2014 and February 19, 2019. Patients who received radium-223 monotherapy were compared to patients who received a combination of radium-223 plus either abiraterone or enzalutamide. The primary endpoint was overall survival. Secondary endpoints included progression-free survival, time to symptomatic skeletal event, symptomatic skeletal event-free survival, and incidence of drug-related adverse events. Time-to-event analyses were estimated by log rank tests using Kaplan-Meier curves. Hazard ratios and 95% confidence intervals were derived from Cox proportional hazards models. Chi-square tests evaluated difference in serious adverse events between the two arms. RESULTS: A total of 60 patients met inclusion criteria (n = 41 in the monotherapy arm, n = 19 in the combination arm). Differences in median overall survival were not observed (12.7 vs. 12.8 months; HR 1.15, 95% CI 0.59-2.23; P = 0.68), but median progression-free survival was significantly longer in the combination arm (7.6 vs. 4.9 months; HR 1.94, 95% CI 1.11-3.40; P = 0.02). Significant differences were not observed in time to first SSE (P = 0.97), SSE-free survival (P = 0.16), or in the overall incidence of serious adverse events (P = 0.45). CONCLUSION: Combination radium-223 plus abiraterone or enzalutamide did not improve overall survival, but prolonged progression-free survival without increasing the incidence of serious adverse events in metastatic castration-resistant prostate cancer patients with bone metastases. However, these results are limited by small numbers and patient selection inherent in retrospective analysis.

Impact of High Volume Energy Drink Consumption on Electrocardiographic and Blood Pressure Parameters: A Randomized Trial.

Background Energy drinks have been linked to an increase in emergency room visits and deaths. We aim to determine the impact of energy drinks on electrocardiographic and hemodynamic parameters in young healthy volunteers. Methods and Results A randomized, double-masked, placebo-controlled, crossover study was conducted in healthy volunteers. Participants consumed 32 oz of either energy drink A, energy drink B, or placebo within 60 minutes on 3 study days with a 6-day washout period in between. The primary end point of QT c interval and secondary end points of QT interval, PR interval, QRS duration, heart rate, and brachial and central blood pressures were measured at baseline, and every 30 minutes for 240 minutes. A repeated-measures 2-way analysis of variance was performed with the main effects of intervention, time, and an interaction of intervention and time. Thirty-four participants were included (age 22.1±3.0 years). The interaction term of intervention and time was statistically significant for Bazett's corrected QT interval, Fridericia's corrected QT interval, QT , PR , QRS duration, heart rate, systolic blood pressure, diastolic blood pressure, central systolic blood pressure, and central diastolic blood pressure (all P<0.001). The maximum change from baseline in Bazett's corrected QT interval for drinks A, B, and placebo were +17.9±13.9, +19.6±15.8, and +11.9±11.1 ms, respectively ( P=0.005 for ANOVA ) ( P=0.04 and <0.01, respectively compared with placebo). Peripheral and central systolic and diastolic blood pressure were statistically significantly different compared with placebo (all P<0.001). Conclusion Energy drinks significantly prolong the QT c interval and raise blood pressure. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT03196908.