Long-term safety and efficacy outcomes of valoctocogene roxaparvovec gene transfer up to 6 years post-treatment.

INTRODUCTION: Valoctocogene roxaparvovec uses an adeno-associated virus serotype 5 (AAV5) vector to transfer a factor VIII (FVIII) coding sequence to individuals with severe haemophilia A, providing bleeding protection. AIM: To assess safety and efficacy of valoctocogene roxaparvovec 5-6 years post-treatment. METHODS: In a phase 1/2 trial, adult male participants with severe haemophilia A (FVIII ≤1 IU/dL) without FVIII inhibitors or anti-AAV5 antibodies received valoctocogene roxaparvovec and were followed for 6 (6 × 1013 vg/kg; n = 7) and 5 (4 × 1013 vg/kg; n = 6) years. Safety, including investigation of potential associations between a malignancy and gene therapy, and efficacy are reported. RESULTS: No new treatment-related safety signals emerged. During year 6, a participant in the 6 × 1013  vg/kg cohort was diagnosed with grade 2 parotid gland acinar cell carcinoma; definitive treatment was uncomplicated parotidectomy with lymph node dissection. Target enrichment sequencing of tumour and adjacent healthy tissue revealed low vector integration (8.25 × 10-5 per diploid cell). Integrations were not elevated in tumour samples, no insertions appeared to drive tumorigenesis, and no clonal expansion of integration-containing cells occurred. During all follow-ups, >90% decreases from baseline in annualised treated bleeds and FVIII infusion rates were maintained. At the end of years 6 and 5, mean FVIII activity (chromogenic assay) was 9.8 IU/dL (median, 5.6 IU/dL) and 7.6 IU/dL (median, 7.1 IU/dL) for the 6 × 1013 and 4 × 1013 vg/kg cohorts, respectively, representing proportionally smaller year-over-year declines than earlier timepoints. CONCLUSIONS: Valoctocogene roxaparvovec safety and efficacy profiles remain largely unchanged; genomic investigations showed no association with a parotid tumour.

Non-surgical management and analgesia strategies for older adults with multiple rib fractures: A systematic review, meta-analysis, and joint practice management guideline from the Eastern Association for the Surgery of Trauma and the Chest Wall Injury Society.

BACKGROUND: Chest wall injury in older adults is a significant cause of morbidity and mortality. Optimal nonsurgical management strategies for these patients have not been fully defined regarding level of care, incentive spirometry (IS), noninvasive positive pressure ventilation (NIPPV), and the use of ketamine, epidural, and other locoregional approaches to analgesia. METHODS: Relevant questions regarding older patients with significant chest wall injury with patient population(s), intervention(s), comparison(s), and appropriate selected outcomes were chosen. These focused on intensive care unit (ICU) admission, IS, NIPPV, and analgesia including ketamine, epidural analgesia, and locoregional nerve blocks. A systematic literature search and review were conducted, our data were analyzed qualitatively and quantitatively, and the quality of evidence was assessed per the Grading of Recommendations Assessment, Development, and Evaluation methodology. No funding was used. RESULTS: Our literature review (PROSPERO 2020-CRD42020201241, MEDLINE, EMBASE, Cochrane, Web of Science, January 15, 2020) resulted in 151 studies. Intensive care unit admission was qualitatively not superior for any defined cohort other than by clinical assessment. Poor IS performance was associated with prolonged hospital length of stay, pulmonary complications, and unplanned ICU admission. Noninvasive positive pressure ventilation was associated with 85% reduction in odds of pneumonia ( p < 0.0001) and 81% reduction in odds of mortality ( p = 0.03) in suitable patients without risk of airway loss. Ketamine use demonstrated no significant reduction in pain score but a trend toward reduced opioid use. Epidural and other locoregional analgesia techniques did not affect pneumonia, length of mechanical ventilation, hospital length of stay, or mortality. CONCLUSION: We do not recommend for or against routine ICU admission. We recommend use of IS to inform ICU status and conditionally recommend use of NIPPV in patients without risk of airway loss. We offer no recommendation for or against ketamine, epidural, or other locoregional analgesia. LEVEL OF EVIDENCE: Systematic Review/Meta-analysis; Level IV.

Massive Transfusion Protocol Predictive Modeling in the Modern Electronic Medical Record.

Objectives: Integrate a predictive model for massive transfusion protocol (MTP) activation and delivery in the electronic medical record (EMR) using prospectively gathered data; externally validate the model and assess the accuracy and precision of the model over time. Background: The Emory model for predicting MTP using only four input variables was chosen to be integrated into our hospital's EMR to provide a real time clinical decision support tool. The continuous variable output allows for periodic re-calibration of the model to optimize sensitivity and specificity. Methods: Prospectively collected data from level 1 and 2 trauma activations were used to input heart rate, systolic blood pressure, base excess (BE) and mechanism of injury into the EMR-integrated model for predicting MTP activation and delivery. MTP delivery was defined as: 6 units of packed red blood cells/6 hours (MTP1) or 10 units in 24 hours (MTP2). The probability of MTP was reported in the EMR. ROC and PR curves were constructed at 6, 12, and 20 months to assess the adequacy of the model. Results: Data from 1162 patients were included. Areas under ROC for MTP activation, MTP1 and MTP2 delivery at 6, 12, and 20 months were 0.800, 0.821, and 0.831; 0.796, 0.861, and 0.879; and 0.809, 0.875, and 0.905 (all P < 0.001). The areas under the PR curves also improved, reaching values at 20 months of 0.371, 0.339, and 0.355 for MTP activation, MTP1 delivery, and MTP2 delivery. Conclusions: A predictive model for MTP activation and delivery was integrated into our EMR using prospectively collected data to externally validate the model. The model's performance improved over time. The ability to choose the cut-points of the ROC and PR curves due to the continuous variable output of probability of MTP allows one to optimize sensitivity or specificity.

A Meta-Analysis of Higher-risk Myelodysplastic Syndrome Trials to Evaluate the Relationship between Short-term Endpoints and Overall Survival.

Background: The objective of this work was to evaluate the relationship between the response rates and median overall survival (OS) in higher-risk myelodysplastic syndrome (HR-MDS) to determine whether response rates could be used as predictors of median OS. Methods: Relevant MDS clinical trials were identified through a review of published literature. Weighted linear regression was performed with various linearizing transformations of response rates and median OS using the in-house built HR-MDS clinical trials database. Covariates of interest were evaluated using a forward inclusion, backward elimination covariate model building procedure at α=0.01 and α=0.005, respectively. Results: Twenty-five trials involving 38 cohorts were included in the meta-analysis. The analysis demonstrated that partial response (PR) or better rate (sum of complete response (CR), marrow complete response (mCR) and PR rates) was a strong predictor of median OS (adjusted R2=0.64). The median OS was 3.3 months longer (P < 0.005) with azacitidine treatment compared to treatment with other drugs for a given response rate and prior therapy status. We also have shown that the median OS of treatment naïve HR-MDS patients was 4.5 months longer (P < 0.0001) compared to that of previously treated patients for a given response rate and treatment group. Conclusion: Significant correlation between PR or better rate and median OS in HR-MDS highlights the potential to use PR or better rate as a surrogate endpoint to accelerate development of novel therapies for MDS.

Pharmacokinetics of the BCL-2 Inhibitor Venetoclax in Subjects with Hepatic Impairment.

INTRODUCTION: Venetoclax is a selective B cell lymphoma-2 inhibitor. It is approved for treatment of chronic lymphocytic leukemia and is being investigated for other hematological malignancies. Venetoclax is predominantly eliminated by the liver; therefore, there is a need to investigate the effect of hepatic insufficiency on venetoclax pharmacokinetics. METHODS: A phase I study was carried out in 24 women with normal hepatic function or mild, moderate, or severe hepatic impairment (based on Child-Pugh scores), who received a single 50 mg dose of venetoclax with a low-fat meal. Blood samples were collected up to 120 h after venetoclax administration. Pharmacokinetic parameters were estimated using non-compartmental methods. RESULTS: Venetoclax maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) in subjects with mild or moderate hepatic impairment were similar to subjects with normal hepatic function. Mean venetoclax AUC in subjects with severe hepatic impairment was 2.3- to 2.7-fold higher than in subjects with normal hepatic function. The half-life of venetoclax in subjects with severe hepatic impairment was approximately two-fold longer than in subjects with normal hepatic function and subjects with mild or moderate hepatic impairment. Unbound fractions of venetoclax in subjects with mild, moderate, and severe hepatic impairment were similar to the subjects with normal hepatic function. No significant adverse safety events were reported. CONCLUSIONS: No venetoclax dosage adjustment is required in subjects with mild or moderate hepatic impairment. In subjects with severe hepatic impairment, a 50% dose reduction of venetoclax is recommended to account for higher exposures and the longer half-life.

What's in a Name? Provider Perception of Injured John Doe Patients.

BACKGROUND: We previously demonstrated that unidentified aliased patients, John Doe's (DOEs), are one of the highest risk and most medically fragile populations of injured patients. Aliasing can result in misplaced information and confusion that must be overcome by health care professionals. DOE alias use is institutionally dependent and not uniform, which may lead to significant variation in perception of confusion and error. We sought to determine if health care practitioners experience confusion that may result in compromised care when caring for injured DOE patients. METHODS: After obtaining institutional review board approval, we surveyed critical care nurses, nurse practitioners, resident physicians, and surgeons who care for DOE patients at two academic level I trauma centers with separate DOE alias practices. Surveys asked whether caring for DOE patients created possible or actual confusion and possible or actual patient care errors. In one institution (Selective DOE), only unidentified patients were given an alias that was reconciled when information became available. At the other institution (All DOE), all trauma patients were admitted with an alias that was reconciled within 24 h. Respondents were invited to complete an anonymous questionnaire regarding the care for DOE patients. Results were analyzed with Wilcoxon rank-sum tests, and significance was assessed at a level of 0.05. RESULTS: Of 176 total respondents, 120 (68.2%) reported from Selective DOE and 56 (31.8%) from All DOE. Overall 53.1% reported that DOE use can cause serious confusion. Specifically, 31.3% reported experiencing actual confusion, although only 4% reported actual errors. Nurses had significantly higher perceived risk of confusion in the system of All DOE versus Selective DOE assignment (17.9% versus 4.2%, P < 0.01). Resident physicians reported significantly more frequent actual mistakes within the All DOE versus Selective DOE (24.1% versus 6.6%, P < 0.01), despite finding no significant difference in resident perception of confusion (21.4% versus 12.5%, respectively, P = 0.18). CONCLUSIONS: Our study sheds light on clinical consequences of EMR use and aliases for end users. We show that nurses perceive that there are greater potential complications associated with DOE aliases use, and this varies depending on the system used for managing unidentified patients. Minimizing DOE alias use may help to minimize provider confusion, risk for error, and patient safety.

Socioeconomic Status Affects Outcomes After Severity-Stratified Traumatic Brain Injury.

BACKGROUND: Socioeconomic status (SES) and race have been shown to increase the incidence of being afflicted by a traumatic brain injury (TBI) resulting in worse posthospitalization outcomes. The goal of this study was to determine the effect disparities have on in-hospital mortality, discharge to inpatient rehabilitation, hospital length of stay (LOS), and TBI procedures performed stratified by severity of TBI. METHODS: This was a retrospective cohort study of patients with closed head injuries using the National Trauma Data Bank (2012-2015). Multivariate logistic/linear regression models were created to determine the impact of race and insurance status in groups graded by head Abbreviated Injury Scale (AIS). RESULTS: We analyzed 131,461 TBI patients from NTDB. Uninsured patients experienced greater mortality at an AIS of 5 (odds ratio [OR] = 1.052, P = 0.001). Uninsured patients had a decreased likelihood of being discharged to inpatient rehabilitation with an increasing AIS beginning from an AIS of 2 (OR = 0.987, P = 0.008) to an AIS of 5 (OR = 0.879, P < 0.001). Black patients had an increased LOS as their AIS increased from an AIS of 2 (0.153 d, P < 0.001) to 5 (0.984 d, P < 0.001) with the largest discrepancy in LOS occurring at an AIS of 5. CONCLUSIONS: Disparities in race and SES are associated with differences in mortality, LOS, and discharge to inpatient rehabilitation. Patients with more severe TBI have the greatest divergence in treatment and outcome when stratified by race and ethnicity as well as SES.

Effect of Azithromycin on Venetoclax Pharmacokinetics in Healthy Volunteers: Implications for Dosing Venetoclax with P-gp Inhibitors.

INTRODUCTION: Venetoclax, a substrate of cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp), is approved for the treatment of patients with chronic lymphocytic leukemia who have received at least one prior therapy. This study evaluated the effect of azithromycin, a commonly used antibiotic in cancer patients and a P-gp inhibitor, on the pharmacokinetics of venetoclax. METHODS: In this single-center, open-label, nonfasting, two-period study, 12 healthy female subjects received a single 100 mg dose of venetoclax on day 1 of period 1 and day 3 of period 2. Subjects received azithromycin 500 mg on day 1 and 250 mg once daily on days 2 through 5. Serial blood samples for the determination of venetoclax concentrations were collected after dosing in both periods. Safety was evaluated throughout the study. RESULTS: Following coadministration of venetoclax with multiple doses of azithromycin, venetoclax maximum concentration and area under the curve to infinite time were 25% and 35% lower, respectively, compared to venetoclax administered alone. Venetoclax half-life and time to maximum concentration remained relatively unchanged when administered with azithromycin. Venetoclax was well tolerated with no serious adverse events reported. CONCLUSIONS: The modest changes in venetoclax exposures when given with azithromycin indicate that no dose adjustment would be needed when venetoclax is coadministered with azithromycin or other drugs with P-gp inhibitory potential. Azithromycin represents an alternative to other antimicrobial agents with higher potential to alter venetoclax pharmacokinetics such as clarithromycin, erythromycin, and ciprofloxacin. FUNDING: AbbVie in collaboration with Genentech/Roche.

Statins enhance efficacy of venetoclax in blood cancers.

Statins have shown promise as anticancer agents in experimental and epidemiologic research. However, any benefit that they provide is likely context-dependent, for example, applicable only to certain cancers or in combination with specific anticancer drugs. We report that inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) using statins enhances the proapoptotic activity of the B cell lymphoma-2 (BCL2) inhibitor venetoclax (ABT-199) in primary leukemia and lymphoma cells but not in normal human peripheral blood mononuclear cells. By blocking mevalonate production, HMGCR inhibition suppressed protein geranylgeranylation, resulting in up-regulation of proapoptotic protein p53 up-regulated modulator of apoptosis (PUMA). In support of these findings, dynamic BH3 profiling confirmed that statins primed cells for apoptosis. Furthermore, in retrospective analyses of three clinical studies of chronic lymphocytic leukemia, background statin use was associated with enhanced response to venetoclax, as demonstrated by more frequent complete responses. Together, this work provides mechanistic justification and clinical evidence to warrant prospective clinical investigation of this combination in hematologic malignancies.

Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study.

BACKGROUND: Elderly patients (aged ≥65 years) with acute myeloid leukaemia have poor outcomes and no effective standard-of-care therapy exists. Treatment with hypomethylating agents such as azacitidine and decitabine is common, but responses are modest and typically short-lived. The oral anti-apoptotic B-cell lymphoma 2 protein inhibitor, venetoclax, has shown promising single-agent activity in patients with relapsed or refractory acute myeloid leukaemia and preclinical data suggested synergy between hypomethylating agents and venetoclax, which led to this combination phase 1b study. METHODS: Previously untreated patients aged 65 years and over with acute myeloid leukaemia who were ineligible for standard induction therapy were enrolled into this non-randomised, open-label, phase 1b study. Patients were required to have an Eastern Cooperative Oncology Group performance status of 0-2 and either intermediate-risk or poor-risk cytogenetics. Patients were enrolled into one of three groups for the dose-escalation phase of this study: group A (venetoclax and intravenous decitabine 20 mg/m2 [days 1-5 of each 28-day cycle]), group B (venetoclax and subcutaneous or intravenous azacitidine 75 mg/m2 [days 1-7 of each 28-day cycle]), and group C (a venetoclax and decitabine substudy with the oral CYP3A inhibitor posaconazole, 300 mg twice on cycle 1, day 21, and 300 mg once daily from cycle 1, days 22-28, to assess its effect on venetoclax pharmacokinetics). Dose escalation followed a standard 3 + 3 design with at least three evaluable patients enrolled per cohort; daily target doses of venetoclax for groups A and B were 400 mg (cohort 1), 800 mg (cohorts 2 and 3), and 1200 mg (cohort 4), and 400 mg for group C. The primary endpoints were the safety and pharmacokinetics of venetoclax plus decitabine or azacitidine, and to determine the maximum tolerated dose and recommended phase 2 dose. Secondary endpoints included the preliminary anti-leukaemic activity of venetoclax with decitabine or azacitidine through the analysis of overall response, duration of response, and overall survival. We analysed safety, pharmacokinetics, and anti-leukaemic activity in all patients who received one or more venetoclax doses. The expansion phase of the study is ongoing but is closed to accrual. This trial is registered with ClinicalTrials.gov, number NCT02203773. FINDINGS: 57 patients were enrolled in the study. 23 patients in group A and 22 patients in group B were enrolled between Nov 19, 2014, and Dec 15, 2015, and 12 patients in group C were enrolled between June 14, 2015, and Jan 16, 2016. As of data cutoff on June 15, 2016, the most common grade 3-4 treatment-emergent adverse events were thrombocytopenia (27 [47%] of 57 patients; nine in group A, 13 in group B, and five in group C), febrile neutropenia (24 [42%] of 57; 11 in group A, ten in group B, and three in group C), and neutropenia (23 [40%] of 57; 12 in group A, eight in group B, and three in group C). The most common serious treatment-emergent adverse event in groups A and B was febrile neutropenia (seven [30%] of 23 patients vs seven [32%] of 22), whereas in group C it was lung infection (four [33%] of 12 patients). 49 (86%) of 57 patients had treatment-related adverse events; the most common in groups A and B included nausea (12 [52%] patients vs seven [32%] patients), fatigue (six [26%] patients vs seven [32%]), and decreased neutrophil count (six [26%] patients vs six [27%]), whereas in group C the most common were nausea (seven [58%] of 12 patients), leucopenia (six [50%]), vomiting (five [42%]), and decreased platelet count (five [42%]). The maximum tolerated dose was not reached. The recommended phase 2 dose was 400 mg once a day or 800 mg with an interrupted dosing schedule (safety expansion). In total, four (7%) of 57 patients had died within 30 days of the first venetoclax dose caused by sepsis (group B), bacteraemia (group A), lung infection (group C), and respiratory failure (group A). Tumour lysis syndrome was not observed. Decitabine and azacitidine did not substantially affect venetoclax exposures. Overall, 35 (61%; 95% CI 47·6-74·0) of 57 patients achieved complete remission or complete remission with incomplete marrow recovery. In groups A and B, 27 (60%; 95% CI 44·3-74·3) of 45 patients had complete remission or complete remission with incomplete marrow recovery. INTERPRETATION: Venetoclax plus hypomethylating agent therapy seems to be a novel, well-tolerated regimen with promising activity in this underserved patient population. Evaluation of expansion cohorts is ongoing at 400 mg and 800 mg doses using both hypomethylating agent combinations. FUNDING: AbbVie and Genentech.

Pharmacokinetics of the BCL-2 Inhibitor Venetoclax in Healthy Chinese Subjects.

Venetoclax has been approved in the United States, Europe, Canada, and Australia for appropriate patients with difficult-to-treat chronic lymphocytic leukemia (CLL). The objective of this phase 1 study was to evaluate the pharmacokinetics of venetoclax in Chinese subjects to inform the dose selection of venetoclax in a phase 2 study of patients with relapsed/refractory (R/R) CLL in China. Twelve healthy first-generation Han Chinese subjects received a single 100-mg dose of venetoclax following a low-fat breakfast. Pharmacokinetic parameters were estimated using noncompartmental methods. After a single dose of venetoclax in healthy Chinese subjects, the median time to peak concentration was 6 hours (range, 4 to 6 hours), and the mean ± SD Cmax , AUCinf , and terminal half-life were 1.0 ± 0.32 µg/mL, 12.6 ± 5.4 µg·h/mL, and 18.4 ± 2.97 hours, respectively. On average, venetoclax Cmax and AUCinf values were 94% and 66% higher, respectively, in Chinese subjects compared with those observed historically for non-Asian subjects receiving the same dose. Based on these pharmacokinetic results and the established exposure-response relationship of venetoclax in non-Asian CLL subjects, a 400-mg once-daily dosage regimen was selected for evaluating the venetoclax pharmacokinetics, efficacy, and safety in the venetoclax phase 2 open-label study in Chinese subjects with R/R CLL.

Patient-Centered Outcome Spectrum: An Evidence-based Framework to Aid in Shared Decision-making.

OBJECTIVE: Our objective was to develop an alternate construct for reporting anticipated outcomes after emergency general surgery (EGS) that presents risk in terms of a composite measure. BACKGROUND: Currently available prediction tools generate risk outputs for discrete as opposed to composite measures of postoperative outcomes. A construct to synthesize multiple discrete estimates into a global understanding of a patient's likely postoperative health status is lacking and could augment shared decision-making conversations. METHODS: Using the 2012 to 2014 American College of Surgeons National Surgical Quality Improvement Program Participant Use File, we developed the Patient-Centered Outcomes Spectrum (PCOS) for patients ≥65 years old who underwent an EGS operation. The PCOS defines 3 exclusive types of global outcomes (good, intermediate, and bad outcomes) and allows patients to be prospectively stratified by both their EGS diagnosis and preoperative surgical risk profile. RESULTS: Of the patients in our study population, 13,330 (46.4%) experienced a 30-day postoperative course considered a good outcome. Conversely, 3791 (13.2%) of study patients experienced a bad outcome. The remainder of patients (11,617; 40.4%) were classified as experiencing an intermediate outcome. The incidence of good, intermediate, and bad outcomes was 69.7%, 28.2%, and 2.1% for low-risk patients, and 22.0%, 48.9%, and 29.1% for high-risk patients. Diagnosis-specific PCOS constructs are also provided. CONCLUSIONS: Consistent with the goals of shared decision-making, the PCOS provides an evidence-based construct based upon a composite outcome measure for patients and providers as they weigh the risks of undergoing EGS.

Identifying Nontechnical Skill Deficits in Trainees Through Interdisciplinary Trauma Simulation.

OBJECTIVE: The goal of this study was to investigate nontechnical skills in a simulated trauma setting both before and after a debriefing session in order to better understand areas to target for the development of educational interventions. DESIGN: Wilcoxon signed rank tests were used to compare scores on the 5 domains of the T-NOTECHS pre- and postdebriefings. A qualitative analysis using the PEARLS debriefing framework was performed to provide a rich description of the strategies used by the debriefing facilitators. SETTING: The Joint Trauma Simulation Program is an interdisciplinary project designed to improve the quality of trauma care through simulation exercises emphasizing nontechnical skills development. PARTICIPANTS: Thirteen teams of 5 trauma trainees participated in trauma resuscitation simulations: a surgical chief resident, a surgical junior resident, an emergency medicine resident, and 2 emergency medicine nurses. RESULTS: Teams significantly improved on communication and interaction skills in the simulation scenarios from pre- to postdebriefing. The debrief facilitators spent most of their time engaged in Directive Performance Feedback (56.13%). CONCLUSIONS: Interprofessional team simulation in trauma resuscitation scenarios followed by debriefing differently affected individual nontechnical skills domains. Additional facilitation strategies, such as focused facilitation and encouraging learner self-assessment, may target other nontechnical skills in different ways.

Race, insurance status, and traumatic brain injury outcomes before and after enactment of the Affordable Care Act.

BACKGROUND: The Affordable Care Act aims to improve patient outcomes. Race/ethnicity and insurance status impact outcomes after traumatic brain injury. We sought to gauge the Affordable Care Act's effect on outcomes after traumatic brain injury, as graded by race/ethnicity and insurance status. METHODS: The National Trauma Data Bank was utilized to identify traumatic brain injury patients before and after the Affordable Care Act. Patient outcomes comprised of hospital duration of stay, in-hospital mortality, discharge to rehabilitation, and surgical procedures. Using regression analysis, we evaluated the impact of race/ethnicity and insurance status on traumatic brain injury outcomes, then compared them before and after the Affordable Care Act. RESULTS: Mortality decreased for blacks (odds ratio = 0.96 [confidence interval 0.83-1.10] to odds ratio = 0.79 [confidence interval = 0.70-0.89], and Hispanics (odds ratio = 1.03 [confidence interval = 0.90-1.17] to odds ratio = 0.79 [confidence interval = 0.70-0.89]). Mortality increased for the uninsured (odds ratio = 1.28 [confidence interval = 1.11-1.47] to odds ratio = 1.40 [confidence interval = 1.24-1.58]). Medicaid patients underwent decreased duration of stay, (coefficient = 2.75 [confidence interval = 2.49-3.02] to coefficient = 2.17, [confidence interval = 1.98-2.37]), discharge to rehabilitation (odds ratio = 1.15, [confidence interval = 1.04-1.26] to odds ratio = 0.95 [confidence interval = 0.87-1.03]), and surgical procedures (odds ratio = 1.28 [confidence interval = 1.13-1.45] to odds ratio = 1.18, [confidence interval = 1.07-1.30]), while mortality remained unchanged. CONCLUSION: After the Affordable Care Act traumatic brain injury mortality decreased for blacks and Hispanics, but increased for the uninsured. Decreasing trends in resource consumption were also evident, especially for Medicaid patients. These results may illustrate altered delivery of care.

Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma.

Venetoclax is a selective, orally bioavailable BCL-2 inhibitor that induces cell death in multiple myeloma (MM) cells, particularly in those harboring t(11;14), which express high levels of BCL-2 relative to BCL-XL and MCL-1. In this phase 1 study, patients with relapsed/refractory MM received venetoclax monotherapy. After a 2-week lead-in with weekly dose escalation, daily venetoclax was given at 300, 600, 900, or 1200 mg in dose-escalation cohorts and 1200 mg in the safety expansion. Dexamethasone could be added on progression during treatment. Sixty-six patients were enrolled (30, dose-escalation cohorts; 36, safety expansion). Patients received a median of 5 prior therapies (range, 1-15); 61% were bortezomib and lenalidomide double refractory, and 46% had t(11;14). Venetoclax was generally well tolerated. Most common adverse events included mild gastrointestinal symptoms (nausea [47%], diarrhea [36%], vomiting [21%]). Cytopenias were the most common grade 3/4 events, with thrombocytopenia (32%), neutropenia (27%), anemia (23%), and leukopenia (23%) reported. The overall response rate (ORR) was 21% (14/66), and 15% achieved very good partial response or better (≥VGPR). Most responses (12/14 [86%]) were reported in patients with t(11;14). In this group, ORR was 40%, with 27% of patients achieving ≥VGPR. Biomarker analysis confirmed that response to venetoclax correlated with higher BCL2:BCL2L1 and BCL2:MCL1 mRNA expression ratios. Venetoclax monotherapy at a daily dose up to 1200 mg has an acceptable safety profile and evidence of single-agent antimyeloma activity in patients with relapsed/refractory MM, predominantly in patients with t(11;14) abnormality and those with a favorable BCL2 family profile. Registered at www.clinicaltrials.gov: #NCT01794520.

Response Rates as Predictors of Overall Survival: A Meta-Analysis of Acute Myeloid Leukemia Trials.

Background: Response rates such as overall response rate (ORR), complete response (CR) and complete response with incomplete blood recovery (CRi) can be evaluated in a much shorter period of time than overall survival (OS), potentially accelerating decision making during drug development. The objective of this work was to evaluate the relationship between ORR, CR, CRi or better (CRi+CR) rates and median OS to determine whether response rates could be used as predictors of median OS in acute myeloid leukemia (AML). Methods: A review of published literature was conducted to identify relevant AML clinical trials. Weighted linear regression was performed with various linearizing transformations of response rates and median OS. Covariates of interest were evaluated using a forward inclusion, backward elimination covariate model building procedure at α=0.01 and α=0.005, respectively. Results: Twenty trials involving 26 cohorts were included in the meta-analysis. Azactidine treatment was a significant predictor with longer OS compared to decitabine or low dose cytarabine for a given response rate (P < 0.005). Linear regression analysis indicated that the correlation of both CRi or better rates and CR rates with median OS was higher than that of ORR with median OS. The final model showed a strong correlation between CRi or better rates and median OS (R2=0.66). Conclusion: Significant correlation between CRi or better rates and median OS in AML highlights the potential for CRi or better rate, in addition to CR rate, to serve as surrogate markers for median OS.

Pharmacokinetics of venetoclax in patients with 17p deletion chronic lymphocytic leukemia.

Venetoclax is a first-in-class orally available, B-cell lymphoma (BCL)-2 inhibitor indicated for the treatment of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) harboring the 17p deletion. We used a novel approach for evaluating venetoclax pharmacokinetics using only sparse sampling in 155 patients enrolled in a phase 2, multicenter, open-label study in CLL patients with the 17p deletion. Patients received venetoclax doses within 30 min after the completion of breakfast or the first meal of the day, with no specific recommendations for the fat content in the meal. Blood samples for venetoclax assay were collected during the ramp-up period and on day 1 of weeks 8, 12, 16, 24, and every 12 weeks thereafter. The mean postdose (8 h) plasma venetoclax concentrations increased with increasing weekly venetoclax dose during the ramp-up period to reach 1.89 µg/ml on week 5 day 1 at the 400 mg dose. The mean predose concentration at the 400 mg dose ranged between 0.69 and 0.99 µg/ml across visits between weeks 8 and 120. Repeated-measures analysis detected no statistical significance (P≥0.05) for the mean predose concentrations at any of the times tested from weeks 8 to 24. The study shows that the pharmacokinetic profile of venetoclax in CLL patients with the 17p deletion is comparable to the overall CLL as well as non-Hodgkin's lymphoma patient populations. Furthermore, no specific recommendation in terms of fat content in the meal is needed for the intake of venetoclax in patients with CLL.