Murad, M. Hassan

Abstract Background: Central nervous system (CNS) complications are among the most common, devastating sequelae of sickle cell disease (SCD) occurring throughout the lifespan. Objective: These evidence-based guidelines of the American Society of Hematology are intended to support the SCD community in decisions about prevention, diagnosis, and treatment of the most common neurological morbidities in SCD. Methods: The Mayo Evidence-Based Practice Research Program supported the guideline development process, including updating or performing systematic evidence reviews. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE evidence-to-decision frameworks, to assess evidence and make recommendations. Results: The panel placed a higher value on maintaining cognitive function than on being alive with significantly less than baseline cognitive function. The panel developed 19 recommendations with evidence-based strategies to prevent, diagnose, and treat CNS complications of SCD in low-middle– and high-income settings. Conclusions: Three of 19 recommendations immediately impact clinical care. These recommendations include: use of transcranial Doppler ultrasound screening and hydroxyurea for primary stroke prevention in children with hemoglobin SS (HbSS) and hemoglobin Sβ0 (HbSβ0) thalassemia living in low-middle–income settings; surveillance for developmental delay, cognitive impairments, and neurodevelopmental disorders in children; and use of magnetic resonance imaging of the brain without sedation to detect silent cerebral infarcts at least once in early-school-age children and once in adults with HbSS or HbSβ0 thalassemia. Individuals with SCD, their family members, and clinicians should become aware of and implement these recommendations to reduce the burden of CNS complications in children and adults with SCD.

Introduction The purpose of this systematic review and meta-analysis was to evaluate the diagnostic accuracy of liver and spleen stiffness on magnetic resonance elastography (MRE) for detecting clinically significant portal hypertension. Methods A systematic review of MEDLINE, EMBASE, Scopus, the Cochrane Library, and the Grey Literature through to 15 August 2019 was performed. Original articles with >10 patients evaluating liver and/or spleen stiffness on MRE using a reference standard of portal hypertension defined as intractable ascites, esophageal varices, encephalopathy and/or death were included in analysis. Patient, clinical, MRI, and diagnostic performance was independently acquired by two reviewers. Meta-analysis was performed using a bivariate mixed-effects regression model. Results Fourteen studies were included with 12 studies evaluating liver stiffness and eight studies evaluating spleen stiffness. The pooled and weighted sensitivity, specificity, and area under the curve (AUC) values for liver stiffness on MRE were 83% [95% confidence interval (CI) 72–90%], 80% (95% CI 70–88%), and 88% (95% CI 85–91%), respectively. The pooled and weighted sensitivity, specificity, and AUC values for spleen stiffness on MRE were 79% (95% CI 61–90%), 90% (95% CI 80–95%), and 92% (95% CI 89–94%), respectively. The liver and spleen stiffness sensitivity and specificity values were comparable when evaluating for esophageal varices only at of 80% (95% CI 66–89%) and 76% (95% CI 62–86%) for liver stiffness, and 75% (95% CI 52–90%) and 89% (95% CI 70–96%) for spleen stiffness. Discussion Liver and spleen stiffness on MRE can serve as a supplemental noninvasive assessment tools for detecting clinically significant portal hypertension. Spleen stiffness may be more specific and accurate than liver stiffness for detecting portal hypertension.

Background and Aims Chronic hepatitis B (CHB) can lead to hepatocellular carcinoma (HCC). While both tenofovir disoproxil (TDF) and entecavir (ETV) have been shown to reduce the risk of HCC, their comparative effectiveness is unclear. We estimated the comparative effectiveness of these two agents in reducing the risk of HCC in patients with CHB, through a systematic review and meta‐analysis. Approach and Results We searched multiple electronic databases from January 1, 1998, to October 31, 2019, for randomized controlled trials and observational comparative effectiveness studies in adults with CHB treated with ETV compared to TDF, reporting the incidence of HCC (minimum follow‐up 12 months). Primary outcome was incidence of HCC, calculated as incidence rate ratio (IRR) with 95% confidence interval (CI, unadjusted analysis) and hazard ratio (HR) with 95% CI (adjusted analysis, where reported). Of 1,971 records identified, 14 studies (263,947 person‐years) were included for quantitative analysis. On unadjusted meta‐analysis of 14 studies, the risk of HCC was not statistically different between ETV and TDF (IRR, 1.28; 95% CI, 0.99‐1.66). When using available adjusted data (multivariate or propensity‐matched data), the risk of HCC among patients treated with ETV was 27% higher when compared to TDF (seven studies; 95% CI, 1.01‐1.60, P = 0.04). Additional analysis of adjusted data when separately reported among patients with cirrhosis demonstrated an adjusted HR of 0.90 (95% CI, 0.66‐1.23), suggesting no difference between ETV‐treated and TDF‐treated groups. The overall confidence in estimates was very low (observational studies, high heterogeneity). Conclusions TDF may be associated with lower risk of HCC when compared to ETV.

AbstractOver the last 5 years, there have been more than 140 new drug approvals in the field of Oncology alone, all based on newly published clinical trials. These approvals have led to an ongoing change in clinical practice, offering new therapeutic options for patients. Therefore, it is important for healthcare providers to be able to appraise a clinical trial and determine its validity, understand its results, and be able to apply such results to their patients. In this guide, we provide a simplified approach tailored to practicing clinicians and trainees. The same concepts and principles apply to other medical specialties.

Objectives The primary objective was to examine the association between hyperlipidaemia (HLP) and 5-year survival after incident acute myocardial infarction (AMI). The secondary objectives were to assess the effect of HLP on survival to discharge across patient subgroups, and the impact of statin prescription, intensity and long-term statin adherence on 5-year survival. Methods Retrospective cohort study of 7071 patients hospitalised for AMI at Mayo Clinic from 2001 through 2011. Of these, 2091 patients with HLP (age (mean±SD) 69.7±13.5) were propensity score matched to 2091 patients without HLP (age 70.6±14.2). Results In matched patients, HLP was associated with higher rate of survival to discharge than no HLP (95% vs 91%; log-rank <0.0001). At year 5, the adjusted HR for all-cause mortality in patients with HLP versus no HLP was 0.66 (95% CI 0.58–0.74), and patients with prescription statin versus no statin was 0.24 (95% CI 0.21 to 0.28). The mean survival was 0.35 year greater in patients with HLP than in those with no HLP (95% CI 0.25 to 0.46). Patients with HLP gained on an average 0.17 life year and those treated with statin 0.67 life year at 5 years after AMI. The benefit of concurrent HLP was consistent across study subgroups. Conclusions In patients with AMI, concomitant HLP was associated with increased survival and a net gain in life years, independent of survival benefit from statin therapy. The results also reaffirm the role of statin prescription, intensity and adherence in reducing the mortality after incident AMI.

e19503 Background: The risk of venous thromboembolic events (VTE) despite mandatory thromboprophylaxis (TPx) in patients with multiple myeloma (MM) receiving contemporary lenalidomide (Len)-based regimens is not well-defined. Methods: Medline, Embase, and CENTRAL databases were queried to identify phase 1-3 clinical trials of Len-based regimens with mandatory TPx published until April 2018. Random effects meta-analysis was performed using CMAv3 software to obtain crude, and per 100 patient-cycle incidence rate (IR). Prespecified subgroup analyses were performed to obtain IR for VTE by (1) line of treatment (newly diagnosed [ND], relapsed/refractory [RR] and maintenance [Mx] phase) and (2) different Len-based regimens. Results: We screened 1069 citations and analyzed data from 43 trials with 8696 patients, including 17 in ND, 23 in RR and 3 in Mx phase. 12 out of 43 were Phase 3 randomized controlled trials. The overall incidence of VTE in 8696 patients was 4.6% (95% CI, 3.7-5.8%), with 1.0 event (95% CI, 0.7-1.4%) per 100 patient cycles. In patients with NDMM (n = 3295), 193 (5.9%) experienced VTE with a pooled IR of 0.9 (95% CI, 0.3-2.3) per 100 patient-cycle. Among RRMM patients (n = 3981), 251 (6.3%) experienced VTE with a pooled IR of 1.0 (95% CI, 0.4-2.3) per 100 patient-cycle. The incidence of VTE was highest with the following triplet regimens: Rd + Proteasome inhibitor (PIs) and Rd + Anthracycline (Ac) [+/- Vincristine], with the latter having a high risk of VTE regardless of the treatment phase (table). With Len Mx (n = 1420), 38 (2.7%) patients had VTE, with a pooled IR of 0.2 (95% CI, 0-2.1) per 100 patient-cycle. Conclusions: Patients with MM undergoing treatment with Len-based regimens remain at risk of VTE despite current TPx strategies. The estimates of VTE IR provided by this analysis can guide clinicians in assessing treatment-related risk of VTE in this setting. [Table: see text]

709 Background: Several immunotherapy (IMT) combinations either as an IMT doublet or IMT in combination with TKIs are now available for first-line therapy of metastatic renal cell carcinoma (mRCC). In the absence of head-to-head clinical trials, we performed an indirect comparison of frontline treatment options to provide clinical guidance. Methods: Medline, Embase and Cochrane Library were searched to identify relevant trials. Hazard ratios (HR) and confidence interval (CI) for primary outcome of progression-free survival (PFS) and secondary outcome of overall survival (OS) were abstracted. Network meta-analysis was performed using a multivariate, consistency model, random-effects meta-regression. Data on Grade 3 or higher AEs was abstracted and meta-analyzed. Pre-specified subgroup analyses were performed based on risk categories (high risk vs low and intermediate vs), history of prior nephrectomy, PD-L1 positivity, age and sex. Risk for bias(RoB) was assessed using the Cochrane Collaboration’s tool. Results: Nine studies were included for PFS analysis, and 6 studies for OS analysis. Avelumab-axitinib (AA) (HR 0.69, 0.48-0.96), and Pembrolizumab-Axitinib (PA) (HR 0.89, 0.50-0.96) significantly improved PFS, while there was no significant PFS benefit with atezolizumab-bevacizumab (AB) (HR 0.83, 0.62-1.13) and nivolumab-ipilimumab (NI) (HR 0.85, 0.63-1.15) as compared to Sunitinib. PA (HR 0.53, 0.38-0.75) and NI (HR 0.63, 0.44-0.90) significantly improved OS, while AB (HR 0.93, 0.75-1.12) showed no significant OS benefit as compared to Sunitinib. NI and AB had significantly fewer grade ≥3 AE than sunitinib. No significant interaction was found by risk group, age, sex or prior nephrectomy. Significant interaction was found by PD-L1 expression(p<0.001), with significant PFS improvement in PD-L1 positive (HR 0.62, 0.53-0.73) but not in PD-L1 negative patients (HR 0.92, 0.81-1.05). Overall, RoB was low amongst included studies. Conclusions: AA improved PFS, NI improved OS, whereas PA improve both PFS and OS as compared to sunitinib monotherapy. However, no IMT combination was superior to other combinations. Cost effectiveness analysis will be reported separately.

708 Background: Patients with high risk non-metastatic renal cell cancer (RCC) are at significant risk of recurrence following nephrectomy. Previously, we reported no benefit of adjuvant tyrosine kinase inhibitor (TKI) treatment in high-risk patients. Since our most recent publication, efficacy results from the multicenter double-blind SORCE trial have become available. We updated our meta-analysis to include these additional data and performed a cumulative meta-analysis. Methods: PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Trials were searched to identify relevant RCTs. A generic variance-weighted random effects model was used to derive estimates for efficacy. Heterogeneity was assessed using the Cochran Q statistic and was quantified using the I2 test. The primary outcome was disease-free survival (DFS), defined as the interval between randomization and the first recurrence, the occurrence of metastasis or a secondary cancer, or death due to any cause. Statistical analysis was performed using Comprehensive Meta-Analysis version 3 (Biostat). Results: Five phase 3 trials were identified, enrolling 6531 patients. Two trials compared sunitinib with placebo (S-TRAC and ECOG-ACRIN), two compared sorafenib with placebo (ECOG-ACRIN and SORCE) and one trial each compared pazopanib (PROTECT) and axitinib (ATLAS) vs placebo. Cumulative evidence suggests that adjuvant therapy with TKIs showed no significant improvement in (DFS) hazard ratio [HR] of 0.93 (95% CI, 0.85-1.02), compared to placebo. There was no significant heterogeneity among included trials ( I2= 52%, P= .41). Overall, the trials were at low risk of bias. Conclusions: Adjuvant vascular endothelial growth factor tyrosine kinase inhibitors in high-risk renal cell carcinoma did not improve DFS as compared to placebo. Improved patient selection using better prognostic biomarkers or scoring systems may identify subsets of patients who can benefit from adjuvant treatments. Toxicity estimates will be updated as data from SORCE trial publication becomes available.

335 Background: Network meta-analysis can provide useful evidence for relative efficacy and toxicity of different treatment options in absence of head-to-head trials. Previously, we reported no difference in efficacy between Apalutamide (APA) and Enzalutamide (ENZA). In this analysis, we provide updated indirect comparisons of all FDA approved agents (APA,ENZA, Darolutamide(DARO) for the treatment of M0CRPC with rapid PSA doubling time. Methods: MEDLINE, EMBASE and Cochrane Library were searched to identify relevant clinical trials. Hazard ratios (HR) and 95% confidence interval (CI) for Metastasis Free Survival (MFS), Overall Survival (OS) and data on grade 3 or higher AEs were abstracted. Bayesian network meta-analysis was conducted using WinBUGS 1.4.3 software (MRC Biostatistics Unit, Cambridge, UK) to perform an indirect comparisons. Risk for bias was assessed using the Cochrane Collaboration’s tool. Results: Three RCTs (SPARTAN, PROSPER and ARAMIS) compared APA, ENZA and DARO respectively in combination with ADT to ADT alone. A total of 4117 patients were included in efficacy analysis (2694 received novel hormonal agents and 1423 received ADT and placebo). There were no statistically significant differences in MFS (HR 0.97, 95% CrI 0.74 - 1.30) between APA and ENZA; however, both APA 0.69 (95% CI 0.52 -0.92) and ENZA 0.71 (95% CrI 0.53, 0.92) significantly improved MFS as compared to DARO. There were no statistically significant differences in OS between these drugs. DARO had fewer grade 3 or higher adverse events of fatigue (HR 0.09, 95% CrI 0.01 – 0.51) compared to ENZA. However other common adverse events such as hypertension, falls, coronary artery disease/myocardial infarction and diarrhea were not significantly different between treatment groups. There was low risk of bias amongst included studies. Conclusions: APNA and ENZA provide significant improved in MFS as compared to DARO in patients with M0CRPC. The drugs have similar toxicity profile except that DARO was associated with lower incidence of fatigue compared to ENZA. Cost effective analysis of these drugs will be reported separately.