Irbaz Bin Riaz

Blocking “don't eat me” signal of CD47-SIRPα in hematological malignancies, an in-depth review

Hematological malignancies express high levels of CD47 as a mechanism of immune evasion. CD47-SIRPα triggers a cascade of events that inhibit phagocytosis. Preclinical research supports several models of antibody-mediated blockade of CD47-SIRPα resulting in cell death signaling, phagocytosis of cells bearing stress signals, and priming of tumor-specific T cell responses. Four different antibody molecules designed to target the CD47-SIRPα interaction in malignancy are currently being studied in clinical trials: Hu5F9-G4, CC-90002, TTI-621, and ALX-148. Hu5F9-G4, a humanized anti-CD47 blocking antibody is currently being studied in four different Phase I trials. These studies may lay the groundwork for therapeutic bispecific antibodies. Bispecific antibody (CD20-CD47SL) fusion of anti-CD20 (Rituximab) and anti-CD47 also demonstrated a synergistic effect against lymphoma in preclinical models. This review summarizes the large body of preclinical evidence and emerging clinical data supporting the use of antibodies designed to target the CD47-SIRPα interaction in leukemia, lymphoma and multiple myeloma.

A Bayesian network meta-analysis of PCSK9 inhibitors, statins and ezetimibe with or without statins for cardiovascular outcomes

Background The comparative effects of statins, ezetimibe with or without statins and proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors remain unassessed. Design Bayesian network meta-analysis was conducted to compare treatment groups. Methods Thirty-nine randomized controlled trials were selected using MEDLINE, EMBASE, and CENTRAL (inception – September 2017). Results In network meta-analysis of 189,116 patients, PCSK9 inhibitors were ranked as the best treatment for prevention of major adverse cardiovascular events (Surface Under Cumulative Ranking Curve (SUCRA), 85%), myocardial infarction (SUCRA, 84%) and stroke (SUCRA, 80%). PCSK9 inhibitors reduced the risk of major adverse cardiovascular events compared with ezetimibeu2009+u2009statin (odds ratio (OR): 0.72; 95% credible interval (CrI), 0.55–0.95; Grading of Recommendation Assessment, Development and Evaluation (GRADE) criteria: moderate), statin (OR: 0.78; 95% CrI: 0.62–0.97; GRADE: moderate) and placebo (OR: 0.63; 95% CrI: 0.49–0.79; GRADE: high). The PCSK9 inhibitors were consistently superior to groups for major adverse cardiovascular event reduction in secondary prevention trials (SUCRA, 95%). Statins had the highest probability of having lowest rates of all-cause mortality (SUCRA, 82%) and cardiovascular mortality (SUCRA, 84%). Compared with placebo, statins reduced the risk of all-cause mortality (OR: 0.88; 95% CrI: 0.83–0.94; GRADE: moderate) and cardiovascular mortality (OR: 0.84; 95% CrI: 0.77–0.90; GRADE: high). For cardiovascular mortality, PCSK9 inhibitors were ranked as the second best treatment (SUCRA, 78%) followed by ezetimibeu2009+u2009statin (SUCRA, 50%). Conclusion PCSK9 inhibitors were ranked as the most effective treatment for reducing major adverse cardiovascular events, myocardial infarction and stroke, without having major safety concerns. Statins were ranked as the most effective therapy for reducing mortality.

Efficacy and toxicity profile of carfilzomib based regimens for treatment of multiple myeloma: A systematic review

Standard induction therapy for multiple myeloma is three-drug combination based on following classes of drugs: proteasome inhibitors, immunomodulators and steroids. Despite its notable efficacy, bortezomib has side effects like peripheral neuropathy (PNP) with reported incidence of grade ≥3 PNP between 2%-23% Schlafer et al., 2017. Carfilzomib (CFZ) has high selectivity and minimal off-target adverse effects including lower rates of PNP. CFZ is already approved for treatment of relapsed and refractory multiple myeloma (RRMM) as single agent as well as in combination with lenalidomide and/or dexamethasone. Extensive literature search identified a total of 1839 articles. Twenty-six articles (nu202f=u202f5980) met the inclusion criteria, 15 in newly diagnosed multiple myeloma (NDMM) and 11 in RRMM group. CFZ demonstrates comparable or even better efficacy to bortezomib with much favorable AE profile. Deep, rapid and sustainable response using KRd with safer toxicity profile supports extension of KRd therapy to frontline therapy for all risk categories of MM. High incidence of grade ≥3 HTN underscores the importance of serial BP monitoring. In RRMM, CFZ has documented efficacy with standard 20-27mg/m2 dose. Further large-scale trials are needed to study benefit-to-risk profile of 20-56 and 20-70u202fmg/m2 dose of CFZ vs standard 20-27u202fmg/m2 dose in NDMM and RRMM.

Meta-Analysis of the Safety and Efficacy of the Oral Anticoagulant Agents (Apixaban, Rivaroxaban, Dabigatran) in Patients With Acute Coronary Syndrome

The significance of adding new oral anticoagulants (NOACs) to antiplatelet therapy in patients with acute coronary syndrome (ACS) is unclear. We conducted a meta-analysis to assess the safety and efficacy of adding NOACs (apixaban, rivaroxaban, and dabigatran) to single antiplatelet agent (SAP) or dual antiplatelet therapy (DAPT) in patients with ACS. Seven randomized controlled trials were selected using PubMed or MEDLINE, Scopus, and Cochrane library (inception to August 2017). The summary measure was random effects hazard ratio (HR) with 95% confidence interval (CI). The primary safety outcome was clinically significant bleeding. The secondary efficacy outcome was major adverse cardiovascular events (MACE; composite of myocardial infarction, stroke, and all-cause mortality). In 31,574 patients, addition of NOAC to SAP did not increase the risk of clinically significant bleeding (HR 0.82, 95% CI 0.56 to 1.20, pu2009=u20090.31); however, the risk of clinically significant bleeding was significantly increased with NOAC plus DAPT (HR 2.24, 95% CI 1.75 to 2.87, pu2009<u20090.001). NOACs had no statistically beneficial effect on MACE when used with SAP (HR 0.82, 95% CI 0.66 to 1.04, pu2009=u20090.10); however, a modest reduction in MACE was observed when NOACs were combined with DAPT (HR 0.86, 95% CI 0.78 to 0.93, pu2009<u20090.001). In conclusion, in patients with ACS, the addition of NOAC to DAPT resulted in increased risk of clinically significant bleeding, whereas only a modest reduction in MACE was achieved. The addition of NOACs to SAP did not result in significant reduction of MACE or increase in clinically significant bleeding.

Liquid biopsy approach in the management of prostate cancer

Liquid biopsies examine tumor cells or tumor genomic content in circulating fluids. In advanced prostate cancer which metastasizes frequently to the bone, it is difficult to evaluate underlying and evolving genomic heterogeneity of skeletal metastases for effecting clinical care for which reason liquid biopsies offer an alternate approach. In this review, we will summarize the current state of a wide variety of liquid biopsy-based biomarker assays currently being investigated and developed for managing prostate cancer. We will also highlight technical and clinical challenges and opportunities for translating liquid biopsies into clinical applications.

Psoriasis and Psoriatic Spectrum Disease: A Primer for the Primary Care Physician

Psoriasis is a chronic, immune-mediated disorder that affects approximately 7.5 million people in the United States. Individuals with psoriasis may develop cutaneous, articular, and systemic manifestations, which are a source of significant morbidity and a heightened risk of mortality, and may adversely impact patient-reported quality of life measures. Psoriasis is now recognized as a risk factor for cardiovascular disease, metabolic syndrome, peripheral vascular disease, inflammatory bowel disease, certain malignancies, and chronic renal disease. Therefore, it has become increasingly relevant that primary care physicians have a basic working knowledge and an understanding of fundamental management principles of psoriasis. This review highlights the salient clinical features of psoriasis and psoriatic spectrum disease, emphasizing key updates with respect to systemic disease and associated conditions, and briefly outlines a therapeutic algorithm for the primary care physician.

Representation of Minorities and Elderly Patients in Multiple Myeloma Clinical Trials

Multiple myeloma (MM) occurs in all races, but the incidence in non-Hispanic black patients (NHBs) is two to three times higher than in non-Hispanic white patients (NHWs). We determined the representation of minorities and elderly patients in MM clinical trials. Enrollment data from all therapeutic trials reported in ClinicalTrials.gov from 2000 to 2016 were analyzed. Enrollment fraction (EF) was defined as the number of trial enrollees divided by the 2014 MM prevalence. Participation in MM clinical trials varied significantly across racial and ethnic groups; NHWs were more likely to be enrolled in clinical trials (EF 0.18%) than NHBs (EF 0.06%, pu2009<u2009.0001) and Hispanic patients (EF 0.04%, pu2009<u2009.0001). The median age of trial participants was 62 years, with 7,956 participants (66%) being less than 65 years of age. Collaborations between investigators, sponsors, and the community are necessary to increase access to clinical trials to our minority and elderly patients.

Meta-analysis of duration of dual antiplatelet therapy in patients with acute coronary syndrome after percutaneous coronary intervention

The residual risk for secondary cardiovascular events is highest during the first 12 months after acute coronary syndrome (ACS). Dual antiplatelet therapy (DAPT) is the cornerstone of treatment to encounter this high thrombotic risk after ACS. While long-term aspirin monotherapy is considered a standard approach for the secondary prevention of major adverse cardiovascular events (MACEs) in patients with coronary artery disease, the duration of DAPT in ACS remains a debatable topic. The current professional guidelines recommendDAPT for 12months in the setting of low bleeding risk and for 6months with high bleeding risk after ACS; however, recent data have shown conflicting evidence regarding the duration of DAPT. The preliminary results of DAPT STEMI favored 6 months therapy for having comparable results to 12 months DAPT in ACS cohorts. Conversely, the SMART DATE endorsed 12 months or longer DAPT for better protection against MACEs. To address this controversy, we conducted a meta-analysis of randomized controlled trials (RCTs) comparing the duration of DAPT (3–6 months vs. 12 months) in ACS patients treated with newer generation drug-eluting stents (DESs). A comprehensive search strategy was devised using MEDLINE, EMBASE and CENTRAL (inception to 20 March 2018) to identify published RCTs. The outcomes from each trial were selected to most closely approximate the primary and secondary composite endpoints in ACS cohorts. The primary endpoint was MACEs (composite of myocardial infarction, stroke, revascularization, stent thrombosis and death) and the secondary endpoint was an expanded MACE (composite of myocardial infarction, stroke, stent thrombosis, death and major bleeding). Quality assessment of each trial was performed using the Cochrane risk of bias tool. The literature search, data extraction and bias risk assessment were performed by two authors (ANL and HR) independently. Estimates were pooled using a generic invariance random effects model and reported as hazard ratio (HR) with 95% confidence interval (CI). Heterogeneity was quantified by I with values greater than 75% consistent with high grade heterogeneity. If HRs were not available, risk ratios were pooled as HRs if the risk of the event did not vary over time. Publication bias was assessed using Egger’s regression test. Analyses were conducted at 5% significance. Comprehensive Meta-Analysis (version 3) was used for meta-analysis. Eight RCTs (10,130 patients) were included in this meta-analyses (Table 1). MACEs were extracted from four trials (6242 patients) and expanded MACEs were reported in four trials (3888 patients). There was no significant difference between both groups in terms of MACEs (HR 1.03, 95% CI 0.83– 1.29; P1⁄4 0.78, I1⁄4 0) or expanded MACE (HR 1.06, 95% CI 0.77–1.47; P1⁄4 0.72, I1⁄4 0) (Figure 1). The outcomes had low statistical heterogeneity and Egger’s regression test did not detect publication bias (intercept 0.39, 95% CI 2.06–1.26; P1⁄4 0.58). This meta-analysis suggests that there were no significant differences between 3–6 months versus 12 months of longer of DAPT in terms of MACEs or expanded MACEs among ACS subjects treated with

Role of one, two and three doses of high-dose chemotherapy with autologous transplantation in the treatment of high-risk or relapsed testicular cancer: a systematic review

Approximately 20–30% of patients with metastatic germ cell cancers (GCCs) can develop relapsed or refractory (RR) disease, about 40–50% of patients who relapse after salvage chemotherapy may reach long-term remission. The goal of this review was to identify patients who appear to benefit from high-dose chemotherapy (HDCT) and autologous stem cell transplant (ASCT). To access this, we performed a systematic medical literature review to evaluate the effectiveness of HDCT in the frontline setting, as well as in patients with RR testicular cancer. We searched databases for interventional clinical studies and identified 5883 studies. We selected 49 studies for inclusion, which included a total of 5985 patients. Seventeen studies reported results of newly diagnosed poor-risk GCC patients and 32 studies reported results of RR patients. For newly diagnosed patients with poor prognostic predictors, a risk adjusted strategy using unfavorable tumor marker decline with initial standard chemotherapy regimen and upfront HDCT demonstrated improved outcomes. Our data suggest a minimum of two HDCT cycles with ASCT should be standard of care for patients with RR GCC. Failure of HDCT results in a poor prognosis with only 10% of patients achieving lasting remission with salvage therapy.

Prophylaxis for Hepatitis B Virus Reactivation after Allogeneic Stem Cell Transplantation in the Era of Drug Resistance and Newer Antivirals: A Systematic Review and Meta-Analysis

Patients undergoing allogenic hematopoietic stem cell transplantation (allo-HSCT) are at a very high risk of hepatitis B virus reactivation (HBVr). Lamivudine is commonly used as prophylaxis against HBVr in high-risk patients undergoing allo-HSCT. Unfortunately, its efficacy is diminishing due to the development of HBV mutant drug-resistant strains. With the availability of newer antiviral agents such as entecavir, telbivudine, adefovir, and tenofovir, it is important to assess their role in HBVr prophylaxis. A comprehensive search of 7 databases was performed to evaluate efficacy of antiviral prophylaxis against HBVr in allo-HSCT patients (PubMed/Medline, Embase, Scopus, Cochrane Library, Web of Science, CINAHL, and ClinicalTrials.gov (June 21, 2017)). We identified 10 studies, with 2067 patients undergoing allo-HSCT; these primarily evaluated the use of lamivudine and entecavir as prophylaxis against HBVr in patients undergoing allo-HSCT because there were little or no data about adefovir, telbivudine, or tenofovir as prophylaxis in this specific patient population. Thus, included studies were categorized into 2 main prophylaxis groups: lamivudine and entecavir. Results of our meta-analysis suggest that entecavir is very effective against HBVr, although further clinical trials are required to test efficacy of new antivirals and explore the emerging threat of drug resistance.