Bleeding Risk Reduction in Relation to Predicted Factor IX Levels in Hemophilia B Patients Receiving Idelvion (rIX-FP)

MedicalResearch.com Interview with:

Jerry Powell MD Medical Director North America Commercial Operations CSL Behring

Dr. Jerry Powell

Jerry Powell MD
Medical Director
North America Commercial Operations
CSL Behring

MedicalResearch.com: What is the background for this study?

Response: The new IDELVION results presented at the American Society of Hematology (ASH) are from a pooled analysis of clinical studies from the global PROLONG-9FP clinical development program. The analysis assessed the relationship between estimated factor IX activity levels and clinical bleeding risk in adult hemophilia B patients treated with IDELVION using prophylaxis or on-demand (episodic) treatment.

The PROLONG-9FP clinical development program included five Phase I through Phase III open-label, multicenter studies evaluating the pharmacokinetics, safety and efficacy of IDELVION in children and adults with hemophilia B.

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Computerized Working Memory Training in Pediatric Sickle Cell Disease

MedicalResearch.com Interview with:

Steven J. Hardy, PhD Licensed Clinical Psychologist Divisions of Hematology and Oncology Children’s National Health System Assistant Professor of Pediatrics and Psychiatry & Behavioral Sciences George Washington School of Medicine and Health Sciences Washington, DC

Dr. Steven J. Hardy

Steven J. Hardy, Phd
Licensed Clinical Psychologist
Divisions of Hematology and Oncology
Children’s National Health System
Assistant Professor of Pediatrics and Psychiatry & Behavioral Sciences
George Washington School of Medicine and Health Sciences Washington, DC

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Children with sickle cell disease exhibit neurocognitive deficits as a consequence of either silent or overt cerebral infarction or disease-related non-infarct central nervous system effects (likely resulting from chronic anemia and hypoxic events). These complications often lead to impairment in executive functioning (e.g., working memory, attention, inhibition, cognitive flexibility), which can make it difficult to focus in class, plan for long-term school projects, remember and carry out multi-step tasks or assignments, and stay organized. The literature on interventions to reduce neurocognitive sequelae of sickle cell disease is extremely limited.

Our research team investigated a promising home-based, computerized cognitive training program (Cogmed) involving repeated practice on performance-adapted exercises targeting working memory with a sample of youth (ages 7 – 16) with sickle cell disease. Of the participants who have enrolled in the study (n = 70), 49% exhibited working memory deficits (<25% in the general population have a working memory deficit) and were randomized to an eight-week waitlist or to begin Cogmed immediately. Participants who used Cogmed demonstrated significant improvements on multiple measures of working memory, while those randomized to the waitlist group only exhibited such improvements after receiving Cogmed. Approximately 25% of participants completed the recommended number of Cogmed sessions (20 – 25 sessions). However, analyses revealed that participants who completed at least 10 sessions (about 50% of the participants) showed comparable levels of working memory improvement.

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Monoclonal Antibody Crizanlizumab Reduces Sickle Cell Pain Crisis

MedicalResearch.com Interview with:

Kenneth I. Ataga, MD Division of Hematology/Oncology University of North Carolina at Chapel Hill Chapel Hill, NC

Dr. Kenneth I. Ataga

Kenneth I. Ataga, MD
Division of Hematology/Oncology
University of North Carolina at Chapel Hill
Chapel Hill, NC

MedicalResearch.com: What is the background for this study? What are the main findings?
Response: The available treatments for acute painful episodes (also referred to as vaso-occlusive crises), the most common complication of sickle cell disease, are limited.

Findings from the Phase II SUSTAIN study showed that crizanlizumab (formerly SelG1) at 5 mg/kg reduced the median rate of sickle cell disease-related pain crises per year by 45.3% vs. placebo in patients with or without concomitant hydroxyurea therapy. In addition, clinically meaningful reductions in the frequency of painful crises were observed regardless of sickle cell disease genotype. 

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Key Barriers To Development of Artificial Red Blood Cells Overcome

MedicalResearch.com Interview with:

Allan Doctor, MD Pediatric Critical Care Medicine Professor of Pediatrics and (Associate) Biochemistry Washington University School of Medicine & Saint Louis Children’s Hospital St. Louis, Missouri

Dr. Allan Doctor

Allan Doctor, MD
Pediatric Critical Care Medicine
Professor of Pediatrics and (Associate) Biochemistry
Washington University School of Medicine &
Saint Louis Children’s Hospital
St. Louis, Missouri

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Our research team has developed the first nanoscale artificial cells designed to emulate vital functions of natural red blood cells. If ultimately confirmed safe for use in humans, this nanotechnology-based product, called ‘ErythroMer’, could represent a new and innovative alternative to blood transfusions that would be especially valuable in situations where stored blood is needed, but difficult to obtain or use, such as in pre-hospital or battlefield settings. The artificial cells are designed to be freeze-dried, stored for extended periods at ambient temperatures, and simply reconstituted with water for immediate use.

This year, the National Academy of Sciences estimated that 30,000 civilian trauma deaths/year are preventable and of these, two-thirds arise from hemorrhage in the pre-hospital phase of care. One key goal for our team is to advance treatment for trauma victims or soldiers in austere environments by initiating resuscitation in the field, particularly when transport is prolonged. ErythroMer could be a blood substitute that medics carry in their pack and literally take it out, add water, and inject. There are currently no simple, practical means to bring transfusion to most trauma victims outside of hospitals. Delays in resuscitation significantly impact outcomes; it is our goal to push timely, effective care to field settings.

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Two Different European Strategies Achieve KDIGO Renal Anemia Targets

MedicalResearch.com Interview with:

Dorota Drozdz M.D., Ph.D Jagiellonian University Kraków

Dr. Dorota Drozdz

Dorota Drozdz M.D., Ph.D
Jagiellonian University
Kraków

Response: In Poland and Portugal we use EPO beta for anemia treatment. Our interest was to find differences in clinical patterns taking in consideration that both countries are adherent to KDIGO recommendations an guidelines.

We found that in both countries the mean hemoglobin (Hb) level and percentage of patients in target Hb level (10-12 g/dl on ESA treatment) are the same, but the approaches were different – in Poland the ESA dose was statistically lower than in Portugal and iron dose was statistically higher than in Portugal. Most other lab tests results were similar. Future secondary outcomes analysis should answer the question, which method is safer.

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Peripheral IV Lines Linked To Lower Risk of Blood Clots After Transfusion

MedicalResearch.com Interview with:
Mary A.M. Rogers, PhD, MS

Research Associate Professor
Research Director, Patient Safety Enhancement Program
Department of Internal Medicine
University of Michigan
Ann Arbor, MI

MedicalResearch.com: What is the background for this study?

Response: Peripherally inserted central catheters (PICCs) are commonly used for vascular access in hospitalized patients. Previous studies have shown that PICCs of larger gauge (diameter) increase the risk of developing venous thromboembolism (blood clots in the deep veins that sometimes travel to the lung). Red blood cell transfusion is also known to increase the risk of venous thromboembolism. Because PICCs are often used to transfuse blood, we designed a study to investigate whether the method of transfusion delivery influences the risk of developing venous thromboembolism.

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No Iron Benefit To Mother From Eating Placenta

MedicalResearch.com Interview with:

Daniel C Benyshek, PhD Professor, Department of Anthropology Adjunct Professor, UNLV School of Medicine Co-Director, Metabolism, Anthropometry and Nutrition Lab UNLV

Dr. Daniel C Benyshek

Daniel C Benyshek, PhD
Professor, Department of Anthropology
Adjunct Professor, UNLV School of Medicine
Co-Director, Metabolism, Anthropometry and Nutrition Lab
University of Nevada, Las Vegas

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Maternal placentophagy is ubiquitous among nearly all terrestrial mammals, but is rare to non-existent among humans in the historic and cross-cultural records. Recently, however, human maternal placentophagy has emerged as a popular trend among a small but growing number of women in many industrialized countries. Most women engaging in the practice today consume their processed placenta in capsule form, taken daily, over several weeks postpartum. While human maternal placentophagy advocates claim many maternal health benefits from the practice, including improved postpartum mood, increased breast-milk production, and improved energy, among others, no carefully designed, placebo-controlled studies have evaluated these claims.

Our randomized, double-blind, placebo-controlled pilot study (N=23) investigated some of these claims. Our study found that the postpartum iron status of participants who consumed their own encapsulated placenta (based on the three week daily intake recommendation of one prominent placenta encapsulation service), was no different from those women who consumed the same amount of beef placebo.

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Minimally Invasive Gene Editing Cured Thalassemia in Mice

MedicalResearch.com Interview with:

Peter M. Glazer, MD, PhD Robert E. Hunter Professor of Therapeutic Radiology and Professor of Genetics; Chair, Department of Therapeutic Radiology Yale University

Dr. Peter M. Glazer

Peter M. Glazer, MD, PhD
Robert E. Hunter Professor of Therapeutic Radiology and Professor of Genetics; Chair, Department of Therapeutic Radiology
Yale University

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: It is generally recognized that gene editing in blood stem cells could provide a strategy for treatment of inherited disorders such as sickle cell disease and thalassaemia. Recent excitement has focused on CRISPR/Cas9 technology because of it is so easy to use. However, the CRISPR approach introduces an active DNA cutting enzyme into cells, which can lead to off-target cuts in the genome. As an alternative, we have pursued triplex-forming peptide nucleic acids (PNAs) designed to bind site-specifically to genomic DNA via strand invasion and formation of PNA/DNA/PNA triplexes. PNAs consist of a charge-neutral peptide-like backbone and nucleobases enabling hybridization with DNA with high affinity. PNA/DNA/PNA triplexes recruit the cell’s own DNA repair machinery to initiate site-specific editing of the genome when single-stranded ‘donor DNAs’ are co-delivered as templates containing the desired sequence modification.

We found that triplex-forming PNAs substituted at the gamma position yielded high levels of gene editing in blood stem cells in a mouse model of human β-thalassaemia. Injection of thalassemic mice with nanoparticles containing gamma PNAs and donor DNAs ameliorated the disease phenotype, with sustained elevation of blood hemoglobin levels into the normal range and up to 7% β-globin gene correction in stem cells, with extremely low off-target effects. We conclude that the combination of nanoparticle delivery and next generation PNAs may offer a minimally invasive treatment for genetic disorders of the blood that can be achieved safely and simply by intravenous administration.

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PAD: MarrowStim PAD Kit Uses Patient’s Bone Marrow Cells To Improve Critical Critical Limb Ischemia

MedicalResearch.com Interview with:

Michael P. Murphy, MD

Dr. Michael Murphy

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Critical limb ischemia (CLI) is the most severe form of peripheral arterial disease whereby a severe obstruction of the arteries markedly reduces blood flow to the extremities (hands, feet and legs) causing severe pain, skin ulcers, sores, or gangrene.  Up to 30% of patients with CLI do not qualify for conventional interventions, such as a bypass or angioplasty, putting them at risk for amputation.

The MOBILE trial (MarrOwStim™ PAD Kit for the Treatment of Critical LimB IschemIa in Subjects with Severe Peripheral ArteriaL DiseasE) was designed to assess the safety and efficacy of using autologous concentrated bone marrow aspirate (cBMA), cells derived from the patient’s own bone marrow, to restore blood flow and prevent amputations in patients with CLI.

MOBILE is a Phase 3, double-blind, randomized, placebo-controlled trial that evaluated 152 patients with CLI at 24 centers in the U.S. Patients were randomized to receive cBMA or placebo via injection at 40 sites on the symptomatic leg.  The cBMA was obtained from each patient using the MarrowStim PAD kit.  The placebo group underwent a sham bone marrow aspiration and received needle punctures in the index leg.

The primary efficacy endpoint was amputation-free survival, defined as freedom from all causes of death and/or major amputation, at 52 weeks after treatment. Other endpoints included changes in blood flow in the leg, wound healing, measures of pain and quality of life, and distance walked in 6 minutes. The trial completed in June 2016, and a preliminary analysis found that cBMA demonstrated a meaningful improvement in amputation-free survival and a comparable safety profile to placebo.

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IV Iron Postoperatively May Reduce Infections, Transfusions and Length of Hospital Stay

MedicalResearch.com Interview with:
Alhossain A. Khalafallah, Clinical Professor
Menzies Institute for Medical Research,
University of Tasmania, Australia
Consultant Haematologist
Launceston General Hospital
Australia

MedicalResearch.com: What is the background for this study?

Response: There are limited data regarding the effect of postoperative anemia on patient’s outcomes. The issue of postoperative anemia was noticeably to affect a large cohort of patients world-wide.

This study was aiming at comparing the new approach with a single ferric carboxymaltose infusion versus standard or routine usual care for management of postoperative anemia.

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Anemia Increases Mortality From Stroke

MedicalResearch.com Interview with:
Raphae Barlas M.A
3rd year MBChB student
The Institute of Applied Health Sciences
Aberdeen

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Anemia and stroke are both common conditions. While previous studies have found an association between anemia on admission and increased mortality in stroke patients, this was not consistent throughout the literature. We aimed to comprehensively assess this association by conducting our own observational study, consisting of 8000 patients from UK regional stroke registry data. We then aggregated our findings into a systematic review and meta-analysis of the existing literature for a total study population of approximately 30,000 patients.

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ALPROLIX – Recombinant Factor IX Fc Fusion Protein – Resolved Joint Bleeds in Hemophilia B

MedicalResearch.com:
Nisha Jain, Director
Global Medical at Biogen

Regarding: Post Hoc Analysis to Evaluate the Effect of Recombinant Factor IX Fc Fusion Protein (rFIXFc) Prophylaxis in Adults and Adolescents with Target Joints and Hemophilia B being presented at the World Federation of Hemophilia (WFH) 2016 World Congress

MedicalResearch.com: What is the background for this study?

Response: People with hemophilia B experience prolonged bleeding episodes that can cause pain, irreversible joint damage and life-threatening hemorrhages. For people with severe hemophilia, most bleeding events occur in joints, with joint damage being the most common complication of the condition.(1) Over time, joints can become severely damaged and an individual can suffer from acute pain as well as restricted range of motion in those joints.(1)

MedicalResearch.com: What are the main findings?

Response: The B-LONG and B-YOND trials evaluated ALPROLIX® [Coagulation Factor IX (Recombinant), Fc Fusion Protein] in hemophilia B patients. In this post-hoc analysis of 37 patients with target joints in B-LONG and B-YOND, most (98.9%) target joints were considered resolved using the International Society on Thrombosis and Haemostasis (ISTH) definition of resolution as ≤ 2 bleeds into the joint within a consecutive 12-month period.

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Sickle Cell Trait Not Associated With Increased Mortality in Military Population

MedicalResearch.com Interview with:
D. Alan Nelson, MPAS, PhD
Postdoctoral research fellow
Stanford Medicine

MedicalResearch.com: What is the background for this study?

Response: The study was inspired by the uncertainty surrounding sickle cell trait (SCT) and its association with serious exertional collapse events and mortality in active populations. I conducted initial, exploratory analyses on these topics in 2014-15 while examining a range of military readiness predictors and outcomes. The early work indicated that the risk of mortality, rhabdomyolysis and other exertional events arising from SCT might be substantially lower than that suggested by prior work in the research literature.

Dr. Lianne Kurina and I decided to conduct further, focused study at the Stanford University School of Medicine to confirm or refute these findings. In considering best approaches, we noted that there was an absence of prior research in which the  sickle cell trait status of an entire, large, physically-active study population was known. This limitation could introduce bias to inflate the apparent impact of a theorized predictive factor.

Aside from the challenges in studying the impact of SCT on exertional outcomes, with respect to prevention, a further concern is that  sickle cell trait is a non-modifiable trait. If it were a serious risk factor for rhabdomyolysis and/or mortality, despite careful exertional injury precautions such as those employed by the Army, this might present great challenges for prevention efforts. To maximize the potential for new research to provide actionable prevention information, our interests included examining a range of modifiable risk factors for rhabdomyolysis.

Dr. Kurina and I have employed large, longitudinal military datasets for about five years to examine critical military health outcomes, making this study a natural progression of our joint work. The research proceeded with the support of the Uniformed Services University of the Health Sciences, and in cooperation with a distinguished group of experts who co-authored the paper and advised the project. The study was conducted using de-identified records of all SCT-tested African American US Army soldiers on active duty during 2011 – 2014 (N = 47,944).

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IV Iron Administered Post-Op May Improve Surgical Outcomes

MedicalResearch.com Interview with:
Clinical Professor Alhossain A.Khalafallah
Menzies Institute for Medical Research,
University of Tasmania, Australia
Consultant Haematologist
Senior Staff Specialist
Launceston General Hospital,
Australia

MedicalResearch.com: What is the background for this study?

Response:
1. Iron deficiency is one of the most common nutritional deficiencies worldwide, affecting up to one third of the population worldwide.
2. Prevalence of anaemia in orthopaedic surgery ranges between 10-20% with the main cause of anaemia identified as nutritional deficiency.
3. New intravenous iron preparations have been developed at a higher purchase price than oral iron. Iron carboxymaltose, as one example, remains underutilised in the treatment of perioperative anaemia.
4. To our knowledge, this study is the first to compare the efficacy, safety and long term effect on iron stores and length of hospital stay in the postoperative anaemia setting.

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Iron Levels Should Be Checked During Pregnancy

MedicalResearch.com Interview with:
Kris Poppe, MD, PhD
Co-Head Endocrine Unit
CHU St-Pierre UMC
Université libre de Bruxelles

MedicalResearch.com: What is the background for this study? 

Response: Pregnant women are often referred by gynecologists to my endocrine practice, for altered thyroid function. At that occasion, I often noticed that the women also had low iron/ferritin levels (ferritin is the iron reserve). Searching in literature did not reveal many publications on the association between iron (deficiency) and thyroid function during pregnancy and so that was the background/aim to perform this study.

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Iron Deficiency Common In Heart Failure Patients and Linked To Worse Outcomes

MedicalResearch.com Interview with:

John G. F. Cleland, MD, FRCP, FESC Department of Cardiology Hull York Medical School, University of Hull, Castle Hill Hospital, Kingston-Upon-Hull National Heart and Lung Institute Royal Brompton and Harefield Hospitals Imperial College London, United Kingdom

Dr. John Cleland

John G. F. Cleland, MD, FRCP, FESC
Department of Cardiology
Hull York Medical School, University of Hull, Castle Hill Hospital, Kingston-Upon-Hull
National Heart and Lung Institute
Royal Brompton and Harefield Hospitals Imperial College
London, United Kingdom

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: This analysis shows that iron deficiency is very common in patients with heart failure and often leads to anaemia and that the prevalence of both iron deficiency and anaemia are highly sensitivity to the criteria used to define them. The World Health Organization defines anaemia as a haemoglobin concentration of <13g/dL in men and <12g/dL in women but doctors should realise this is the lower limit of normal and haemoglobin concentrations should ideally be about 2g/dL higher than this. A man with a haemoglobin of 12g/dL is quite severely anaemic. This study suggest that iron deficiency is common when haemoglobin drops below 14g/dL for men and 13g/dL for women.

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HIV Lymphoma Patients Now Candidates For Stem Cell Transplants

MedicalResearch.com Interview with:

Joseph Alvarnas, MD Associate clinical professor Department of hematology and Director of value-based analytics City of Hope National Medical Center Duarte, CA

Dr. Joseph Alvarnas

Joseph Alvarnas, MD
Associate clinical professor
Department of hematology and Director of value-based analytics
City of Hope National Medical Center
Duarte, CA

MedicalResearch.com: What is the background for this study?

Dr. Alvarnas: Patients with HIV infection have a significantly increased risk of non-Hodgkin lymphoma and Hodgkin lymphoma. Prior to the availability of effective anti-retroviral therapy, HIV-infected patients with lymphoma had very poor treatment outcomes. Following the availability of effective anti-HIV therapy, patient outcomes for HIV-infected patients now parallel those of non-infected patients. Historically, however, HIV infection has been used as a criterion for not offering patients autologous blood stem cell transplantation outside of centers with unique expertise. The purpose of this trial was to evaluate outcomes, complication rates, and immunological reconstitution of HIV-infected patients following autologous blood stem cell transplantation.
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Sickle Cell Anemia: Discontinuing Blood Exchange After Transition to Adulthood Linked with Increased Mortality

MedicalResearch.com Interview with:

Samir K. Ballas MD FACP Emeritus Professor of Medicine and Pediatrics Department of Medicine/Cardeza Foundation for Hematologic Research Thomas Jefferson University Philadelphia, PA

Dr. Samir Ballas

Samir K. Ballas MD FACP
Emeritus Professor of Medicine and Pediatrics
Department of Medicine/Cardeza Foundation for Hematologic Research
Thomas Jefferson University
Philadelphia, PA

Medicalresearch.com: What is the background for this study?

Dr. Ballas: Previous studies have shown that the incidence of overt stroke is about 11% in children with sickle cell anemia by ages 2 – 20 years. Untreated stokes recur periodically with increasing severity and mortality. Transfusion therapy has been documented to decrease the frequency and morbidity of stroke in children by 90%. Accordingly, children who develop overt stroke are treated with chronic blood exchange transfusion to prevent the recurrence of additional strokes. When children reach the age of 18-20 years their medical care is transitioned to adult programs. This transition process is associated with several issues one of which is the discontinuation of chronic blood exchange transfusion in patients with history of overt stokes partly due to logistic considerations and partly due to lack of research in strokes in adult patients and the complications of chronic blood transfusion .

Medicalresearch.com: What are the main findings?

Dr. Ballas: The major finding of the study is that the discontinuation of chronic blood exchange after transition to adult programs is associated with increased mortality. All the patients who discontinued blood transfusion died within 3-5 years after transition whereas patients who continued having blood exchange transfusion survived to a mean age of 36 years at the time of writing this study.
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Should Dose of EPO in CKD Be Individualized For Patient’s Quality of Life?

MedicalResearch.com Interview with:
Dr. Navdeep Tangri
Attending physician and Assistant Professor in the Division of Nephrology
Department of Medicine and the Department of Community Health Sciences
University of Manitoba

and Dr. David Collister 
Seven Oaks General Hospital Renal Program
Winnipeg, Manitoba Canada. 

Medical Research: What is the background for this study? What are the main findings?

Response: Anemia is common in chronic kidney disease (CKD) including dialysis and its treatment with erythopoetin stimulating agents (ESAs) reduces the need for blood transfusions and has varying effects on morbidity and mortality. The optimal hemoglobin (HGB) targets for treating anemia in CKD are controversial with safety concerns around the normalization of hemoglobin levels due to an increase in cardiovascular (CV) events. The effects of ESAs on health related quality of life (HRQOL) are unclear with individualization o fhemoglobin targets being controversial as clinicians and patients attempt to balance perceived HRQOL benefits with cardiovascular risk.

We performed an updated meta-analysis of randomized controlled trials (RCTs) that evaluated the treatment of anemia in CKD with ESAs that targeted higher versus lower hemoglobin targets using validated HRQOL metrics including SF-36 and KDQ. We included 17 studies and found that higher hemoglobin targets compared to lower HGB targets did result in a statistically significant difference in HRQOL and thus did not improve HRQOL beyond a clinically meaningful threshold. Any change in HRQOL was further attenuated in dialysis subgroups.

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Nanobody is Potentially First Targeted Therapy for TTP

MedicalResearch.com Interview with:
Dr. Filip Callewaert PhD
Senior Clinical Scientist
Clinical Development, Ablynx
Zwijnaarde, Belgium

Medical Research: What is the background for this study? What are the main findings?

Dr. Callewaert: Acquired thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening coagulation disorder, in which accumulation of ultra-large von Willebrand factor (ULvWF) multimers is implicated, leading to an increased risk of thrombus formation in small blood vessels due to excessive platelet aggregation. There are no approved pharmacological therapies for acquired TTP. Despite treatment with the current standard of care (plasma exchange and immunosuppressive therapy), mortality remains at 10-20% and there is significant neurological, cardiac, and renal morbidity.

Caplacizumab is a bivalent Nanobody that binds to the A1 domain of vWF thereby preventing vWF-mediated platelet aggregation. The clinical effects of caplacizumab were demonstrated in the phase II randomised, placebo-controlled TITAN study in 75 patients with acquired TTP. Compared to placebo, there was a nearly 40% reduction in median time to platelet count normalisation in the caplacizumab group (p = 0.005). Treatment with caplacizumab reduced the use of daily plasma exchange and prevented further consumption of platelets in microthrombi and small blood vessel occlusion. In addition, there were fewer recurrences of TTP requiring re-initiation of daily plasma exchange during treatment with caplacizumab (N=3) vs. placebo (N=11). The safety profile of caplacizumab was favorable, with a slightly higher tendency of mostly mild bleeding events.  Continue reading

Hemophilia: New Fusion Protein Allows For Less Frequent Dosing To Prevent Bleeding

Dr. Elena Santagostino

Dr. Elena Santagostino

MedicalResearch.com Interview with:
Dr. Elena Santagostino, MD PhD
Angelo Bianchi Bonomi Hemophilia and Thrombosis Center
Ca’ Granda Foundation
Maggiore Hospital Policlinico, Milan, Italy

Medical Research: What is the background for this study? What are the main findings?

Dr. Santagostino: Two of our abstracts presented at the 57th ASH Annual Meeting are part of the PROLONG-9FP clinical program evaluating the efficacy and safety of CSL Behring’s investigational long-acting fusion protein linking recombinant coagulation factor IX with recombinant albumin (rIX-FP).  The first is an oral presentation on results from two Phase III studies and an ongoing extension study of rIX-FP for routine prophylaxis in previously-treated people with hemophilia B.

The two Phase III studies included adolescents and adults (ages 12 to 61) treated with dosing intervals of up to 14 days for 12 to 18 months, and children (ages 1 to 11) who received seven-day prophylaxis treatment for approximately 12 months. Overall, the median annualized spontaneous bleeding rate (AsBR) was 0.00 for all treatment intervals. The extension study is examining longer treatment intervals, including 10- and 14-day intervals in patients younger than 12 and more prolonged treatment intervals in patients older than 18, and so far has reported favorable long-term tolerability with no serious adverse reactions such as the development of inhibitors to factor IX or antibodies to rIX-FP.

A second abstract reported on a surgical sub-study in these trials found that a single pre-operative dose of rIX-FP maintained hemostasis during surgery with responses rated by investigators as “excellent” or “good.” Oven a 14-day perioperative period, patients needed six or seven infusions, and none developed inhibitors to factor IX or antibodies to rIX-FP.

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Triplet Therapy Induces Durable Response In Refractory Myeloma

MedicalResearch.com Interview with:
Dr. Ajai Chari MD
Associate Professor
Medicine, Hematology and Medical Oncology
Tisch Cancer Institute
Mount Sinai School of Medicine
New York, NY

Medical Research: What is the background for this study?

Dr. Chari: This is a heavily pretreated population where the median progression free survival (PFS) of the pomalidomide dexamethasone is only 4 months and ORR is only 31%. While the anti CD38 monoclonal antibody daratumumab has single agent has activity in this setting, patients with rapidly progressive disease need combination therapy to achieve rapid and deep responses. Pomalidomide also upregulates CD38 on MM cells and like daratumumab, increases the effector cell activity against myeloma. Thus, there is a strong preclinical and clinical rationale for combining daratumumab with pomalidomide and dexamethasone.

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Stored Blood For Transfusions Works As Well As Fresh Blood

Dr. Walter H. Dzik MD Associate Pathologist, Massachusetts General Hospital Associate Professor of Pathology Harvard Medical Schoo

Dr. Walter Dzik

MedicalResearch.com Interview with:
Dr. Walter H. Dzik MD
Associate Pathologist, Massachusetts General Hospital
Associate Professor of Pathology
Harvard Medical School

Medical Research: What is the background for this study? What are the main findings?

Dr. Dzik: Millions of Red Blood Cell transfusions are given each year.  To maintain adequate blood inventories worldwide, Red Blood Cell units are stored under refrigerated conditions.  Previous animal and laboratory research has highlighted the fact that red cells undergo biochemical, morphologic, and biophysical changes during prolonged refrigerated blood storage.    Researchers and clnicians have questioned whether the changes that occur during storage would impair the ability of transfused Red Cells to delivery oxygen to tissues.

Our study was a randomized controlled trial conducted in patients with extreme anemia and insufficient global tissue oxygenation.    We randomly assigned children with severe anemia and lactic acidosis to receive Red Blood Cells stored 1-10 days versus Red Blood Cells stored 25-35 days.   We measured the recovery from lactic acidosis in response to transfusion in the two groups.   We also measured cerebral tissue oxygenation using a non-invasive tissue oximeter.    We found that the proportion of patients who achieved reversal of lactic acidosis was the same in the two RBC storage-duration groups.   The rate of decline of lactic acidosis was also equal.   There was also no difference in cerebral oxygenation, resolution of acidosis, correction of vital signs, clinical recovery, survival and 30-day followup.   
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FDA Study Compares Anaphylactic Risk of IV Iron Products

Cunlin Wang, MD, PhD Division of Epidemiology I, Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research US Food and Drug Administration

Dr. Wang

MedicalResearch.com Interview with:
Cunlin Wang, MD, PhD
Division of Epidemiology I,
Office of Surveillance and Epidemiology,
Center for Drug Evaluation and Research
US Food and Drug Administration

MedicalResearch: What is the background for this study? What are the main findings?

Dr. Wang:  IV Iron has been known for its risk of anaphylactic reaction, but there has been little research on the comparative safety of individual IV Iron products from a large population-based study. This study included 688,183 new users of IV iron not on dialysis from the U.S. Medicare program over a ten-year span (January 2003 to December 2013). The main findings of the study are:  the risk for anaphylaxis at first exposure was higher for iron dextran than non-dextran IV iron products combined (iron sucrose, gluconate and ferumoxytol).  When individual IV Iron products were compared, the data suggested that iron dextran has the highest risk of anaphylaxis and Iron sucrose has the lowest risk, estimated both at the first time exposure and after cumulative exposures.  The low and high molecular weight dextran products could not be individually identified during most of study period. However,  from January 2006 through March 2008, during which the use of two dextran products could be distinguished, there was very low use of high molecular weight dextran (Dexferrum@). This suggested that the study results likely represent the risk of the low molecular weight dextran (Infed@).

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IV Iron in Hospitalized Hemodialysis Patients Not Linked With Worsening Infections

Dr. Julie H. Ishida MD San Francisco Veterans Affairs Medical Center Nephrology Section San Francisco, CAMedicalResearch.com Interview with:
Dr. Julie H. Ishida MD
San Francisco Veterans Affairs Medical Center
Nephrology Section
San Francisco, CA

Medical Research: What is the background for this study? What are the main findings?

Dr. Ishida: Intravenous iron is important in the treatment of anemia of end-stage renal disease, but it is biologically plausible that iron may increase infection risk. While results from epidemiologic studies evaluating the association between intravenous iron and infection in hemodialysis patients have been conflicting, guidelines for the treatment of anemia of chronic kidney disease have recommended caution in prescribing, avoidance and withholding of intravenous iron in the setting of active infection. However, no data specifically support the recommendation to withhold intravenous iron during active infection.

Our study observed that among hemodialysis patients hospitalized for bacterial infection who had been receiving intravenous iron as an outpatient, continued receipt of intravenous iron was not associated with higher all-cause mortality, readmission for infection, or longer hospital stay.

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Biomarker May Predict Cancers Grow With Anemia Drug

Anil K. Sood, M.D

Dr. Anil Sood

MedicalResearch.com Interview with:
Anil K. Sood, M.D.
Professor of Gynecologic Oncology and Reproductive Medicine
The University of Texas MD Anderson Cancer Center

Medical Research: What is the background for this study? What are the main findings?

Dr. Sood: Erythropoietin is an important drug for managing anemia, but concerns have surfaced that it might promote cancer growth. The data with the conventional epo-receptor were not convincing with regard to an explanation for why tumor growth might increase. Therefore, we considered whether there could be an alternative receptor to explain these findings. We carried out a systematic search and identified EphB4 as the alternative receptor that explained the increased tumor growth in response to epo.

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Serum Phosphorus Level May Be a Biomarker For Anemia

MedicalResearch.com Interview with:
Lac Tran, MD
Division of Nephrology and Hypertension
Kaiser Permanente Los Angeles Medical Center
Los Angeles, CA

Medical Research: What is the background for this study? What are the main findings?

Dr. Tran: Abnormal serum phosphorus levels have been associated with adverse cardiovascular outcomes and progression to renal failure.  Given phosphorus’s important biological roles in cellular replication and bone mineral metabolism, we sought to investigate the association between phosphorus levels and anemia in normal kidney function and early chronic kidney disease.

Our study is a population-based study among a large racially/ethnically diverse population within the Kaiser Permanente Southern California health system.
Among 155, 974 individuals, 4.1% had moderate anemia and 12.9% had mild anemia.  We found that phosphorus levels greater than 3.5 mg/dL and less than 2.0 mg/dL showed a greater likelihood for moderate anemia.  Every 0.5 mg/dL phosphorus level increase demonstrated a 16% greater likelihood for moderate anemia.  The highest phosphorus tertile of our population had a 26% greater likelihood for anemia compared to the middle tertile.  We also found that female sex, Asian race, diabetes, low albumin, and low iron saturation were risk factors for anemia.

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Patient-Derived Stem Cells May Be Able To Reverse Hemophilia A

Dong-Wook Kim Center for Genome Engineering, Institute for Basic Science Yonsei University College of Medicine Seoul, KoreaMedicalResearch.com Interview with:
Dong-Wook Kim
Center for Genome Engineering, Institute for Basic Science
Yonsei University College of Medicine
Seoul, Korea

Medical Research: What is the background for this study?

Response: Hemophilia A is an X-linked genetic disorder caused by mutations in the F8 gene, which encodes the blood coagulation factor VIII. Almost half of all severe hemophilia A cases result from two gross (140-kbp or 600-kbp) chromosomal inversions. We derived induced pluripotent stem cells (iPSCs) from patients with these inversion genotypes and used CRISPR-Cas9 nucleases to revert these chromosomal segments back to the WT situation.

Medical Research: What are the main findings?

Response: We isolated inversion-corrected iPSCs with frequencies of up to 6.7% without detectable off-target mutations based on whole-genome sequencing or targeted deep sequencing. Endothelial cells differentiated from corrected iPSCs expressed the F8 gene and functionally rescued factor VIII deficiency in an otherwise lethal mouse model of hemophilia.

Medical Research: What should clinicians and patients take away from your report?

Response: Our results provide a proof of principle for functional correction of large chromosomal inversions in Hemophilia patient-derived induced pluripotent stem cells and suggest potential therapeutic applications in the future.

Medical Research: What recommendations do you have for future research as a result of this study?

Response: We need to prove the safety of patient-derived iPSCs before we move towards clinics.

The safety of iPSCs means to prevent teratoma formation when we do clinical trials.

For that purpose, we need to develop good differentiation protocols into EC cells and to purify the cells as well. In addition, we need much more animal study.

Citation:

Functional Correction of Large Factor VIII Gene Chromosomal Inversions in Hemophilia A Patient-Derived iPSCs Using CRISPR-Cas9

Chul-Yong Park Duk Hyoung Kim Jeong Sang Son Jin Jea Sung Jaehun Lee Sangsu Bae Jong-Hoon Kim Dong-Wook Kim Jin-Soo Kim

Cell Stem Cell Available online 23 July 2015

doi:10.1016/j.stem.2015.07.001

Dong-Wook Kim (2015). Patient-Derived Stem Cells May Be Able To Reverse Hemophilia

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Iron Deficiency Anemia May Complicate Diagnosis of Diabetes

MedicalResearch.com Interview with:
Emma English PhD

Lecturer in Healthcare Science and Academic Lead for Clinical Biochemistry
University of Nottingham, School of Medicine
Royal Derby Hospital, UK

MedicalResearch: What is the background for this study? What are the main findings?

Dr. English: HbA1c is widely used for monitoring glycaemic control in people with diabetes as there is clear evidence that lowering HbA1c values leads to reductions in the rates of diabetes complications. Recently the World Health Organization and the American Diabetes Association have both advocated the use of HbA1c for the diagnosis of Type 2 diabetes at a value of ≥48 mmol/mol (6.5%). Whilst there are many advantages to the use of HbA1c as a diagnostic tool there are equally some significant limitations to its use. A widely cited confounder is anaemia, however to what extent and which types of anaemia affect HbA1c results was not clearly understood. When HbA1c was introduced as a diagnostic test in England we received many queries from healthcare professionals asking questions such as ‘at what level of anaemia should I not use HbA1c?’ and ‘should I routinely screen patients for anaemia when using HbA1c? And if so, what test should I use?’. In order to answer these questions we conducted a systematic review of the literature to determine what was known on this subject.

Our findings, presented in Diabetologia, suggest that iron deficiency and iron deficiency anaemia may lead to a spuriously elevated HbA1c level, thus may lead a false positive diagnosis of diabetes. However, non-iron deficiency anaemias can lead to an artificially lower HbA1c and may lead to a false negative result where a diagnosis of diabetes would be missed. There is no clear evidence to suggest at what levels anaemia can give rise to these effects on HbA1c value and also there does not appear to be a single ideal test for identifying patients where this could be an issue.

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Major Disease States Cause Slowdown in Red Blood Cell Production and Destruction

MedicalResearch.com Interview with:
John M. Higgins, MD
MGH Center for Systems Biology
Boston, MA

Medical Research: What is the background for this study? What are the main findings?

Dr. Higgins: Hundreds of studies over the past 8 years have shown that increased variation in the size of red blood cells (RBCs) is associated with increased risk for a very wide range of common diseases, like heart disease, many types of cancer, infection, many autoimmune diseases, and lots of other conditions.  The size of red blood cells (RBCs) in the circulation of a healthy person usually varies by about 12-14%, meaning that if you took a sample of the cells, most of the bigger cells would be about 14% larger than the smaller cells.  People whose red blood cells show more variation in size have a greater risk of developing a wide range of diseases.  Also, among patients already diagnosed with many common diseases like heart disease or cancer, those with higher RBC size variation have worse outcomes.  It is unknown how all of these different diseases could be connected to variation in the size of red blood cells.  The study explains a major cause for this connection.  We find that the human body seems to slow down the production and destruction of RBCs in just about every major disease very slightly.  Since red blood cells gradually become smaller as they age, a delay in destruction will increase the fraction of small cells, and the overall variation in size increases.  The study also describes a method to estimate a patient’s RBC clearance rate.

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