Showing 9 ideas for tag "anemia"

Goal 3: Advance Translational Research

Allogeneic transplantation as a safe and universally available therapeutic strategy for treating non-malignant blood diseases

Can new advances in allogeneic blood or marrow transplantation (BMT) make the procedure a safe and universally available therapeutic strategy for treating non-malignant blood and immune disorders such as sickle cell anemia, thalassemia, aplastic anemia, and severe combined immune deficiency?

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? Compelling Question (CQ)

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The ability of allogeneic blood or marrow transplantation (BMT) to cure diverse non-malignant diseases is well-documented. However, widespread use in diseases such as sickle cell anemia that cause substantial morbidity and shorten life but are not immediately life-threatening, has been limited by transplant-related toxicity and mortality especially in the majority of these patients who lack HLA-matched donors. Several new therapeutic approaches now exist that are promising strategies, separately or in combination, for addressing issues of donor availability, graft rejection, organ toxicity and acute and chronic graft-versus-host disease more effectively. Evaluation and refinement of these therapeutic strategies in both preclinical and Phase I-III clinical trials now offers a real possibility that allogeneic BMT could be applied early in the course of these diseases, allowing normal growth, development, quality of life and lifespan. If successful, allogeneic BMT offers a major advantage over gene therapy approaches even if such approaches become possible in the future; i.e., allogeneic BMT can be done with low-dose, non-toxic conditioning while gene therapy requires high-dose myeloablative therapy which not only can be toxic/fatal to these patients who often have end-organ dysfunction but also universally induces infertility, a major concern of patient groups who usually survive beyond child-bearing years.

Feasibility and challenges of addressing this CQ or CC

There are now single institution and registry (CIBMTR) data showing that related haploidentical allogeneic BMT using post-transplantation cyclophosphamide (PTCy) produces results similar to those seen with HLA-matched sibling donors. Accordingly, every patient in need of allogeneic BMT now can safely undergo the procedure, including those ethnic groups (such as African-Americans and Hispanics) who are unlikely to find a donor in unrelated registries. Combining PTCy with other approaches for preventing graft-versus-host disease (GVHD) can even eliminate GVHD and transplant-related mortality. Although recurrence of malignant diseases remains an issue, especially as GVHD is eliminated, relapse is not a concern for non-malignant diseases after successful allogeneic engraftment. Moreover, the average cost of allogeneic BMT, about $150K, is a cost-savings over the long-term management of many of these diseases. The NHLBI-funded BMT Clinical Trials Network (CTN) has developed the infrastructure to rapidly and efficiently carry out large multi-institutional BMT trials. Over the last 15 year, thousands of patients have been entered on BMT CTN trials. Of note, African-Americans and Hispanics remarkably represent 30% of the accruals on one such trial, CTN1101, studying unrelated umbilical cord and related haploidentical allogeneic BMT. However, funding for the infrastructure for continuing this work remains problematic, since BMT trials generally lack corporate funding.

Name of idea submitter and other team members who worked on this idea Rick Jones

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214 up votes
50 down votes
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Goal 2: Reduce Human Disease

Transplantation across HLA barriers in aplastic anemia

Allogeneic stem cell transplantation is curative in aplastic anemia with much less intrinsic toxicity than transplantation in hematologic malignancies. The recent BMT-CTN trial demonstrated 97% survival at one year with little subsequent decline. However patients without matched related or unrelated donors have graft-rejection rates of up to 50%. Preliminary data from the Netherlands suggests that anti-thymocyte globulin... more »

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? Compelling Question (CQ)

Details on the impact of addressing this CQ or CC

The use of umbilical cord blood or haploidentical donors has proven effective in patients with hematologic malignancies, but in non-malignant disorders outcomes are limited by graft rejection. Overcoming rejection in this context would be applicable to other non-malignant disorders such as thalassemia, sickle cell anemia, and other congenital disorders of hematopoiesis.

Feasibility and challenges of addressing this CQ or CC

It will require a large coordinated network like BMT-CTN to obtain sufficient patients studied in a uniform fashion to provide consistent reproducible data. .

Name of idea submitter and other team members who worked on this idea Joseph Antin

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110 net votes
137 up votes
27 down votes
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Goal 2: Reduce Human Disease

Sickle Cell anemia and Aplastic anemia survivors: Late effects and quality of life issues in Stem Cell Transplant Survivors

Most of the patients suffering from non-malignant hematologic conditions are cured of the original disease with Hematopoitec Stem Cell Transplant (HSCT) but still their survival is less compared to age matched general population, and additionally they suffer from unique complications of HSCT culminating into a variety of late physical, psychologic, financial, and social complications (“late effects”). Considerable improvements... more »

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? Compelling Question (CQ)

Details on the impact of addressing this CQ or CC

One million HSCT mile stone was recently reached and the utilization of HSCTs continues to increase. For many non-malignant hematologic conditions particularly sickle cell anemia and bone marrow failure syndromes, HSCT is the only potentially curative option. Most HSCT survivors are living beyond a year, but can suffer from devastating complications of HSCT which include graft-versus-host-disease, second cancers, diabetes, infertility, congestive heart failure, blindness, and bronchiolitis obliterans, besides many others which lead to increased overall HSCT related disease burden. A lot of efforts are currently being put in cancer survivorship by the ACS, NCI, ASCO and other societies, but very little emphasis is being laid on sickle cell or aplastic anemia survivors. This area of HSCT survivorship becomes more important from health disparities perspective too, since majority of the hemoglobinopathy HSCTs performed in the US are in racial minorities. Comparative effectiveness research (CER) in HSCT survivorship is essential to delineate the overall disease burden this population and understand the risks and outcomes of HSCT late effects. To compare the effectiveness of survivorship programs and research, especially for those survivors who are at risk of health disparities is a top priority of the Institute of Medicine CER 2009 initiative.

Feasibility and challenges of addressing this CQ or CC

Majority of the HSCT survivors of benign hematologic conditions are now living beyond 2 years post-HSCT. Blood and Marrow Transplant (BMT) Clinical Trials Network (CTN) was established in 2001 to conduct large Multi-Institutional clinical trials and is funded by the NHLBI. Since the infrastructure is in place to conduct studies related to all aspects of HSCT, this would be an area to explore first from feasibility perspective since thousands of patients have already been successfully enrolled through the BMT-CTN studies. From NHLBI strategic perspective, this would place CTN (and Emmes Corporation) in an excellent unique position of addressing CER for survivorship issues and health disparities within one study, since the population understudy would mainly be consistent of racial minorities – with the overall goal of improving the long term health, preventing late effects, improving quality of life, and reduce the overall health burden (DALYs and societal costs) of thousands of HSCT survivors in the US and globally.

Name of idea submitter and other team members who worked on this idea Shahrukh Hashmi

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71 net votes
89 up votes
18 down votes
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Goal 2: Reduce Human Disease

Anemia, oxygen delivery, and red blood cell transfusion

In neonatal, pediatric, and adult patients with critical illness, what is the best means to identify: (1) the degree to which anemia contributes to insufficient oxygen (O2) delivery and (2) the likelihood that O2 delivery will be improved by red blood cell (RBC) transfusion?

These questions are most relevant to critically ill populations that exhibit unique physiology, including those with low cardiac output (cardiac... more »

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? Compelling Question (CQ)

Details on the impact of addressing this CQ or CC

In the critically ill, RBC transfusion is indicated to improve O2 delivery. Although RBC transfusion increases hemoglobin concentration (Hb) and thereby blood O2 content, it does not necessarily follow that O2 delivery to tissues is likewise increased. Current approaches to transfusion decision making in critical care settings maintain an ‘adequate’ RBC mass well above a level that may limit tissue O2 delivery. With improved understanding of vascular signaling and gas transport by RBCs and of the array of defects comprising the RBC ‘storage lesion’, we appreciate that this strategy must be balanced by consideration that: (1) donor and recipient RBCs do not exhibit similar physiology and (2) RBC transfusion may cause harm (beyond transfusion reactions and transmission of infection) – and that this harm appears progressive with: transfusion volume, frequency and donor exposure. As such, ‘restrictive’ Hb thresholds for RBC transfusion are appreciated to be at least non-inferior to ‘liberal’ Hb thresholds for a broad array of conditions. A paradigm shift is emerging in approach to the critically ill, with re-consideration of the ‘Hb trigger’ strategy, itself. Ideally, the decision to transfuse should be based upon individual and context-specific consideration of the degree to which anemia contributes to tissue O2 delivery.

Feasibility and challenges of addressing this CQ or CC

We need to identify specific physiologic endpoints linked to outcomes as well as determine the appropriate thresholds for these goals. We must improve current means to assess functionality of the circulating RBC mass and its specific relationship to tissue O2 delivery in both humans and animal models. Approaches to resolve this gap could be conducted in the following areas during the next 3-5 years (studies may be independent or ancillary to clinical transfusion trials). Examples include but are not limited to the following: (1) clinical and translational research studies examining physiologic tolerance of acute and chronic anemia in the critically ill populations; (2) basic and clinical research exploring accuracy, precision and reliability of novel approaches to quantify and monitor O2 consumption and delivery (global/regional). Investigations should also determine the relationship of these measures to clinically relevant patient outcomes, both global (mortality, ventilator dependence, length of stay, etc.) and organ-specific; and (3) studies evaluating the process of transfusion decision making in the setting of critical illness.

Name of idea submitter and other team members who worked on this idea Nareg Roubinian, MD and Naomi Luban, MD for the 2015 NHLBI State of the Science in Transfusion Medicine.

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40 net votes
54 up votes
14 down votes
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Goal 1: Promote Human Health

Epigenetics and Genomics

There is a need to investigate hemoglobin biosynthesis in order to develop novel approaches to treat sickle cell disease, thalassemia, and other anemias.

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? Critical Challenge (CC)

Details on the impact of addressing this CQ or CC

Studies on epigenetic mechanisms have extraordinary promise for the development of transformative therapeutic approaches for non-malignant hematologic disorders, however, limited progress has been made in advancing therapies to counteract the often crippling complications of these conditions. In the case of sickle cell disease, an ensemble of proteins has been implicated in mediating the epigenetic repression of gamma-globin expression, raising the possibility that antagonizing the actions of these proteins to increase gamma-globin expression may be a useful treatment strategy. However, in certain cases, some of these proteins are deemed “undruggable,” based on their structural attributes. There is a critical need to identify druggable components of the multi-step epigenetic mechanisms as well as develop better models and assays that will more effectively identify modulators of “undruggable” proteins. Given the rich proteome and improved technologies available today, studies of proteomics, metabolomics, and regulatory RNAs are likely to reveal promising translational avenues. In addition, approaches to modifying the expression of the components of this pathway are underway using developing gene therapy strategies, such as viral vectors and/or gene editing can quickly advance therapy in sickle cell disease and β-thalassmia.

Name of idea submitter and other team members who worked on this idea Alice Kuaban on behalf of the American Society of Hematology (ASH)

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42 net votes
62 up votes
20 down votes
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Goal 3: Advance Translational Research

Can SYK or BTK inhibition ameliorate autoimmune hemolytic anemia after stem cell transplantation

Experimental mouse models of ITP and AIHA are dependent on FcgR-signaling, which in turn depends on Syk kinase activity for activation of phagocytes. A significant and refractory complication of stem cell transplantation is immune hemolytic anemia. This can be either autoimmune or alloimmune. In either case it is likely that clearance of RBC and RBC progenitors is dependent on extravascular mechanisms involving activation... more »

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? Compelling Question (CQ)

Details on the impact of addressing this CQ or CC

Autoimmune hemolytic anemia occurs in about 5% of allogeneic stem cell transplants as a late immunologic complication of immune dysregulation. This occurs either in the setting of chronic GVHD or independently. ABO incompatibility also results in hemolytic anemia which may be complicated by transplant-related mortality or pure red blood cell aplasia. Often ABO incompatible donors are the only option. Targeting of FcgR has not been assessed in this setting and would 1) provide clinical benefit, 2) shed light on the role of FcgR inhibition in a more general way in BMT-related complications.

Feasibility and challenges of addressing this CQ or CC

This interesting question can best be addressed in the context of a network study, since the development of AIHA is uncommon. BMT-CTN would be a superb mechanism to assess feasibility and efficacy and it would be well-positioned to study scientific offshoots of this approach.

Name of idea submitter and other team members who worked on this idea Joseph Antin

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23 net votes
52 up votes
29 down votes
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Goal 2: Reduce Human Disease

Blood specific diseases due to defects in ubiquitous pathways

Why are some blood diseases called by genetic mutations in ubiquitous pathways. Diamond Blackfan anemia is due to a mutation in ribosomal proteins.

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? Compelling Question (CQ)

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A number of blood diseases are due to signaling defects in ubiquitous pathways. Why would a ribosomal protein mutation lead to a red blood cell specific disorder. Certain anemias or myelodysplastic syndromes are due to mutations in chromatic factors. The chromatin factor defects can lead to clonal hematopoiesis.

Feasibility and challenges of addressing this CQ or CC

A large scale centralized effort could select projects on blood specific diseases due to defects in ubiquitous pathways. A correlation of gene expression, translation, or transcription could lead to a better understanding of responses of blood cells to the stress of defects in common pathways.

Name of idea submitter and other team members who worked on this idea Leonard Zon

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2 net votes
9 up votes
7 down votes
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Goal 3: Advance Translational Research

Immune-Mediated hematologic disorders

What is the optimal approach to prevent and treat immune mediated hematologic disorders (autoimmune hemolytic anemia, immune thrombocytopenic purpura, etc) and complications of hematologic disease (inhibitors in hemophilia, transfusion-related alloimmunization, etc)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? Compelling Question (CQ)

Details on the impact of addressing this CQ or CC

Therapies for these disorders are suboptimal and current treatments are associated with significant side effects. Transfusion is limited by development of alloantibodies..

Feasibility and challenges of addressing this CQ or CC

NHLBI should support clinical trials in this area. Improved understanding of the biology and biomarkers predictive of disease development would aid in defining therapeutic approaches and trials.

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Goal 3: Advance Translational Research

Role of anemia and iron deficiency anemia on hemoglobin A1C%

Many forms of anemia are associated with lowering HbA1C% but iron deficiency anemia modestly raises HbA1C%. The exact mechanism of anemia and iron deficiency anemia's effect on HbA1c levels is unclear. This impacts our treatment of diabetes mellitus and diabetes mellitus co-morbidity with HIV, Hepatitis C and other diseases in the presence of anemia.

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? Critical Challenge (CC)

Details on the impact of addressing this CQ or CC

Hemoglobin A1c (HbA1C%) is a widely used marker for the diagnosis and treatment of diabetes mellitus (DM). Understanding how anemia and iron deficiency anemia affects HbA1C% informs the practitioner on proper dosing of oral and insulin based medication regimens, on the impact of diet and exercise in HbA1C% and erythrocyte turnover, and the incidence and prevalence of DM in sub-populations.

Feasibility and challenges of addressing this CQ or CC

With the advent of continous glucose monitoring, studies can be set up for measuring impact of disease state, medication and lifestyle on erythrocyte and seum glucose in addition to basic science on hemoglobin/RBC changes under varying glucose concentrations

Name of idea submitter and other team members who worked on this idea JocelynR

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-2 net votes
10 up votes
12 down votes
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