Showing 51 ideas for tag "cell"

Goal 2: Reduce Human Disease

The Importance of the Microbiome in Recovery after Hematopoietic Stem Cell Transplantation

Do modifications in the recipient gut or lung microbiome affect development of tolerance and immunologic recovery after allogeneic hematopoietic stem cell transplantation (HCT) and can re-institution of a more normal microbiome lead to improved outcomes?

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

Details on the impact of addressing this CQ or CC

HCT leads to profound changes in the host microbiome. Some small studies indicate that differential recovery of the gut microbiome is associated with differential outcomes, including graft-versus-host disease and mortality. Less is known about the pulmonary microbiome. Better understanding of the role of the microbiome in facilitating posttransplant recovery could lead to easily administered interventions and provide important insights into the role of different subpopulations of the microbiome on the health of all people.

Feasibility and challenges of addressing this CQ or CC

Preclinical and clinical studies of this area would be greatly facilitated by a microbiome repository linked to high quality clinical data and would provide opportunity for insight into the role of the microbiome in health and disease.

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

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117 net votes
152 up votes
35 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

What is the place of curative therapies in the management of Sickle Cell Disease

Advances in the care of pediatric patients with sickle cell disease ( SCD) have resulted in improved survival to adulthood.However, adulthood is marked by rapid disease progression, impaired quality of life and premature mortality. Hematopoietic cell transplantation(HCT) from matched sibling donor has curative potential, but has been offered mainly to children. Refinements in the conditioning regimen, supportive care,... 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

To overcome this obstacle to progress in the field, we propose the creation of the funding mechanisms for a multicenter clinical trial consortium which would bring together investigators in field and facilitate study the outcomes of CT for patients with different types of donors and stem cell sources and compare them to outcomes in phenotypically matched controls receiving best available standard of care.Answering the compelling question about the role of CT in the management of SCD has the potential to have a catalytic effect in progress in this field. Patients are are then more likely to receive CT or standard of care at the appropriate time and in the manner in which they are most likely to have a positive outcome. This has the potential to reduce morbidity and premature mortality and in the long run, to decrease the burden of the disease on the healthcare system. The advent of clinical trials of gene therapies for SCD offers the prospect of even greater applicability of curative therapies. Thus, a consortium developed to answer this CQ would serve as a crucial vehicle for providing access to a greater proportion of patient to these personalized curative therapies . Such studies would also be powered to answer the question about who should receive the curative therapy, when they should receive it, and how it would impact their SCD related complications, late effects, survival and quality of life and help families make informed choice appropriate for their situation.

Feasibility and challenges of addressing this CQ or CC

The increasing applicability and acceptability of HCT for SCD is evidenced by the doubling in the number of such procedures reported to CIBMTR in the decade starting 2001. Refinements in conditioning regimen and supportive care continue to improve outcomes in children and now in adults with SCD undergoing HCT from HLA matched related donors. Recently, HCT from unrelated donors and from haplo-identical donors have further increased the applicability of HCT. Opening of gene therapy trials has further raised the prospect of cure for a greater proportion of patients. These developments are evidence of the feasibility of recruitment to large multi-center comparative trials of SCD and standard of care. Recently, there has been increasing collaboration among investigators in the field with informal consortia being developed by investigators coming together to study HCT for children, adults or HCT from haplo-identical donors. These groups are also increasingly working with SCD hematologists, families and other stakeholders. There is also increasing cross-cutting collaborations with other medical specialists and behavioral and translational scientists Thus, the convergence of several factors described above suggests that the time is fortuitous for a major initiative from the NHLBI to bring investigators together and create the infrastructure that will enable these investigators to seek definitive answers to the challenging question “What is the place of curative therapy in SCD?”.

Name of idea submitter and other team members who worked on this idea Lakshmanan Krishnamurti, MD, Allistair Abraham MD, John Horan MD and members of the Sickle cell Transplantation and Research Alliance

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112 net votes
141 up votes
29 down votes
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Goal 2: Reduce Human Disease

Can we break the silos at NHLBI? Why are we not working on studiying heart and lung issues in blood cancer survivors?

There is an increasing number of blood cancer survivors in the United States. Many of them have treatment induced heart and lung comorbidities (i.e CHF, pulmonary fibrosis, early aging, etc). However, there does not seem to be a concerted effort by the NHLBI to leverage their relationship with the NCI or the BMT CTN to address this issue. NHLBI should be developing a funding mechanism for cardiopulmonary researchers to... more »

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

Details on the impact of addressing this CQ or CC

Would create an infrastructure for cardiopulmonary researchers to work with hematology researchers.
Reduce burden of therapy with curative intent
Develop insight into cardiopulmonary diseases outside of the cancer arenal

Feasibility and challenges of addressing this CQ or CC

Very feasible with the Blood and Marrow Transplant Clinical Trials Network and the National Clinical Trials Network

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

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66 net votes
96 up votes
30 down votes
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Goal 2: Reduce Human Disease

Predictors of Sickle Cell Disease Severity

Can better predictors of disease severity such as specific biomarkers and/or genetic polymorphisms be identified so as to help understand the course and progression of sickle cell disease in various patients?

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 high clinical variability in sickle cell disease (SCD) and the lack of sufficient data to help understand and or predict the course of an individual’s disease warrants the identification of better predictors of disease severity. The identification of predictors of disease severity, such as biomarkers, will be vital in the management and treatment of SCD, especially since more recently several plasma biomarkers and certain genetic polymorphisms have been proposed to influence specific clinical outcomes, including stroke, sickle cell nephropathy, and survival. Furthermore, studies of biomarkers or genetic markers in the context of clinical drug trials may be helpful in predicting response rates, thus allowing for more personalized therapeutic decisions.

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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58 net votes
76 up votes
18 down votes
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Goal 2: Reduce Human Disease

Optimization of Existing Therapies for Sickle Cell Disease

How can the safety, dosing and benefits of existing therapies for sickle cell disease such as hydroxyurea, be optimized in order to increase its efficacy and improve patient adherence?

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

Details on the impact of addressing this CQ or CC

Hydroxyurea is a widely available disease-modifying therapy for sickle cell disease (SCD), but its effectiveness is currently limited by inadequate utilization, and less than optimal response. Research is needed to improve adherence to this evidence-based therapy and emphasis needs to be placed on determining whether therapy with hydroxyurea can prevent or even reverse organ dysfunction. In addition, research identifying new adjunct therapies to blood transfusion and hydroxyurea, as well as disease-specific therapies for co-morbidities such as kidney disease, hypertension, obstructive lung disease, and pulmonary hypertension will be valuable in the management and treatment of SCD.

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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54 net votes
74 up votes
20 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

Apheresis Medicine in the Management of Sickle Cell Disease

Despite advances in care, patients with sickle cell disease have significant morbidity and mortality. One challenge is the optimal use of simple vs exchange transfusion vs no transfusion when managing these patients. Simple transfusions lead to iron overload while exchange transfusions may expose patients to increase numbers of red blood cell units. The mechanism of benefit from transfusion (oxygen delivery vs marrow... more »

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

Details on the impact of addressing this CQ or CC

SCD is the most common genetic disease in the United States affecting 100,000 individuals or 1 in 400 African American births. Pain, stroke, acute chest syndrome and priapism are common morbidities affecting patients with sickle cell disease, which often result in emergency room visits and/or hospitalizations. Despite advances in treatment, sickle cell disease is associated with significant mortality and shortened life expectancy. Defining the optimal role of red blood cell exchange and plasma exchange (which may be used to remove plasma molecules such as inflammatory factors and free hemoglobin) in the management and prevention of the complications of sickle cell disease and may not only prolong the life of these patients but is expected to improve the quality of their lives. In addition, clearly defining the indications for simple verses exchange transfusion therapy has the potential to minimize both alloimmunization to red blood cells (reported to occur in up to 75% of patients with sickle cell disease) and iron overload associated with transfusion.

Transfusion therapy may be efficacious to sickle cell patients by providing increased oxygen delivery to tissues and/or decreasing the amount of sickle hemoglobin present by suppression of erythropoiesis. Understanding the relative contributions of these mechanisms will assist with optimal use of transfusion therapy as well as inform the development of novel alternative therapies

Feasibility and challenges of addressing this CQ or CC

Multi-center trials should be feasible, given the number of patients with sickle cell disease in the US. Participation by larger academic centers which care for sickle cell patients should facilitate trials. Methods for automated red cell exchange and plasma exchange are available and in common use at many centers. Great interest exists among physicians caring for sickle cell patients (as exemplified by the recent NIH consensus document and ASFA sickle cell consensus conference) which is a strength of this proposal. Challenges include agreement on standard treatment protocols across centers and long term follow up of patients. Maintaining vascular access in sickle cell patients is another challenge when performing apheresis procedures on sickle cell patients

Name of idea submitter and other team members who worked on this idea Bruce Sachais on behalf of ASFA

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130 net votes
152 up votes
22 down votes
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Goal 2: Reduce Human Disease

The role of Extracorporeal Photopheresis (ECP) in the prophylaxis and treatment of acute & chronic Graft Versus Host Disease

In Acute Graft Versus Host Disease (aGVHD), we would like to examine whether early and intensified delivery of ECP as part of standard prophylaxis will decrease overall corticosteroid exposure while preserving expected relapse rates in patients undergoing unrelated donor hematopoietic stem cell transplantation (HSCT).
Chronic GVHD (cGVHD) is common after HSCT (30-50% recipients) and is a major contributor to late transplant-related... 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

Patients who develop aGVHD undergo toxic therapy with high-dose corticosteroids, often for long durations, resulting in high morbidity and treatment related mortality. Alternatively, T cell depletion of the donor graft to reduce GVHD is associated with high rates of infection and relapse of the disease that led to the HSCT. Targeting other pathways of GVHD pathogenesis may preserve the beneficial immune reconstitution and graft-versus-tumor (GVT) effects, while ameliorating the severity of GVHD. One such pathway involves regulatory T cells (T regs), which inhibit T cell alloreactivity, and are correlated with the incidence and severity of GVHD without loss of GVT. To date, there is no consensus on a standard second-line therapy for aGVHD, and current approaches focus mainly on intensification of immunosuppression. Addressing this compelling question will help to decrease overall corticosteroid exposure while preserving the expected relapse rates in patients undergoing unrelated donor HSCT.

Appropriate initial therapy for cGVHD involves high doses & prolonged use (yrs) of corticosteroids, while patients still develop irreversible sclerotic manifestations of disease. Early intervention prior to disease onset may help prevent cGVHD development or lessen its severity, requiring less corticosteroid exposure. Addressing the compelling question for cGVHD will help decrease exposure to drugs with associated morbidity, while preserving expected relapse rates in these patients.

Feasibility and challenges of addressing this CQ or CC

Feasibility:

  • GVHD has relatively high incidence after HSCT and at the same time there is a lack of consensus on standard second line therapy for the disease. Thus, there will be increased interest in developing and participation in those studies.

** ECP is generally well tolerated and complications are infrequent.

*** There is a great potential for multi-discipline collaboration approach in this patients’ population.

*** There is an opportunity to engage industry partners in the design and support for these studies.

**** There are numerous scientific opportunities for meritorious science as there have been limited systematic studies of ECP mechanisms of as well as standardization of apheresis protocols based on GVHD disease state.

 

 

Challenges:

  • Limited number of institutions providing ECP treatment.

** Cost of the procedures (although Centers for Medicare and Medicaid Services now covers ECP for cGVHD).

*** There is a very limited number of animal models available for apheresis research in general, and studies of the mechanism(s) of action of photopheresis have been very limited as well as difficult and expensive to perform. However understanding pathological mechanisms and its relationship to response to apheresis is critical for optimization and advancement of patient care.

****Lack of infra-structure for apheresis research.

Name of idea submitter and other team members who worked on this idea Joseph Schwartz on behalf of ASFA

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103 net votes
126 up votes
23 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 2: Reduce Human Disease

Biology of Red Blood Cell Alloimmunization

What determines which individuals will develop RBC alloimmune responses resulting in clinically meaningful sequelae?

This question encompasses: 1) the generation of alloantibodies that limit the availability of compatible blood or cause hemolytic disease of the fetus or newborn (HDFN); 2) the distinction between clinically significant and insignificant alloantibody responses, especially within alloantibody specificities... 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

Humans exposed to RBC alloantigens, following therapeutic transfusion or in pregnancy following maternal exposure to fetal RBCs, can generate humoral alloantibodies capable of leading to hemolytic transfusion reaction, (HTR), or of leading to HDFN. RBC transfusions can also induce autoantibodies, and can lead to hyperhemolysis. It is poorly understood why some patients mount a detectable alloantibody response (“responders”), whereas others do not (“non-responders”). Within the responder population, alloantibodies may be categorized as “clinically significant” or “clinically insignificant”, based upon whether the resultant specific alloantibodies have been previously reported to cause HTR or HDFN. However, incompatible transfusion will only result in meaningful in vivo hemolysis in some patients, even with antibody specificities classified as clinically significant.

The ability to define responder/non-responder status before initial RBC exposure has the potential to: 1) decrease rates of RBC alloimmunization in responders through the provision of extended matched RBCs for initial and subsequent RBC exposure; 2) conserve valuable antigen negative RBC units for patients who will derive the greatest benefit; 3) conserve transfusion service resources in terms of time spent identifying antibodies and procuring antigen negative RBC units; and 4) decrease rates of HTR and HDFN.

Feasibility and challenges of addressing this CQ or CC

Patients with hemoglobinopathies, especially those with SCD and thalassemia, have high rates of RBC alloimmunization and thus are important target populations for these studies. The impact of methods to reduce RBC antigen exposure or pathogen inactivation on neoantigen development remains unknown. The health impact of addressing the question of RBC alloimmunization is that the discovery of mechanistic underpinnings will provide a rational basis for the development and translation of novel diagnostic and therapeutic approaches, with a goal of increasing transfusion safety.

Though these questions are unlikely to be completely answered within the next 3-10 years, existing and emerging immunohematology and genomics tools, evolving sophistication of animal models, and existing and novel systems for human studies including donor-recipient repositories have the potential to increase the understanding of when and how alloimmunity to RBCs evolves, in what contexts it is clinically significant—even life-threatening—and how this important, but currently challenging and poorly understood condition, might be prevented and/or mitigated.

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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44 net votes
58 up votes
14 down votes
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Goal 2: Reduce Human Disease

Evidence based approaches to Red Blood Cell transfusion

What are the optimal RBC transfusion thresholds for adult and pediatric cancer patients undergoing chemotherapy regimens that may improve functional status and quality of life?

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

Details on the impact of addressing this CQ or CC

Cancer patients undergo intensive medical and surgical therapies to treat their underlying disease. Treatment commonly results in anemia requiring RBC and platelet transfusions to support the patient through the hypoproliferative phase of chemotherapy. This is particularly true for those patients requiring hematopoetic stem cell transplantation (HSCT). Following therapy, cancer outpatients commonly receive RBC transfusions for weeks to months to maintain their functional status.

Common causes of death in patients with hematological malignancies and other cancers are infections and bleeding. A meta-analysis of clinical trials suggested that liberal transfusion is associated with greater risk of infection. Conversely, restrictive transfusion could adversely affect quality of life and functional status in oncology populations. In addition, pre-clinical and clinical studies support that concomitant anemia and thrombocytopenia significantly compound bleeding risk, and that hemostasis can be optimized in thrombocytopenia by maintaining a higher hematocrit. Although bleeding risks in relation to platelet transfusion thresholds are well studied in patients with hematological malignancy, optimal hemoglobin levels in thrombocytopenic patients are not known. Despite the significant allocation of blood components to cancer patients as a whole, RBC transfusion practices are not well studied within this group.

Feasibility and challenges of addressing this CQ or CC

Randomized controlled clinical trials and other studies investigating optimal transfusion thresholds and other measures of practice are required to provide health care providers with evidence to guide one of the most common therapies administered in the setting of malignancy. The clinically important end points of well-designed studies could include: 1) quality of life and functional status for both inpatients and outpatients; 2) neurocognitive development in pediatric populations; 3) bleeding events / bleeding scores; 4) impact on immunity including immunomodulation and infection; 5) reconstitution of hematopoiesis; and 6) survival and/or recurrence of disease.. Besides a generalizable study population, certain target populations of interest are those with high risk disease, HSCT patients, patients undergoing radiation therapy, and pediatric patients.

There are >1.6 million new cases of cancer annually in the USA, including >50,000 with leukemia and >6,000 with HSCT. Cancer therapies are rapidly advancing in the era of genomics and immunotherapy. Capitalizing on the tradition of research in cancer, single and multicenter studies of RBC transfusion are feasible using randomized controlled designs in conjunction with clinical trials of chemotherapeutic regimens. The results of these studies will impact a large patient population’s quality of life, and may ultimately impact healthcare cost and blood demand.

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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43 net votes
61 up votes
18 down votes
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Goal 2: Reduce Human Disease

Immunologic Treatment of Hematologic Malignancies

How can the effectiveness of existing curative therapies be improved for allogeneic hematopoietic stem cell transplantation?

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

Details on the impact of addressing this CQ or CC

Much remains to be understood about immunotherapies in order to facilitate their broad use in the treatment of hematologic disorders. While studies to date have demonstrated significant potential applications, longer-term studies are necessary to further improve the profile of these therapies, including enhancing their overall efficacy while reducing associated toxicities. The efficacy of existing curative therapies can be enhanced by evaluating the mechanisms involved in producing cytokine release syndrome; a condition which has been observed in several patients receiving this therapy. Furthermore, a careful grading scheme to predict toxicity so as to guide the development of preventive and therapeutic strategies is also required. Target identification is another important issue to advance the field. While targeting CD19 appears to be promising, it results in loss of B-cell immunity and requires prolonged immunoglobulin replacement therapies and/or allo-transplantation and new immunologic targets need to be identified in both B cell and T cell malignancies as was as acute and chronic myeloid leukemias. Minimizing the off-tumor target-mediated toxicity of both CAR T-cell and checkpoint blockade therapies would help optimize their utility.

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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63 up votes
20 down votes
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Goal 2: Reduce Human Disease

Stem Cell Biology

There is a need to develop an artificial and functional hematopoietic stem cell (HSC) niche that allows for the expansion of repopulating HSCs.

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

Details on the impact of addressing this CQ or CC

Methods to expand hematopoietic stem cells have continued to be examined extensively because stem cell numbers in the graft are important for clinical outcomes following transplantation. These numbers are particularly relevant in umbilical cord blood (UCB) transplantation, where low numbers of stem cells are directly related to delayed hematopoietic and immune reconstitution. Improved HSC expansion strategies may significantly impact transplantation outcome, enabling broader applications beyond UCB transplantation. Furthermore, these strategies are also needed to realize the full therapeutic potential of genome editing technologies to correct hematopoietic stem cells derived from patients with hematologic disorders. Since efforts to expand HSCs in cytokine-supported liquid cultures have been largely unsuccessful, efficient expansion will require an appropriate context that is provided by the hematopoietic stem cell niche. Future studies must also evaluate how niche signals regulate stem cell function to optimize cell expansion, and proper humanized mouse models must be developed to help predict stem cell function and regulation by the niche.

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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28 net votes
46 up votes
18 down votes
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Goal 2: Reduce Human Disease

Enhanced Pain Research in Sickle Cell Disease

There is a need for more enhanced pain research in order to help improve sickle cell disease patient outcomes and quality of life.

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

Details on the impact of addressing this CQ or CC

Pain is the most common clinical manifestation of sickle cell disease (SCD) and accounts for a large proportion of emergency department visits and hospitalizations. Due to its impact on the patients’ quality of life, there is a need for more basic and clinical research studies focused on understanding the mechanisms of different pain syndromes as well as the role of neurotransmitters and inflammation in acute and chronic SCD pain. Also, comparative effectiveness studies in the management of chronic pain will be crucial in helping to improve the patients’ overall quality of life.

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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39 net votes
58 up votes
19 down votes
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