Strategic Goal: Goal 3: Advance Translational Research

Should Allogeneic stem cell transplantation be considered as an upfront treatment in high risk double hit DLBCL?

Double-hit lymphomas (DHL’s) are high-grade B-cell lymphomas characterized by chromosomal rearrangements of MYC gene with BCL2 and less commonly, BCL6.Large analysis of patients with de novo DLBCL have shown that conventional chemotherapy does not improve the survival of DHL Aggressive upfront chemotherapy followed by autologous stem cell transplantation (ASCT) has become a standard treatment in eligible patients. Retrospective ...more »

Submitted by (@shahram.mori.md)

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

Details on the impact of addressing this CQ or CC :

There are currently no recommendations regarding upfront allogeneic stem cell transplantation of high-risk DHL patients in CR. Harnessing graft versus lymphoma activity may be a potential strategy to improve responses in such patients

Feasibility and challenges of addressing this CQ or CC :

The challenge of this question is the definition of DHL. FISH is commonly used to characterize DHL’s but may miss a significant portion of patients with aggressive disease. Including the cohort DLBCL patients identified by IHC expands the number of patients. Majority of patients with DHL are older but the ability to perform reduced-intensity and haploidentical -transplants will increase the number of eligible patients. The use of post-transplant therapies is needed to keep the lymphoma in check while graft versus lymphoma responses take effect.

Name of idea submitter and other team members who worked on this idea : Shahram Mori

Voting

2 net votes
3 up votes
1 down votes
Active

Strategic Goal: Goal 2: Reduce Human Disease

Neurocognitive development and delays in sickle cell disease

Are neurocognitive developmental delays significantly present in children and adolescents living with sickle cell disease? What effect do these delays have on the overall morbidity associated with sickle cell disease?

Submitted by (@sicklecellwarrior)

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

Details on the impact of addressing this CQ or CC :

Conversations among the sickle cell population are increasingly focusing on mental health, neuropsycology as it relates to mental health, and the need to develop community life skills and personal development.

Name of idea submitter and other team members who worked on this idea : Sickle Cell Warriors, Inc. community members

Voting

30 net votes
41 up votes
11 down votes
Active

Strategic Goal: 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 »

Submitted by (@lakshmanankrishnamurti)

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

Voting

112 net votes
141 up votes
29 down votes
Active

Strategic Goal: Goal 2: Reduce Human Disease

Pulmonary Complications of Sickle Cell Disease

What are the risk factors and components of clinical course associated with progression to restrictive lung disease, and what approaches to treatment can limit this progression?

Submitted by (@nhlbiforumadministrator)

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

Details on the impact of addressing this CQ or CC :

RLD is a major risk factor for death in adults, but there is minimal knowledge of the sequelae of contributing factors. There is no longitudinal study to demonstrate the risk factors, determinants, biological. A cross sectional study of adults could determine prevalence of lung function abnormalities, obstructive and restrictive, using standardized testing and understand the factors associated with the presence of these abnormalities. This study could be associated with a clinical trial of treatment of RLD with outcomes of symptom reduction as well as improvement of the restriction.

Name of idea submitter and other team members who worked on this idea : ATS Member

Voting

1 net vote
2 up votes
1 down votes
Active

Strategic Goal: Goal 3: Advance Translational Research

Improving Community-Based Care for Sickle Cell Disease

Sickle cell treatment centers are located throughout the United States, primarily in urban areas, and play an invaluable role. However, there is a critical need to identify and educate primary care providers who can provide routine and preventive care, but will also know when to consult with/refer to hematologists and other appropriate providers when necessary.

Submitted by (@nhlbiforumadministrator)

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

Details on the impact of addressing this CQ or CC :

For the first time, comprehensive guidelines addressing the management of sickle cell disease were issued in 2014 by the NHLBI. (Previous guidelines were not comprehensive.) The 2014 guidelines, which address issues such as health maintenance and the treatment of acute and chronic complications, are based on a systematic review of available evidence; consensus of an expert panel; and published, vetted guidelines by other organizations when evidence was unavailable or insufficient. These guidelines can provide a solid overview of the knowledge essential for the care of people with sickle cell disease.

 

Identifying primary care providers who can provide routine and preventive care but at the same time are knowledgeable about sickle cell disease, should be a more efficient, less costly method of provide important health services to people with sickle cell disease and should ultimately improve the health and well being of this population, particularly for people who do not live near a sickle cell center.

Feasibility and challenges of addressing this CQ or CC :

Addressing this question is very feasible. However, for a variety of reasons, including misconceptions about patients with the condition, it may be challenging to recruit large numbers of primary care providers.

Name of idea submitter and other team members who worked on this idea : The Sickle Cell Association of New Jersey

Voting

9 net votes
9 up votes
0 down votes
Active

Strategic Goal: Goal 3: Advance Translational Research

Implementation Science to Improve Care in Sickle Cell Disease

There are approximately 100,000 individuals living with sickle cell disease in the US, however study after study has shown that many lack access to the few existing evidence based interventions such as hydroxyurea. We need to investigate novel ways to increase acess to hematology care and disease modifying therapies.

Submitted by (@amy.sobota)

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

Voting

12 net votes
14 up votes
2 down votes
Active

Strategic Goal: Goal 3: Advance Translational Research

Develop an Effective and Functional Biological Pacemaker

There is a need to develop a biological pacemaker for pediatric patients that would react to neurohumoral factors that normally modulate heart function, as well as adapt to the growing heart.

Submitted by (@nhlbiforumadministrator)

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

Details on the impact of addressing this CQ or CC :

Reduce risks associated with the increasing use implantable pacemakers. Increase reliability of artificial electrical pacemakers.

Feasibility and challenges of addressing this CQ or CC :

Animal studies have already demonstrated feasibility of cell- and gene-based as well as hybrid approaches.

The introduction of implantable medical devices using electrical impulses through electrodes placed in the heart to regulate its beating in patients whose native cardiac pacemakers fail— i.e., implantable electronic pacemakers— have permitted hundreds of thousands of individuals to live extended, relatively normal lives. Many advances since the introduction of implantable pacemakers into medical practice during the latter half of the 20th century have improved reliability, but their use still carries significant risks; e.g., lead fracture, infection, malfunction, and the need for replacement.

To date experimental cell therapy, gene therapy, and hybrid approaches have been used to create biological pacemakers in animal models. These incorporate the use of human embryonic stem cells or induced pluripotent stem cells or overexpression of the transcription factor, TBX18, to produce functional biological pacemakers in large animal models. Other gene therapy approaches have also been used to generate functional biological pacemakers in animals. These include overexpression of ion channels impacting diastolic membrane depolarization and excitability in non-pace making regions of large animal hearts. Beta-2 receptor or adenylyl cyclase overexpression represent other strategies that have been employed. Finally, a hybrid approach has used human mesenchymal stem cells loaded with the pacemaker gene HCN2is to induce pacemaker activity in large animals. Thus multiple approaches exist and collaboration is needed between investigative groups to overcome the challenge of creating and testing an effective and reliable biological pacemaker in humans.

Name of idea submitter and other team members who worked on this idea : NHLBI Staff

Voting

8 net votes
23 up votes
15 down votes
Active

Strategic Goal: 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?

Submitted by (@rjjones)

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 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

Voting

164 net votes
214 up votes
50 down votes
Active

Strategic Goal: Goal 3: Advance Translational Research

Arrhythmia Therapies Based on Understanding Mechanisms

There is a need to translate these new insights of genetic, molecular, cellular, and tissue arrhythmia mechanisms into the development of novel, safe, and new therapeutic interventions for the treatment and prevention of cardiac arrhythmias.

Submitted by (@nhlbiforumadministrator1)

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

Details on the impact of addressing this CQ or CC :

Reduced socioeconomic burden of cardiac arrhythmias. Development of new technologies and recognition of new arrhythmia mechanisms.

Feasibility and challenges of addressing this CQ or CC :

Several studies have already recognized the unexpected antiarrhythmic effects of some therapies intended for other cardiovascular disease. For example statins, aldosterone blockers, and possibly some essential fatty acids may reduce arrhythmia burden in patients receiving these interventions. Clinical trials should be developed to demonstrate the efficacy of these interventions, and arrhythmia endpoints, including those for atrial fibrillation and sudden cardiac death, should be incorporated into other large clinical trials. Research into novel antiarrhythmic might focus on (a) drug development; (b) cell/gene-based therapy and tissue engineering; and (c) improvements in development and use of devices and ablation to prevent or inhibit arrhythmic electrical activity. Continued research might also focus on targeting of upstream regulatory cascades of ion channel expression and function. Continued antiarrhythmic strategies might include the exploration of novel delivery systems (e.g., utilizing advances in nanotechnology and microelectronics), biological pacemakers, AV node repair/bypass, and treatment and/or reversal of disease-induced myocardial remodeling and tachyarrhythmias. Evaluation of new therapies should include a cost analysis. Studies in both children and adults with congenital heart are needed. New interventions might include new pharmacologic approaches as well as advances in electrophysiologic imaging and improved approaches to ablation.

Name of idea submitter and other team members who worked on this idea : NHLBI Staff

Voting

51 net votes
86 up votes
35 down votes
Active

Strategic Goal: Goal 2: Reduce Human Disease

A Chidren's Oncology Group (COG) for sickle cell disease (SCD)?

We have all witnessed the success of the National Cancer Institute (NCI) funded Children's Oncology Group - an organization that has made tremendous advancements in the care of children with cancer, very rare compared to sickle cell disease. COG has been able to not only create a database of the numerous studies, but has the unique ability to make "smaller" institutions feel important as is evident by patient enrollment. ...more »

Submitted by (@smajumdar)

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

Details on the impact of addressing this CQ or CC :

- A database of all ongoing studies related to sickle cell disease that will be easily accessible by all pediatric hematologists

- A unified system of enrolling patients from academic centers for all the different studies, no matter how big or small

- Studies can be grouped depending on condition - renal disease, pulmonary hypertension etc.

- Should allow greater involvement/recruitment for patients into phase 1 studies

Name of idea submitter and other team members who worked on this idea : Suvankar Majumdar MD

Voting

23 net votes
28 up votes
5 down votes
Active

Strategic Goal: 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 »

Submitted by (@js2745)

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

Voting

103 net votes
126 up votes
23 down votes
Active

Strategic Goal: Goal 3: Advance Translational Research

Overcoming barriers to translational regenerative medicine

Current stem cell based approaches to translational medicine predominantly show modest efficacy. Most research rest on accepting existing limitations and focusing upon "tweaks" to the experimental model rather than taking on important barriers head on. The efficacy of stem cell-based regenerative medicine will never be fully realized unless we stop trying overly simplistic approaches such as"more is better" and start ...more »

Submitted by (@heartman4ever)

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

Details on the impact of addressing this CQ or CC :

The field of regenerative medicine holds great potential but we risk losing the public trust by hyperbolic promises, modest efficacy, and incremental research steps. Truly innovative research will transform the landscape and offer truly novel therapeutic approaches to many current incurable conditions. The result is a dramatic shift in the practice of medicine, new options for treatment, enhanced engagement of the public in biomedical research and new growth opportunities for the NIH and biotech sectors.

Feasibility and challenges of addressing this CQ or CC :

The future is here for regenerative medicine, but for the most part the potential and practice has been unrealized or poorly executed. The challenge is to identify the limiting factors and sweep them aside. There is broad and surprisingly consistent consensus on what the barriers are to successful regenerative therapy, but it seems most researchers are complacent and accept these limitations as inherent in the system rather than try to find truly combative approaches to overcome the barriers to enhancing regenerative processes. So it is essential to change the current mindset and push for a full frontal attack on the barriers that impede successful regeneration rather than minor modifications or uninspired brute force approaches that ignore the underlying mechanistic issues. Also, a major challenge is the hyperbole and overselling of research findings and impact by researchers and their institutions looking to capitalize upon the "discovery de jour." Such overly optimistic and unrealistic promises undermine our position in the public eye and compromise our future ability to earn the public trust.

Name of idea submitter and other team members who worked on this idea : M Sussman

Voting

-6 net votes
14 up votes
20 down votes
Active