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

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Goal 3: Advance Translational Research

Bone Marrow Stem Cell Transplant in Peds sibling matched SCD

There is a need to improve accessibility of Bone Marrow Stem Cell Transplantation (BMSCT) for Sickle Cell Disease patients who are most likely to benefit from this treatment option. 1. Building a culture of trust between and among primary care providers, specialists, patients/families, and other stakeholders 2. Consensus building around BMSCT as an acceptable treatment alternative (as opposed to another research endeavor) ...more »

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 :

1. It could potentially decrease the prevalence of SCD and significantly decrease the overall morbidity and mortality associated with SCD in children with matched sibling donors.

2. It could increase the awareness of health professionals who have a low awareness of the role of BMSCT in the treatment and cure of SCD (i.e., those in rural areas)

3. It can improve patient/family access to information and communications to facilitate informed discussion and choice for all SCD treatment options

4. It could open the gateway for more therapeutic applications for other genetic diseases

Feasibility and challenges of addressing this CQ or CC :

1. The science in this has evolved substantially such that BMSCT is a viable therapeutic option with reduced morbidity and mortality in the sibling matched population

2. There is an opportunity to broaden current collaborations with other agencies and the BMSCT community to expand the accessibility of their research forward.

3. Other agencies are emphasizing work in the area of BMSCT particularly for hemoglobinopathies.

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

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52 net votes
80 up votes
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Goal 3: Advance Translational Research

Modulating Immune Checkpoints to Enhance Curative Potential of Autologous Transplantation in classical Hodgkin lymphoma (cHL)

PD-L1 and PD-L2, engage PD-1 receptors on activated T cells and induce T-cell exhaustion. Antibody-mediated PD-1 blockade has already been successfully exploited as a therapeutic strategy in solid tumors. PD-L1 is expressed on suppressor immune cells in the tumor microenvironment and in cHL tumors. PD1 blockade has shown clinical activity in cHL. Disease relapse, post autoHCT; however remains the most common cause of ...more »

Submitted by (@mehdihamadani)

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

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26 net votes
46 up votes
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Goal 2: Reduce Human Disease

Immunologic Treatment of Hematologic Malignancies

How can the use of CAR T-cell and checkpoint blockade strategies be optimized in order to cure hematologic diseases?

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

Details on the impact of addressing this CQ or CC :

As the body of evidence continues to grow on the potential applications for advanced immunotherapies, next-generation research must focus on addressing the possible curative effects that checkpoint blockades or adoptive CAR T-cell strategies can have for blood diseases including hematologic cancers. This will require specific research programs to fully understand the optimal role for these therapies within the continuum of care. To optimize these strategies for treatment of hematologic diseases, studies are needed to decipher specific hematologic diseases and circumstances under which these checkpoint blockers and CAR T-cell therapies may be employed as frontline approaches. Furthermore, while the optimal approach for these therapies is unclear, advanced studies are needed to elucidate the potential benefit in combining these promising approaches and whether patients can be better identified a priori for these therapies.

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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13 net votes
28 up votes
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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?

Submitted by (@marymh)

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

Measuring and Improving Physical Fitness to improve outcomes after Hematopoietic Stem Cell Transplantation

Can cardiorespiratory fitness prior to hematopoietic cell transplantation be improved and will this limit morbidity and mortality following transplantation?

Submitted by (@sheat0)

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 is associated with high rates of morbidity and mortality from transplant-related complications, the reduction of which would lead to higher transplant-mediated cure rates for life-threatening benign and malignant hematologic disorders. Comorbidity and patient-reported functional status impairment are known to increase the risk for transplant-related mortality, but unlike comorbidity, cardiorespiratory fitness is potentially modifiable. The optimal way to improve fitness through pre-transplant exercise and lifestyle interventions is not known, however, and understanding how to affect through a short term intervention would also benefit other cancer and non-cancer health conditions in which future treatment is intensive and associated with significant risk.

Feasibility and challenges of addressing this CQ or CC :

Feasibility and Challenges of Addressing the CG or CC:

 

Understanding how to improve cardiorespiratory fitness in a short period of time will require a research agenda that addresses the following challenges: how to measure cardiorespiratory fitness in a generalized and scalable way, which may or may not require maximal exercise testing for all participants; how to design intensive exercise interventions that are at least partially home-based in order to minimize resource burden on patients and centers; and how to personalize intervention delivery and testing in a way that is tailored to the baseline fitness levels and capabilities of each participant. Meeting these challenges will enable large-scale, personalized exercise testing and intervention delivery in other non-transplant populations.

Name of idea submitter and other team members who worked on this idea : Thomas Shea and William Wood

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69 up votes
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Goal 1: Promote Human Health

Host and environmental factors effect on transplantation biology and regenerative medicine

How does inflammation and cell injury induce the immune system during transplant rejection? How do we control immune responses to enable cell- and tissue-regenerative strategies? • How does inflammation and cell injury induce the immune system during transplant rejection? • How do we control immune responses to enable cell and tissue regenerative strategies? • How do we use iPS cell based and gene editing based therapies ...more »

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 :

Treatment of human diseases

Feasibility and challenges of addressing this CQ or CC :

Facilitated by progress in genome editing, stem cell biology, immunology

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

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34 net votes
48 up votes
14 down votes
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Goal 2: Reduce Human Disease

Lung Transplantation

Although the majority of lung recipients experience significant health improvement, they also frequently face serious symptom distress, impaired physical functioning and poor quality of life due to post-transplant morbidity, such as chronic rejection, infection and multiple side-effects of immunosuppression. a) Conduct clinical trials of interventions designed to maximize clinicians' support of patients' self-management ...more »

Submitted by (@nhlbiforumadministrator)

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

Feasibility and challenges of addressing this CQ or CC :

a) Conduct clinical trials of interventions designed to maximize clinicians' support of patients' self-management behaviors so that patients and clinicians working together can achieve optimal control of disease, reduce symptom distress and complications, and promote quality of life.

 

b) Evaluate the impact of integrating palliative care and transplant care for symptom management, goal setting and advanced care planning along the entire lung transplant illness trajectory (pre, post and end of life).

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

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1 up votes
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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

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3 up 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 »

Submitted by (@giralts)

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

Improving cardiorespiratory fitness prior to hematopoietic cell transplantation

Can cardiorespiratory fitness prior to hematopoietic cell transplantation be improved and will this limit morbidity and mortality following transplantation?

Submitted by (@wawood)

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

Details on the impact of addressing this CQ or CC :

HCT is associated with high rates of morbidity and mortality from transplant-related complications. Reduction in transplant-related mortality would lead to more favorable risk/benefit assessments for the ability of transplant to cure life-threatening hematologic disorders including non-malignant conditions. Comorbidity and patient-reported functional status impairment are known to increase the risk for transplant-related mortality. Single institution studies suggest that cardiorespiratory fitness may serve a similar role as a predictive pre-transplant variable. Unlike comorbidity, cardiorespiratory fitness is potentially modifiable. However, the optimal way to improve cardiorespiratory fitness through pre-transplant exercise and lifestyle interventions is not known. Understanding how to improve cardiorespiratory fitness through a short term intervention would also benefit other health conditions relevant to the NHLBI in which future treatment is intensive and associated with significant risk.

Feasibility and challenges of addressing this CQ or CC :

Understanding how to improve cardiorespiratory fitness in a short period of time will require a research agenda that addresses the following challenges: how to measure cardiorespiratory fitness in a generalized and scalable way, which may or may not require maximal exercise testing for all participants; how to design intensive exercise interventions that are at least partially home-based, in order to minimize resource burden on patients and centers; and how to personalize intervention delivery and testing in a way that is tailored to the baseline fitness levels and capabilities of each participant. Meeting these challenges will enable large-scale, personalized exercise testing and intervention delivery in other non-transplant populations.

Name of idea submitter and other team members who worked on this idea : William Wood, Thomas Shea

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21 net votes
42 up votes
21 down votes
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Goal 3: Advance Translational Research

How can we develop more selective immunosuppression for allogeneic hematopoietic cell transplantation?

Graft versus host disease (GVHD) remains the most significant complication of allogeneic hematopoietic stem cell transplantation (HCT). While the use of HCT has grown significantly safer and has demonstrated broad efficacy in the setting of a broad range of blood diseases, immunosuppressive therapy has not dramatically evolved since the introduction of calcineurin inhibitor-based approaches decades ago. The availability ...more »

Submitted by (@kkomanduri)

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

Details on the impact of addressing this CQ or CC :

GVHD remains a critical problem and major barrier to the more widespread utilization of HCT, especially for nonmalignant diseases, where tolerance of treatment-related mortality is understandably low.

 

There is a compelling need for novel immunosuppressive agents that can effectively limit alloreactivity mediated by donor T and B cells, while relatively sparing pathogen-specific T cells, including those mediating antiviral T cell responses important in the post-HCT interval.

 

In the past decade, drug development has facilitated the introduction into preclinical and clinical trials of a broad range of agents that in addition to targeting pathways of interest in target cells (e.g., aberrant signaling in cancer cells) may also effectively inhibit T and/or B cell responses. Examples include hypomethylating agents (e.g., azacitidine), HDAC inhibitors (e.g., vorinostat), MEK inhibitors (e.g., trametinib) and BTK inhibitors (e.g., ibrutinib). Each of these classes of agents has been demonstrated in preclinical and/or clinical studies to also limit alloreactive T cells, and/or augment regulatory T cell responses, leading to a net reduction of alloreactivity. Unlike traditional agents (e.g., the calcineurin inhibitors) these agents appear to be more selective, and in some cases may have dual benefit in reducing relapse.

 

The NHLBI can facilitate the identification and translation to clinical practice in the setting of HCT trials of novel immunosuppressive agents.

Feasibility and challenges of addressing this CQ or CC :

Research funding targeted to improving the pipeline of novel immunosuppressive agents could have immediate and dramatic impact in the field of HCT, especially impacting its application for nonmalignant diseases. Patients lacking optimal registry donors, especially those from underrepresented minority groups, will particularly benefit from improvements in immunosuppression, as patients receiving less than optimally matched donors are at much higher risk of GVHD.

 

The NHLBI can encourage and facilitate research that tests compounds that have already passed through the drug development process, but in many cases were not intended to function as immunosuppressive agents. Compelling preclinical studies have suggested that targeted inhibition of T and B cells, and/or epigenetic modifiers can lessen alloreactivity while preserving beneficial cellular immune responses and facilitating immune reconstitution.

 

It will be far easier to appropriate therapeutic agents already developed for another purpose than to do novel drug development from scratch. In many cases, preclinical studies have highlighted the therapeutic potential in immunosuppression for agents that have been developed to treat malignancies, but yielded suboptimal success. Research that encourages the development of these drugs as part of a combined immunosuppressive/immunomodulation approach may rescue such compounds, while yielding potential dramatic advances in clinical HCT.

Name of idea submitter and other team members who worked on this idea : Krishna Komanduri, M.D.

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129 up votes
23 down votes
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