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

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

Voting

117 net votes
152 up votes
35 down votes
Active

Goal 2: Reduce Human Disease

Harnessing Lung Regenerative Capacity to Improve and Increase Donor Lungs for Transplantation.

Using knowledge of matrix biology and lung development, what are useable methods to modify cadaveric donor lungs to provide a durable, effective organ replacement therapy?

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 :

A major advance in this area will increase the number of donor lungs available for lung transplantation

Feasibility and challenges of addressing this CQ or CC :

A number of stem and progenitor cells involved in lung repair and regeneration have been identified. Targeting them for expansions in damaged donor lungs may turn these damaged lungs into healthier lungs that can then be used for lung transplant safely.

Most of the donor lungs are not suitable for lung transplantation because the premorbid conditions of the donors often also damaged the lungs. Bioreactors have been used to “rehab” these damaged lungs and optimizing the ex vivo condition in these bioreactors may accelerate the lung repair process.

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

Voting

1 net vote
18 up votes
17 down votes
Active

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

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

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

Voting

66 net votes
96 up votes
30 down votes
Active

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)

Voting

13 net votes
28 up votes
15 down votes
Active

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

Voting

34 net votes
48 up votes
14 down votes
Active

Goal 2: Reduce Human Disease

Improving Outcomes for Lung Transplantation

How can the relatively poor outcomes of lung transplantation be improved through better understanding of basic biology and/or clinical care?

Submitted by (@skrenrich)

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

Name of idea submitter and other team members who worked on this idea : Cystic Fibrosis Foundation

Voting

-1 net votes
3 up votes
4 down votes
Active

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

Voting

1 net vote
1 up votes
0 down votes
Active

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

Voting

21 net votes
42 up votes
21 down votes
Active

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

Voting

47 net votes
69 up votes
22 down votes
Active