ASH Contributes to the NHLBI's Strategic Visioning Process

The National Heart, Lung, and Blood Institute (NHLBI) is conducting a strategic visioning exercise that aims to identify compelling questions and critical challenges in scientific knowledge, healthcare quality, and workforce issues that should be addressed within the next decade. ASH has submitted several recommendations that address priority gaps in scientific knowledge in the field of hematology. These recommendations were based on the newly released ASH Agenda for Hematology Research and ASH’s Sickle Cell Disease Priorities.

ASH members are encouraged to participate in this process by visiting the NHLBI’s interactive online forum to read, comment on and vote on ideas submitted by the public and ASH. The deadline for comments is May 15^th 2015.

ASH Recommendations

Genome Profiling

1. Critical Challenge: There is a need to facilitate the integration of genomic and epigenomic profiling into drug discovery efforts by using genomic methods to sequence and analyze blood disease subtypes.

   Opportunity: Despite the important information that has been generated from sequencing studies in various blood disorders, for many hematologic disease subtypes, the limited scope of sequencing and the insufficient number of cases sequenced has prevented researchers from gaining truly useful insights. Whole-genome sequencing of large numbers of samples, with an emphasis on poorly studied and rare entities, is required to fully define the landscape of genetic changes underlying the development of blood diseases. Further, genetic and epigenetic alterations that drive hematologic diseases and the extent to which normal cells are distinct from malignant cells needs to be more broadly elucidated since many blood diseases, including hematopoietic cancers, disturb epigenetic regulators. The knowledge gained from understanding these processes and integrating genomic and epigenomic profiles could provide additional precision medicine opportunities and guide drug discovery efforts.

2. Compelling Question: How can proper infrastructure be designed to host sequencing data from hematologic diseases so as to enable its efficient interpretation and use in clinical care?

   Rationale: Accurate and consistent analysis of genetic data is crucial for both basic research and clinical applications, however, the complexity of sequence mutations in several blood disorders as well as the immense amounts of raw data produced during the sequencing and analysis process, make accurate bioinformatics analysis a challenge. Furthermore, the lack of consistency in the analysis of the non-coding genome and variations in correlating this information with transcriptional and epigenetic data pose an additional challenge in obtaining a comprehensive portrait of various hematologic diseases.

   To overcome these challenges, content-rich portals that can offer cost-effective and regulated access to raw genomic data for interrogating and sharing sequencing results without compromising patient privacy must be designed. Also, the biologic and clinical relevance of genetic alterations found in these portals must be reliable and sufficiently comprehensive in order to foster proper interpretation.

3. Compelling Question: What structural changes need to be implemented in the health-care community in order to support the use of genomic information in clinical trials and drug development for hematologic diseases?

   Rationale: In various blood disorders, including hematologic malignancies, there are both inherited and somatic genetic alterations that contribute to predisposition, transformation, disease progression, responsiveness to therapy, and treatment complications. The presence of such genetic alterations underscore the need for the identification of rare but traceable mutations as well as the integration of such genomic information into clinical trials. By implementing a few structural changes in the healthcare sector, a clinical trial infrastructure can be established that accounts for proper application of sequencing technology. Some examples include the creation of genome diagnostic networks that address accrual of sufficient patients, procurement of suitable tumor/non-tumor material for sequencing, as well as pharmacodynamic and correlative biology studies in hematologic diseases.

Genome Editing and Gene Therapy

1. Critical Challenge: There is a critical need for the establishment of strategies that will determine the efficacy, safety, and toxicity of genome editing techniques specifically in hematologic diseases.

   Opportunity: Inherited monogenic hematologic diseases such as hemophilia, beta-thalassemia and sickle cell disease are prime targets for future application of genome editing technology. However, studies are still needed to advance our understanding of the biology of genome editing as well as determine which other disorders are amenable to genome editing correction. Emphasis on preclinical research that focuses on determining the accuracy, safety and efficiency of this technology in order to help minimize off-target mutations and reduce toxicity, is essential for effective translation of this technology into the clinic. Once preclinical efficacy is established, support will be needed for clinical vector production, toxicity testing of the vectors/reagents used, and the performance of clinical trials. The gene correction strategies developed for inherited disorders will also be attractive for other hematologic diseases, and autoimmune disorders like lupus, rheumatoid arthritis, and type I diabetes). There is also a critical need for supporting preclinical validation studies, scale-up and GMP cell manufacturing, all of which could be shared infrastructures across multiple diseases in the NHLBI portfolio.

Epigenetics and Genomics

1. Critical Challenge: There is a need to target epigenetic mechanisms as new treatment options for hematologic disorders.

   Opportunity: Advances in the field of epigenetics and the understanding of various epigenetic mechanisms has provided a completely new ensemble of therapeutic targets for treating hematologic disorders – both non-malignant and malignant. These mechanisms have enormous implications for understanding the molecular underpinnings of the normal orderly development of hematologic disorders. Although one of the greatest challenges in effectively treating hematologic disorders is the diversity of molecular abnormalities that underlie a disease, there are a number of common threads emerging, including alterations in proteins that function through epigenetic mechanisms. Additional research focusing on epigenetic alterations and emerging targets is needed to identify the role of such proteins in the development of hematologic disorders in order to design potential targeted treatments to counter their effects. This research will further lay the groundwork for precision medicine, and will help to provide more insight on potentially critical determinants of responsiveness to therapeutic regimens.

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

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

Immunologic Treatment of Hematologic Malignancies

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

   Rationale: 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.

2. Compelling Question: How can the effectiveness of existing curative therapies be improved for allogeneic hematopoietic stem cell transplantation?

   Rationale: 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.

Stem Cell Biology

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

   Opportunity: 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.

2. Critical Challenge:There is a need to develop “designer platelets” and “designer red cells,” as well as facilitate large-scale production of these products for therapeutic and diagnostic use.

   Opportunity: The reprogramming of adult stem cells has resulted in the generation of induced pluripotent stem cells (iPSCs) that can develop into any tissue of the body. These iPSCs ultimately may be used as a transplantable source of stem cells for a variety of hematologic diseases. Although this technology has enabled the generation of patient-specific or disease-specific stem cells that are also amenable to genetic manipulation, the major scientific hurdle has been the ability to create clinically meaningful functional blood products, including transplantable HSCs from differentiating iPSCs. The production of clinically functional blood products -- i.e. red blood cells derived from autologous iPSCs --could replace allogeneic products in highly immunized patients and the generation of megakaryocytes for patient-specific platelet production from iPSCs could drive significant progress in this area. Furthermore, disease-specific iPSCs could serve as targets for both drug development and drug screening in patients with rare hematologic disorders. In addition, support for scale-up and GMP processes, which are difficult to fund via the R01 mechanism will require specific grant opportunities tailored to infrastructure and process development.

Venous Thromboembolism

1. Critical Challenge: There is a great need for the development and evaluation of biomarkers for the study of venous thromboembolism (VTE) pathophysiology and risk assessment.

   Opportunity: Recent efforts to evaluate biomarkers for VTE occurrence and recurrence have led to the identification of multiple potential candidates, including P-selectin, E-selectin, D-dimer, various microparticles, and various inflammatory cytokines. However, no specific biomarker has yet emerged for routine clinical use for individual VTE risk stratification and personal targeted therapeutics. The development of improved animal models will advance the study of VTE pathophysiology, allowing for more accurate evaluation of emerging biomarkers and initial assessments of potential advanced therapeutic interventions. Also, the identification and prioritization of novel VTE biomarkers will be needed to help improve our understanding of the molecular mechanisms underlying VTE, so as to shepherd the development of novel mechanisms of therapy beyond anticoagulation.

2. Compelling Question: How can individual VTE risk-assessment scoring be combined with promising biomarker candidates in order to help predict risk in the general patient population and prevent unprovoked low-risk VTE cases?

   Rationale: The VTE field is approaching a new era of therapy in which predictive measures at the primary care level will identify those patients most at risk for VTE. With the identification of predictive biomarkers for VTE occurrence, efforts will be necessary to develop point-of-care or in-home biomarker testing devices to improve risk-assessment scoring and identification, so that patients could then be treated before progression. It will also be critical to accelerate risk-scoring systems that are beginning to incorporate biomarker candidates into the algorithm for use in clinical trials. Studies that will focus on correlating risk-assessment scores and biomarker research findings will provide a more accurate risk prediction and diagnostic value.

Sickle Cell Disease

1. Compelling Question: 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?

   Rationale: 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.

2. Compelling Question: 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?

   Rationale: 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.

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

   Opportunity: 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.