NATIONAL HEART, LUNG, AND BLOOD INSTITUTE NATIONAL INSTITUTES OF HEALTH MINUTES OF THE SPECIAL EMPHASIS PANEL ON RESEARCH PRIORITIES IN BLOOD DISEASES AND RESOURCES September 29-30, 1997 Rockledge Building, Room 9104 National Institutes of Health Bethesda, Maryland PANEL MEMBERS PRESENT: Bertram Lubin, M.D., Chairperson H. Franklin Bunn, M.D. David Ginsburg, M.D. Kenneth G. Mann, Ph.D. Robertson Parkman, M.D. Peter J. Quesenberry, M.D. Leslie Silberstein, M.D. Pearl Toy, M.D. NATIONAL HEART, LUNG, AND BLOOD INSTITUTE STAFF PRESENT: Dr. Junius Adams Dr. Ivan Bains Dr. Luiz Barbosa Dr. Duane Bonds Dr. Eric Brown Ms. Joyce Creamer Dr. Pankaj Ganguly Ms. Bette Houston Dr. LeeAnn Jensen Ms. Elene Johnson Dr. Carol Letendre Ms. Kathryn Lightbody Dr. Rebecca Link Dr. Paul McCurdy Ms. Lea McDaniel Dr. Helena Mishoe Dr. George Nemo Ms. Susan Pucie Dr. Diane Reid VISITORS: Robert I. Handin, M.D., American Society of Hematology Carolyn F. Whitsett, M.D., Member, National Heart, Lung, and Blood Advisory Council Mr. Michael Wyan, Association of American Blood Banks Call to Order and Opening Remarks Dr. Clarice Reid, Director of the Division of Blood Diseases and Resources, called the meeting to order at 9 am, September 29-30, 1997. The Panel members, staff, and meeting attendees were introduced. The meeting had been announced in the Federal Register and was open to the public. This Special Emphasis Panel (SEP) was organized to advise the National Heart, Lung, and Blood Institute (NHLBI) and the Division of Blood Diseases and Resources (DBDR) on its extramural program in blood diseases and resources. Dr. Carol Letendre, Deputy Director, Division of Blood Diseases and Resources, reviewed the objectives and format of the meeting. She also reviewed the agenda and the material mailed to the Panel as well as information newly available. Review of DBDR Program Areas The leaders of each of DBDR's Scientific Research Groups described the areas of science supported, gave an overview of mechanisms such as Centers, contracts, and other items of interest, as well as highlights of activities including Workshops, SEPs, and initiatives supported over the past several years. Ms. Joyce Creamer presented a report of numbers of applications received and applications funded in DBDR's training and career development programs since 1991. Discussion of Initiatives Dr. Bertram Lubin, chairperson of the Special Emphasis Panel, reviewed the objectives of the meeting. The research interests of the Division have been divided into four topic areas: Stem Cell Biology and Medicine, Transfusion Medicine, Thrombosis and Hemostasis, and Sickle Cell Disease. Within each topic area, the SEP would consider recommendations from previous Workshops and SEPS, proposed draft initiatives and concepts developed by staff. Panel members had been encouraged to bring new ideas and topics for consideration that were not already proposed. Topic Area: Stem Cell Biology and Medicine 1. Hormone Therapy in Cooley's Anemia: SEP members discussed recommendations for an initiative resulting from an FY 1997 SEP held by the Division. This topic was also of interest to Congress. SEP members concluded that any initiative should not be focused exclusively on Cooley's anemia but should encompass the broader issue of iron overload, perhaps even including a link with hemochromatosis. Several suggestions were made including joint sponsorship of an iron toxicity initiative with NIDDK linking their endocrinology interests as well as including hormone therapy in the initiative "Clinical Research on Cooley's Anemia" which is currently open for applications. 2. Stem Cell Transplantation for Sickle Cell Disease: The recommendations of this FY 1997 SEP were discussed. One of the SEP recommendations for studies of novel preparative regimens was thought to be even more important with the availability of peripheral blood stem cells. Dr. Parkman raised a new concept which is that a partial repopulation with normal stem cells might be an alternative to gene therapy for sickle cell disease and thalassemia. The availability of an excellent mouse model for sickle cell disease is also an important factor in studying the effect of less than full-donor chimerism on sickle cell disease. The SEP recommended development of an initiative focusing on basic and pre-clinical studies of novel, less toxic conditioning regimens and other factors which would positively impact engraftment. 3. A recommendation of the SEP on Stem Cell Transplantation in Sickle Cell Disease (in vitro expansion of stem cells) plus one of the goals of the proposed Program announcement (Origin of Vascular and Hematopoietic Stem Cells) (identification and characterization of inducers that regulate stem cell self-renewal, proliferation, and differentiation in the early embryo and fetus) were discussed together. The Panel members recommended that a Workshop be held to address the major needs in this area which should include an evaluation of in vitro and in vivo assays, and an analysis of existing assays as to whether they can accurately identify the cell type responsible for engraftment be it the stem cell, stem cell plus progenitors, or facilitator cells. 4. Four concepts proposed by DBDR staff members were discussed by the Panel. Concepts 1 and 2 having to do with proper stem cell dose for engraftment and with efforts to reduce graft failure and toxicity were covered under other Panel recommendations. The third concept which relates to better understanding of a bone marrow transplant patient's compromised immune function post-transplant was thought to be an important question and one which does not do well in study section review because of the clinical aspects. A recommendation was made to consider an RFA for studies of Immunologic Recovery (or Immunocompetence) Post-transplant. The Panel felt that the science related to the fourth concept, that of learning more about the role of HLA-C in GvHD and graft failure, was already proceeding. For example, the National Marrow Donor Program plans to retrospectively type patients for HLA-C. Topic Area: Transfusion Medicine 1. Retrovirus Epidemiology in Donors Study (REDS): The continuation of the REDS study was brought to the Panel for concept clearance. Members of the Panel expressed unqualified support of the plans for continuation. However, they expressed dismay that the next generation of REDS would be limited to AIDS-related viruses since the study has demonstrated its unique ability to monitor and protect the blood supply from both AIDS and non-AIDS-related organisms. It was noted that it would be crucial to assuring the safety of the blood supply to also continue the non-AIDS related aspects of the study. Therefore, the Panel made the following recommendations: A. The continuation of REDS should proceed as proposed; B. The non-AIDS portion of REDS should be continued by whatever means possible. Suggestions for support include NHLBI non-AIDS funds, co-support by the CDC, or co-funding by the NIH Office of Research on Minority Health (ORMH). 2. Creutzfeldt-Jakob Disease: The results of a SEP on Creutzfeldt-Jakob Disease (CJD) held on September 24, 1997, were described. The greatest need is for a test for blood donors. Animal models now require at least six months to show evidence of disease. Although transmission of CJD through blood and blood products has still not been demonstrated, development of a test for blood donors was viewed as extremely important, especially for concerned communities such as hemophiliacs and for the safety of the blood supply. Even with no demonstrated transmission, many millions of dollars have been lost in blood product recall when it was learned that a blood donor subsequently developed CJD. The Panel endorsed the NHLBI's proposal to develop tests to be used for blood donors and suggested that small businesses be solicited , such as through an RFA, for development of a spectrum of tests including monoclonal antibodies against the infectious agent as well as genetic tests which would detect the mutant gene responsible in 10% of familial cases. 3. Clinical Network for Transfusion Medicine: Dr. Toy noted that there were a number of clinical questions in the area of transfusion medicine including When to Transfuse? and What is the transfusion end-point? There is not yet an organized approach to solving problems in transfusion medicine. She suggested that a clinical network such as that proposed for sickle cell disease and Cooley's anemia would be ideal for transfusion medicine. Dr. Quesenberry noted that his institution does "bloodless surgery all the time on Jehovah's Witnesses and they do fine." Examples like this would be perfect for such a clinical network to study with the intent of broadening findings from a homogeneous population to a heterogeneous one. The Panel suggested the convening of a small working group to consider the framework which would best address the clinical needs in transfusion medicine. 4. Three concepts put forward by Dr. Leslie Silberstein were discussed. A. Emerging new viruses in blood and bone marrow transplantation - particularly herpes viruses such as CMV and HHV-8. REDS investigators are planning to establish a blood donor/recipient repository for use in evaluating new assay systems for infectious agents and in determining if recently discovered or emerging agents are transmitted by blood transfusion. The REDS contract will be doing HHV-8 studies (for which no good tests yet exist) under the AIDS portion. It was noted that most centers now use gancyclovir in CMV-negative marrow recipients, so the CMV problem is somewhat better controlled. The biggest problem is CMV reactivation. CMV studies will be included under the non-AIDS portion of the REDS contract extension. The conclusion of the CMV discussion was that it was thought to be an important topic but a way to carry the concept forward at this time was not obvious. The Panel stressed the importance of incorporating these studies into the non-AIDS REDS extension. B. Receptor Biology of committed progenitor cells: It was recommended that this topic be included in the stem cell workshop discussed earlier. C. Biology of auto-and alloimmune responses to blood group antigens: Transfused -thalassemia and sickle cell disease patients become refractory to blood group antigens, make antibodies, and cannot be further transfused. It would be interesting and important to define responders and non-responders - to define genetic and other mechanisms to characterize genetic predisposition to refractoriness. At this time, epitopes are not known nor is it known what the immune response actually is. Now, pegylation of red blood cells is used to circumvent the problem. Dr. Quesenberry will incorporate these questions into the November Worcester Conference on autoimmunity and transplantation. Topic Area: Thrombosis and Hemostasis 1. Genetic and Other Risk Factors of Arterial Thrombosis: Panel members reviewed the report of the Committee on Research Opportunities in Arterial Thrombosis and a pending initiative entitled "Genetic and Other Risk Factors of Arterial Thrombosis." Discussion centered on this being a "hot area" with much research going on and the fact that identifying genetic risk factors has been productive on the venous side. Extremely important are transgenic and knock-out mice animal models. The challenge of this area is the needed integration of blood and heart interests. A need for population-based studies was recognized and Panel members questioned whether samples from a specified cohort could be made available to all funded under such an initiative. An important question will be "What does a risk factor mean in an individual versus what happens in a population of individuals?" The existing comprehensive cancer centers are a good model for a center concept in cardiovascular disease. This would integrate areas such as thrombosis, atherosclerosis, and hypertension which are currently supported as separate SCOR areas in NHLBI. Other much-needed research such as the development of new anticoagulants as well as monitoring efficacy and evaluation of anticoagulation could be carried out under the Center infrastructure. The SEP recommendation was to pursue research on arterial thrombosis through basic studies (transgenic and knock-out animal studies) as well as population-based studies, ideally using a single cohort in a multi-center study. The best way to proceed would be through centers modeled on the cancer centers which could also address other questions. 2. An initiative entitled Hereditary Hemorrhagic Telangiectasia has been developed based on recommendations from a 1997 Workshop on this topic. SEP members were unanimous in recommending proceeding with an initiative based on these recommendations. 3. Hemophilia Thrombophilia Centers: This concept is based on the fact that thrombosis is a major clinical problem yet lacks identity because it is viewed as secondary to other primary diseases. HRSA supports an established network of hemophilia centers and it is proposed that these centers be used to stimulate research in basic and clinical thrombosis. Panel members felt that it would be more successful to merge this concept with the Centers recommended above, since it would likely be more successful to start with a strong vascular biology infrastructure rather than with the hemophilia centers which have their own programs of interest (e.g., AIDS, inhibitor therapy). The Panel agreed that a small Workshop would be a good starting point to explore some of the needs and the infrastructure best suited to achieving them. 4. Increased thrombosis risk in obesity: A staff concept proposing an initiative in this area was discussed. Panel members agreed that this is a timely topic in a "hot area," although narrowly focused, and of particular interest because of the high incidence of obesity in African Americans. It was recommended that this area be pursued through a Program Announcement broadened to address diabetes and including a focus on the African American population. Other NIH Institutes may be involved. Topic Area: Sickle Cell Disease 1. An existing initiative, Molecular Mechanisms of Vasculopathy and Vasocclusion in Sickle Cell Disease, was discussed. This initiative would explore the interaction between sickled cells and the endothelium. The availability of transgenic mice showing outstanding sickle cell pathology is very attractive as a means to accomplish the objectives of this RFA. Dr. Parkman suggested that transplantation and split chimerism be added to the background. There was unanimous enthusiasm for this initiative. 2. The concept, genetic variability of vasocclusive events in sickle cell disease, was thought to be be an important one and that sickle cell disease would be an ideal disease model. The members recommended that, if possible, existing DNA from on-going or completed studies (e.g., CSSCD) along with the relevant clinical information be used. The issue of informed consents would be important to evaluate in the context of these new studies. Several ideas were put forward: a) an intramural lab in the NHGRI might be interested in genotyping the samples, b) genotypes could be put in a data base and made available to the scientific community for study. The Panel recommended convening a workshop to be discuss the optimal way to approach this question with existing samples if possible. The adequacy of the informed consents associated with existing samples must to included in the discussions. 3. SEP members discussed the issue of immune deficiency in sickle cell disease which had been raised in several previous meetings; however, a decision had never been made as to how to bring new insights into sickle cell disease-associated immune deficiencies. It was noted that there is some new information about delayed maturation of B-cells in sickle cell disease as well as defects in the complement pathway. Panel members agreed that a set-aside of funds would to be necessary in order to bring immunologists into the area and that the area would need to be to be broadened; however, Panel members recommended bringing in other expertise to identify the specifics of an initiative. 4. Pediatric Hydroxyurea Phase III Clinical Trial: Panel members were informed that the Phase II safety/dosing study in children was winding down and that, based on that information, Bristol-Meyer Squibb will be able to propose to the FDA that hydroxyurea be labeled for children with the indication of prevention of vasocclusive crisis. Because of new observations such as those made by Dr. Frempong in which hydroxyurea was found to be responsible for decreased brain cells size in newborn mice, further studies with the drug would seem to be warranted. It was suggested that secondary prevention studies comparing transfusion to hydroxyurea in children with chronic end-organ damage would be the proper follow-up. Panel members noted that additional trials were needed but they were not in a position to design the specifics. It was recommended that such trials be designed and carried out under the auspices of a network. 5. Clinical Network for the Treatment of Patients with Sickle Cell Disease and Cooley's Anemia: The concept of a network which would facilitate development and conduct of collaborative studies of treatment regimens or trials of specific drugs for patients with hemoglobinopathies was endorsed unanimously. Not only would this approach allow the Institute to utilize an existing infrastructure when testing a new drug therapy but it would take advantage of expertise which might be outside the funded sickle cell comprehensive centers. 6. Concepts brought for discussion by Dr. Bunn: Dissemination of practice standards: Clinical care guidelines such as Management and Therapy of Sickle Cell Disease developed by the NHLBI should be more widely disseminated into such areas as emergency rooms and pediatrician's offices. Dr. Handin suggested that the review and endorsement of guidelines by ASH be expanded to include documents developed by sources other than ASH. This endorsement would increase the availability of such documents. He will look into this possibility and get back to DBDR. Development of membrane-active agents to reduce intracellular hemoglobin concentration: The SEP members suggested that this was an appropriate activity to be carried out under the auspices of the network recommended above. It will also be an important topic in DBDR's proposed Special Emphasis Panel, Development of Pharmacologic Agents that Prevent Sickle Hemoglobin Polymer Formation, to be held in FY 1998. Adjournment: The meeting was adjourned at 11:45 am on Tuesday, September 30. We hereby certify that, to the best of our knowledge, the foregoing minutes are accurate and complete. _______________________________ __________________________________ Bertram Lubin, M.D. Date Carol H. Letendre, Ph.D. Date Chairperson Executive Secretary Attachments: SEP Agenda SEP Roster