DEPARTMENT OF HEALTH AND HUMAN SERVICES NATIONAL INSTITUTES OF HEALTH NATIONAL HEART, LUNG, AND BLOOD INSTITUTE MINUTES OF THE SPECIAL EMPHASIS PANEL ON STEM CELL TRANSPLANTATION IN SICKLE CELL DISEASE April 30, 1997 The meeting of the Special Emphasis Panel on Stem Cell Transplantation in Sickle Cell Disease was convened on April 30, 1997, at 10:00 A.M., at the National Institutes of Health, 6701 Rockledge Drive, Room 9112, Bethesda, Maryland. In accordance with Public Law 92-463, the entire meeting was open to the public (10:00 A.M. to 4:00 P.M.). Howard Pearson, M.D. presided as Chair. PANEL MEMBERS (see attached Panel roster) Drs. Howard Pearson (Chair), Miguel Abboud, John Barrett, John DiPersio, Mary Horowitz (Not Present), Robertson Parkman, Orah Platt, Wendell Rosse, Keith Sullivan, Christiane Vermylen, John Wagner, and Doris Wethers MEMBERS OF THE PUBLIC PRESENT Drs. Cage Johnson, Lillian McMahon, and Ernest Turner (Directors, SCD Centers), Bertram Lubin and Mr. Nathaniel Polster, HLB Newsletter FEDERAL EMPLOYEES PRESENT Clarice Reid, M.D., NHLBI, NIH Carol Letendre, Ph.D., NHLBI, NIH Alan Levine, Ph.D., NHLBI, NIH Paul McCurdy, M.D., NHLBI, NIH Ms. Susan Pucie, NHLBI, NIH Duane Bonds, M.D., NHLBI, NIH Pan Ganguly, Ph.D., NHLBI, NIH Rebecca Link, Ph.D., NHLBI, NIH Helena O. Mishoe, Ph.D., NHLBI, NIH LeeAnn Jensen, Ph.D., NHLBI, NIH Ms. Joyce Creamer, NHLBI, NIH Ms. Bette Houston, NHLBI, NIH Griffin Rodgers, M.D., NIDDK, NIH Cynthia Dunbar, M.D., NHLBI, NIH NATIONAL HEART, LUNG, AND BLOOD ADVISORY COUNCIL MEMBERS PRESENT Ernest Beutler, M.D. Carolyn Whitsett, M.D. OPEN MEETING I. Call to order Dr. Helena O. Mishoe called the meeting to order with a statement of the purpose of the meeting which was to review current progress and identify future research directions in the use of stem cell transplantation for the treatment of sickle cell disease. II. Review of Confidentiality and Conflict of Interest Procedures Dr. Helena O. Mishoe explained policies and procedures regarding confidentiality and avoidance of conflict of interest. Panel members signed the requisite forms. III. Scientific Presentations Dr. Christiane Vermylen presented the European experience with 85 stem cell transplants in patients with sickle cell disease (SCD). She also discussed briefly the use of HLA-matched umbilical cord blood transplants (UCB) for SCD in Europe. The U.S. experience represented 61 stem cell transplants and results were presented by Drs. Miguel Abboud, John Barrett (U.S. data in IBMTR) , and Keith Sullivan. Although patient selection criteria and preparative regimens varied between studies, event free survival was approximately 80% and the risk of mortality from the procedure approximately 10%. Dr. John Wagner discussed the status of unrelated and related UCB transplantation in the U.S. Analysis of the first 85 UCB tranplants done at Duke University and the University of Minnesota was presented. Issues such as graft-versus-host disease (GVHD), choosing a donor in the unrelated setting, effect of cell dose, and identifying factors that predict better engraftment were discussed. Dr. Barrett presented information regarding the value of exploring, in certain patient populations, novel preparative regimens using immunosuppressive agents that are not myeloablative which would result in less toxicity and GVHD. Dr. DiPersio presented data on 120 peripheral blood allogeneic transplants and discussed the cellular characteristics of individuals identified as good mobilizers with G-CSF. The number of resting CD34+ cells in peripheral blood prior to G-CSF administration appears to be important and thus the need to understand regulation of the level of circulating CD34+ cells in donors is critical. IV. Discussion Discussion topics included patient selection criteria, timing of transplants, preparative regimens, transplantation associated risks, potential use of alternative stem cell sources, and research needs relevant to stem cell transplantation in sickle cell disease. The group reached the general conclusion that HLA-matched stem cell transplantation for SCD performed in Europe and the U.S. has benefited the select group of patients experiencing recurrent neurological, pulmonary, and vaso-occlusive events. It was noted that substantial progress in the area of bone marrow transplantation (BMT) for malignancies has been made in which currently, transplant results obtained with unrelated BMT closely mimic those seen with a matched sibling BMT. No comparable data exists in SCD primarily because the clinical course is highly variable and unpredictable. This was further emphasized by Dr. Orah Platt who presented five hypothetical clinical courses of SCD, all of which are initially asymptomatic and indistinguishable in terms of the disease. Currently, there are no reliable predictors to identify the SCD patients that are at the greatest risk of progressing to significant morbidity and mortality. A major discussion item was the tremendous need to identify the high risk patients on a genetic basis instead of the variable clinical indicators currently used. Detailed genetic studies of family members, sibling pairs, and twins with SCD were strongly emphasized by the Panel. These important studies may allow the identification of genomic markers that may influence the outcome of patients with SCD, and thus would be predictors of the clinical course. Continued research is needed to determine the beneficial effects of greater stem cell numbers in transplantation and to design less myeloablative regimens. Alternative sources of stem cells for transplantation in SCD was discussed and matched cord blood was considered a potential option. However, bone marrow or cord blood from unmatched donors was not considered an alternative source of cells for SCD transplants at this time. The importance of a team approach to assist the patient/family in decision-making regarding a transplant option was strongly emphasized. Such a team may include the hematologist, transplant physician, nurse, and other families who have gone through the transplant process. The panel concluded that it was important to continue to investigate in parallel other interventions of treatment and cure for SCD. V. The following future research efforts emerged for NHLBI consideration. (1) Continued support of basic and clinical studies in BMT in SCD on patient selection criteria, novel preparative regimens for myelosuppression/myeloablation, and transplantation associated risks. (2) Definition of the at-risk population of stroke patients who could be considered for early transplantation. (3) Identification of regions of the genome, other than the F-cell production locus, that influence the clinical course of SCD. (4) In-vitro expansion of hematopoietic stem cells to overcome engraftment issues and provide a benefit for individuals with rare haplotypes. ADJOURNMENT The meeting was adjourned at 4:00 P.M. on April 30, 1997. CERTIFICATION I hereby certify that the foregoing minutes are accurate and complete. ____________________________ Howard Pearson, M.D. Helena O. Mishoe, Ph.D. Chairman Executive Secretary Special Emphasis Panel on Special Emphasis Panel on Stem Cell Transplantation in Sickle Stem Cell Transplantation in Sickle Cell Disease Cell Disease .