DEPARTMENT OF HEALTH AND HUMAN SERVICES NATIONAL INSTITUTES OF HEALTH NATIONAL HEART, LUNG, AND BLOOD INSTITUTE MINUTES OF THE SPECIAL EMPHASIS PANEL ON HORMONE THERAPY FOR COOLEY'S ANEMIA June 3, 1997 The meeting of the Special Emphasis Panel on Hormone Therapy for Cooley's Anemia was convened on June 3, 1997, at 8:00 A.M., at the Royal Sonesta Hotel, Cambridge, Massachusetts. In accordance with Public Law 92-463, the entire meeting was open to the public (8:00 A.M. to 4:00 P.M.). Alan R. Cohen, M.D. presided as Chair. PANEL MEMBERS (see attached Panel roster) Dr. Alan R. Cohen (Chair), Ms. Sherry Bush, Dr. Vincenzo De Sanctis, Dr. Patricia J. Giardina, Dr. Maria I. New, Dr. Nancy F. Olivieri, Dr. John B. Porter, Dr. Elliott Vichinsky, and Dr. Beatrix Wonke. MEMBERS OF THE PUBLIC PRESENT Mr. Ralph Cazzetta (Cooley's Anemia Foundation), Dr. Nursen Gurtunca (University of Witwatersrand, Johannesburg, South Africa), Ms. Susan Kurth, R.N. (Children's Hospital, Boston), Dr. Duru Malyali (TADAD, Istanbul, Turkey), Dr. Janet Poole (University of Witwatersrand), Ms. Angela Sabatino, R.N. (Cornell Medical Center), Ms. Juliana Shen, R.N. (Cornell Medical Center), and Dr. Michael Wajnrajch (Cornell Medical Center). FEDERAL EMPLOYEES PRESENT Alan Levine, Ph.D., NHLBI, NIH Helena O. Mishoe, Ph.D., NHLBI, NIH OPEN MEETING I. Call to order Dr. Alan Levine called the meeting to order with a statement of the purpose of the meeting. Clinical advances in the treatment of Cooley's anemia have helped to substantially increase the life expectancy of patients. The patients of today represent the first generation of adult thalassemics. As patients enter puberty, they begin to experience a variety of endocrine abnormalities, presumably the result of anemia and tissue iron deposition from the chronic transfusion therapy. During the past decade hormone replacement or supplemental therapy has become part of the medical management of thalassemia. This Special Emphasis Panel has the task of assessing the current state of hormone therapy for treating endocrine abnormalities and to determine whether research opportunities now exist for studying (1) the mechanisms for delayed sexual development, infertility, and osteoporosis in Cooley's anemia patients and (2) the role of hormone therapy and its long-term effects in the treatment of these endocrine disorders, and (3) the psychological impact of hormone therapy on self-esteem, body image, social relations, and sexuality. Il. Review of Confidentiality and Conflict of Interest Procedures Dr. Levine explained policies and procedures regarding confidentiality and avoidance of conflict of interest. Panel members signed the requisite forms. Ill. Presentations Mr. Ralph Cazetta, a member of the public and himself a Cooley's Anemia patient, addressed the panel and provided the members with an important context in which to place the endocrine problems that affect nearly all adolescent and adult patients with thalassemia major. Mr. Cazetta, the Director of Patient Services of the Cooley's Anemia Foundation, emphasized that as a child he had a profound need to feel accepted by his peers, to be able to participate in the same activities as his peers, to grow and mature at the same pace as his peers, to develop meaningful relationships with peers and especially members of the opposite sex, to bear children, and to be a productive member of the community. Dr. Nancy Olivieri provided an overview of iron in endocrine organs and impairment of growth, and sexual development. She noted that deferoxamine therapy to remove excess iron has no effect on the poor pubertal growth and sexual development. Dr. Elliott Vishinsky discussed the natural history of endocrinopathies in hemoglobin E-beta-thalassemia. Dr. Vincenzo De Sanctis discussed the effects of chelation therapy on growth and endocrine complications in a large group of Italian patients. Dr. Beatrix Wonke discussed hormone replacement therapy and fertility and Dr. John Porter presented data on the treatment of osteoporosis in thalassemia. Dr. Maria New and her colleagues presented their findings on diabetes in thalassemia. The final presentation and video shown by Ms. Sherry Bush emphasized the psychosocial impact of hormone therapy in the thalassemia patient. A letter from Ms. Lorraine Alessi-Schiano, a parent of a thalassemia patient, detailing their experiences during childhood and puberty, was shared with the Panel. IV. The following future research efforts emerged for NHLBI consideration. 1. Natural History: A prospective, longitudinal study is needed to define the natural history of endocrinopathies in thalassemia. Such a study would help clarify the relative contributions of the primary hemolytic anemia and the secondary iron overload to the endocrine abnormalities. Particular attention should be paid to patients with E-betař- thalassemia who may have a unique set of risk factors such as diet and for whom normative data should be carefully collected. The increasing proportion of patients in the United States with hemoglobin E-betař-thalassemia and related syndromes make this group a particularly important part of such studies. 2. Deferoxamine and Bone Toxicity: The potential toxicity of deferoxamine on bone growth and development requires further investigation. The precise role of the chelator in the bone abnormalities seen particularly in pre-pubertal patients with thalassemia requires definition, and the possible contribution of growth hormone therapy to the detrimental effects of deferoxamine needs further study. 3. Predicting and Detectinq Endocrine Damage: Studies are needed to define the role of tissue imaging in the detection and monitoring of endocrine disorders. The relative values of tissue imaging, tissue iron determinations and other markers of iron overload should be assessed in regard to their value in predicting or detecting endocrine damage. 4. Fertilityv and Pregnancy: Issues regarding fertility and pregnancy are particularly important as the life span of patients with thalassemia increases. Specific issues include defining the rate of infertility, identifying regimens of hormonal therapy to induce fertility, and studying the outcome of pregnancy. Additional areas of investigation related to pregnancy include the study of the effect of pregnancy on iron overload and related organ function, the safety of deferoxamine use during pregnancy (and, conversely, the dangers of stopping chelation therapy during pregnancy), and the outcome of infants born to parents with thalassemia after hormonal therapy (e.g., growth and development, neuropsychologic findings, etc.). 5. Hormonal Replacement Therapy: Studies are needed to assess the role of hormonal replacement therapy in thalassemia patients with delayed puberty. The studies would address the appropriate timing of, and criteria for, hormonal replacement therapy, the application of new treatments such as transdermal patches, and cellular and biochemical measures of hormonal replacement therapy. 6. Osteoporosis: Osteopenia and osteoporosis have been identified as common complications of thalassemia that may contribute substantially to the morbidity of the disease. Investigations in these areas could be divided into three parts. Phase I studies would identify the optimal methods, such as bone density scans and histomorphometry, to investigate bone abnormalities. Phase ll studies would evaluate the extent of the clinical problem in patients with thalassemia while Phase lll studies would address possible therapies and the monitoring of any intervention. In addition, studies of bone disease should look at other possible genetic predeterminants such as vitamin D receptors that may interact with thalassemia in causing significant bone disease. The role of bone disease in thalassemia major and thalassemia intermedia should be compared using cellular and biochemical markers. 7. Diabetes: Diabetes remains a particularly important endocrine disorder in thalassemia. Suggested studies include definition of the proper monitoring of insulin and glucose dysregulation, study of the optimal time of intervention, and comparison of various agents in regard to their ability to prevent or delay insulin dependency. In addition, the possible contribution of intensive iron chelation therapy to the reversal of early diabetes should be investigated. 8. Psychosocial Issues: Psychosocial issues are an extremely important component of virtually all endocrine abnormalities associated with thalassemia. The study of these disturbances goes hand-in-hand with the investigation of etiologies and therapies. In particular, studies are needed to define the relationship between endocrine problems, self-esteem and compliance with chelation therapy. In addition, the impact of delayed growth and sexual development on psychosocial functioning should be explored. Cultural and psychological issues affecting compliance with iron chelation therapy and hormonal replacement therapy require definition. The effect of hormonal replacement therapy, pregnancy and other therapeutic and natural events related to endocrine disorders in thalassemia should be assessed in regard to their effect on overall psychosocial function including self-esteem, employment, education, etc. ADJOURNMENT The meeting was adjourned at 4:00 P.M. on June 3, 1997. CERTIFICATION We hereby certify that the foregoing minutes are accurate and complete. Alan R. Cohen, M.D. Alan S. Levine, Ph.D. Chairman Executive Secretary Special Emphasis Panel on Special Emphasis Panel on Hormone Therapy for Hormone Therapy for Cooley's Anemia Cooley's Anemia .