Bethesda, Maryland

June 3, 2002


Dr. Gilda Barabino, J. Hoxi Jones-Carranza, Dr. Oswaldo Castro, Dr. Peter Lane, Dr. Herbert Meiselman, Dr. Jeanne Smith, Dr. Marie Stuart, Dr. Paul Swerdlow, Dr. Joseph Telfair, Dr. Tim Townes




Dr. Joseph DeSimone, Dr. Marie Mann


Dr. William Hannon, Dr. Robert Sheffler


Ms. Barbara Adam, (CDC); Dr. Barbara Alving, NHLBI/OD; Dr. Sushrut Babhulkar, Nagpar, India; Dr. Duane Bonds, DBDR/SCDSRG; Dr. Gregory Evans, DBDR/SCDSRG; Dr. Paul Frenette, Mount Sinai;Dr. Charles Peterson, DBDR/BDP; Mr. Nathaniel Polster, HLB Newsletter; Ms. Susan Pucie, DBDR/BDP; Ms. Sonya Ross, SCDAA, Dr. Ellen Werner, DBDR/BDP; Dr. Russell Ware, Duke University; William P. Winter, Howard University SCD Program

Executive Secretary - Dr. Charles M. Peterson

Secretary - Ms. Petronella A. Barrow

Dr. Charles Peterson called the meeting to order at 9:05 am and read the required notification regarding conflicts of interest and reminded those present to sign in on the required sign-in sheets. Certificates of recognition for service on the committee were presented to Dr. Jeanne Smith, Dr. Paul Swerdlow, and Dr. Tim Townes. It was announced that Dr. Peter Lane will assume the Chair with the next meeting.

  1. Dr. Swedlow called for review of the minutes of June 4, 2001 they were reviewed and approved.
  2. Dr. Swerdlow welcomed the members and guests.
  3. Dr. Swerdlow introduced the Scientific Presentations.

    A. Dr. Jeffrey Miller spoke on Erythroid Cell Genomics and Sickle Cell Disease. Current hypotheses for the prevention or treatment of the thalassemia and sickle-cell syndromes are based on a model conceived over a decade ago of hemoglobin accumulation during adult erythropoiesis. This model includes a switch from fetal-type to adult-type hemoglobin during the proerythroblast-basophilic normoblast stage of differentiation. Accordingly, Dr. Miller expected to identify a majority of fetal globin transcripts within his laboratory’s erythroid genomics database (http://hembase.niddk.nih.gov/) derived from immature erythroid cells. Instead, the result was that expressed hemoglobin genes included over 85% adult-type transcripts. For this reason, Dr. Miller developed the hypothesis that hemoglobin biosynthesis in adult humans may not be consistent with the previous “compressed switch” model for erythropoiesis. To test this hypothesis, the accumulation of hemoglobin was directly measured among differentiating cells harvested from the peripheral blood and bone marrow of normal volunteers. Using the peripheral blood cells, Dr. Miller was able to monitor several cell biology parameters, in addition to hemoglobin accumulation, including morphology, cell cycle phase, and surface phenotype. Careful direct quantitation of hemoglobin species was performed using high-pressure liquid chromatography. Dr. Miller’s team found that fetal hemoglobin does not precede adult hemoglobin accumulation during the differentiation process. These analyses additionally revealed a “coordinated” rather than “switched” pattern of hemoglobin accumulation. Examination of fresh bone marrow as well as quantitative PCR analyses revealed the same coordinated patterns. Dr. Miller and collaborators have proposed a model of globin “modulation” rather than “switching” to explain hemoglobin biosynthesis in adults. Importantly, they also determined that the pattern of hemoglobin accumulation during adult erythropoiesis is directly related to the proliferation of the cells. These results have several implications with regard to the interpretation of data gained from therapies aimed at hemoglobin modulation, and future clinical approaches for patients with sickle-cell syndromes.

    B. Dr. Sushrut Babhulkar spoke on Management of Avascular Necrosis of the Hip in India. These approaches are reviewed in the appended slides. [Append]

  4. Chairman’s Report: Dr. Swerdlow reviewed two meetings that he had attended that were of interest to the group. One was an FDA meeting of the Anesthetic and Life Support Drugs Advisory Committee. Sickle Cell Disease was recognized and addressed specifically by the committee as an example of the issue of chronic pain management. He felt that the tone of the meeting reflected the best interests of persons with sickle cell disease and did not feel that a specific response from the Sickle Cell Advisory Committee was necessary. The second meeting was of the American Association of Blood Banks on alternative blood products. While there was no new data on alternatives to transfused red cells regarding persons with sickle cell disease, there are a number of new potentially useful products in the developmental pipeline.

  5. DBDR Director’s Report: Dr Peterson reviewed the meeting of the Armed Forces Epidemiological Board where he presented the committees views on screening for sickle cell trait by the military. Further information on this meeting may be obtained at:
  6. Action Items from previous meeting were completed or discussed as follows:

    A. Dr. Swerdlow noted the importance of pain therapy for patients with sickle cell disease and volunteered to attend the FDA meeting of the Anesthetic and Life Support Drugs Advisory Committee and coordinate a response of the Sickle Cell Disease Advisory Committee as necessary.

    Dr. Swerdlow’s comments are noted above under the Chairman’s Report.

    B. The BABY HUG Protocol Review Committee/Data and Safety Monitoring Board are still reviewing the protocol, age of participants, and considerations of therapeutic endpoints and potential toxicities. Since the protocol is still under review, this clinical trial is on hold.

    Dr. Bonds asked that a full report be postponed until the next meeting.

    C. The Committee concurred on the lack of data regarding quality of life issues and health services utilization and encouraged development of a workshop and a working group in the area. Members interested in serving on the working group are: Dr. Paul Swerdlow, Dr. Marie Mann, Dr. Joseph DeSimone, Dr. Joseph Telfair, Dr. Peter Lane and Ms. J. Hoxi Jones-Carranza.

    Dr. Ellen Werner reported for the workshop committee. The Title of the workshop is Adults with Sickle Cell Disease: Meeting Unmet Needs. The date is June 13-14, 2002 at the Natcher Building, (45) of the NIH campus in Bethesda, Maryland. The registration for the workshop is now full and overflow rooms have been booked. Further information on the workshop and an opportunity for comments can be found at: The objectives of the workshop are to review the major medical, economic, and social problems in adults with sickle cell disease and develop long-term strategies to address their needs through collaborative efforts with other government agencies (e.g., HRSA) and with patient advocacy groups such as the Sickle Cell Disease Association of America, (SCDAA).

    D. Dr. Swerdlow will convene an ad hoc committee to draft a statement on behalf of the Committee prior to the next meeting regarding ICD 9 codes for diagnoses of hemoglobinopathies as well as various sequelae of the main diseases. Dr. Lane will assist.

    It was not possible to do this up to this point but Dr. Swerdlow will continue with these efforts. The committee requested that Dr. Swerdlow come to the next meeting and report on his progress and he agreed.

    E. Three draft initiatives that had been discussed at the previous meeting were reviewed by the committee (Comparison of Membrane Active Drugs in Adults with Sickle Cell Disease; Clinical Effectiveness of Hydroxyurea in Hb SC Disease, and the Effects of Sickle Cell Disease on the Lung). The committee rated the Lung initiative as top priority, followed by membrane active drugs and Hb SC disease/hydroxyurea.

    Dr. Bonds noted that the initiative on Sickle Cell Disease and the Lung received a favorable rating from the Board of Extramural Advisors as well as Council. Funding will determine if this initiative can be released in the coming fiscal year. The other two initiatives were felt by the committee to warrant further work. Dr. Marie Stuart will review these two initiatives with a critical eye and see whether there might be a way to merge the two SC initiatives.

  7. Agency Reports
  8. A. Centers for Disease Control: Ms. Adams noted the many changes occurring in the methods of testing being used for neonatal screening. A laboratory has been established at the CDC to address issues in newborn screening quality assurance and quality control with new equipment and additional personnel time. She will continue to update the committee on the progress in the area of newborn screening with newer technologies.

    B. Health Resources and Services Administration: Dr. Marie Mann also announced a new program in newborn screening with $4 million targeted towards sickle cell disease. This program will involve follow up and counseling following early testing. The Secretary’s Advisory Committee on Genetic Testing (SACGT) assessment of HHS efforts to advance the appropriate use of genetic tests was discussed. The Sickle Cell Disease Advisory Committee was concerned about the lack of quality assurance in the testing being done by such programs except as monitored at the state level.

    It was moved, seconded and unanimously approved that the : As part of the Federal effort in the area of genetic testing that The Sickle Cell Disease Advisory Committee would recommend 1) Quality Control laboratories be established and 2) at least one reference laboratory be established.

    C. Veterans Administration: No report given.

    D. Department of the Army: No report given.

  9. Update on Program Activities
  10. A. Comprehensive Sickle Cell Centers Renewal Progress: Applications were received September 25, 2001, and there was a strong response. The review has taken place and investigators have been notified of their overall program scores. The summary statements with the full review and rating of the sub-projects should be available within approximately 6 weeks. Funding decisions will be made following secondary review by the NHLBI Advisory Council September 5-6, 2002.

    B. Strategic Plan for a Gene-Based Cure for Beta-Chain Hemoglobinopathies: As reported to this committee previously, extramural investigators have proposed a two-armed, 11 part Strategic Plan for Gene-Based Cures for Beta-Chain Hemoglobinopathies. One arm deals with various aspects of the study of the mechanistic basis of induction of endogenous fetal hemoglobin genes, and the other arm deals with the development of gene therapy as a therapeutic modality for sickle cell disease and Cooley’s anemia. To date, from this plan two RFAs have been published, and one of these has been subsequently funded. The RFA that has been funded is entitled Transactivation of Fetal Hemoglobin Genes for Treatment of Sickle Cell Disease and Cooley’s Anemia. The other RFA that has been released but not yet funded is entitled Mechanisms of Fetal Hemoglobin Gene Silencing for Treatment of Sickle Cell Disease and Cooley’s Anemia. It will be funded in April, 2003. Additional RFAs are under consideration by the Institute. A Program Announcement targeted to small businesses has also been approved for release and is under development. It is entitled Chemical Screens for New Inducers of Fetal Hemoglobin for Treatment of Sickle Cell Disease and Cooley’s Anemia.

    C. Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG): This contract began in August, 2000 with the funding of 10 peripheral clinical sites and a medical coordinating center. The investigator group has spent the first two years of the contract finalizing the protocol and trial design.

    D. MSH Patients’ Follow-up: This prospective epidemiologic cohort study of the subjects who were originally enrolled in the Multicenter Study of Hydroxyurea (MSH Trial) is now entering its 5th year. The investigator group has demonstrated decreased mortality in those subjects who were begun on hydroxyurea in 1992 and who have continued on the drug with good fetal hemoglobin response since that time. Long term efficacy has been demonstrated in terms of persistence of fetal hemoglobin response, total hemoglobin response, and decreased morbidity secondary to consequences of decreased sickling. However, this patient population continues to have a high mortality rate secondary to the severity of their sickle cell anemia at time of study entry (3 or more crises per year). The leading causes of death in this cohort are death in acute crisis and pulmonary hypertension/chronic sickle lung disease. For this latter reason pulmonary testing is being included in further follow up.

    E. Parvovirus B19 Study: This prospective epidemiologic cohort study involves pediatric subjects with sickle cell syndromes enrolled at 7 of the 10 current NHLBI-funded Comprehensive Sickle Cell Centers. These subjects are being followed to ascertain the B19 parvovirus seroprevalance, the seroconversion rate from negative to positive after B19 exposure, and the association, if any, between seroconversion and acute adverse events such as aplastic bone marrow crises or acute chest syndrome. Approximately 1,000 patients have been enrolled to date, and approximately 30% of subjects are seropositive so far. This study is scheduled to end in October, 2003. Infection by B19 parvovirus (which targets erythroid precursor cells) can be life-threatening for patients with hemolytic anemia. The NHLBI is evaluating plans to follow this study with clinical trials of an anti-B19 vaccine initially developed by Dr. Neal Young in intramural NHLBI, and subsequently tested in Phase I-II clinical trials by Medimmune. Medimmune is no longer involved in the clinical development of this vaccine, so NHLBI is evaluating plans to identify a new vaccine producer, and to potentially support additional Phase II and Phase III clinical trials.

    F. STOP II Trial: This investigator initiated randomized clinical trial is designed to answer the question of whether or not chronic transfusion therapy can be safely withdrawn from subjects after 30 months of blood transfusions and normal transcranial doppler (TCD) surveillance studies.

    G. Hip Core Trial: This investigator initiated randomized clinical trial is designed to ascertain the possible utility of hip coring as a treatment for patients with avascular necrosis of the hip.

    H. CSSCD Cohort Study: The repository DNA samples are beginning to run out of material for analysis. The Sickle Cell Disease Advisory Committee encourages NHLBI to consider ways by which the utility of this resource can be prolonged and establish a minimum amount below which no more samples will be withdrawn anticipating a yet to be developed expansion technology.

    I. Workshops and Projects 2002/2003

      Title: Adults with Sickle Cell Disease: Meeting Unmet Needs (Workshop) Date: June 13-14, 2002 Place: Natcher Building, (45) Bethesda, Maryland

      Title: SCDAA National Sickle Cell Conference Date: September 17-22, 2002 Washington Hilton Hotel

    There was concern on the part of the committee regarding the cost of housing for this latter meeting such that it might inhibit attendance by trainees and families. The SCDAA will evaluate the possibility of alternative housing for future meetings.

  11. Dates of Next Meetings
  12. November 4, 2002

    June 2, 2003

  13. Areas of Program Needs and Opportunities

    A. The issues of behavioral and psychosocial research were identified in particular with hopes expressed that the workshop on unmet needs will develop a strategic plan in these areas.

    B. Staff was asked to identify speakers for the next meeting who could address statistical approaches and issues of small N clinical trials in pain research and potential surrogate markers of eye and bone disease in patients with SC disease.

  14. Summary List of Action Items
  15. A. The Protocol Review/DSMB Committees of BABY HUG are requested to report to the Committee regarding development of the protocol, age of participants, and considerations of therapeutic endpoints and potential toxicities. This clinical trial is on hold pending completion of review by NHLBI.

    B. Dr. Swerdlow would also convene an ad hoc committee to draft a statement on behalf of the Committee prior to the next meeting. Dr. Swerdlow noted that he would coordinate an outreach for the Committee to the AMA regarding the ICD 9 codes for SC disease and sickle beta thalassemia disorders, Dr. Lane will assist.

    C. Dr. Marie Stuart will review the two SC initiatives with a critical eye and see whether there might be a way to merge the two SC initiatives.

    D. NHLBI will consider ways by which the utility of the CSSCD DNA resource can be prolonged and establish a minimum amount below which no more samples will be withdrawn thus anticipating a yet to be developed expansion technology.


    Paul Swerdlow, M.D.


    Sickle Cell Disease Advisory Committee


    Charles M. Peterson, M.D.

    Executive Secretary

    Sickle Cell Disease Advisory Committee

    Last updated: October 28, 2007

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