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MINUTES OF THE SEVENTY-SEVENTH MEETING OF THE SICKLE CELL DISEASE ADVISORY COMMITTEE

Bethesda, Maryland
June 5, 2000

COMMITTEE MEMBERS PRESENT
Dr. Kenneth Bridges, Dr. Joseph DeSimone, Dr. Peter Lane, Dr. Vipul Mankad, Ms. Sonya Ross, Dr. Marie Stuart,  Dr. Paul Swerdlow, Dr. Tim Townes.

COMMITTEE MEMBERS ABSENT
Dr. Herbert Meiselman, Dr. Jeanne Smith

EX-OFFICIO MEMBERS PRESENT
Dr. Martin Steinberg, Dr. Marie  Mann

EX-OFFICIO MEMBERS ABSENT
Dr. Scott Wegner, Dr. William Hannon

PROGRAM STAFF AND AFFILIATED ORGANIZATION REPRESENTATIVES:
Dr. Barbara Alving, DBDR; Dr. Gilda Barabino, Northeastern University; Dr. Lenette Benjamin, Sickle Cell Disease Association of America, Albert Einstein College of Medicine,  Dr. Michael Terrin, Maryland Medical Research Institute; Arlene Hawkins, DBDR/BDP,  Dr. Cage Johnson, USC; Dr. Barbara Alving, DBDR; Dr. Duane Bonds, DBDR/SCDSRG; Dr. Gregory Evans, DBDR/SCDSRG; Dr. Carol H. Letendre, DBDR; Dr. Charles Peterson, DBDR/BDP; Dr. Joseph Telfair, University of Alabama, Dr. Ellen Werner, Temple University Institute for Survey Research, Dr. Nevada Winrow, Johns Hopkins School of Medicine.

Executive Secretary  - Dr. Charles M. Peterson
Secretary  - Ms. Petronella A. Barrow

I. Dr. Kenneth Bridges called the meeting to order at 9AM.
Dr. Charles Peterson read the required notification regarding conflicts of interest and remind ed those present to sign in on the required sign-in sheets. A presentation and certificate was presented to retiring members: Dr. Bridges, Dr. DeSimone, and Dr. Mankad.
Dr. Paul Swerdlow was welcomed as the New Chair of the Committee beginning with the next meeting.  Other new members will be Dr. Gilda Barabino, Northeastern University, Dr. Oswaldo Castro, Howard University and Dr. Joseph Telfair, University of Alabama.

II.  Dr. Alving welcomed the group and gave a brief overview of items from the Division of importance to Sickle Cell Disease. Of particular note is  the August 10, 2000 meeting on Stem Cell Transplantation coordinated by Dr. Helena Mishoe to be held at NIH. Dr. Alving gave an update on the Management and Therapy of Sickle Cell Disease book that is scheduled to be completed by the end of the summer. She emphasized the need for timely input by all the authors and reviewers on this book

III. The Minutes of November 15, 1999 were reviewed and approved.

IV.  Dr. Bridges thanked Dr. Martin Steinberg for his work for the committee and noted that Dr. Steinberg will be moving to Boston to direct the Sickle Cell Center there. The move will mean that the Sickle Cell Disease Advisory  Committee will lose his counsel as representative of the VA System. Dr. Steinberg will ask the VA to appoint his successor prior to the next meeting.

V.  Dr. Duane Bonds introduced the Scientific Presentations.

 A. Dr. Tim Townes spoke on Human Globin Gene Regulation in Development: Studies in Transgenic mice.
 B.  Dr. Michael Terrin of Maryland Medical Research Institute discussed the findings that were described in the abstract below.  This presentation was made as a background to discussing further follow-up of patients in the MSH trial.

RISKS AND BENEFITS OF HYDROXYUREA (HU) IN ADULT SICKLE CELL ANEMIA.  EFFECTS AT 6 TO 7-YEARS.  M.H. Steinberg, F. Barton*, O. Castro, M. Koshy, J.Eckman, M. Terrin* for the MSH Patients Follow-up.  VA Medical Center and Univ. of Mississippi, Jackson, MS, Maryland Medical Research Institute, Baltimore, MD, Howard Univ. Washington, DC, Univ. of Illinois, Chicago, IL, Emory Univ. Atlanta, GA.

Two-hundred ninety-nine adults with moderate-to-severely symptomatic sickle cell anemia were randomly assigned to treatment with maximally tolerated doses of HU or with placebo (PL) in the Multicenter Study of HU in Sickle Cell Anemia (MSH).  As previously reported, HU reduced painful episodes by almost 50% over 28-months.  Randomized treatment was then stopped and unmasked.  Patients have now been followed for 6- to - 7 years for a total of 1, 914 patient-years; 744 -patient-years of HU treatment documented and 1170-patient years without HU treatment documented. In patients now taking vs. those not now on HU there is evidence for sustained reduction of hemolysis with higher hemoglobin concentrations (mean ± SD:8.7 ± 1.8 vs. 8.2 ± 1.2 g/dL, p=0.08) and lower reticulocyte counts (189 ± 122 vs.260 ± 116 k/mm3, p=0.007) and bilirubin levels (0.4 ± 0.5 vs. 0.7 ± 0.7 g/dL, p=0.06) Fifty-one patients have died, 21 among the 152 originally assigned to receive HU and 30 among the 147 assigned to PL (p=0.13).  Pulmonary disease was the most common cause of death.  Five strokes occurred in the original HU group (3 fatal) and 3 strokes in the original PL group (none fatal).  Since the start of randomized treatment, unexpected adverse events have not been found and no patients have developed neoplasm.  At present, HU usage is not known for 27 patients originally assigned to HU and 29 patients assigned to PL.  Seven deaths have occurred during periods HU exposure compared to 44 deaths occurring in periods with no HU reported, or 0.009 deaths/patient-year on HU and 0.038 deaths/patient-year off HU.  Cumulative mortality was modeled with Cox proportional hazards using periods of exposure to HU compared to non-exposure as a time-dependent covariate.  Depending upon the assumptions made about patients whose HU usage since the conclusion of the randomized trials is not reported, the risk of mortality (odds ratio) for HU usage compared to no HU usage ranges from 0.59, p=0.08 to 0.39, p=0.001. Estimates of risk reduction did not change when covariates such as age, sex or number of pain episodes were included.  These data show that the hematological effects of HU are sustained over 6 - to 7-years and that adverse effects of HU are infrequent.  They also suggest that in moderate-to-severely affected adults with sickle cell anemia, treatment with HU may be associated with a reduction of mortality.

VI.  Action Items from previous meeting

 A. Drs. Swerdlow, Lane, and  Smith had volunteered to help with the evaluation of Management and Treatment of Sickle Cell Disease. The advisory committee role in the book was further discussed. How a role for the SCDAC best might be accomplished was referred to the subcommittee of volunteers noted above. Many members of the committee volunteered to help with the drafting and review of chapters prior to the end of the summer. Dr. Samuel Charache was commended for the reviewing work that he has performed to date, and additional names for reviewers of specific chapters were provided.

 B. The use of hydroxyurea in hemoglobin SC disease remains controversial.  Dr. Bonds distributed the draft initiative of July 1, 1998 to interested committee members. It was recognized that the time for and evaluation of hydroxyurea for this indication may have passed  but the SCDAC noted that it would look into the potential endpoints and feasibility of such an effort and report back to Dr. Bonds. The committee again agreed that this is an important clinical problem. Those with SC may warrant treatment with hydroxyurea or conversely, those being treated off label may be being treated unnecessarily. The critical issues are availability of sufficient patients and the definition of well defined endpoints for an intervention study that would be convincing. Dr. Marie Stuart, Dr. Martin Steinberg, and Dr. Michael Terrin will consider the issue of a clinical study of hydroxyurea in SC disease in more detail. Dr. Stuart will return with a recommendation for the committee to consider.

 C. Dr.  Mann noted that HRSA had a meeting of a task force that recommended a need for quality assurance. A recommendation for a reference lab will come out of this task force. The report is in press in Pediatrics and is scheduled for publication in August.

 D. The issue of sickle cell trait as a public health problem as well as a problem for the military will be considered in future meetings. The committee will continue to try and see if someone from the military can address the issue at  a future meeting.

 E. Dr. Steinberg's  recently completed  review on sickle cell trait was made available to the committee.

 F.  The Committee discussed possible trial designs for conjugate pneumococcal vaccines in children with sickle cell disease. When the conjugate pneumococcal vaccine becomes available, it will be standard of care to vaccinate all children. Thus it would be difficult to conduct a randomized trial of the vaccine in children with sickle cell disease. The interactions of the current vaccines and the new vaccines and the optimum frequency of re-vaccination remain important questions. Another question is whether there are reliable surrogate endpoints for immunological response to vaccine in these (or other) high risk patients. There are now two vaccine preparations available.

Since it is now recommended that all children under two receive penumococcal vaccine, a separate study in subjects with sickle cell disease does not appear warranted. Questions regarding the optimum vaccination regimen including comparisons of the 7-valent vs the 23-valent vs the combined vaccines and the need for re-vaccination to protect against emerging pneumococcal species that are resistant to penicillin were raised.

 G.  Dr. Meiselman will be asked to address the issue of vasculopathy at the next meeting.

VII.  Dr. Bridges gave the Chairman's report. He thanked the committee for its support and looked forward to continuing to work on the projects of the committee in the future.

VIII.  Dr. Alving gave the Director's Report from the Division of Blood Diseases and Resources.  She recognized the importance of the Sickle Cell Disease Advisory Committee to the Division and the Institute.

IX.  Agency Reports

 A. The Department of Veterans Affairs. Dr. Martin Steinberg reported that there was little activity in the VA regarding Sickle Cell Disease in the past six months and that, due to his departure from the VA, he will be seeking a replacement over the summer.

 B. Health Resources and Services Administration. Dr. Marie Mann noted that the executive committee report of the HRSA group on integrating genetic medicine into practice is available at <www.ichp.edu>. Six of ten recent grants on outcomes are related to Sickle Cell Disease and many involve newborn screening.  The abstracts of these grants are posted as part of the meeting on the web site.  The Hemophilia Treatment Centers also have a data base that is tracking hepatitis C and there is a hepatitis C initiative for the Centers.  HRSA is trying to address issues of infection in blood products received by patients with Thalassemia, Hemophilia, and Sickle Cell Disease.  Sickle Cell Disease is part of the ten-year planning process for HRSA.  HRSA has generated a memorandum of understanding among several agencies that provides a formal  base into which all of the agencies can formalize relationships. There is also an ongoing project with the March of Dimes to educate the consumer regarding genetic issues. In addition, HRSA has an effort to evaluate and compare different approaches to screening for hemoglobinopathies in various ethnic groups in two states: California and Texas.

X. Update on Program Activities

 A. Comprehensive Sickle Cell Centers Review. Dr. Gregory Evans reviewed the timeline for the renewal of the RFA for the Sickle Cell Centers and discussed the May 15 working group meeting in which outside experts discussed potential new ideas for the RFA for the Sickle Cell Centers.  Advisory members received a written summary of the May 15 meeting and a list of participants.  Advisory members discussed the merits of trying to include small scale collaborative clinical research as a new component of the RFA, and were generally supportive, recognizing that funding for the Centers would probably not be sufficient to include major clinical trial projects related to sickle cell disease. Advisory committee members were split in their opinions on the idea, from the working group, of requiring each Sickle Cell Center to have a scientific theme.

TIMELINE FOR RECOMPETITION OF NHLBI COMPREHENSIVE SICKLE CELL CENTERS (CSCCs)

CSCC Working Group Meeting: May 2000

Sickle Cell Disease Advisory Group Meeting: June 2000

Development of Pre-Solicitation Document Within NHLBI: Summer 2000

Final deadline for feedback to NHLBI from the SCD Advisory Committee and current CSCC grantees: July 15, 2000

Presentation of Pre-Solicitation Document to NHLB Advisory Council: October 2000

Publication of Solicitation (RFA) in NIH Guide: December 2000

Application Receipt: Fall 2001

Merit Review: Spring 2002

Presentation of Proposed Funding Plan to NHLB Advisory Council: September 2002

Award April 2003

The current program was also briefly reviewed as were recommendations received to date for the next RFA. Members of the committee were encouraged to forward recommendations and thoughts regarding the renewal of the Sickle Cell Centers to Dr. Evans.

 B.  Dr. Evans reported on a proposed Strategic Plan for a Gene-Based Cure for Beta-Chain Hemoglobinopathies. While genetic approaches to the hemoglobinopathies has often led the field into new and exciting areas of science, the problem remains one of the more daunting endeavors in genetic therapy.

 C. Genetic Variability. Dr. Greg Evans reviewed the status of an NHLBI initiative in the area. The initiative in clinical and basic science issues related to genetic variability in sickle cell disease has been widened to include other mongenic diseases. It was approved by the Board of Extramural Advisors and the NHLB Advisory Council.

 D. Hydroxyurea trials. Dr. Duane Bonds noted that The Multi-Center Study of Hydroxyurea (MSH) follow-up is now at a time where possible renewal needs to be considered. In view of the clear clinical benefit from hydroxyurea therapy, the need for definitive assessment of toxicity is paramount. The potential for leukemia and other long term sequelae of chronic administration of the compound requires further follow up of these patients. The concept of further follow up of MSH Study patients was moved seconded and unanimously approved. The BABY HUG Phase 3 Clinical Trial has identified participant centers and is in the final stages of funding the contracts.
 
 E.  Parvovirus B19 Study. Dr. Duane Bonds announced that a cumulative incidence epidemiologic study has been  initiated  through nine of the ten Sickle Cell Centers.

 F. CSSCD Issues. Dr. Duane Bonds noted that the clinical severity paper has recently been published by the New England Journal of Medicine.

(Miller ST, Sleeper LA, Pegelow CH, Enos LE, Wang WC, Weiner SJ, Wethers DL, Smith J, Kinney TR. Prediction of adverse outcomes in children with sickle cell disease. N Engl J Med. 2000 Jan 13;342(2):83-9.)

 G.  Workshop/Projects for FY 2000
 1. Management and Therapy of Sickle Cell Disease - Drs. Alving, Bridges, Lubin, Peterson
 2. Stem Cell Workshop August 10 - Dr. Mishoe, Rockledge Building
 3. Nitric Oxide in Sickle Cell Disease and Other Vascular Diseases - Dr. Evans September 5,6 Lister Hill.
 4. The Brain in Sickle Cell Disease - Dr. Bonds September 18 followed by the Sickle Cell Clinical Research Meetings of September 19 and 20 at NHLBI.
 
XI.  Other

The Committee moved seconded and approved unanimously that NHLBI consider permanent consumer participation as part of the Sickle Cell Disease Advisory Committee.

XII. The meeting was adjourned at 3:15 PM.

XIII. Dates of Next Meetings

November 13, 2000
June 4, 2001

XIV.  Summary List of Action Items

Dr. Marie Stuart, Dr. Martin Steinberg, and Dr. Michael Terrin will consider the issue of a clinical study of hydroxyurea in hemoglobin SC disease in more detail. Dr. Stuart will return with a recommendation for the committee to consider.

The issue of sickle cell trait as a public health problem as well as a problem for the military will be considered in future meetings. The committee will continue to try and see if someone from the military can address the issue at  a future meeting.

Dr. Meiselman will be asked to address the issue of vasculopathy at the next meeting.

Dr. Steinberg will ask the VA to appoint his successor prior to the next meeting.

The concept of further follow up of MSH Study patients was moved seconded and unanimously approved.

The Committee moved seconded and approved unanimously that NHLBI consider permanent consumer participation as part of the Sickle Cell Disease Advisory Committee.

I hereby certify that to the best of  our knowledge, the foregoing minutes are accurate and complete.

___________________________                                    _____________
Kenneth Bridges, M.D.                                                   Date
Chairman
Sickle Cell Disease Advisory Committee

___________________________                                     ______________
Charles M. Peterson, M.D.                                                 Date
Executive Secretary
Sickle Cell Disease Advisory Committee
 

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