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

Bethesda, Maryland
November 13, 2000

COMMITTEE MEMBERS PRESENT
Dr. Gilda Barabino, Dr. Oswaldo Castro, Dr. Peter Lane, Dr. Herbert Meiselman, Ms. Sonya Ross, Dr. Jeanne Smith, Dr. Marie Stuart,  Dr. Paul Swerdlow, Dr. Joseph Telfair, Dr. Tim Townes.

COMMITTEE MEMBERS ABSENT
None

EX-OFFICIO MEMBERS PRESENT
None

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

PROGRAM STAFF AND AFFILIATED ORGANIZATION REPRESENTATIVES:
Ms. Barbara Adam, CDC; Dr. Barbara Alving, DBDR; Dr. Luiz Barbosa, DBDR/BRP;  Dr. Duane Bonds, DBDR/SCDSRG; Dr. Gregory Evans, DBDR/SCDSRG; Dr. Carol H. Letendre, DBDR; Dr. Helena Mishoe DBDR/BDP; Dr. Richard Olney, CDC;  Dr. Charles Peterson, DBDR/BDP; Dr. B.N. Setty, Jefferson Medical College; Dr. Ellen Werner, DBDR/BDP;  Dr. Nevada Winrow, Johns Hopkins School of Medicine.

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

I. Dr. Paul Swerdlow called the meeting to order at 9:05 AM.
Dr. Charles Peterson read the required notification regarding conflicts of interest and reminded those present to sign in on the required sign-in sheets.

II.  The Minutes of June 5, 2000 were reviewed and approved.

III.  Dr. Swerdlow introduced the Scientific Presentations.

 A. Dr. Herbert Meiselman spoke on PEG-Coated RBC in Sickle Cell Disease.

Polyethylene glycol (PEG) can be covalently coupled to red blood cells in vitro dramatically altering red cell aggregation, viscosity and adhesion.  While a compound containing PEG continues to be evaluated as an acute infusion for crisis in patients with sickle cell disease, a T1/2 elimination time of 3-4 hours limits its usefulness. PEG coupled in vitro to red cells has the capacity to mask antigenic determinants which could dramatically aid in blood crossmatching as well as with autoimmune hemolytic disease.  PEG also masks phosphatidylserine residues and could interrupt the procoagulant state associated with sickle cell disease. These compounds might have potential utility in sickle cell disease in terms of decreasing the frequency of transfusion, increasing blood units available for treansfusion to alloimmunized individuals and minimizing sickling sequelae. Experiments are now underway to test these hypotheses.

B.  Dr. Marie Stuart and Dr. B.N.  Setty spoke on Comparison of Hemoglobin SS and SC Adhesive Responsiveness.

In sickle cell disease, loss of erythrocyte membrane phospholipid asymmetry occurs with the exposure of phosphatidylserine, which provides a docking site for coagulation proteins.
In vivo sickling/desickling, with resulting red cell membrane changes and microvesicle formation, appears to be one of the factors responsible for PS exposure. Their group evaluated children with SCD homozygous for sickle hemoglobin (SS disease) and controls and demonstrated that high levels of fetal hemoglobin (assessed as F cells) are associated with decreased microvesicle formation, PS exposure, and thrombin generation. F cells correlated inversely with both microvesicles and PS positivity in SS disease. Multiple regression analyses using various hematologic parameters as independent variables, and either microvesicles or PS positivity as the dependent variable, showed a strong relationship only with F cells. Additionally, plasma prothrombin fragment F1.2 levels (a marker for thrombin generation) correlated with both PS positivity (P <.001) and F cells (P <.01). An F-cell level of approximately 70% or HbF level of 15 - 20% was associated with normal levels of prothrombin fragment F1.2 and with microvesicle formation indistinguishable from control values. These levels of Hb F are generally present until about 1 year of age. Similar findings occur in patients with SC disease but are quantitatively much less.

IV.  Action Items from previous meeting were completed or discussed as follows:

A. Dr. Steinberg will ask the VA to appoint his successor prior to the next meeting. This has been completed and Dr. Joseph De Simone will be assuming the position.

B. 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 was discussed in depth along with the discussion of the above presentation. It was felt that there were not sufficient subjects with the degree of illness to support such a randomized phase 3 efficacy study in the U.S. There was some interest in a comparison of toxicity versus other therapies of potential utility in SC disease for examples compounds designed to increase intracellular hydration that would not necessarily raise hematocrit levels.

C. 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.  To date it has not been possible to get a person.  Dr. Alving will contact the Army Surgeon General to see if she can find someone to address the committee.  It was felt that it is important to maintain the issue on the agenda and continue to continue to provide visibility for it.

D. The Committee moved seconded and approved unanimously that NHLBI consider permanent consumer participation as part of the Sickle Cell Disease Advisory Committee.  A person has been identified and should be able to attend the next meeting.

V.  Dr. Swerdlow gave the Chairman's report. He reviewed the meeting of the October NHLBI Council and highlighted the discussion on the new RFA for the Sickle Cell Centers and on the RFAs that are part of a Strategic Plan for a Gene-Based Cure for Beta-Chain Hemoglobinopathies.

VI.  Dr. Alving gave the Director's Report from the Division of Blood Diseases and Resources.
The progress on the book Management and Therapy of Sickle Cell Disease was reviewed. Most of the chapters have been received and reviewed.  It was decided to send out the complete electronic copy to the Sickle Cell Advisory Committee for review during the last two weeks of January and the first two weeks of February.

Dr. Alving noted that she, Dr. Evans and Dr. Lenfant attended the September National Meeting of the Sickle Cell Disease Association of America. She noted that it was not only an opportunity for NHLBI to communicate to vital stakeholders in our efforts on behalf of those with sickle cell disease but also a good time to learn about the impact of our programs and needs from patients, families, investigators, and trainees.

The pamphlets describing the Division of Blood Diseases and Resources and the Training Programs were passed out to the members of the Committee.  Three new members of DBDR were introduced: Drs. Liana Harvath, John Thomas, and Ellen Werner. Dr. Alving also noted that Dr. Carol Letendre after many years of invaluable service would be retiring from the Division by the end of the year.

VII.  Agency Reports

A. Centers for Disease Control. Ms. Barbara Adam gave the report with the participation of Dr. Richard Olney. She noted that there are many changes occurring in the methods of testing being used for neonatal screening. A number of gene based kits are beginning to appear as are new methods using tandem, MALDI, and ESI-mass spectroscopy for detecting hemoglobin variants.  There is some interest on the part of the CDC in participating in or convening a workshop on new methods but any commitments on the part of the agency will have to await the availability of a budget.

B. Health Resources and Services Administration. Dr. Marie Mann could not be present. Dr. Peter Lane directed the Committee’s attention to three recent publications.

 1. Newborn Screening Task Force. A report from the newborn screening task force convened in Washington DC, May 10-11, 1999. Pediatrics 106 (Suppl.): 383-427, 2000.

 2. Pass KA, Lane PA, Fernhoff PM et al. U.S. newborn screening system guidelines II: Follow-up of children, diagnosis, management, and evaluation statement of the Council of Regional Networks for Genetic Services. J. of Pediatrics 137 (Suppl.): 1-46, 2000.

 3. Newborn Screening Committee. The Council of Regional Networks for Genetic Services (CORN), National Newborn Screening Report - 1995, CORN, Atlanta, September 1999.

VIII. Update on Program Activities

 A. Comprehensive Sickle Cell Centers Renewal. Dr. Gregory Evans reviewed the time line for the renewal of the RFA for the Sickle Cell Centers and noted that suggestions from the committee regarding small scale collaborative clinical research as a new component of the RFA were taken to heart in the new RFA. He noted that following release of the RFA there would be a meeting for potential applicants as the American Society of Hematology Meeting on Friday December 1 at the Sheraton Palace Hotel in the Seacliff Room from 7 - 10 PM during which time the RFA would be discussed..

TIME LINE FOR RECOMPETITION OF NHLBI COMPREHENSIVE SICKLE CELL CENTERS  (CSCCs)
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

 B.  Dr. Evans reported on a proposed Strategic Plan for a Gene-Based Cure for Beta-Chain Hemoglobinopathies.  The first 3 of 11 potential initiatives were presented to the Bureau of Extramural Advisors (BEA) and the Council.  These three initiatives dealt with approaches to increasing hemoglobin F.  At least one of the initiatives appears to be moving forward in the coming fiscal year.

 C. MSH Patients’ Follow-up Cohort Trial. Dr. Duane Bonds reviewed the status of trial and noted that an additional 5 years of follow-up was being planned by NHLBI.

 D. BABY Hug Phase 3 Clinical Trial. A letter regarding the trial and potential toxicities was distributed to the Committee.  Dr. Duane Bonds noted that participant centers are identified, the steering committee is finalizing protocols and that protocol review and data safety and monitoring processes are beginning as is customary for NHLBI clinical trials.  It was moved, seconded and unanimously approved that the Protocol Review/DSMB Committees report to the Committee regarding development of the protocol, age of participants, and considerations of therapeutic endpoints and potential toxicities.

 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 and recruitment of patients is proceeding.

 F. STOP 2 Trial. Dr. Bonds reported that the trial was underway and will begin recruitment soon.

G. Additional Clinical Trials in Progress. Dr. Bonds reported that the Hip Core Trial continues to recruit patients.  This trial and a planned trial in Acute Chest Syndrome are being coordinated through the Oakland Sickle Cell Center.  The Cooperative Study of Sickle Cell Disease Cohort Study continues to encourage investigators to apply for ancillary funds to further evaluate data. Interested investigators should contact Dr. Bonds.

H. Clinical Trials under Development. A number of trials have been proposed to the NHLBI from investigators and several have been suggested for NHLBI coordination.  It was proposed, seconded and unanimously approved that speakers for the next meeting be sought who could address the issues of clinical trials that increase cellular hydration with magnesium and feasible clinical trials in SC disease.

I. It was recommended by the committee that the Sickle Cell Disease Research Group distribute an ongoing list of clinical trials and brief progress report on each as well as potential studies and current priorities prior to the Committee Meeting. This would provide the Committee information that would help advise NHLBI on priorities.
 

IX. Dates of Next Meetings

June 4, 2001
November 5, 2001

X. Summary List of Action Items

A. It was recommended by the committee that the Sickle Cell Disease Research Group distribute an ongoing list of clinical trials and brief progress report on each as well as potential studies and current priorities prior to the Committee Meeting.

B. Speakers for the next meeting should be sought who could address the issues of clinical trials that increase cellular hydration by ion channel inhibition and feasible clinical trials in SC disease.

C. 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.

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.  To date it has not been possible to get a person.  Dr. Alving will contact the Army Surgeon General to see if she can find someone to address the committee.
 

__________________________ _____________
 
Paul Swerdlow, M.D.   Date
Chairman
Sickle Cell Disease Advisory Committee
 
 
 

___________________________ ______________

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