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 Committees
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
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