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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