MINUTES OF THE SEVENTY-SIXTH MEETING
OF THE SICKLE CELL DISEASE ADVISORY COMMITTEE
Bethesda, Maryland June 7,
1999
COMMITTEE MEMBERS PRESENT
Dr. Kenneth Bridges, Dr. Iris Buchanan, Dr. Marie
Mann, Dr. Vipul Mankad, Dr. William Mentzer, Ms. Sonya Ross, Dr. Jeanne Smith,
Dr. Paul Swerdlow, Dr. Tim Townes.
COMMITTEE MEMBERS ABSENT
Dr. Jessica Davis, Dr. Joseph DeSimone
EX-OFFICIO MEMBERS PRESENT
Dr. Martin Steinberg
EX-OFFICIO MEMBERS ABSENT
Dr. William Hannon, Dr. Scott Wegner
PROGRAM STAFF AND AFFILIATED ORGANIZATION
REPRESENTATIVES:
Dr. Charles Peterson, DBDR; Dr. Barbara Alving, DBDR;
Dr. Carol H. Letendre, DBDR; Dr. Duane Bonds, SCDSRG; Dr. Gregory Evans,
SCDSRG; Ms. Susan Pucie, DBDR; Dr. Camille King, DBDR; Dr. Eugene Orringer,
University of North Carolina, Dr. Peter Lane, University of Colorado; Ms. Lisa
Douglas, Dr. Oswaldo Castro, Howard University; Dr. Seigo Ohi, Howard
University; Dr. William P. Winter, Howard University, Ms. Barbara Adam, CDC
Executive Secretary - Dr. Charles Peterson
Secretary - Ms. Petronella A. Barrow
I. The meeting was called to order by Dr. William
Mentzer at 9:08 AM.
II. The Minutes of November 13, 1998 were reviewed and
approved.
III. Opening Remarks Dr. William
Mentzer
Dr. Mentzer opened the meeting by expressing
appreciation to the speakers and welcomed Dr. Barbara Alving as Director of The
Division of Blood Diseases and Resources.
- Director's Report DBDR Dr. Barbara
Alving
Dr. Alving welcomed everyone and said that each member
of the Committee should feel free to communicate concerns and issues both
positive and negative directly to her. Her e-mail address is <
alvingb@nih.gov>. Due to its protean nature, sickle cell disease impacts
every area of hematology and hence every scientific research group of the
Division. Thus it is important to view sickle cell disease in a broad context
and to take even an international approach toward the planning of research and
treatment for the disease. She raised the issue of where we in the sickle cell
disease community will be and would like to be in five years and emphasized the
role of the Sickle Cell Disease Advisory Committee in defining and achieving
these goals. She announced the recent formation of The Board of External
Advisors for the National Heart, Lung, and Blood Institute. This Board will
serve in part as a board of advisors for each Division within NHLBI.
V. Scientific Presentations
A. Update on Newborn Screening and State Managed Care
Programs. Dr. Peter Lane
Dr. Lane presented an overview of the current state of
the art in terms of guidelines for screening, acute care, and chronic care of
the person with sickle cell disease. These issues are becoming increasingly
important as managed care penetrates the medical market place. A number of
excellent resources are available. Managed care provides a number of barriers
to care for the person with sickle cell disease. In the mountain states, some
persons with sickle cell disease are granted authority to have immediate
interaction with specialty care thus bypassing the requirement of a primary
care gatekeeper. Nevertheless, there are no outcome data regarding
comprehensive care benefits for sickle cell disease that is generally accepted
by managed care providers. The State of Maryland may have some of the best data
that may serve as a model for other states. At present, each state is
responsible for the development of guidelines and their implementation.
Questions and points made included:
- How can we improve the NHLBI book: Management and
Therapy of Sickle Cell Disease? Each Sickle Cell Disease Advisory Committee
member was encouraged to read and comment on the book. Dr. Lane will also
submit suggestions for the book.
- What is the cost of care for a person with Sickle
Cell Disease? Estimates have ranged from $7,000 to $135,000/year. These cost
estimates are based in part on severity of the disease. For example it is
estimated that patients with greater than 3 crises/year are responsible for
approximately 80% of the health care costs related to the condition. These data
are important for creating approaches to costs and care in this disease.
- While consensus statements may not be based on
phase III double blind randomized trials, they nevertheless represent the state
of the art and are important. This position needs to be emphasized in future
editions of the NHLBI book.
B. Artificial Hemoglobin Dr. Eugene
Orringer
Background: The painful episodes of sickle cell
disease (SCD) involve vaso-occlusion and impaired oxygen delivery. HBOC-201, a
hemoglobin-based oxygen carrier, has been shown to support oxygen delivery in
animal studies and to be safe and well tolerated in normal human volunteers. We
therefore speculated that it might have a therapeutic role in SCD.
Methods: Eighteen adults with SCD who were
asymptomatic at the time of study were enrolled in a Phase I/II single-blind,
placebo-controlled, dose-escalation study of HBOC-201, the primary purpose of
which was to assess the safety of the material in this patient population. In
addition, as a surrogate marker of efficacy, each subject underwent a variety
of exercise tests before and after HBOC-201 was given.
Results: All HBOC-201 infusions were well
tolerated by the study subjects and no evidence of toxicity was noted. In
addition, there was a significant difference in heart rate response to the
identical aerobic exercise workload when the study subjects who received
HBOC-201 were compared to the subjects who received placebo.
Conclusions: HBOC-201 was safely administered
to patients with SCD who were not in crisis at the time of study. Furthermore,
following infusion of the study material, SCD subjects performed the identical
aerobic exercise-induced workload with an increase in heart rate that was
significantly less than the increase observed in the subjects who received an
infusion of the saline placebo. These safety and surrogate efficacy data
support the notion that HBOC-201 could have efficacy as a treatment for the
vaso-occlusive episodes of SCD.
Comments from the group included that Dr. Orringer did
describe the onset of a vaso-occlusive crisis in one recipient that was
temporally related to infusion of HBOC-201 and there was some concern raised
that the increase in circulating lymphokines etc. associated with the infusion
might exacerbate the shunt associated with acute chest syndrome.
VI. Action Items from previous meeting
A. Follow up on the issue of individuals with sickle
cell trait (HbAS) in the military.
Dr. Steinberg
- Dr. Steinberg recommended that we invite John Kark
to talk about the issues of HbAS in the military. After the initial report led
to changes in the protocol for basic training such as greater attention to
hydration status, the morbidity and mortality of patients with HbAS approached
that of the non-HbAS population. Then with more rigorous training, the death
rate began to rise again. It was moved and seconded to invite Dr. Kark to
present his data. It was further moved, seconded and approved that the member
from the Department of Defense be encouraged to come to the meeting and be
prepared to respond to the issue. Dr. Alving volunteered to contact Dr.
Kark.
B. How the Committee might widen to include
more input from patients and their families. Dr. Mentzer
- It was suggested to include as an ad hoc member
Janet Frempong ( a parent of a child with sickle cell disease). The question
remains how to formalize the process of increasing this type of input to the
Sickle Cell Disease Advisory Committee. The process of choosing such a person
could be as important as a given individual who might be chosen at any one
time. It was moved that we have a member of the Sickle Cell Disease Advisory
Committee who is either a parent of a patient or a patient with sickle cell
disease. It was so seconded and approved unanimously. This action can be made
by the committee on an ad hoc basis and implemented at the next round of
membership recruitment. Mrs. Frempong will be invited to the next meeting.
Staff will look into whether the charter can be modified to accommodate an
additional member or whether the goal should be accomplished within the current
structure.
C. Recent trends in the number of submitted sickle
cell R01 and training applications, and in their success rate. Dr.
Evans
Firstly, the annual number of investigator-initiated
research grant applications submitted in the sickle cell area has not changed
significantly in the last 10 years, but is 40-50% lower than it was in the
early 1980s. So, sickle cell research has not suffered as much recently as some
have claimed. It was emphasized that a number of grants are funded that relate
to sickle cell disease (hemoglobin or membrane related grants for example) that
are not coded for sickle cell disease by DBDR. Hence the picture could be more
optimistic than might be assumed from the above figures. Secondly, the funding
success rate over the last 18 years for Sickle Cell Disease Applications was 22
+ 6% and for DBDR in general was 28 + 6%. Thirdly, over the last 7 years,
NHLBI-initiated RFAs (including those for the Comprehensive Sickle Cell
Centers, mandated by Congress), have accounted for approximately two-thirds of
the sickle cell program budget. The committee should decide for itself whether
this is a problem or not. If one combines the numbers of funded sickle cell
grants with those for 2 other DBDR areas which will likely have a significant
impact on the treatment of sickle cell disease in the future, namely bone
marrow transplantation and cellular hematology, there is a marked increase in
the number of funded grants over the past 17 years.
D. Treatment "handbooks". Dr.
Mann
Dr. Mann brought several samples of handbooks.
Maternal and Child Health Bureau of HRSA (MCH) has traditionally supported the
publication of patient oriented materials. She spoke with Dr. Eckman who is in
the process of reissuing his manual with support from MCH. In the past, 8,000
copies were distributed. This document is also available on the Emory Web site
for Sickle Cell Disease. New topics will include social barriers and
depression. Regional networks have often produced their own handbooks and
guidelines. A Parents Handbook parts I and II by Lessing and Vichinsky from the
Northern California Comprehensive Sickle Cell Center is also available through
the MCH Clearinghouse. There is a waiting list of over a 1,000 requests for
these books at the present time. Alternate means of publicizing these products
might be through CD ROM. Questions raised included: 1. How can these resources
be made available to more patients? 2. Can these books be made available as a
result of screening programs, as is done in California? 3. Would it be possible
for NHLBI/DBDR and MCH to partner in making materials available? It was
suggested that the DBDR Website be updated with links. It was also emphasized
how important it is to get accepted input and creating a "consensus" document
that is accepted. The general model of a working group with subcommittees given
an assignment seemed to be a good initial approach. It was recommended that the
references for the NHLBI Management and Therapy of Sickle Cell Disease be
increased to include recommended resources and references with a brief
description of what they involve and with examples that are being used in
different areas of the country. Such an approach would obviate the NHLBI
getting involved in developing specific protocols.
- NHLBI staff will maintain contact with HRSA in
budgeting for the working committee for the revise NHLBI handbook keeping in
mind ways in which we might work together.
E. Lung initiative. Dr.
Bridges
Two issues now make such an initiative timely. There
is new information on what leads to acute chest syndrome and chronic lung
disease. There are also potential treatments such as nitric oxide becoming
available. It would also be timely to collaborate with the Division of Lung
Diseases on such an initiative.
- Dr. Bridges and Dr. Swerdlow will be bringing a
draft initiative forward to the committee at the next meeting.
- It was suggested that a workshop on nitric oxide be
scheduled for the next year.
F. Review of the concept of clinical trials with
pneumococcal vaccine/ Need for speaker
Committee members
It was recommended that we solicit suggestions for a
speaker from Dr. Winkelstein Johns Hopkins University regarding on the
conjugate pneumococcal vaccine. There was concern that it would be almost
impossible to advocate a vaccine trial with other than titers as an endpoint
since standard care mandates penicillin and vaccination. Dr. David Briles also
has information on a vaccine.
- Dr. Bonds will contact Dr. Briles regarding a
speaker for the next meeting.
G. Workshops on areas of Depression and the Impact on
Illness, Lifestyle Issues such as jobs and schooling follow-up. Dr.
Bonds
The issue of potential
workshops was discussed in general. The brain has been an area of intense
interest especially amongst pediatricians. The lung seems to be a higher
priority amongst those in adult medicine. A workshop in the area of behavioral
issues would be worthwhile if it were followed by an RFA and action in the
area. It was noted that Dr. Charles Whitten had identified quality of life
issues as representing an understudied area and a great need in the field. The
sense of the committee was that issues of outcome are important to address on
the part of the NHLBI especially in the area of sickle cell disease where few
other agencies or NIH Institutes are available to address these issues.
H. Review the charter of the Committee. Dr.
Bonds
The charter has been approved and it was felt that
further review was not necessary except regarding point B above.
VII. Chairman's Report Dr. William
Mentzer
Dr. Mentzer gave his appreciation to the Committee and
noted his pleasure in having been Chair. He announced that three new members
will be joining the SCDAC: Drs. Marie Stewart, Herbert Meisselman, and Peter
Lane.
VIII. Update on Council of Regional Network (CORN)
Activities Ms. Sonya Ross
The guidelines for newborn screening have been
completed and approved by CORN. The Sickle Cell, Thalassemia and Other
Hemoglobin Variants subcommittee is going to try and stay functioning as a unit
but at present there is no active funding (HRSA funding has expired). Dr. Peter
Lane noted that there are still issues regarding health care delivery: 1.
Access to health care services. 2. Follow up of carriers is still and issue. 3.
Education regarding hemoglobinopathies for primary care providers,
pathologists, and insurance carriers. 4. Discrimination issues in health
insurance remain. 5. What should be done with all the unknown hemoglobin
variants that are picked up. There are 12,444 infants/year with such a variant,
representing a huge number of infants and families that receive no guidance.
Dr. Steinberg noted that Dr. Titus Huisman died this past week and there really
are few good reference laboratories available. Consensus guidelines are also
needed regarding how to approach this problem since even a funded reference
laboratory could handle the volume of 12,000 samples. It was noted that neither
individual states nor the College of American Pathologists has mandatory
standards for hemoglobin screening.
IX. Agency Reports
A. Department of Veterans Affairs Dr. Martin
Steinberg
The VA budget constraints have left a dearth of sickle
cell related programs. The quality of programs have suffered through a lack of
interested investigators.
B. Health Resources and Services Administration
Dr. Marie Mann
Funding for the year includes treatment for
hemophilia. There is no funding category for the regional genetic networks but
4 networks have gotten extensions of funding. All have indicated that they will
seek alternate funding from other sources. Funding initiatives include (1)
newborn screening and resource centers, (2) 5-7 grants that will focus on
health outcomes with genetic conditions including sickle cell anemia and
thalassemia, (3) 10 state planning grants to increase tracking and integration
of genetic conditions at the state level (This initiative should speak to the
issue of diagnosis mentioned above). and (4 ) The Newborn Screening Task Force
has been funded and is working on state policy and development. As noted there
are no standards or planning for incorporation of new technologies. Issues of
parental consent and use of specimens will also be addressed and a document
with the proceedings is scheduled for the end of the year. It is hoped that
this effort will serve as a national framework for such programs in the
individual states. An international conference on Hb E and thalassemia was
funded with input from NHLBI in Oakland in April, 1999. The increasing
prevalence of the condition made the conference timely. A 13 member committee
on genetic testing, counseling, technologies, psychology, and consumer advocacy
was appointed by Dr. Shalala, Director of Health and Human Services.
C. Centers for Disease Control Ms. Barbara
Adam
With the exception of Alabama, most states use dried
blood spots for newborn screening. Alabama uses cord blood. The CDC has a
quality control program for dried blood spots. They have found labs identify
the basic 4 hemoglobins quite well. There are often a number of transcription
errors and the failure to detect variants such as hemoglobin E. The CDC is
attempting to develop a program that speaks to specific state programs that
have a wide range of goals and methods. The CDC is always open to feedback on
how to make these programs more useful to the screening community.
- Ms. Adam will follow-up on the possibility of CDC
coordinating an interagency working group on screening for
hemoglobinopathies.
D. Department of Defense Dr. Scott
Wegner
No representative was available to give a report.
X. Update on Program Activities
A. Current Sickle Cell Disease Scientific Research
Group Clinical Trials and Cohort Studies Dr. Duane Bonds
The CSSCD ended patient data collection April 1, 1999
and papers are being written. The MSH Patient Follow Up will have a third Data
Safety and Monitoring Board (DSMB) meeting August 25, 1999. The Steering
Committee is addressing a number of important issues involving long term
efficacy of the drug. The pediatric hydroxyurea phase II trial (PED HUG) has
been accepted for publication in Blood and Bristol Myers Squibb will proceed
with negotiations with the FDA to permit the drug to be on label for children
ages 5 and above. An initiative for a phase III trial in young children is
tentatively scheduled for June 30 release. Dr. Mann questioned whether
hydroxyurea is being reimbursed for adult patients. Others could not speak to
the issue. One center has to use the generic form of hydroxyurea which in turn
requires more frequent follow up visits. This raised the query as to whether
there will be a pediatric preparation. Dr. Bonds noted that the company is
working on such a preparation. Dr. Steinberg questioned the status of the use
of the drug in HbSC disease.
- A motion was made, seconded and passed that an
initiative should be developed for the use of hydroxyurea SC disease. Dr. Bonds
will send out the previous initiative to interested committee members who can
update it as needed since it is one year old.
B. Genetic Variability Dr. Greg
Evans
The genetic modifiers initiative is now on line to be
presented to The NHLBI Council in the Fall through the Board of External
Advisors.
C. The Role of the PMN in Sickle Cell Disease
Pathology Workshop Dr. Greg Evans
The agenda and abstract books were distributed to the
Committee and the workshop reviewed. On May 28th, the NHLBI
sponsored a workshop on the role of the polymorphonuclear leukocyte in sickle
cell disease pathophysiology. We had 5 speakers from the sickle cell community,
and 3 speakers who do not work in areas directly related to sickle cell
disease. A copy of the abstract book is included in each committee member's
packet.
From the speakers who work in the SC community, we
heard about the clinical correlation, in patients with SCD, between frequency
of pain crises and neutrophil or monocyte count, derived from the MSH Trial and
the Cooperative Study of Sickle Cell Disease. We also heard about clinical
correlations between ACS events and white count, and about clinical evidence
for elevated C-reactive protein, serum amyloid A, IL-6, and TNF-alpha, all
markers of inflammation, in patients with SCD. We heard about clinical evidence
for the activation of neutrophils and monocytes from SCD patients, and the
mechanisms thereof. For neutrophils, changes in surface CD11b and CD16
expression were implicated, while for monocytes, intracellular TNF-alpha and
IL-1-beta were implicated. We heard about evidence that hypoxia-reoxygenation
cycles lead to profound stimulation of white cell adhesion, and of expression
of the endothelial adhesion molecule P-selectin, in an animal model of SCD, but
not in a normal animal. And lastly, we heard about the ability in a cell
culture system of sickle red cells but not normal cells to activate
endothelium, accompanied by upregulation of NF-Kappa-B, tissue factor,
E-selectin, ICAM, VCAM, and neutrophil adhesion.
From the 3 outside speakers, we heard about some of
the mechanisms by which inflammation might act in the context of SCD. We heard
about selectin molecules, which are key players in the first step of
inflammation, namely leukocyte tethering and rolling on vessel walls, leading
to extravasation. We heard about the possibility that fluid shear stress alone
could contribute to the activation of endothelial cells in sickle cell disease.
And finally, we heard an update on some of the promising anti-inflammatory
therapeutics now being developed in settings outside of sickle cell disease.
Firstly, a humanized anti-CD18 antibody, a known blocker of neutrophil adhesion
that is capable of completely blocking reperfusion injury in an animal ear
model, is soon to be tested in a phase I trial in the context of hemorrhagic
shock. And secondly, high concentrations of statins, which are currently in
widespread use for cholesterol control, and thus have a proven safety record,
inhibit leukocyte adhesion by virtue of their inhibition of prenylation of RAS
family GTPases. Trials of statins as anti-inflammatory agents may be coming
soon.
At the end of the day, the hypothesis that emerged was
that possibly SCD can be viewed as a chronic, dysregulated inflammatory
process, initiated by sticky, stiff, oxidizing red blood cells that provoke an
inflammatory response as they obstruct flow. The NHLBI Blood Division staff are
interested in pursuing this topic for an RFA, whose scope, in dealing with
inflammation, would definitely overlap that of the Heart and Lung divisions of
NHLBI. The Committee was invited to provide critical comments. The Committee
was enthusiastic about pursuing an initiative in this area. Such an initiative
is timely if only because of the relationship of mortality to the white blood
count in stroke and coronary artery disease and the issues implicating a
chronic inflammatory state and sickle cell disease. The cause an effect issues
remain a problem worthy of further study.
D. Nutrition Workshop Dr. Charles
Peterson
A report on this workshop will be available in the
coming months along with recommendations of the workshop regarding initiatives.
Highlights from the meeting included reports from several investigators that
resting energy expenditure is elevated in persons with sickle cell disease.
Establishment of eucaloric balance is often difficult and patients with the
disease compensate by decreasing activity. A number of nutritional approaches
were noted to have promise for the patient with sickle cell disease and to
warrant further study including magnesium, zinc, antioxidant nutrients, n-3
fatty acids, L-glutamine, and folate. There was a high level of enthusiasm for
continuing nutritional research in sickle cell disease.
E. Parvovirus Trials Dr. Duane
Bonds
It is hoped that a protocol will be developed for this
study in the Comprehensive Sickle Cell Centers in the next several months.
XI. Areas of Program Needs and Opportunities
Drs. Bonds, Evans, Peterson
The Committee was reminded that the Workshop on
Developing Therapeutics for Rare Blood Diseases is to be held July 14, 1999 at
Lister Hill Auditorium. The problem of pursuing phase I and II trials in Sickle
Cell Disease was raised by the committee. Potential liaisons with The General
Clinical Research Center (GCRC) system to conduct these types of trials in the
areas of nonmalignant hematology was suggested as one potential approach to the
problem. International collaborations perhaps with the aid of the Fogarty
Center was also raised as a potential approach.
- Staff will follow up on the potential for working
with both the GCRCs and the Fogarty Center.
XII. Other
Dr. Mentzer raised the issue that the committee may
wish to function between the two annual convened meetings in Bethesda. It was
suggested that certain issues might be addressed through e-mail or by certain
members functioning as ad hoc subcommittees who could then bring issues to the
full committee. The members of the Committee would like to be notified directly
regarding upcoming workshops.
XIII. Future Agenda Items
- It was suggested that the mechanism of performing
phase I, II, and III clinical trials should remain on the agenda for the
subsequent meetings.
- The laboratory quality assurance issues for
diagnosis of hemoglobinopathies was identified as an important one and also
needs to remain on the agenda while in search of a solution.
XIV. Future Meeting Dates
November 15, 1999 June 5, 2000 November 10,
2000
XV. The meeting was adjourned at 2:55 P.M.
XVI. Summary of Action Points
- 1. How can we improve the NHLBI book: Management
and Therapy of Sickle Cell Disease? Each committee member was encouraged to
read and comment on the book. Dr. Lane will also submit suggestions for the
book.
- Dr. Steinberg recommended that we invite John Kark
to talk about the issues of HbAS in the military. Dr. Alving volunteered to
contact Dr. Kark. A member from the Department of Defense will be encouraged to
come to the meeting and be prepared to respond to the issue
- It was suggested to include as an ad hoc member
Janet Frempong ( a parent of a child with sickle cell disease). The question
remains how to formalize the process of increasing this type of input to the
Sickle Cell Disease Advisory Committee. The process of choosing such a person
could be as important as a given individual who might be chosen at any one
time. It was moved that we have a member of the Sickle Cell Disease Advisory
Committee who is either a parent of a patient or a patient with sickle cell
disease. It was so seconded and approved unanimously. This action can be made
by the Sickle Cell Disease Advisory Committee on an ad hoc basis and
implemented at the next round of membership recruitment. Mrs. Frempong will be
invited to the next meeting. Staff will look into whether the charter can be
modified to accommodate an additional member or whether the goal should be
accomplished within the current structure.
- NHLBI staff will maintain contact with Dr. Mann in
budgeting for the working committee for the revise NHLBI handbook keeping in
mind ways in which we might work together.
- Dr. Bridges and Dr. Swerdlow will be bringing a
draft lung initiative forward to the Sickle Cell Disease Advisory Committee at
the next meeting.
- It was suggested that a workshop on nitric oxide be
scheduled for the next year.
- Dr. Bonds will arrange for a speaker on conjugate
pneumococcal vaccines for the next meeting.
- A motion was made, seconded and passed that an
initiative be developed for the use of hydroxyurea in SC disease. Dr. Bonds
will send out the previous initiative to interested committee members
- It was suggested that the mechanism of performing
phase I, II, and III clinical trials should remain on the agenda for the
subsequent meetings.
- Ms. Adam will follow-up on the possibility of CDC
coordinating an interagency working group on screening for
hemoglobinopathies.
- Staff will follow up on the potential for working
with both the GCRCs and the Fogarty Center.
- The laboratory quality assurance issues for
diagnosis of hemoglobinopathies was identified as an important one and also
needs to remain on the agenda while in search of a solution.
I hereby certify that to the best of our knowledge,
the foregoing minutes are accurate and complete.
William C. Mentzer, M.D. Chairman
Sickle Cell Disease Advisory Committee
Charles M. Peterson, M.D. Executive Secretary
Sickle Cell Disease Advisory Committee
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