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:

1. 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.
2. 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.
3. 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 28^th, 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