MINUTES OF THE NINETIETH MEETING OF THE SICKLE CELL DISEASE ADVISORY COMMITTEE

Bethesda, Maryland

June 5, 2006


COMMITTEE MEMBERS PRESENT

Dr. Ted Wun, University of California Davis, Dr. F. Daniel Armstrong, University of Miami, Dr. Paul Frenette, Mount Sinai School of Medicine, New York, Dr. Frans Kuypers, Children’s Hospital of Oakland Research Institute, Dr. Eugene Orringer, University of North Carolina at Chapel Hill, Dr. Russell Ware, St. Jude Children’s Research Institute, Memphis, Dr. Shirley Miller, Southwestern Comprehensive Sickle Cell Center, Dallas.

COMMITTEE MEMBERS ABSENT

Dr. Michael DeBaun, Washington University, St. Louis, Dr. Johnson Haynes, University of South Alabama, Mobile, Dr. Dorothy Moore, Sickle Cell Disease Association of America, Dr. Marie Mann, Health Resources and Services Administration, Dr. Joseph DeSimone, Veteran’s Administration, Chicago.

EX OFFICIO MEMBERS ABSENT:

Dr. Robert Sheffler, Trippler Army Medical Center, Washington DC and Dr. William H. Hannon, Centers for Disease Control, Atlanta

PROGRAM STAFF AND AFFILIATED ORGANIZATION REPRESENTATIVES:

Dr. Susan Shurin, Deputy Director of NHLBI, Dr. Charles Peterson, Director of DBDR, Dr. Greg Evans, Hemoglobin-opathies SRG leader for DBDR, Dr. Ellen Werner, DBDR, Dr. Pankaj Qasba, Dr. Katherine Hassell, University of Colorado (IPA with NHLBI), DBDR, Ms. Michelle MacDonald, Committee Management, Division of Extramural Affairs, NHLBI, Dr. Terry Bishop, NIDDK, Dr. William P. Winter, Howard University, Dr. Oswaldo Castro, Howard University, Dr. Willarda Edwards, President and CEO, Sickle Cell Disease Association of America, Baltimore.

Executive Secretary: Dr. Blaine Moore with the assistance of Ms. Petronella Barrow.

Dr. Blaine Moore called the meeting to order at 8:40 am, welcomed everyone to the meeting and provided brief opening remarks regarding the agenda. Dr. Moore then introduced Dr. Susan Shurin, who also welcomed members and remarked how much NHLBI appreciated their advice in the direction of sickle cell programs within the institute. Dr. Peterson stated that he would reserve his comments for later in the agenda. Dr. Moore turned the meeting over to Dr. Wun, the chair of the committee.

Dr. Wun requested an approval to the minutes. Some members indicated that they needed more time to look the minutes over and it was decided to postpone approval until later in the agenda. Dr. Wun invited Dr. Pankaj Qasba to introduce the two speakers for the morning, Dr. Arthur Nienhuis from St. Jude Children’s Research Hospital in Memphis and Dr. Philippe Leboulch from Brigham and Women’s Hospital in Boston.

  • Dr. Nienhuis: Future of Gene Therapy for the Hemoglobinopathies. The concept of affecting stem cells to illicit a change in red cells has been around form 15 to 20 years. Gene therapy has also seen some successes in the areas of severe combined immunodeficiency (SCID) and chronic granulomatous disease. Some of the challenges which have faced gene therapy in the hemo-globinopathies are low transduction of the stem cells, robust and sustained gene expression within the transduced cells, stability of the vector and safety of the vector. The introduction of animal models in sickle cell disease and thalassemia plus the development of lentiviral vectors have improved the advancement of gene therapy in this field. Currently there have been several successes in the treatment of mice with sickle cell disease or thalassemia using current vectors. Concerns have been raised from other human trials that vectors can integrate randomly in the genome and often close to oncogenes which have the potential of causing leukemogenesis. To reduce or eliminate this possibility new vectors have been modified to have chromatin insulator components that significantly lessen the effects of surrounding genes on the vector and vice versa. Dr. Nienhuis stressed that it is important over the next 5 to 10 years for NHLBI to continue to support the basic, translation and clinical research that will take place to bring this therapy to a reality.
  • Dr. Philippe Leboulch: A Phase I/II Clinical Trial for the Gene herapy of the Beta-Hemo-globinopathies by Lentiviral Vector: Pre-clinical Validation, Trial Design and Prospects.
    Allogeneic sibling-HLA matched bone marrow transplants have been shown to be curative for subjects with sickle cell disease and thalassemia. Unfortunately, less than 10% of subjects are eligible for this procedure and those that do run a 10-15% risk of death and/or morbidity. Gene therapy offers the promise of curative therapy form almost all subjects without the side effect of GVHD because the transplants are autologous. Appropriate vectors containing the globin gene, promoter and LCR components have been constructed and proven effective in animal models. However, there are still concerns over safety of the viral vectors and specific modifications have been made now to reduce the chances of possible adverse and serious adverse events. The first human gene therapy trials for thalassemia and sickle cell disease are scheduled for this summer. At present a few patients with thalassemia and with sickle cell disease have been selected and had their bone marrow cells isolated and CD34+ cells transduced with the lentiviral vector containing the appropriate globin gene. At present the transduced cells are frozen and samples undergoing a battery of analyses to assess their therapeutic use. Re-introduction of the transduced cells is expected in July or August depending on the outcome of the analyses. Dr. Leboulch reiterated that NHLBI needs to continue support of gene therapy research during this time of clinical development.

Questions and Answers

What is the possibility of clonal dominance following transplant? Yes, clonal dominance is possible and there is evidence of this happening in the CGD patients that have been transplanted. This can be good and bad. In one patient the number of transduced cells in situ was initially 20% but eventually became 60% when a dominant clone persisted. However, the dominant clone had low expression of the gene so this was dis-advantageous.

You are using HbSS patients (i.e. homozygous for the gene). Have you considered further genotyping to select certain haplotypes? There was a consideration of selecting sickle cell patients of North African genotype but this has not been done to date.

Cells can now be mobilized without G-CSF. Has this been considered as a mechanism to obtain stem cells? Yes this is possible but the yield of stem cells is lower and it becomes more difficult to obtain sufficient numbers for the procedure.

Do you need "myeloablation?” While there is no great evidence to indicate that this is necessary, it is generally believed to be beneficial.

Why was France selected as the site for these initial gene therapy trials? We had considered beginning these trials in the United States, however the regulations through the RAC, FDA and IRBs are complex and restrictive and would delay the implementation of these trials. The French authorities were supportive of these trials. It is recognized that NIH can not provide the ultimate funding for gene therapy and that industry and venture capitalists will be needed. It is expected that this will happen following the proof of principle, i.e. initial patient success.

Chairman’s Report

Dr. Wun lauded the efforts of the Adult Providers Network that is currently in development and the role Dr. Kathy Hassell in bringing this to a reality in the near future.

Dr. Wun also thanked everyone for allowing him to serve as the Chair of the committee over the last three years. He considered it a very valuable experience.

Agency Reports

Due to the absence of Drs. Mann (HRSA), Sheffler (DOD) and DeSimone (VA) these reports were skipped.

DBDR Director’s Report

Dr. Peterson recognized the efforts of Drs. Wun, Ware and Frenette who have served their four year term and would be leaving the committee after this meeting. An NHLBI certificate of recognition plus a personal letter from Dr. Nabel, the institute director was presented to each of them.

Dr. Peterson announced that the Blood Division had now moved to provide swing space for the renovations that are taking place in Rockledge 2. It is expected that the division will remain at 6700A Rocklege Dr. for approximately 2 years until all of the renovations are complete and at that time move back to the 8th floor in Rockledge 2.

He discussed the Strategic Planning Program that was underway in NHLBI. Currently Level 1 Strategic Planning Meetings were taking place to be completed by the end of the summer. Overall there will be 23 such level 1 meetings addressing areas in Heart, Lung, Blood and Sleep. The Blood Division will have 5 of these meetings – 3 of them have already taken place. When the Level 1 reports are complete they will be made available to the scientific community. Level 2 meetings consisting of the two co-chairs from each of the 23 Level 1 meetings will take place in October of 2006.

Update on Program Activities

The Comprehensive Sickle Cell Centers

Dr. Evans stated that the Centers Program was mandated by congress and came into being in 1972. In recent years it has been revised to incorporate a clinical trials component to address Phase I/II studies. At present there are a number of single center and multi-center studies underway. Studies that are scheduled to get underway include the hydroxyurea + magnesium pidolate study for Hb SC patients and the use of dexamethasone in Acute Chest Syndrome (pending final approval of the DSMB). Other studies in the pipeline are: the decitabine trial and the Genotype/Phenotype study which are currently going through DSMB review this month. At present we are in year 4 of 5 for the current cycle and the RFA for the next cycle is expected to be out soon. The new receipt date for application will be January 23, 2007.

Sickle Cell Disease Clinical Research Network

In Dr. Luksenburg’s absence, Dr. Moore presented the report to the Advisory Committee. Currently there are 8 centers awarded in the network. These centers have had their first in-person meeting, presented their protocols and developed a priority for them. Dr. Lane has been elected as the Chair of the Steering Committee and Dr. Ohene Frempong will be his co-chair. Several members voiced their concern regarding the limited selection of centers (8) when up to15 were originally anticipated for funding in the RFA. They felt that this might seriously jeopardize the success of the network in securing sufficient patients for phase III clinical trials. It was explained that there were additional funds available to identify satellite centers to enroll the patients needed. There was further concern expressed about the incentive for satellite centers to participate when they have little input into the study and are only enrolling patients.

Health Related Quality of Life Contract

Dr. Werner explained that this contract was established to develop and validate a health related quality of life instrument dedicated to adult patients with sickle cell disease. The awarded offeror was the American Institute of Research, the principal investigator being Dr. San Kellor. She was pleased to announce that the progress of the contract was ahead of schedule. She thanked the support of the Sickle Cell Disease Association of America in supporting this work and helping in providing sickle cell subjects who can be of assistance in developing and validating the instrument. She mentioned that a request to the Center for Minority Health has been sent for additional funds to complete a second instrument that will focus on pediatric patients with sickle cell disease.

Dr. Armstrong suggested that in addition to a 7-17 pediatric age group, a 3-7 age group be looked at as well. He felt this was important in light of the fact that major organ damage begins at this early age.

Dr. Castro indicated that the MSH study used the SF32 forms and wondered if the data were still available. Perhaps they could be compared to the new instrument. Dr. Werner replied that the SF32 QOL form is some what generic and used for patients who have many different diseases or disorders.

Patient Outcomes Cores for SCD-CRN

Dr. Werner announced that two Patient Outcomes Cores were awarded – one to Dr. Wally Smith at Virginia Commonwealth University and one to Kevin Schulman and Marilyn Telen at Duke University. There have been discussions about health services research for sickle cell disease and that it can be considered a paradigm.

Adult Providers Network

Dr. Kathy Hassell from the University of Colorado along with Dr. James Eckman at Emory University and Ted Wun at UC Davis are developing a network of adult hematologists with experience in treating sickle cell patients to provide information and guidelines in therapeutic management of adults with this disease. A group of physicians met in Memphis in April at the National Sickle Cell Meeting to discuss the development of this group and another meeting is being planned in Dallas just prior to the SCDAA meeting.

Dr. Miller impressed the importance of physicians listening to their patients many of whom attend the National Sickle Cell Meeting.

Dr. Armstrong emphasized the importance of addressing the transition of patients from the pediatric clinic to the adult clinic. Also, guidelines for the management of adult patients need to be developed since they will probably be different from pediatric guidelines.

Kathy Hassell also indicated the valuable relationship that they have made with Dr. Know Todd, an emergency room physician. He represents a large consortium of ER physicians from around the country who are taking an interest in the proper management of sickle cell patients for pain and other symptoms. Dr. Todd has invited some of the adult hematologists to attend the meeting of emergency room physicians.

SWiTCH Clinical Trial

Stroke with Transfusion Change to Hydroxyurea (SWiTCH) is a clinical trial to assess whether sickle cell patients who have had a history of stroke and are currently on chronic transfusion therapy can by switched to hydroxyurea treatment plus phlebotomy (when needed). The Principal Investigator for the trial is Dr. Russell Ware and the Medical Coordinating Center is headed by Dr. Ronald Helms. The multi-center trial will include about 21 sites. In addition there are external consultants, including Dr. Robert Adams of the Medical College of Georgia who directed the STOP and STOPII trials. Finally there are several core laboratories that will be providing specialized tests for the trial. The protocol has been approved by the DSMB and representatives from all the centers met in Memphis in April, 2006 during the National Sickle Cell Centers Meeting. They will meet again in August during the annual Clinical Centers Meeting for SCD. The various sites are currently seeking IRB approvals and it is hoped that patient enrollment can begin in the near future. The trial is designed to have 130 patients, 65 in each arm.

Will this be a superiority or equivalence designed trial? Actually the trial is somewhat complex because of the endpoints, namely, stroke recurrence and improvement in iron overload.

Will there be interim analyses to assess stroke recurrence rate in the two arms? Well, not interim analyses but we have stopping rules in place to determine if stroke recurrence may be occurring in one arm or the other.

MSH Follow-up Extension

Dr. Moore explained that the MSH trial was the first study to treat adult sickle cell patients with hydroxyurea. The trial took place between 1991 and 1995 and was stopped early because of significant effect. Between 1997 and 2002 a contract was awarded to conduct a follow-up of the patients on the trial to assess potential long term benefits and to identify any possible long term serious adverse events, particularly cancer. From 2002 to the present the contract was re-awarded as an extension to the original follow-up. Currently the follow-up is in year 9 of the proposed 10 years with an expected termination date of December 2007.

During the last two years there have been concerns from the contracting office and the data and safety monitoring board that patient follow-up has been lagging and that data coming in to the coordinating center is below expected. This is due in part to deaths of patients in the study, patients lost to follow-up and sites having difficulties getting IRB approval and sites that are no longer seeing patients due to lost interest. Dr. Moore explained that the MSH follow-up investigators along with the data coordinating center met in Memphis at the National Sickle Cell Meetings. The sites were well represented and there was an interest for the group to reactivate their efforts to complete the data in the contract. A major interest of the group was to formalize the publications committee and develop writing groups for the manuscripts of interest.

Pulmonary Complications of Sickle Cell Disease

Dr. Greg Evans stated that there were five centers awarded under this RFA investigating different areas of pulmonary complications of Sickle Cell Disease. Dr. Ohene-Frempong at the Children’s Hospital of Philadelphia will be studying the significance of oxyhemo-globin desaturation in pulmonary complications and vasculopathy. Dr. Victor Gordeuk from Howard University will determine the prevalence and risk factors of pulmonary hypertension in children and adolescents with sickle cell disease. Dr. Marilyn Telen at Duke University will investigate the natural history of pulmonary hypertension in SCD and conduct a randomized trial of bosentan to treat this condition. Dr. Punam Malik of the Children’s Hospital of Los Angeles will address the role of Placenta Growth Factor in Sickle Cell Acute Chest Syndrome. Finally Dr. Michael DeBaun at Washington University in St. Louis will elucidate the physiologic, genetic and molecular aspects of asthma and nocturnal oxygen desaturation in sickle cell patients and determine if there are any relations to pain episodes. A DSMB has been established for initial approval and monitoring of these protocols. At present 3 of the 5 sites have protocols that have been approved and 2 are resubmitting.

Open Discussion and Advice to the National Heart, Lung and Blood Institute

  • The Sickle Cell Disease Advisory Committee supports the strategic planning process currently underway within NHLBI and looks forward to the initial reports of these meetings in the Fall.
  • Concerns were raised that the recently funded Sickle Cell Disease Clinical Research Network will have insufficient numbers of patients with only 8 sites rather than the 15 sites originally planned.
  • Clinical studies should be designed to have well planned long-term follow-up components
  • It was suggested that there be coordination between the Comprehensive Sickle Cell Centers and the Sickle Cell Disease Clinical Research Network such that promising Phase I/II therapies developed by the centers can be further studied by the network.
  • The transition of clinical care for sickle cell patients moving from the pediatric service to adult service is a current concern within the United States and should be addressed.
  • Effectiveness and Implementation research needs to be conducted to assure that current guidelines for standard of care are used. This particularly important in light of the creation of clinical care centers through HRSA and mandated by the Talent Bill.
  • The SCDAC would like to encourage NHLBI to continue supporting Gene Therapy Research for hemoglobinopathies since this carries the promise of an eventual cure for patients with sickle cell disease.
  • Information regarding the new RAID program (Rapid Access for Interventional Development) was discussed. It was hoped that antibodies or gene vectors may be included in this program in the near future.

___________________________                                    _____________
Theodore Wun, M.D.                                                         Date
Chairman
Sickle Cell Disease Advisory Committee

___________________________                                     ______________
R. Blaine Moore Ph.D.                                                        Date
Executive Secretary
Sickle Cell Disease Advisory Committee
 

Last updated: October 28, 2007

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