National Heart, Lung, and Blood Institute, NIH
Office of Medical
Applications of Research, NIH
National Human Genome Research Institute, NIH
National Institute of
Child Health and Human Development, NIH
National Institute of Diabetes and
Digestive and Kidney Diseases, NIH
National Institute of Neurological
Disorders and Stroke, NIH
Office of Rare Diseases, NIH
Centers for Disease Control and Prevention
Health Resources and
Services Administration
The Agency for Healthcare Research and Quality
provided additional support to the conference development.
About the Program
General
Information
Background
Agenda
Panel Members
Speakers
Planning
Committee
Abstracts
What Is the Efficacy (Results From Clinical Studies) of Hydroxyurea Treatment for Patients Who Have Sickle Cell Disease in Three Groups: Infants, Preadolescents, and Adolescents/Adults?
What Is the Effectiveness (in Everyday Practice) of Hydroxyurea Treatment for Patients Who Have Sickle Cell Disease?
What Are the Short- and Long-Term Harms of Hydroxyurea Treatment?
What Are the Barriers to Hydroxyurea Treatment for Patients Who Have Sickle Cell Disease, and What Are the Potential Solutions?
The National Institutes of Health (NIH) Consensus Development Program has been organizing major conferences since 1977. The Program generates evidence-based consensus statements addressing controversial issues important to healthcare providers, policymakers, patients, researchers, and the general public. The NIH Consensus Development Program holds an average of three conferences a year. The Program is administered by the Office of Medical Applications of Research within the NIH Office of the Director. Typically, the conferences have one major NIH Institute or Center sponsor, with multiple cosponsoring agencies.
NIH Consensus Development and State-of-the-Science Conference topics must satisfy the following criteria:
Two types of conferences fall under the purview of the NIH Consensus Development Program: State-of-the-Science Conferences and Consensus Development Conferences. Both conference types utilize the same structure and methodology; they differ only in the strength of the evidence surrounding the topic under consideration. When it appears that there is very strong evidence about a particular medical topic, but that the information is not in widespread clinical practice, a Consensus Development Conference is typically chosen to consolidate, solidify, and broadly disseminate strong evidence-based recommendations for general practice. Conversely, when the available evidence is weak or contradictory, or when a common practice is not supported by high-quality evidence, the State-of-the-Science label is chosen. This highlights what evidence about a topic is available, the directions future research should take, and alerts physicians that certain practices are not supported by good data.
Before the conference, a systematic evidence review on the chosen topic is performed by one of the Agency for Healthcare Research and Quality’s Evidence-Based Practice Centers. This report is provided to the panel members approximately 6 weeks prior to the conference, and posted to the Consensus Development Program Web site once the conference begins, to serve as a foundation of high-quality evidence upon which the conference will build.
The conferences are held over 2 ½ days. The first day and a half of the conference consist of plenary sessions in which invited expert speakers present information, followed by “town hall forums,” in which open discussion occurs among the speakers, panelists, and the general public in attendance. The panel then develops its draft statement on the afternoon and evening of the second day, and presents it on the morning of the third day for audience commentary. The panel considers these comments in executive session and may revise their draft accordingly. The conference ends with a press briefing, during which reporters are invited to question the panelists about their findings.
Each conference panel comprises 12–16 members who can give balanced, objective, and informed attention to the topic. Panel members:
In addition, the panel as a whole should appropriately reflect racial and ethnic diversity. Panel members are not paid a fee or honorarium for their efforts. They are, however, reimbursed for travel expenses related to their participation in the conference.
The conferences typically feature approximately 21 speakers; 3 present the information found in the Evidence-Based Practice Center’s systematic review of the literature. The other 18 are experts in the topic at hand, have likely published on the topic, and may have strong opinions or beliefs. Where multiple viewpoints on a topic exist, every effort is made to include speakers who address all sides of the issue.
The panel’s draft report is released online late in the conference’s third and final day. The final report is released approximately 6 weeks later. During the intervening period, the panel may edit their statement for clarity and correct any factual errors that might be discovered. No substantive changes to the panel’s findings are made during this period.
Each Consensus Development or State-of-the-Science Conference Statement reflects an independent panel’s assessment of the medical knowledge available at the time the statement was written; as such, it provides a “snapshot in time” of the state of knowledge on the conference topic. It is not a policy statement of the NIH or the Federal Government.
Consensus Development and State-of-the-Science Conference Statements have robust dissemination:
The conference statement is published in a major peer-reviewed journal.
For conference schedules, past statements, and evidence reports, please
contact us:
NIH Consensus Development Program
Information Center
P.O. Box 2577
Kensington, MD 20891
1-888-NIH-CONSENSUS
(888-644-2667)
http://consensus.nih.gov
The National Institutes of Health/Foundation for Advanced Education in the Sciences (NIH/FAES) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
The NIH/FAES designates this educational activity for a maximum of 13.00 AMA PRA Category 1 Credits.™ Physicians should claim only credit that is commensurate with the extent of their participation in the activity.
Your participant packet includes a CME evaluation form, which should be completed and returned either to the conference registration desk or by mail to claim credits.
Each speaker presenting at this conference has been asked to disclose any financial interests or other relationships pertaining to this subject area. Please refer to the material in your participant packet for details.
Panel members signed a confirmation that they have no financial or other conflicts of interest pertaining to the topic under consideration.
Live and archived videocasts may be accessed at http://videocast.nih.gov. Archived videocast will be available approximately 1 week after the conference.
The dining center in the Natcher Conference Center is located on the main level, one floor above the auditorium. It is open from 6:30 a.m. to 2:30 p.m., serving hot breakfast and lunch, sandwiches and salads, and snack items. An additional cafeteria is available from 7:00 a.m. to 3:30 p.m., in Building 38A, level B1, across the street from the main entrance to the Natcher Conference Center.
The telephone number for the message center at the Natcher Conference Center is 301–594–7302.
All materials emanating from the NIH Consensus Development Program are available at http://consensus.nih.gov.
Sickle cell disease is an inherited blood disorder that affects between 50,000 and 75,000 people in the United States, and is most common among people whose ancestors come from sub Saharan Africa, South and Central America, the Middle East, India, and the Mediterranean basin. Sickle cell disease occurs when an infant inherits the gene for sickle hemoglobin from both parents (Hb SS, or sickle cell anemia), or the gene for sickle hemoglobin from one parent and another abnormal hemoglobin gene from the other parent. Each year, approximately 2,000 babies with sickle cell disease are born in the United States. The condition is chronic and lifelong, and it is associated with a decreased lifespan. In addition, approximately 2 million Americans carry the sickle cell trait, which increases the public health burden as this disorder is passed on to future generations.
The red blood cells in people with sickle cell disease become deoxygenated (or depleted of oxygen) and crescent-shaped or “sickled.” The cells become sticky and adhere to blood vessel walls, thereby blocking blood flow within limbs and organs. These changes lead to acute painful episodes, chronic pain, and chronic damage to the brain, heart, lungs, kidneys, liver, and spleen. Infections and lung disease are leading causes of death.
Pain crises are responsible for most emergency room visits and hospitalizations of people with sickle cell disease. Standard treatments for acute pain crises include painkilling medications, fluid replacement, and oxygen. In the mid-1990s, researchers began investigating the potential of hydroxyurea to reduce the number and severity of pain crises in sickle cell patients. Hydroxyurea is in a class of anti-cancer drugs, and it acts to increase the overall percentage of normally structured red blood cells in the circulation. By diluting the number of cells that “sickle,” it may, if taken on a daily basis, reduce their damaging effects. Hydroxyurea was approved by the U.S. Food and Drug Administration for use in adults with sickle cell anemia in 1998. However, there are a number of unresolved issues about the use of hydroxyurea, including a lack of knowledgeable providers who treat sickle cell disease, and patient and practitioner questions about safety and effectiveness, including concerns regarding potential long-term carcinogenesis.
To take a closer look at this important topic, the National Heart, Lung, and Blood Institute and the Office of Medical Applications of Research of the National Institutes of Health convened a Consensus Development Conference from February 25–27, 2008, to assess the available scientific evidence related to the following questions:
|
8:30 a.m. |
Opening Remarks |
|
8:40 a.m. |
Charge to the Panel |
|
9:00 a.m. |
Sickle Cell Anemia: Yesterday, Today, and Tomorrow |
|
9:20 a.m. |
Sickle Cell Disease: The Consumer’s Perspective
|
|
What Is the Efficacy (Results From Clinical Studies) of Hydroxyurea Treatment for Patients Who Have Sickle Cell Disease in Three Groups: Infants, Preadolescents, and Adolescents/Adults? |
|
|
9:40 a.m. |
Evidence-Based Practice Center Presentation I: The Efficacy and
Effectiveness of Hydroxyurea Treatment for Patients Who Have Sickle Cell
Disease |
|
10:00 a.m. |
The Laboratory Evidence of Efficacy of Hydroxyurea in the
Treatment of Sickle Cell Disease |
|
10:20 a.m. |
Summary of the Evidence Regarding Efficacy of Hydroxyurea
Treatment for Sickle Cell Disease in Adults |
|
10:40 a.m. |
Summary of the Evidence Regarding Efficacy of Hydroxyurea
Treatment for Sickle Cell Disease in Children and Adolescents |
|
11:00 a.m. |
Discussion Participants with questions or comments for the speakers should proceed to the microphones and wait to be recognized by the panel chair. Please state your name and affiliation. Questions and comments not heard before the close of the discussion period may be submitted on the computers in the registration area. Please be aware that all statements made at the microphone or submitted later are in the public domain. |
|
Noon |
Lunch |
|
What Is the Effectiveness (in Everyday Practice) of Hydroxyurea Treatment for Patients Who Have Sickle Cell Disease? |
|
|
1:00 p.m. |
Practical Treatment Considerations for Hydroxyurea in Pediatric
and Adult Patients With Sickle Cell Disease, Including Maximum Tolerated Dose,
Labeling of Responders Versus Nonresponders, and Adherence to Therapy
|
|
1:20 p.m. |
Summary of the Evidence Regarding Effectiveness of Hydroxyurea in
the Treatment of Sickle Cell Disease in the Pediatric Population |
|
1:40 p.m. |
Summary of the Evidence Regarding Effectiveness of Hydroxyurea in
the Treatment of Sickle Cell Disease in the Adult Population |
|
2:00 p.m. |
Discussion |
|
What Are the Short– and Long–Term Harms of Hydroxyurea Treatment? |
|
|
2:30 p.m. |
Evidence-Based Practice Center Presentation II: A Systematic
Review of Safety and Harm Associated With Hydroxyurea for the Treatment of
Sickle Cell Disease |
|
2:50 p.m. |
Reproductive and Developmental Effects of Hydroxyurea
|
|
3:10 p.m. |
Adverse Effects of Hydroxyurea From Clinical Studies |
|
3:30 p.m. |
Discussion |
|
What Are the Barriers to Hydroxyurea Treatment for Patients Who Have Sickle Cell Disease, and What Are the Potential Solutions? |
|
|
4:00 p.m. |
Evidence-Based Practice Center Presentation III: Appropriate Use
of Therapies Among Patients With Sickle Cell Disease: A Systematic Review of
Barriers and Interventions To Improve Quality |
|
4:20 p.m. |
Barriers for Pediatric Patients: The Healthcare Providers’
Perspective |
|
4:40 p.m. |
Barriers for Pediatric Patients: The Consumer’s Perspective
|
|
5:00 p.m. |
Discussion |
|
5:30 p.m. |
Adjournment |
|
What Are the Barriers to Hydroxyurea Treatment for Patients Who Have Sickle Cell Disease, and What Are the Potential Solutions? |
|
|
8:30 a.m. |
Barriers for Adult Patients: The Physician’s Perspective
|
|
8:50 a.m. |
Barriers for Adults: The Consumer’s Perspective
|
|
9:10 a.m. |
The Medical Home Model |
|
9:30 a.m. |
Models of Comprehensive Care |
|
9:50 a.m. |
Discussion |
|
10:30 a.m. |
What Do Physicians, Insurers, and Consumers Need To Know About
Hydroxyurea for Appropriate Utilization? The Pediatrician’s Perspective
|
|
10:50 a.m. |
What Do Physicians, Insurers, and Consumers Need To Know About
Hydroxyurea for Appropriate Utilization? The Adult Provider’s Perspective
|
|
11:10 a.m. |
What Do Physicians, Insurers, and Consumers Need To Know About
Hydroxyurea for Appropriate Utilization? The Consumer’s Perspective
|
|
11:30 a.m. |
Discussion |
|
Noon |
Adjournment |
|
9:00 a.m. |
Presentation of the draft Consensus Statement |
|
9:30 a.m. |
Public Discussion The panel chair will call for questions and comments from the audience on the draft statement, beginning with the introduction and continuing through each subsequent section in turn. Please confine your comments to the section under discussion. The chair will use discretion in proceeding to subsequent sections so that comments on the entire statement may be heard during the time allotted. Comments cannot be accepted after 11:30 a.m. |
|
11:00 a.m. |
Panel Meets in Executive Session Panel meets in executive session to review public comments. Conference participants are welcome to return to the main auditorium to attend the press conference at 2:00 p.m.; however, only members of the media are permitted to ask questions during the press conference. |
|
2:00 p.m. |
Press Conference |
|
3:00 p.m. |
Adjournment |
The panel’s draft statement will be posted to http://consensus.nih.gov as soon as possible after the close of proceedings, and the final statement will be posted 4 to 6 weeks later.
Panel Chair: Otis W. Brawley, M.D.
Panel and
Conference Chairperson
Professor of Hematology, Oncology, Medicine, and
Epidemiology
Emory University
Chief Medical Officer
American Cancer
Society
Atlanta, Georgia
Llewellyn J. Cornelius, Ph.D., L.C.S.W.
Professor
University of Maryland School of Social Work
Baltimore, Maryland
Linda R. Edwards, M.D.
Division Chief and Associate
Professor
Division of General Internal Medicine
College of Medicine
University of Florida, Jacksonville
Jacksonville, Florida
Vanessa Northington Gamble, M.D., Ph.D.
University
Professor of Medical Humanities
The George Washington University
Washington, DC
Bettye L. Green, R.N.
Saint Joseph Regional Medical
Center,
Community Outreach/IRB
President Emeritus
African-American
Women in Touch
South Bend, Indiana
Charles Inturrisi, Ph.D.
Professor of Pharmacology
Weill Medical College of Cornell University
New York, New York
Andra H. James, M.D., M.P.H.
Director
Women’s Hemostasis and Thrombosis Clinic
Assistant Professor of
Obstetrics and Gynecology
Duke University Medical Center
Durham, North
Carolina
Danielle Laraque, M.D.
Debra and Leon Black
Professor of Pediatrics
Chief, Division of General Pediatrics
Mount
Sinai School of Medicine
New York, New York
Magda Mendez, M.D.
Assistant Professor of Clinical
Pediatrics
Weill Medical College of Cornell University
Associate
Program Director
Lincoln Medical and Mental Health Center
Bronx, New
York
Carolyn J. Montoya, R.N., M.S.N., C.P.N.P.
President
National Association of Pediatric Nurse Practitioners
Coordinator, Family Nurse Practitioner Concentration
Pediatric Nurse
Practitioner Concentration
College of Nursing
University of New Mexico
Albuquerque, New Mexico
Brad H. Pollock, M.P.H., Ph.D.
Professor and
Chairman
Department of Epidemiology and Biostatistics
School of
Medicine
University of Texas Health Science Center at San Antonio
San
Antonio, Texas
Lawrence Robinson, M.D., M.P.H.
Deputy Health
Commissioner
Philadelphia Department of Public Health
Philadelphia,
Pennsylvania
Aaron P. Scholnik, M.D., F.A.C.P.
Upper Peninsula
Hematology/
Oncology Associates
Director, Cancer Research Office
Marquette General Health System
Marquette, Michigan
Melissa Schori, M.D., M.B.A., F.A.C.P.
Senior Vice
President
Chief Medical Officer
Princeton Healthcare System
Princeton, New Jersey
Kenneth I. Ataga, M.D.
Assistant Professor of
Medicine
Division of Hematology/Oncology
Department of Medicine
School of Medicine
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Mary Catherine Beach, M.D., M.P.H.
Assistant
Professor of Medicine and Health Policy and Management
Division of General
Internal Medicine
School of Medicine
The Johns Hopkins University
Baltimore, Maryland
Melissa S. Creary, M.P.H.
Associate Service Fellow
Division of Blood Disorders
National Center on Birth Defects and
Developmental Disabilities
Centers for Disease Control and Prevention
Atlanta, Georgia
Michael R. DeBaun, M.D., M.P.H.
Professor of
Pediatrics, Biostatistics, and Neurology
Director, Sickle Cell Medical
Treatment and Education Center
Washington University School of Medicine
St. Louis Children’s Hospital
St. Louis, Missouri
James R. Eckman, M.D.
Director
Georgia Sickle
Cell Comprehensive Care Center
Winship Cancer Institute
Emory
University
Atlanta, Georgia
Bruce L. Evatt, M.D.
Clinical Professor of Medicine
Emory University School of Medicine
Retired Former Director
Division of Hereditary Blood Disorders
National Center on Birth Defects
and Developmental Disabilities
Centers for Disease Control and Prevention
Atlanta, Georgia
Regina Hutchins-Pullins
Cincinnati, Ohio
Cage S. Johnson, M.D.
Director
University of
Southern California Comprehensive Sickle Cell Center
Professor of Medicine
Keck School of Medicine
University of Southern California
Los
Angeles, California
Sophie Lanzkron, M.D.
Assistant Professor of
Medicine and Oncology
Director, Sickle Cell Center for Adults at Johns
Hopkins
School of Medicine
The Johns Hopkins University
Baltimore,
Maryland
Erica L. Liebelt, M.D., FACMT, F.A.A.P.
Professor
of Pediatrics and Emergency Medicine
Director, Medical Toxicology Services
University of Alabama School of Medicine
Children’s Hospital and
University Hospital
Co-Medical Director
Regional Poison Control Center
Birmingham, Alabama
Richard Lottenberg, M.D.
Director
University of
Florida Adult Sickle Cell Disease Program
Professor
Division of
Hematology/Oncology
Department of Medicine
University of Florida
Gainesville, Florida
Kwaku Ohene-Frempong, M.D.
Professor of Pediatrics
University of Pennsylvania School of Medicine
Director, Comprehensive
Sickle Cell Center
The Children’s Hospital of Philadelphia
Philadelphia, Pennsylvania
Eugene P. Orringer, M.D.
Professor of Medicine
Executive Associate Dean, Faculty Affairs and Faculty Development
Dean’s Office, School of Medicine
University of North Carolina at
Chapel Hill
Chapel Hill, North Carolina
Griffin P. Rodgers, M.D., M.A.C.P.
Director
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health
Bethesda, Maryland
Wally R. Smith, M.D.
Professor of Medicine
Chairman, Division of Quality Health Care
Department of Internal
Medicine
Virginia Commonwealth University
Richmond, Virginia
Martin H. Steinberg, M.D.
Director
Center of
Excellence in Sickle Cell Disease
Professor of Medicine and Pediatrics
Boston University School of Medicine
Boston, Massachusetts
John J. Strouse, M.D.
Assistant Professor of
Pediatrics
Division of Pediatric Hematology
School of Medicine
The
Johns Hopkins University
Baltimore, Maryland
Trevor K. Thompson, M.A.
Chairman, Patient Advisory
Board
Diggs-Kraus Sickle Cell Center
Memphis, Tennessee
Marsha J. Treadwell, Ph.D.
Director, Patient
Services Core
Northern California Comprehensive Sickle Cell Center
Children’s Hospital and Research Center at Oakland
Oakland,
California
Russell E. Ware, M.D., Ph.D.
Chair
Department
of Hematology
St. Jude Children’s Research Hospital
Memphis,
Tennessee
Richard Watkins
Director of Technical Specialists
Oracle Corporation
Potomac, Maryland
Thomas S. Webb, M.D., M.Sc.
Assistant Professor of
Clinical Internal Medicine and Pediatrics
Principal Investigator,
Cincinnati Sickle Cell Network, HRSA SCD Treatment Demonstration Program
Division of General Internal Medicine
University of Cincinnati
Cincinnati Children’s Hospital
Institute for the Study of Health
Cincinnati, Ohio
Planning Chair: Ellen M. Werner, Ph.D.
Health
Science Administrator
Division of Blood Diseases and
Resources
National Heart, Lung, and Blood Institute
National Institutes of Health
Bethesda, Maryland
Lisa Ahramjian, M.S.
Communication Specialist
Office of Medical Applications of Research
Office of the Director
National Institutes of Health
Bethesda, Maryland
David Atkins, M.D., M.P.H.
Chief Medical Officer
Center for Outcomes and Evidence
Agency for Healthcare Research and
Quality
Rockville, Maryland
Lennette J. Benjamin, M.D.
Professor of Medicine
Albert Einstein College of Medicine
Clinical Director
Comprehensive
Sickle Cell Center
Montefiore Medical Center
Bronx, New York
Otis W. Brawley, M.D.*
Panel
and Conference Chairperson
Professor of Hematology, Oncology,
Medicine,
and Epidemiology
Emory University
Medical Director
Grady Cancer
Center of Excellence
Winship Cancer Institute
Emory University
Atlanta, Georgia
Virginia Cain, Ph.D.
Health Scientist
National
Center for Health Statistics
Centers for Disease Control and Prevention
Hyattsville, Maryland
Beth A. Collins Sharp, Ph.D., R.N.
Director
Evidence-Based Practice Centers Program
Center for Outcomes and
Evidence
Agency for Healthcare Research and Quality
Rockville,
Maryland
Jennifer Miller Croswell, M.D.
Senior Advisor for
the Consensus Development Program
Office of Medical Applications of
Research
Office of the Director
National Institutes of Health
Bethesda, Maryland
George Dover, M.D.
Director
Department of
Pediatrics
Johns Hopkins Medical Center
Baltimore, Maryland
Kathryn Hassell, M.D.
IPA Assignment, NHLBI
Department of Medicine
Division of Hematology
University of
Colorado Health Sciences Center
Denver, Colorado
Cage S. Johnson, M.D.
Director
University of
Southern California Comprehensive Sickle Cell Center
University of Southern
California
Los Angeles, California
Susan K. Jones, R.N.
Clinical Research Supervisor
University of North Carolina Comprehensive Sickle Cell Program
University of North Carolina at Chapel Hill
General Clinical Research
Center
Chapel Hill, North Carolina
Barnett S. Kramer, M.D., M.P.H.
Director
Office
of Medical Applications of Research
Office of the Director
National
Institutes of Health
Bethesda, Maryland
Roshni Kulkarni, M.D.
Director
Division of
Hereditary Blood Disorders
National Center for Birth Defects and
Developmental Disabilities
Centers for Disease Control and Prevention
Atlanta, Georgia
Richard Lottenberg, M.D.
Director
University of
Florida Adult Sickle Cell Disease Program
Professor
Division of
Hematology/Oncology
Department of Medicine
University of Florida
Gainesville, Florida
Harvey Luksenburg, M.D.
Medical Officer/Project
Officer
Division of Blood Diseases and Resources
Blood Diseases Branch
National Heart, Lung, and Blood Institute
Bethesda, Maryland
Marie Y. Mann, M.D., M.P.H.
Medical Officer
Genetic Services Branch
Maternal and Child Health Bureau
U.S.
Department of Health and Human Services
Health Resources and Services
Administration
Rockville, Maryland
Kelli K. Marciel, M.A.
Communications Director
Office of Medical Applications of Research
Office of the Director
National Institutes of Health
Bethesda, Maryland
Ernestine (Tina) Murray, R.N., M.A.S.
Captain
U.S. Public Health Service
Evidence-Based Practice Centers Program
Center for Outcomes and Evidence
Agency for Healthcare Research and
Quality
Rockville, Maryland
Kwaku Ohene-Frempong, M.D.
Professor of Pediatrics
University of Pennsylvania School of Medicine
Director, Comprehensive
Sickle Cell Center
The Children's Hospital of Philadelphia
Philadelphia, Pennsylvania
Betty S. Pace, M.D.
Professor
Department of
Molecular and Cell Biology
Director
Sickle Cell Disease Research Center
University of Texas at Dallas
Richardson, Texas
Kenneth Rivlin, M.D., Ph.D.
Lincoln Medical and
Mental Health Center
Bronx, New York
Kathy Robie Suh, M.D., Ph.D.
Medical Team Leader
for Hematology
Division of Medical Imaging and Hematology Products
Office of Oncology Drug Products
Center for Drug Evaluation and
Research
U.S. Food and Drug Administration
Silver Spring, Maryland
Susan C. Rossi, Ph.D., M.P.H.
Deputy Director
Office of Medical Applications of Research
Office of the Director
National Institutes of Health
Bethesda, Maryland
Susan Shurin, M.D.
Deputy Director
National
Heart, Lung, and Blood Institute
National Institutes of Health
Bethesda, Maryland
Claudia Steiner, M.D., M.P.H.
Senior Research
Physician
Healthcare Cost and Utilization Project
Center for Delivery,
Organization, and Markets
Agency for Healthcare Research and Quality
Rockville, Maryland
Russell E. Ware, M.D., Ph.D. Chair
Department of
Hematology
St. Jude Children's Research Hospital
Memphis, Tennessee
*Otis W. Brawley, M.D., accepted a position at American Cancer Society in November 2007.
The abstracts are designed to inform the panel and conference participants, as well as to serve as a reference document for any other interested parties. We would like to thank the speakers for preparing and presenting their findings on this important topic.
The organizers would also like to thank the planning committee, the panel, The Johns Hopkins University Evidence-Based Practice Center, and the Agency for Healthcare Research and Quality, as well as the Centers for Disease Control and Prevention, the Health Resources and Services Administration, and NIH cosponsoring Institutes and Centers. We appreciate your continued interest in both the NIH Consensus Development Program and the treatment of sickle cell disease.
Please note that where multiple authors are listed on an abstract, the underline denotes the presenting author.
The abstract for the following presentation does not appear:
Sickle
Cell Disease: The Consumer’s Perspective
Richard Watkins
Sickle cell anemia is a severe hemoglobinopathy caused by a single nucleotide substitution in codon 6 of the ß–globin gene. This single mutation leads to the formation of the abnormal hemoglobin, HbS (α2ß2), which is much less soluble than hemoglobin A (HbA, α2ß2) when deoxygenated. This insolubility results in the formation of aggregates of HbS polymer inside sickle erythrocytes as they traverse the circulation. With more extensive deoxygenation, polymer becomes so extensive that the cells become sickled in shape, yet even at high oxygen saturation values there may be sufficient quantities of HbS polymer to alter the rheological properties of the sickle erythrocyte in the absence of morphological changes. These cells can occlude end arterioles, leading to chronic hemolysis and microinfarction of diverse tissues. This process leads to vaso-occlusive crises and irreversible tissue damage.
In recent years, the role of molecular and genetic modifiers, the effects of inflammation, cellular adhesion, and endothelial damage have complemented and expanded our understanding of the pathophysiology of the disease, as has the very recent appreciation of the role of nitric oxide in sickle cell pathogenesis. This improved understanding has led to current therapies to interfere with HbS polymerization based on fetal hemoglobin (HbF) augmentation, to prevent cellular dehydration and endothelial adhesion, and to replace the defective erythroid cell population by allogeneic stem cell transplantation. The opportunity for effective intervention at different points in the pathogenetic pathway strongly suggests that the combination of two or more agents, each with a different mechanism of action, would be additive and perhaps synergistic, similar to multidrug regimens for hypertension and cancer chemotherapy.
At present, hydroxyurea (HU) is the major medical modality with proven efficacy in patients with frequent symptoms related to sickle cell disease (SCD), although there is increasing evidence that HU is prescribed to only a fraction of patients who may benefit from it. A definitive cure is not currently available for most patients. Gene therapy for SCD has proven to be the elusive therapeutic “holy grail,” due to the difficulty in transducing hematopoietic stem cells and the necessity for erythroid-specific, high-;level, and balanced globin gene expression. As a result, increasing attention has been focused on the use of hematopoietic stem cell transplantation-both full intensity and, more recently, nonmyeloablative allogenic regimens. Studies of the clinical variability of the disease attributed to genetic differences in candidate genes based on single nucleotide polymorphisms and/or differences in gene expression profiles of target tissues (i.e., erythroid cells, endothelial cells, etc.) may also identify novel therapeutic targets. Current genomic studies should provide more insights on directing strategies to resolve these therapeutic challenges.
Introduction: Sickle cell disease (SCD) is a genetic disorder caused by a point mutation in the ß-globin gene of hemoglobin that affects nearly 100,000 Americans.¹ In addition to reduced life expectancy of 25–30 years,² patients with SCD experience severe pain and reduced quality of life.³ In February 1998, hydroxyurea (HU) was approved by the U.S. Food and Drug Administration for use in adults with SCD.
Objective: We conducted a systematic review to synthesize the published data on the efficacy and effectiveness of HU treatment for patients with SCD.
Methods: Literature inclusion criteria were tailored for each question based on the availability and applicability of trial evidence and relevance of other study designs. We addressed the efficacy and effectiveness of HU in children and adults separately. Due to limited evidence from randomized controlled trials (RCTs), we included nonrandomized trials, cohort studies with a control population, and pre-poststudies.
Literature sources: We searched for articles published before June 30, 2007, in the MEDLINE®, EMBASE®, TOXLine, and CINAHL databases as well as hand searching reference lists and consulting experts. All searches were limited to English-language articles on treatment of humans. Review articles were excluded from the searches.
Eligibility criteria: An article was included if it addressed a key question and was excluded if it was (1) not written in English, (2) contained no original data, (3) involved animals only, (4) was solely a report of an in vitro experiment, or (5) was a case series. We also excluded studies with fewer than 20 patients.
Article inclusion/exclusion: Paired reviewers excluded articles based on the title, abstract, and full text. Agreement was required to exclude an article based on title; differences in opinions at abstract and inclusion/exclusion review were resolved by consensus adjudication.
Assessment of study quality: For RCTs, we used the scoring system developed by Jadad et al.4 For observational studies (both cohort studies and controlled clinical trials), we created a quality form, based on those previously used by our Evidence-Based Practice Center (EPC). We designed questions to evaluate the potential for selection bias (three items) and confounding (five items). Paired reviewers assessed quality independently. A third reviewer reconciled the results of the first two reviewers for the randomized trials. For the other study designs, the results of the two reviewers were averaged. We considered high-quality studies to be those with a Jadad score of 4 or 5, or receiving 80% or more of available quality points.
Data extraction: We used a sequential review process whereby the primary reviewer abstracted all relevant data into forms and a second reviewer verified the first reviewer’s forms for completeness and accuracy. Differences were resolved by discussion. We created detailed evidence tables containing information extracted from eligible studies.
Grading of the evidence: We adapted the evidence-grading scheme recommended by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group,5 and further developed in the EPC guide,6 to grade the quantity, quality, and consistency of the available evidence addressing the efficacy and effectiveness of HU. We considered the strength of the study designs as best for RCTs, followed by nonrandomized controlled trials and observational studies.
Results: We included 8 articles describing two RCTs and 37 articles describing observational studies (11 with overlapping participants).
Children. A single, small, placebo-controlled randomized trial of HU for 6 months in Belgian children reported significantly lower rates of hospitalization and hospitalized days per year in the HU group (1.1 admissions, p = 0.0016 and 7.1 days hospitalized, p = 0.0027) compared to the placebo group (2.8 admissions and 23.4 days hospitalized). Fetal hemoglobin (HbF%) increased by an absolute 10.7% from baseline in the treated group (p <0.001).7
HbF% was reported as an outcome in 17 observational studies. The mean pretreatment HbF% ranged from 5 to 10%, and the on-treatment values were in the range of 15 to 20%. The percentage of HbF cells was less frequently reported, but it increased from baseline in three of the four pediatric studies. Three of these studies were retrospective; two reported increases in HbF% comparable to that in the prospective studies. Hemoglobin concentration increased modestly (roughly 1 g/dL) but significantly across studies.
The frequency of pain crises decreased in three of five pediatric studies. In one retrospective cohort study in a resource-poor environment, with a median follow-up of 24 months, pain crises declined from three (median) per year to 0.8 per year on treatment. Importantly, these results were attained by using a fixed-dose of HU of 15 mg/kg/day. A small, high-quality prospective study found a decrease in pain events from 3.1 per year in the year prior to HU therapy to 1.2 per year during 18 months of therapy. Hospitalization rates decreased in all four studies describing this outcome. In the retrospective study described above, hospitalization decreased from 4 (median) per year to 0.5 per year while on treatment. In the Belgian Registry, hospitalization declined from 3.2 to 1.1 per patient-year during the third year of treatment.
One study assessed the impact of HU on secondary stroke prevention in 35 children discontinuing chronic transfusions. The rate of recurrent stroke was 5.7 per 100 patient-years (lower than rates usually seen after stopping transfusions). One other study reported stable magnetic resonance imaging of the brain during HU treatment in 24 of 25 children.
Adults. The Multicenter Study of Hydroxyurea in Patients With Sickle Cell Anemia (MSH) randomized 299 adults with SCD. In the HU treatment arm, the median number of painful crises was 44% lower, and the time to the first painful crisis was 3 months compared to 1.5 months in the placebo arm.8 There were fewer episodes of acute chest syndrome and transfusions, but no significant differences in deaths, strokes, and chronic transfusion or hepatic sequestration. The significant hematological effects of HU versus placebo after 2 years were higher total hemoglobin by 0.6 g/dL and higher HbF% by 3.2%. The absolute neutrophil count and reticulocyte count were significantly lower in those receiving HU.9 Use of HU had no significant effect on annualized costs or quality of life.
HbF% increased from a pretreatment baseline of 4–12% to 10–23% during HU treatment in six prospective and one retrospective cohort studies of adults. There was a small increase in hemoglobin in most studies. Three studies described the number of pain crises. In a study of Sicilians with hemoglobin Sß-thalassemia, the frequency of crises decreased significantly from a median of 9 per year to 1.8 per year. In a nonrandomized study, patients receiving HU had fewer pain crises (1.4 per year, p <0.05) than those receiving cognitive behavioral therapy (4.3 per year), but this was not a strong study design for this outcome. Similarly, hospitalization rates decreased consistently for adults treated with HU. In the study of Sicilians, hospitalized days per year declined from 22.4 days to 1.2 days (p <0.0001). In a retrospective effectiveness study, the rates of hospitalization declined from baseline in the group treated for longer than 24 months (3.1 per year to 2.1 per year, p = 0.04). However, among the group treated for fewer than 24 months, there was no significant difference in hospitalization rates from baseline.
Conclusion: Based on our review, the published evidence supports with high likelihood that HU treatment (1) reduces the frequency of hospitalizations in both children and adults with SCD, (2) increases HbF% in both children and adults with SCD, and (3) reduces the frequency of transfusions and pain crises in adults (Table 1).
| Pediatric Outcomes | Evidence Grade | Basis for Grade |
|---|---|---|
| Increase in fetal hemoglobin | High | One good RCT; consistent observational studies |
| Reduction in hospitalizations | High | One good RCT; consistent observational studies |
| Reduction in pain crises | Moderate | One good RCT; inconsistent observational studies |
| Reduction in neurological events | Low | Observational studies |
| Reduction in transfusion frequency | Insufficient | Few observational studies |
| Adult Outcomes | ||
| Increase in fetal hemoglobin | High | One good RCT; consistent observational studies |
| Reduction in pain crises | High | One good RCT; consistent observational studies |
| Reduction in hospitalizations | High | One good RCT; consistent observational studies |
| Reduction in transfusion frequency | High | One good RCT; consistent observational studies |
| Mortality | Low | Inconsistent observational studies |
| Reduction in neurological events | Insufficient | No studies with sufficient events |
RCT = randomized controlled trial
Since its approval by the Food and Drug Administration in 1996, hydroxyurea (HU), a ribonucleotide reductase inhibitor, has had a major impact on the clinical expression of sickle cell disease (SCD). As the first agent clearly demonstrated to reduce the frequency of such sickle cell-related complications as vaso-occlusive crises and episodes of acute chest syndrome, HU has now been given to many patients, particularly those who are severely affected by SCD. Because of concerns regarding its side effects following long-term exposure as well as its potential as a carcinogen, a mutagen, and/or a teratogen, the initial experience with HU in patients who had SCD was limited to adults. Over time, however, when it became apparent that, with careful administration and follow-up, HU could be given safely to adult patients who had SCD, children also began to receive this agent. Initially, children were given HU as participants in clinical trials, but soon thereafter HU also became part of standard therapy for children who have SCD. In most cases, children, like adults, have shown substantial benefit after treatment with HU.
Because data from the Cooperative Study of Sickle Cell Disease indicated that the percentage of fetal hemoglobin (HbF) could influence such manifestations of SCD as the frequency of painful events,1 the occurrence of episodes of acute chest syndrome,2 and overall life expectancy,3 and since HU (and other cytotoxic agents) have been found to enhance HbF production,4–5 it was initially presumed that the beneficial effect of HU was a direct consequence of its ability to increase the percentage of HbF. In the initial multicenter trial in which HU was given to a total of 32 adult patients who had SCD and received the drug for a period of at least 16 weeks, a highly significant increase in the mean circulating level of HbF (from 4% to 15%) was observed.6 Similar increases in F-cells, F-reticulocytes, and the amount of HbF per F-cell were also noted in these patients in the study. Although the study was not designed nor sufficiently powered to demonstrate HU’s clinical benefit in terms of vaso-occlusive episodes, many of the participants in this Phase I safety trial funded by the National Institutes of Health clearly appeared to receive clinical benefit from HU. In addition to the increase in HbF, these patients in the study exhibited a number of highly significant changes in a variety of other hematological parameters, including increases in total hemoglobin and mean corpuscular volume (MCV) and decreases in total white blood cells, neutrophils, reticulocytes, and platelets. The laboratory results from this Phase I study and the favorable safety profile that was observed in these patients served as the basis for the Phase III Multicenter Study of Hydroxyurea in Patients With Sickle Cell Anemia (MSH).7 While the MSH also showed an HU-induced increase in the various HbF measurements, the most prominent increment in these HbF parameters in the patients who were treated with HU occurred during the initial 3 months of therapy. Thereafter, the overall increases in the various HbF measurements trended downward, so that by the end of year 2, the various HbF parameters achieved by the HU-treated patients in the MSH were substantially less than the HbF levels that were noted at the end of the earlier, 16 week Phase I study. Two subsequent analyses, in which the results of the 299 participants in the MSH were subdivided into quartiles according to their response to HU, found that those patients with the best clinical response in terms of vaso-occlusive crises also had the most robust and sustained increases in both HbF and MCV.8–9 However, these same two analyses also found that those patients in the quartile with the fewest vaso-occlusive events also had the lowest numbers of circulating neutrophils, monocytes, reticulocytes, and platelets. Therefore, it was difficult to be certain which of these various changes (or perhaps what combination of changes) was actually responsible for the clinical efficacy of HU observed in this clinical setting.
In children, the response to HU was first examined in the Pediatric Hydroxyurea Safety Trial, often referred to as HUG-KIDS.10 Much like the initial Phase I adult trial described above, the HUG-KIDS study, funded by the National Institutes of Health, was not designed to analyze the clinical efficacy of HU in terms of vaso-occlusive crises. Rather, this Phase I/II safety study showed that HU was safe and well-tolerated in children who had SCD. In addition, as in the original Phase I study conducted in adults, the children who participated in HUG-KIDS showed a substantial increase in the mean circulating level of HbF (7.3%–17.8%) during the 12 months of this study. These investigators also found that those children who achieved the highest HbF responses after 12 months of HU therapy: (1) had the highest levels of HbF at baseline, and (2) were able to tolerate the highest dosages of HU throughout the course of the study. Finally, when the peak HbF response was broken down into quartiles (i.e., maximal to minimal HbF responders), highly significant correlations were observed between the magnitude of the increase in HbF and the extent of (1) the increase in total hemoglobin and MCV, and (2) the decrease in total WBC and reticulocytes. In a second pediatric Phase I Safety Study that was conducted at a single institution, virtually identical hematologic results were observed.11 Although neither of these two pediatric studies looked at the frequency of painful events and/or hospitalizations, a few other studies did. These were not randomized, placebo-controlled trials, but they did obtain baseline data so that the patients treated with HU served as their own controls. Jayabose and colleagues12 treated 14 children who had SCD with HU and found a highly significant decrease in the number of vaso-occlusive events (both painful crises and episodes of acute chest syndrome) compared to the experience of these same children before HU therapy (i.e., 2.5 events per year before HU to 0.87 events per year while taking HU). Ferster and colleagues13 also reported that, after initiation of HU therapy, the 93 children in their study experienced significant decreases in both the number and duration of hospitalizations compared to what had occurred in these same children during the 12 months before initiation of HU therapy. Furthermore, an analysis of the subset of 22 children who had received HU for at least 5 years confirmed a statistically significant difference in hospitalizations (P = 0.0002) as well as days in the hospital (P <0.01). In addition to these clinical responses, both studies observed hematologic findings that were similar to those observed in the other adult and pediatric studies (e.g., increases in total Hb and percentage of HbF and MCV, and decreases in circulating neutrophils, evidence of red cell destruction, etc.). Therefore, just as in the adult studies, it remains unclear which of these various changes (or what combination of these changes) is responsible for the observed reduction in vaso-occlusive events.
With the increased understanding of the pathophysiology of SCD gained over the past 10–15 years, it has become readily apparent that it is not simply the polymerization of hemoglobin S (HbS) and the formation of rigid, sickle erythrocytes that lead to the impairment of blood flow and the resulting vaso-occlusion that is experienced by patients who have SCD. We have learned, for example, that HbS-containing erythrocytes (especially reticulocytes) are sticky and tend to adhere to one another, to the endothelium, and to the various proteins that comprise the subendothelial matrix. In addition, leukocytes, neutrophils, monocytes, inflammation, and blood clotting all appear to make important contributions to the process of vaso-occlusion. As emphasized above, HU can produce significant changes in many of these parameters. Furthermore, virtually all of the HU-induced changes tend to occur in the direction that would be beneficial in this clinical setting. As one example, Charache and colleagues,8 in their extensive evaluation of the MSH, employed a multivariable analysis to provide convincing evidence of an independent association between lower neutrophil counts and lower rates of crises. By contrast, the increase in F-cell levels was associated with lower crisis rates, but only during the initial 3 months of HU therapy.
One final factor that is of critical importance to all of these studies relates to the issue of compliance. No matter how efficacious a therapy might be, it will be effective only if the patient takes it. In the original adult Phase I Study, for example, although those patients who had the poorest HbF responses might have been refractory to the drug, it is important to emphasize that many of them were strongly suspected of noncompliance. Evidence of such noncompliance was suggested by the absence of HU in most of the random plasma samples from these “poor responders.”6 Similarly, in the HUG-KIDS Study, the extent of the increase in HbF level was inversely correlated with compliance with the treatment regimen, as determined by pill counts.10 Notably, Olivieri and Vichinsky14 conducted a study in children who had SCD; the study was specifically designed to evaluate compliance with HU. By using Medication Event Monitoring System caps, they found compliance to be remarkably high (96%) in their patient population. Perhaps because of parental supervision, children who have SCD quite possibly are substantially more compliant with taking the prescribed HU than are their adult counterparts. In any event, compliance is a vitally important factor in this setting, as physicians have all seen “HU-treated” patients who have SCD whose hematological parameters (HbF, MCV, neutrophils, reticulocytes, etc.) fail to change despite their “taking” dosages of HU that often exceed 30 mg/kg/day.
In summary, it is readily apparent that when HU is administered to patients who have SCD, it has a significant effect not just on the clinical expression of the disease, but also on a wide variety of laboratory parameters. Furthermore, in most cases, these changes in laboratory values tend to occur together (i.e., those patients who achieve the highest HbF levels also tend to have the most prominent increases in parameters such as total hemoglobin and MCV as well as the most striking declines in parameters such as total WBC, neutrophils, reticulocytes, and other markers of red cell destruction). Virtually all of these HU-induced changes in laboratory parameters occur in a direction that one would expect to be beneficial in SCD. It is, therefore, difficult to be certain whether one specific change (e.g., the increase in HbF) is responsible for the bulk of the observed clinical benefit, and everything else is a secondary manifestation of this primary effect; or, alternatively, to be certain whether the observed clinical benefit results from a combination of some or all of the various changes that occur in this clinical setting.
Hydroxyurea (HU), a ribonucleotide reductase inhibitor, has been used safely for many years in myeloproliferative disorders and other neoplasms. Its known effects on hematopoiesis suggested that it might lead to the induction of fetal hemoglobin (HbF) in sickle cell anemia (homozygosity for HBB glu6val). Following pilot studies and Phase II trials that suggested that HU could safely increase HbF in adult sickle cell anemia, a pivotal efficacy trial, the Multicenter Study of Hydroxyurea in Patients With Sickle Cell Anemia (MSH), was initiated.1–5 The MSH remains the sole placebo-controlled, double-blinded study of the efficacy of HU in adult sickle cell anemia.
In the MSH, HU reduced by nearly half the frequency of hospitalization and the incidence of pain, acute chest syndrome, and blood transfusion as well as increasing the time to a first painful episode or acute chest syndrome.5 HbF increased from 5% to about 9% after 2 years of treatment.6 Some aspects of quality of life and exercise performance improved.7,8 MSH patients are likely not typical of all patients treated with this drug, as they were older symptomatic adults and were treated with maximal tolerated doses of HU. In a different study, when HU was not pushed to toxicity, HbF levels near 20% were achieved; however, this was not a controlled trial.9
Decreased morbidity due to HU may be associated with reduced mortality. When cumulative mortality was analyzed according to total exposure to HU in the MSH patients’ follow-up, reductions in vaso-occlusive complications, HbF levels ≥0.5 g/dL, absence of acute chest syndrome, and fewer painful episodes were all associated with reduced mortality.10 No relationship between decrements in neutrophil counts and mortality was found. Mortality was reduced 40% during 3 month intervals when patients were taking HU, from an average of 2.6 deaths per 3 months to 1.5 deaths per 3 months. Without a long-term case-control study of the effects of HU on mortality, we must rely on follow-up of MSH patients and on other uncontrolled studies to estimate this important statistic.
Observational trials of HU treatment in adults with sickle cell disease have been reported.3, 11–15 All showed an increase in HbF and a reduction in painful episodes and hospital admissions, albeit of variable size of effect.
An ability to respond to HU in adults could be dependent on the capacity of the marrow to withstand moderate myelosuppression triggering the regeneration of erythroid precursors that synthesize HbF.6 The hematopoietic capacity of the bone marrow might be reflected by the pretreatment reticulocyte and neutrophil count. However, in children, these hematological measurements had little predictive value, whereas baseline HbF level was a reasonable predictor of the response to treatment.16
Unfortunately, predicting which individual patient will respond to HU treatment with an increase in HbF is still not possible. The HbS gene is associated with five major haplotypes of the ß globin gene-like cluster, and these haplotypes are associated with differential expression of the HbF. Individuals with the best HbF response to HU were less likely to have a HbS gene on a Bantu haplotype chromosome.6 In sibling pairs with sickle cell anemia given HU, there was a correlation between siblings in HbF level, both before and after HU treatment, and a possible HU-mediated effect on HbF.17
In uncontrolled studies, HU appeared to increase HbF in HbS-ß0 thalassemia and HbS-ß+ thalassemia.13, 15
Little information is available about the efficacy of HU in HbSC disease (compound heterozygosity for HBB glu6val and glu6lys). In pilot studies, HU was associated with increased mean corpuscular volume and hemoglobin concentration, with variable increments in HbF.18–20 A Phase II placebo-controlled, double-blinded clinical trial of HU in HbSC disease is ongoing.
For almost 25 years, clinical experience has been accumulating regarding the safe and efficacious use of hydroxyurea (HU) therapy for patients with sickle cell disease (SCD). Figure 1 illustrates a timeline for HU treatment in this patient population, beginning with several early “proof of principle” studies in adults.1–4 An important prospective Phase I/II study in adults treated to maximum tolerated dose (MTD)5 was then followed by the pivotal Phase III Multicenter Study of Hydroxyurea in Patients With Sickle Cell Anemia (MSH) trial.6 Subsequently, several reports described pediatric patients who received open–label HU treatment with good results.7–10 The Phase I/II trial of the Pediatric Hydroxyurea Group (HUG-KIDS)11 demonstrated that laboratory efficacy and toxicities were similar for children and adolescents to those previously observed for adults. The Phase I/II Hydroxyurea Safety and Organ Toxicity (HUSOFT) trial12 then reported that infants could tolerate HU (using a liquid formulation) with laboratory and clinical efficacy.
Clinical experience with HU in SCD has been accumulating for almost 25
years, with many studies occurring in the past decade.
*CVA = cerebral
vascular accident (stroke)
† TCD = transcranial Doppler
Long-term follow-up studies of HU for SCD have now been reported for adults,13,14 children,15–17 and even infants.18 These studies showed that laboratory and clinical efficacy of HU therapy is sustained for adherent patients, with no evidence of pharmacological tolerance or resistance. More recently, the clinical efficacy of HU for cerebrovascular disease among children with SCD has been investigated. In open-label studies, HU at MTD has demonstrated efficacy for the prevention of secondary stroke19,20 and also for lowering transcranial Doppler velocities that serve as a surrogate marker for primary stroke risk.15,21,22 Pivotal Phase III randomized clinical trials using HU (BABY HUG and SWiTCH) are now underway.
The short-term toxicities of HU therapy are usually mild and often are none at all. Although occasional patients will describe gastrointestinal symptoms or dermatological changes (e.g., hyperpigmentation, melanonychia),23 these are typically not severe. Dose-dependent cytopenia is a predictable and even desirable effect if the patient is escalated to MTD;5,11,24 any exaggerated hematological changes are transient and reversible with a brief discontinuation of the drug. Table 1 illustrates the cumulative incidence of short-term laboratory toxicity associated with HU therapy at MTD for children with SCD. Even with the conservative thresholds used in the HUG-KIDS study,11 few severe hematological toxicities were observed. Table 2 illustrates that HU at MTD has similar laboratory efficacy for children as it does for adults with SCD.
| % Patients | % Visits | |
|---|---|---|
| Neutropenia | 67 | 5.2 |
| Reticulocytopenia | 42 | 1.6 |
| Anemia | 32 | 1.1 |
| ALT elevation | 13 | 0.4 |
| Thrombocytopenia | 8 | 0.3 |
| Creatinine elevation | 0 | 0.0 |
| Adults | Children | |
|---|---|---|
| MTD (mg/kg/day) | 21.3 | 25.6 |
| Δ Hb (gm/dL) | + 1.2 | + 1.2 |
| Δ Hb (gm/dL) | + 23 | + 14 |
| Δ HbF (%) | + 11.2 | + 9.6 |
| Δ Reticulocytes (109/L) | - 158 | – 146 |
| Δ WBC (109/L) | – 5.0 | – 4.2 |
| Δ ANC (109/L) | – 2.8 | – 2.2 |
| Δ Bilirubin (109/L) | – 2.0 | – 1.0 |
Data are from published Phase I/II trials for adults5 and children11 with sickle cell anemia.
The documented clinical efficacy of HU for prevention of acute vaso-occlusive events has not been formally proven for children with SCD in the setting of a Phase III placebo-controlled randomized clinical trial. In open-label trials, however, there is substantial evidence that HU works similarly for children as for adults, with reductions in the number of painful events or acute chest syndrome events, compared with historical controls.15,17,18,25 Early concerns about negative effects on growth and development have not been realized; HU actually leads to reduced energy expenditure among children,26 as well as improved growth rates (height, weight) and development for school-aged children11,16,27 and even infants with SCD.18
Critically important questions regarding the potential of HU to prevent chronic organ damage among children with SCD, or possibly to preserve existing organ function, have not yet been answered definitively. However, there is accumulating evidence that HU can have a salutary effect on preservation of organ function in children with SCD, specifically for brain,19,22 spleen,12,18,28,29 lung,30 and kidney.31 The ongoing BABY HUG trial should provide important data regarding these questions; the primary endpoint of this placebo-controlled Phase III trial is the prevention or reduction of chronic spleen and kidney damage. Finally, despite the benefits of HU for clinical efficacy related to both acute and chronic complications of SCD, its potential to be an in vivo clastogenic, teratogenic, mutagenic, and even carcinogenic agent have not been fully addressed. To date, however, studies have not documented any clinically relevant changes or increases in malignancy beyond those observed in untreated patients with SCD.32,33
Hydroxyurea (HU) remains the only drug specifically approved for the prevention of complications related to sickle cell disease (SCD). We undertook a systematic review of the maximum tolerated dose (MTD), labeling of responders versus nonresponders, and adherence to therapy for HU. We searched MEDLINE® and the Cochrane Collaborative resources, excluding studies that: (1) were not published in English, (2) had fewer than 20 subjects, or (3) did not report information pertinent to the key clinical questions. Despite the paucity of high quality evidence, a summary of the best available literature that evaluated these subjects was compiled.
The data for adequate dosing of HU are limited by the number of adequately controlled clinical trials. Furthermore, there are no trials comparing the efficacy of HU in patients with SCD using the MTD to other dosing regimens. The Multicenter Study of Hydroxyurea in Patients With Sickle Cell Anemia (MSH) reported a statistically significant decrease in the annual rate of pain crises, episodes of acute chest syndrome, and transfusions when adult patients on HU were compared with those on placebo.1 In this study, the dose of HU was escalated to 35mg/kg/day or MTD, with only 21% of patients receiving the maximal prescribed dose. Multiple studies report on improvements in clinical and hematological parameters in patients with SCD when the dose of HU is escalated to the MTD.2–10 However, several other studies report similar improvements using fixed doses of HU.11–14 In one prospective, multicenter, open-label study in children that compared hematologic indices after treatment with a fixed dose of HU versus dose escalation of HU,6 dose escalation of HU produced significantly higher levels of fetal hemoglobin (HbF), but other indices were not significantly different. Finally, as a result of increased systemic exposure and decreased urinary recovery, patients with SCD and renal insufficiency may require a lower starting dose of HU and very careful dose titration.15
Although escalation of the dose of HU appears to increase HbF levels, there are insufficient data to say that MTD produces more clinical benefits compared with fixed doses of HU.
The majority of studies of HU treatment have not assessed the factors that determine the clinical response of patients; rather, they have evaluated factors that are associated with increased HbF levels. An early study of HU suggested that the most significant factors associated with HbF level are the last plasma HU level, initial white blood cell (WBC) count, and the initial HbF concentration, but not ß–globin haplotype or α–globin gene number.16 However, plasma HU clearances are not a useful guide to MTD, and the ability to measure plasma levels of HU generally is not available to most physicians. In the MSH, increases in HbF level at 2 years were greatest in patients with the highest baseline reticulocyte and neutrophil counts, two or more episodes of study-defined myelotoxicity, and absence of a Bantu haplotype, suggesting that the ability to respond to HU may depend on bone marrow reserve or the capacity of the marrow to withstand moderate doses of HU with acceptable myelotoxicity.17,18 Surprisingly, the initial HbF level was not associated with final HbF response. In the highest quartile of HbF response, myelosuppression developed in less than 6 months, patient compliance rates with the drug regimen were highest, and final doses of HU were 15–22.5 mg/kg. Results from the Phase I–II trial of the Pediatric Hydroxyurea Group (HUG KIDS), involving 53 children, showed that baseline HbF values, MTD of HU, and patient compliance with therapy were associated with higher HbF levels at MTD.19 The baseline reticulocyte and WBC counts were significantly associated with higher HbF levels at MTD only after adjusting for variations in baseline HbF. In a smaller study of 29 children, HbF at maximal response was not related to HU dosage.20 However, change in HbF was strongly correlated with change in mean corpuscular volume (MCV) but not with baseline reticulocyte or neutrophil counts.
In the MSH, it was not clear that clinical improvement was associated with an increase in HbF.21 When patients were compared on the basis of rates of crises within 2 years, those with lower rates of crises had higher F-cell counts and MCVs as well as lower neutrophil counts. However, in multivariable analyses, only lower neutrophil counts were independently associated with lower rates of crises rates, while F-cells were associated with the rate of crises only in the first 3 months of therapy.
One small study reported on HU compliance by using computerized pill bottles containing cap microprocessors which monitor the frequency of bottle openings.22 Over a period of 18.5 ± 2.1 months, compliance with HU (determined by the percent of prescribed drug actually taken) was 96 ± 2%, resulting in increased levels of mean HbF. Despite the excellent compliance in this study, insufficient data remain on adherence to HU therapy in SCD.
Sickle cell disease (SCD) is a complex disease with clinical pathology involving many organ systems. The clinical pathology of the disease can be broadly divided into three categories: hemolytic anemia, vascular occlusion and damage, and tissue and organ damage. These pathologic features are typically chronic, with superimposition of unpredictable acute exacerbations. The disease is also characterized by a wide variation in the spectrum of acute complications and chronic organ damage seen in patients. With the possible exception of the degree of anemia, no feature of SCD uniformly typifies any of its genotypes by rate or severity of occurrence. In designing clinical trials, it is customary to select the most common and easily countable clinical events to serve as the primary outcome measure. In SCD, this measure is usually pain episodes. However, some of the major complications of the disease, such as stroke and acute chest syndrome, are not related to pain in rates of occurrence.
The use of hydroxyurea (HU) therapy in children with SCD began in the early 1990s, soon after the early Phase II trials in adults were reported. There have since been several reports of clinical trials to determine the short-term efficacy and toxicity profile of HU in children with SCD.1–4 On the basis of the Multicenter Study of Hydroxyurea in Patients With Sickle Cell Anemia (MSH),5 HU was licensed for the treatment of SCD “specifically for patients over 18 who have had at least three ‘painful crises’ in the previous year—to reduce the frequency of these crises and the need for blood transfusions.”6 However, HU, by increasing the level of