The first multi-center study of bone marrow transplantation in children with sickle cell disease has demonstrated that this procedure can provide a cure for young sickle cell patients who have a matched sibling, researchers supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health reported today.
A team of U.S. and international researchers, led by Dr. Keith M. Sullivan of the Fred Hutchinson Cancer Research Center in Seattle, said that after a median followup of 2 years, the overall survival rate was 90 percent, and 73 percent of the participants were successfully transplanted and free of sickle cell disease. These results are similar to those from several earlier single-center European trials, although this latest study involves patients with more severe symptoms and advanced disease.
"Bone Marrow Transplantation for Sickle Cell Disease: A Multicenter Collaborative Investigation," appears in the August 8th New England Journal of Medicine.
"This study represents an important first step in our ongoing efforts to find a potential cure for patients with sickle cell disease," said NHLBI Director Dr. Claude Lenfant. "Only when we can identify children with the disease who are at significant risk for complications before they exhibit symptoms and provide successful transplants, will we be able to prevent disabilities and premature deaths that may result from this devastating disease."
Sickle cell disease is a term used to describe a group of genetic disorders involving hemoglobin, including sickle cell anemia and sickle B-thalassemia. In this country, it affects primarily African Americans, occurring in approximately one in every 400 African-American births. An estimated 80,000 Americans have the disease.
In the five-year trial, 22 children with severe sickle cell disease, ages 3-14, received transplants of marrow donated by HLA-identical siblings during 1991-1995. With up to four years of followup (13-52 months), 20 of the children are alive. Sixteen demonstrate long-term engraftment of normal blood-forming cells from their donor marrow, no evidence of organ damage beyond that experienced prior to the transplant, and no sickle cell symptoms.
Four of the 22 patients, or 18 percent, experienced graft rejection, and two patients died. This rejection rate is similar to the 12 percent rejection rate reported in children with B-thalassemia major who have received matched sibling marrow transplants. B-thalassemia major, often referred to as Cooley's Anemia, is another category of genetic blood disorders involving hemoglobin. Bone marrow transplantation is now considered a cure for B-thalassemia major. However, B-thalassemia major has a more predictable clinical course than sickle cell disease, making it easier to determine which patients will benefit from the procedure.
Graft rejection after HLA-matched marrow transplantation occurs more frequently in patients with hemoglobin disorders than in patients with other blood diseases, such as aplastic anemia or leukemia, for which the rejection rate after marrow transplantation from matched siblings is less than 3 percent. Some experts believe that the repeated blood transfusions given to patients with hemoglobin disorders to increase their volume of healthy red cells may increase the risk of graft rejection. Sixteen of the sickle cell patients in the study had received frequent blood transfusions prior to their transplants, and six had developed antibodies to elements in the blood, a condition called alloimmunization.
An important feature in the sickle cell study was the use of standardized procedures by all of the participating centers for enrolling patients, preparing them for transplant, and treating them after the procedure. The study enrolled only children who had already experienced at least one stroke or recurrent episodes of acute chest syndrome or painful crises, three of the most common and disabling symptoms of sickle cell disease. However, none of the children had yet developed the end-stage organ failure that can result from sickle cell disease.
To prepare them for the transplant, all patients were given chemotherapeutic drugs to destroy their own marrow and immunosuppressive agents to prevent rejection of the healthy donor marrow. After four of the first seven patients experienced neurologic complications following the transplant, medications to prevent convulsions and measures to prevent neurologic complications were added to the treatment plan.
The study will continue for an additional 5 years, during which time more patients, including young adults, will be recruited for transplants. All of the patients receiving transplants will be followed for the duration of the study.
Currently, there is no specific treatment for children with sickle cell disease. Pain-killing drugs and oral and intravenous fluids, and blood transfusions are used to reduce pain and prevent complications, and complications are treated as they occur. Although hydroxyurea has been shown to reduce painful crises, acute chest syndrome, and the need for blood transfusions in adults with sickle cell anemia, its safety and effectiveness in children is still under investigation.
In individuals with sickle cell disease, the hemoglobin molecules are defective. Each time they give up their oxygen, they tend to cluster together and form long, rod-like structures. These structures cause some of the red blood cells to become stiff and assume a sickle shape. The sickled red cells then lose their ability to squeeze through tiny blood vessels, depriving the organs and tissue of an adequate blood supply.
The first U.S. bone marrow transplant for sickle cell disease was reported in 1984 for a person with both sickle cell anemia and acute leukemia. Subsequently, a small number of sickle cell patients who had other life-threatening blood disorders, underwent successful marrow transplants in this country.
Simultaneously, a small number of European centers began to perform marrow transplants in patients with sickle cell anemia.
The following U.S. centers were part of the collaborative study group that enrolled patients or performed the transplants: Emory University, Atlanta; the Dana Farber Institute, The Children's Hospital, Harvard University, and the Boston Comprehensive Sickle Cell Center, Boston; University of North Carolina, Chapel Hill; University of Texas, Dallas and Houston; Duke University, Durham; Indiana University School of Medicine, Indianapolis; University of Southern California, Los Angeles; Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee; Yale University; Children's Hospital of Oakland; University of Pennsylvania, Philadelphia; University of South Florida, Saint Petersburg; St. Louis University; University of California, San Francisco; Fred Hutchinson Cancer Research Center and the University of Washington, Seattle; Stanford University; and Children's Hospital National Medical Center, George Washington University, and Howard University, Washington, DC.
Outside the U.S., the participating centers were the University of Bonn, Augustin, Germany; Birmingham Children's Hospital National Health Service Trust, Birmingham, UK; the Hopital Henri Mondor, Creteil, France; Royal Postgraduate Medical School, London; University of Campinas, Sao Paolo, Brazil; and Hospital for Sick Children, Toronto.
Recent additions to the collaborative study include centers in New York City; Chicago; Miami; Gainesville, FL; Brooklyn, NY; Hackensack, NJ; New Orleans and Shreveport, LA; Denver, and Pittsburgh.
The National Cancer Institute of the National Institutes of Health also provided funding for this study.
Note: Adults with sickle cell disease and parents of children with sickle cell disease who are interested in participating in this ongoing study should discuss with their physicians the possibility of referral to one of the participating transplant centers. All participants must have an HLA-identical sibling and meet the other enrollment criteria.