SICKLE CELL DISEASE TREATED SUCCESSFULLY WITH BONE MARROW TRANSPLANTATION

August 9, 1996

Media Contacts: Sarah Goodwin, 404/727-3366 - sgoodwi@emory.edu
Kathi Ovnic, 404/727-9371 - covnic@emory.edu
http://www.emory.edu/WHSC/



Bone marrow transplantation appears to be the first treatment for sickle cell anemia with the potential to completely eradicate the disease in some patients, report researchers from Emory University, Fred Hutchinson Cancer Research Center and elsewhere in this week's New England Journal of Medicine.

Nearly three-fourths of 22 children with severe sickle cell disease entered into a five-year study remain free of the disease an average of two years after transplantation. Between 1991 and 1995 the children aged 3 to 14 each received bone marrow from a sibling with the same type of marrow.

"This study determines that bone marrow transplantation is curative therapy for children with severe sickle cell disease," says James Eckman, M.D., a co-author of the paper and director of Emory's sickle cell program. "Transplantation can be done with acceptable complications. Finally, we can offer some patients hope for a cure."

Twenty of the study participants are surviving and 16 show no symptoms of sickle cell disease, including two children who received transplants at by the Bone Marrow Transplant Service at Egleston Children's Hospital of Emory University.

"The 10 percent death rate and potential for long-term complications of bone marrow transplant meant that this therapy should be reserved for the 25 to 30 percent of children who will have severe complications of sickle cell disease," says Dr. Eckman, who is professor of Medicine (Hematology-Oncology) at the Emory University School of Medicine.

The multicenter effort was partly funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health.

The study has been extended for five more years and is now open to young adults. For information, call 404/616-3572.



August 9, 1996



SEPTEMBER IS NATIONAL SICKLE CELL MONTH:

Progress of Emory's $7.5 Million NIH

Sickle Cell Program Grant Recognized


Current research conducted by sickle cell anemia experts at the Emory University School of Medicine is supported by a $7.5 million grant from the National Institutes of Health.

"Without a doubt, early detection and treatment of sickle cell anemia has dramatically improved the length and quality of life of children with this disease," says James Eckman, M.D., director of Emory's sickle cell program and principal investigator of the NIH grant. "Still, we believe much more can be done to treat the painful manifestations of this childhood disease."

Past and ongoing sickle cell research at Emory has included clinical studies of analgesic agents for alleviating acute pain, transfusion therapy for neurologic and surgical complications, and the use of hydroxyurea for chemotherapy. Research with the NIH grant includes the following:


FACTORS THAT IMPEDE BLOOD FLOW

A variety of researchers at Emory and the Georgia Institute of Technology are investigating ways to prevent the adhesion of sickle cells to blood vessel walls. This adhesion plagues patients in two ways: first, it clogs vessels and keeps blood from properly nourishing tissue. Blood-starved tissue, called ischemia, can cause severe pain and organ damage. A goal of the Center's research is to eventually develop ways to inhibit sickle cell adhesion in patients in the beginning stages of a pain crisis.

Secondly, adhesion may play a major role in acute chest syndrome - a sudden and severe inflammation of the lungs and a common manifestation of sickle cell disease. Sickle cells may stimulate the cells lining blood vessels in the lungs to express adhesion receptors, leading to acute inflammation and lung damage.

Much of the research on cell adhesion is done in collaboration with the Georgia Institute of Technology, where engineers use an in vitro flow model of the blood vessel to study how sickle cells interact with endothelial cells lining the vessel wall.

From an engineering perspective, the way sickle cells affect the circulation goes beyond biology to matters of force, flow rate, and shear stress. Factors that trigger adhesion are affected by flow and shear stress, as are plasma proteins and viruses. Endothelial cells may even be structurally or genetically altered when sickle cells merely collide with them, let alone adhere to them.


BONE MARROW TRANSPLANTATION

One of the newest alternatives for treating selective cases of sickle cell anemia is bone marrow transplantation. As part of the NIH comprehensive sickle cell grant, Emory offers BMT as an option for children and young adults with sickle cell anemia whose disease is uncontrolled by conventional forms of supportive care and who have a poor prognosis for achieving a good quality of life into adulthood. Emory hematologists expect to perform transplants in six to 12 children each year for at least five years.

Thus far, about two dozen children in this country and Europe have received bone marrow transplants for sickle cell anemia, with a cure rate of 70 to 80 percent.



CLOT-PROMOTING PROPERTIES OF SICKLE CELLS

Dr. Eckman and his colleagues believe that once cells begin to sickle and damage endothelial cells, they release factors which activate platelets in the blood, leading to clotting. They are looking at the effects of fish oil (dietary omega-3 fatty acids) supplements, which have been shown in nonhuman primates to stop blood clot formation at sites of vessel injury.


CHRONIC ORGAN DAMAGE

As patients with sickle cell disease live longer due to early and careful management, physicians must deal with problems resulting from chronic organ damage. Renal failure is becoming an important cause of death in older sickle cell patients. Early on, patients with renal problems have protein in the urine, which later progresses to a more severe decrease in renal function, sometimes requiring dialysis. Kidney experts are studying how the kidneys filter protein, how damage occurs, and how signs of early kidney disease may be recognized.

Dr. Eckman came to Emory in 1978 to establish Atlanta's first comprehensive program for adults and children with sickle cell anemia. Soon after, he and his colleagues obtained a federal grant from the Maternal Child Health Program of the U.S. Department of Health and Human Services to establish a newborn screening program at Grady Memorial Hospital for sickle cell disease and a basic follow-up for hospital patients. These programs were immediately successful in saving lives and improving care.

Emory physicians and Grady administrators joined a vocal parent-patient group in 1984 to petition the Georgia General Assembly for support of sickle cell anemia outpatient care. Legislators responded by providing $550,000 to partially fund a 24-hour, dedicated, comprehensive sickle cell acute care center: the Georgia Sickle Cell Center - still in place on the 15th floor of Grady. The center's mission is to provide 24-hour primary care and tertiary care for all Georgians with sickle cell disease. It currently serves 2,000 patients, about 1,200 of whom are treated on a regular basis. Each year, 115 new patients enter the center's program.

"Even though the patient population has doubled over the past decade, hospital admission rate for sickle cell disease in Emory's program has decreased," Dr. Eckman says. In 1985, the center recorded 215 hospital admissions per 100 patient years for adults; in 1991, there were but 68 admissions per 100 patient years for adults.

Sickle cell screening for newborns is now a statewide program. About 90 percent of children born with sickle cell anemia now survive to at least age 20.


SICKLE CELL ANEMIA


F a c t s


One in 400 African-American babies is born with homozygous sickle cell anemia

(the most common form); one in 12 carries the sickle cell trait. About 80,000 Americans have sickle cell disease. Until the mid 1970s, one-fourth of children born with sickle cell anemia died of overwhelming infections before age 5.


Anemia associated with sickle cell causes fatigue and a susceptibility to infections. Blocked capillaries and veins lead to ischemia (lack of blood) in tissues, causing excruciating bone and muscle pain, and progressive organ damage.


Red blood cells carrying the abnormal molecule known as hemoglobin S travel through the arterial circulation until they are deoxygenated. Hemoglobin S molecules often form long, rigid rods, causing the normally circular cells to stiffen and distort into a sickle shape. These sickle cells have difficulty moving through small capillaries. As blood flow slows, endothelial cells lining the vessel wall become sticky, attracting the sickle cells and causing congestion in the vessel.


These changes are partly reversible through the normal process of reoxygenation; however, once the reversal takes place, the damage has been done. The spleen traps and destroys many of the abnormal sickle cells, resulting in rapid turnover of red blood cells and chronic hemolytic anemia.


Sickle cell anemia and sickle B-thalassemia are among the genetic blood disorders involving hemoglobin that comprise sickle cell disease. B-thalassemia major (Cooley's anemia) is a related genetic blood disorder that is even more amenable to bone marrow transplantation than sickle cell anemia.


Matched-sibling bone marrow graft rejection rates of genetic blood disorders:

less than3 percent Aplastic anemia or leukemia (doesn't involve hemoglobin)

12 percent B-thalassemia major (involves hemoglobin)

18 percent Sickle cell anemia (involves hemoglobin)

Patients with hemoglobin disorders require frequent blood transfusions -- which experts hypothesize may increase likelihood of graft rejection.


Many patients survive to adulthood - sometimes into their 50s, 60s and beyond. Some patients lead fairly normal lives, attending school and work with only occasional pain episodes and slowly progressive organ damage. Others are plagued from an early age with lengthy pain crises (sometimes up to 15 or 20 each year); strokes, bone and joint deterioration; and pulmonary, gallbladder, kidney, or eye disease - all requiring frequent hospitalization.


Sickle cell anemia was the first illness to be labeled a "molecular disease." In 1949,

Linus Paulding et al. published the landmark paper describing the discovery that sickle cell anemia is caused by a genetic mutation in which one amino acid is substituted for another in a long chain of 146.

For more general information on The Robert W. Woodruff Health Sciences Center, call Health Sciences News and Information at 404-727-5686, or send e-mail to hsnews@emory.edu.


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