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BMT for Sickle Cell Disease Sickle cell disease is an inherited blood disorder that causes pain, organ damage and early death. It is most prominent in Africa where an estimated 120,000 infants are born each year with sickle cell disease. Of the approximately 80,000 persons who have sickle cell disease in the U.S., most are of African descent. Sickle cell disease is also prevalent in Southern Italy, Northern Greece, Southern Turkey, India and the Eastern Province of Saudi Arabia. Persons with sickle cell disease have abnormal hemoglobin in their red blood cells. Hemoglobin carries oxygen from the lungs to every part of the body. Red blood cells with normal hemoglobin are round, flexible and can pass easily through the blood stream. But in persons with sickle cell disease, the hemoglobin molecules cluster together after releasing oxygen, causing the red blood cells to become rigid and curved like a sickle.
The sickle-shaped cells get trapped in the blood stream, and can no longer deliver oxygen to organs and tissues. Some are destroyed by the liver or spleen. The body is not able to produce new red blood cells rapidly enough to replace the trapped or destroyed cells. As a result, organs and tissues do not get sufficient oxygen and pain and/or organ damage occurs. Sickle cell disease is an inherited disorder. Both parents must have at least one sickle cell gene and pass it on to their child in order for the child to have sickle cell disease. Approximately one in every twelve African-Americans have the sickle cell trait--one sickle cell gene. They are carriers of the disease, but are not afflicted by the disease. If two persons with the sickle cell trait conceive a child, there is a 50 percent chance the child will inherit the sickle cell trait, and a 25 percent chance that he will have sickle cell disease. There are several types of sickle cell disease. The most common among African-Americans are sickle cell anemia (Hb SS), where the child inherits two sickle cell genes; sickle-hemoglobin C disease (Hb SC), where the child inherits one sickle cell gene and another abnormal type of hemoglobin called "C;" and sickle beta-thalassemia, where the child inherits one sickle cell gene and one gene for another blood disorder called Thalassemia. Symptoms Frequent episodes of pain are the most common symptom of sickle cell disease, usually in the arms, legs, hands, feet and abdomen. Pain may be moderate or severe enough to require several hospitalizations each year. Other symptoms include frequent infections and anemia. The spleen, bones, lungs and brain are particularly susceptible to damage in the early years of life among patients with sickle cell disease. Six to 12 percent of young patients experience a stroke and must receive periodic blood transfusions to prevent additional strokes. Although frequent transfusions prevent additional strokes in 70 percent to 90 percent of patients, they also increase the risk of viral infection and iron overload. These problems, in turn, can cause organ damage. Repeated episodes of chest pain, fever and infection in the lungs occurs in 15 percent to 50 percent of patients, and can also result in early death. Early detection and careful management of the disease with pain relievers, periodic doses of antibiotics in childhood to prevent infections and blood transfusions enable 95 percent of patients with sickle cell disease to survive beyond age 20. Nonetheless, their life expectancy is 30 years less than that of a healthy individual, due to progressive organ damage and the risk of stroke. Currently, bone marrow transplantation (BMT) is the only known cure for sickle cell disease. Bone Marrow Transplantation The first BMT for sickle cell disease was reported in 1984. The patient had both sickle cell anemia and acute leukemia. Subsequently, a handful of other patients who had both sickle cell disease and another blood disorder underwent successful BMTs, and it was observed that their sickle cell disease was eliminated.
Three large clinical trials--one in Belgium, another in France and a third in the US--have reported results of BMT for 116 patients with sickle cell disease. All but three of the patients received marrow from a matched related donor--a relative whose marrow type was similar to the patient's. The remaining three were transplanted with cord blood which, like bone marrow, is rich in stem cell--the cells that produce most of the body's blood cells. Of the 116 patients, 91 (78 percent) were alive and disease-free two to four years following BMT. An additional 16 were alive, but had rejected the donor marrow or cord blood (graft rejection), and continued to have symptoms of sickle cell disease. Neurological problems such as bleeding in the brain developed in about 25 percent of patients following BMT. Patients who had experienced a stroke prior to BMT developed neurological complications more often than those who had not. Seizures were also common, but responded to treatment. The large number of neurological problems following BMT have prompted most centers to try to prevent these problems--administering anticonvulsant medications, strictly controlling high blood pressure, giving patients magnesium when needed, and making sure the number of platelets (the blood cells that enable clotting) in the patient's bloodstream are at a safe level. Chronic graft-versus-host disease--a condition in which the donor's marrow orchestrates an attack on some of the patient's tissues and organs--occurred in 10 percent of patients, resulting in three deaths. Other long-term complications included infertility, premature menopause, and delayed growth in some patients. Nearly all of the 116 patients were children. All had severe symptoms of the disease prior to transplant--stroke, lung problems, or repeated episodes of severe pain. The questions now facing researchers are whether this treatment should be offered to patients with less severe symptoms, especially those at risk for developing a stroke or another serious complication, and whether BMT can also cure adults. Investigators are also looking at ways to make BMT less toxic, so that more patients survive the procedure. Who's a Good Candidate? Unlike most blood disorders, the cause of sickle cell disease is well understood. However, it is difficult to predict how the disease will progress in each individual. Some patients with sickle cell disease have few if any symptoms for many years. Others experience repeated episodes of extreme pain, lung problems and/or other organ damage. Some patients who develop a severe complication, such as a stroke, have very few symptoms of the disease beforehand, although it may have already damaged some of their organs. The unpredictable course of the disease has made it difficult to determine the best time to offer BMT to patients. Most patients with sickle cell disease survive the first ten years of their life without major complications. However, all will eventually develop more severe complications, and most will not survive beyond age 45. While BMT can cure patients with sickle cell disease, some will die as a result of the treatment and some survivors will have long-term problems that affect their quality of life to varying degrees. Patients who already are experiencing severe complications are the most logical candidates for BMT. Currently, most BMT centers in the U.S. who treat patients with sickle cell disease accept patients for BMT only if they have already experienced severe symptoms such as stroke, repeated severe episodes of pain, or lung problems, and do not have irreversible organ damage. However, patients who have not yet experienced serious complications, but are nonetheless at risk of developing severe complications, may actually be better candidates for BMT. One medical center in Belgium has reported results of BMT for 14 patients with sickle cell disease who were transplanted earlier in the course of their disease and had not received more than three blood transfusions prior to BMT. More than 90 percent were alive and disease free at a median of five years post-BMT. The incidence of graft rejection and graft-versus-host disease was lower than in patients transplanted later in the course of their disease, although the lower incidence of GVHD may be related to the younger age of the patients. These results, as well as new techniques for identifying patients that are likely to develop severe complications have prompted researchers to suggest that BMT be offered to certain patients earlier in the course of their disease. It was demonstrated recently that routine screening of sickle cell patients with a painless device called the transcranial Doppler ultrasound, which measures blood flow in the brain, can identify those most likely to develop a stroke. Forty-four U.S. centers are now investigating marrow transplantation for sickle cell disease. "Initial results have been encouraging," says Keith Sullivan MD of the Fred Hutchinson Cancer Research Center. During these trials it has been observed that not all donor stem cells need to engraft in order to eliminate the sickling. This, says Sullivan, may mean that sickle cell patients might not require toxic doses of chemotherapy before infusion of donor stem cells to eliminate sickle cell disease. "If this less toxic, inexpensive approach is successful, the impact on global health care will be profound." "Until we find ways to decrease the toxicities associated with bone marrow transplantation, the decision to undergo BMT will be very difficult, and the product of painstaking and thoughtful discussion among the individual patient, family and health care team," says Eva Guinan MD, at the Dana-Farber Cancer Institute. |
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