Bone marrow transplants are emerging as a potential new treatment for sickle cell disease -- the blood ailment that afflicts some 50,000 black Americans annually.
In two separate experiments, researchers at the University of Chicago and at the Institut Jules Bordet et Hopital Erasme in Belgium have used bone marrow transplants to treat successfully patients who had both sickle cell disease and leukemia, a cancer of the white blood cells.
One patient, a 13-year-old girl, shows no signs of either sickle cell disease or leukemia, 4 1/2 years after the transplant.
"She is doing extremely well and is leading a normal life, although she is smaller than she would have been without the treatment," said Dr. F. Leonard Johnson of the University of Chicago Medical Center, who reported his findings at a special conference on sickle cell disease, sponsored by Howard University and the National Institute of Child Health and Human Development (NICHD).
The other patient -- a 23-year-old man -- was treated by doctors in Brussels and now, more than nine months later, also shows no sign of either sickle cell disease or leukemia, Johnson said.
Based on these two cases, Johnson and his colleagues will begin bone marrow transplants on a trial basis at the University of Chicago.
Although promising, bone marrow transplants won't be the answer for most people with sickle cell disease. Only the most severe cases -- "probably only 10 percent of patients," Johnson said -- might benefit.
Prime candidates for bone marrow transplants are very young patients who have already suffered strokes as a result of their sickle cell disease and are at great risk of sudden death from another stroke. Usually, these children also suffer from iron buildup in organs -- a complication of the multiple blood transfusions used to treat the illness.
Other patients who could be helped by bone marrow treatment are young adults who are so debilitated by the disease that they are hospitalized 95 percent of the time.
"They are having so many sickle cell crises that their quality of life is dreadful and they are just emotionally wiped out," said Johnson, who is head of the Division of Pediatric Hematology/Oncology at the University of Chicago Medical Center.
With such a severe form of the disease, sickle cell patients face almost certain death from complications, usually from the failure of a major organ, such as the liver or the heart. Most patients with the disease live only until their late twenties or early thirties.
Bone marrow transplants could cure up to 70 percent of patients with the more severe form of the disease, Johnson said. But the procedure is expensive -- running about $100,000. What's more, to undergo transplantation, sickle cell patients must find a donor, usually a close relative, whose bone marrow is almost a perfect match to the patient's. For bone marrow transplants to have the best chance of succeeding, donor and recipient must match perfectly on four genetic measures, called histocompatibility complexes or antigens.
Prior to the transplant, doctors must destroy all the bone marrow in the sickle cell patient so that the donated marrow will be able to thrive and colonize. In the two cases performed, whole body radiation was used to wipe out the bone marrow because the two patients had both sickle cell disease and leukemia. For patients who suffer from sickle cell disease alone, drugs would be used to destroy the marrow, Johnson said.
Until the transplanted marrow colonizes and grows, the sickle cell patient is left with a compromised immune system and is extremely vulnerable to infection. There is also a chance that even with careful selection of donors, the new bone marrow will not be a close enough match and will mount an attack against the recipient's tissues -- a process called graft vs. host disease. These and other complications mean that about 30 percent of the time, the transplant will fail and the patient will die.
"The dilemma," Johnson said, "is that the therapy can cure the patient, but it can also potentially shorten the patient's life."
For this reason, bone marrow transplants will be appropriate only for people with very severe forms of the disease. "We need to know more about the severity of sickle cell disease in terms of deciding which types will be most suitable for bone marrow transplants," said Dr. Roland Scott, director of Howard University's Sickle Cell Disease Center. Sickle cell disease is an inherited blood disorder that strikes about one in every 500 American blacks and about one in every 1,200 American whites. In addition, one in 12 American blacks are carriers of the disease, a generally symptom-free condition called sickle cell trait.
The disease first appeared in areas of the world where malaria is rampant. Carriers of sickle cell trait are usually immune to malaria, suggesting that the trait evolved to protect the body.
A full-blown case of sickle cell disease occurs when an individual inherits genes for the illness from both parents, who may also have the full-blown disease or may be trait carriers.
Sickle cell disease causes the production of an abnormal type of hemoglobin -- the substance that carries oxygen throughout the body in red blood cells. When the blood's oxygen content drops, or when it becomes more acidic, this abnormal hemoglobin, known as hemoglobin S, distorts the red blood cells. Instead of being plump and round, they become sickle-shaped and have difficulty moving through the tiniest blood vessels, called capillaries. Sickle cells are also stickier than normal red cells. The combination of shape and stickiness makes it likely that these cells will clump together and cut off blood flow to areas of the body.
If this happens to a major blood vessel in the brain, the result is a stroke. In the heart, it can cause a heart attack. In other parts of the body, it may result in painful attacks called crises, which are marked by fever, loss of appetite, generalized weakness and sometimes a striking drop in the number of red blood cells.
Carriers of the trait generally have enough normal hemoglobin to compensate for the abnormal hemoglobin S and show no symptoms of disease. At the same time, a new study of more than 2 million Army recruits found that sickle cell trait carriers were 28 times more likely to die suddenly during or after physical exertion than people without the trait. Results of the study were published in last week's New England Journal of Medicine.
Current treatment for a patient suffering a sickle cell crisis usually involves hospitalization, where blood transfusions and painkillers help alleviate some symptoms. But repeated transfusions have their own risks, including iron buildup in different organs and the chance of developing a blood-borne disease, such as hepatitis or cytomegalovirus. There is also a small possibility of being exposed to acquired immune deficiency syndrome (AIDS), although the risk is negligible now that blood is routinely screened for the AIDS virus.
New drugs, now under development, may one day help ease the symptoms of sickle cell disease and extend life. Dr. Donald Abraham and his colleagues at the University of Pittsburgh are using computer modeling to develop drugs that alter the way oxygen is carried by the defective hemoglobin S. One drug called ethacrynic acid looks promising, but is still at least several years away from clinical trials. Burroughs Wellcome Co. is working with University of North Carolina researchers on a class of drugs called acid aldehyde derivatives that also shift how hemoglobin delivers oxygen to the tissues throughout the body. Both types of drugs are the first that attempt to treat the disease rather than the symptoms, Abraham said. The ultimate goal in sickle cell research is to correct the actual genetic defect passed from one generation to the next. To do that, researchers must be successful at gene therapy -- a still experimental technique, which would allow the repair of the defective hemoglobin gene.
Early attempts in the laboratory at inserting human hemoglobin genes into the cells of mice at the National Institutes of Health have been partially successful. In one gene therapy experiment, researchers fused pieces of virus with hemoglobin-producing genes. The virus carries the human gene into the cell's nucleus and inserts it into the mouse DNA -- in effect changing the basic genetic code of the mouse.
Dr. Stefan Karlsson reported last week that four to five weeks after gene therapy, the mouse cells were producing some human hemoglobin, showing that a basic genetic change had taken place. But it will still be many years before this type of therapy is attempted in human sickle cell patients, Karlsson said.