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Stephen J. Rosenfeld, M.D.
National Institutes of Health
What is ATG?
ATG is purified animal serum that reacts against specific cells of the human immune system. These cells are T-lymphocytes, and in patients with aplastic anemia they actively destroy or suppress the cells in the bone marrow that give rise to platelets, red blood cells, and granulocytes. ATG is made by first purifying these cells from normal blood. The purified lymphocytes are then injected into an animal, usually a horse. This process is very similar to a vaccine. When you are give a vaccine, your body recognizes that the material in the vaccine is unfamiliar, or foreign. Your immune system acts to defend you against this foreign substance by producing antibodies, proteins that are constructed to recognize the substance. They circulate in your blood, waiting to defend you against these foreign materials should you encounter them again. If the vaccine was for a virus, the antibodies will bind to the virus and allow your body to remove it from your blood before it can infect you. In the same way, the horse will recognize the human lymphocytes as foreign, and make antibodies against them. These are purified even further, until only the antibodies that will bind to human lymphocytes remain. There is no way to purify these antibodies completely, which is why ATG can also bind to other human blood cells.
How is ATG given? ATG is given intravenously, or directly into the bloodstream. It is given very slowly, often over four or more hours, to reduce the side effects. At the National Institutes of Health we give it every day for four consecutive days, but other institutions may use different schedules. No schedule has been shown to be better than another.
What are the side effects of ATG?
ATG has many side effects, some serious and others very uncomfortable. Most of these side effects occur because ATG itself is made up of foreign proteins. Most drugs are very small, and even though they are foreign, they are too small for our immune system to see. Antibodies are large, and our immune system reacts against them just as the horse's immune system reacted against the human lymphocytes. Even if you have not been given horse serum before, you may have antibodies that cross-react with ATG. And if you have received a previous course of ATG you are very likely to still have antibodies in your blood that will recognize the horse proteins. The most serious reaction these antibodies can cause is anaphylaxis.
Anaphylaxis is an overreaction of the immune system. It only occurs rarely as a reaction to ATG, but occurs much more frequently with some other substances, like bee stings. When someone is "allergic to bee stings," it means they may have an anaphylactic reaction if they are stung. In an anaphylactic reaction your body releases substances that cause your blood pressure to drop and make breathing difficult. You can die if you are not treated quickly. The only way we know to predict who will react this way is to inject very small doses of ATG under the skin. If you have the kind of antibodies that can cause anaphylaxis your skin will react at the site of the injection. Even people who have a "positive skin test" can receive ATG safely after a procedure called desensitization.
Most people who are given ATG do not develop anaphylaxis, but almost everybody develops less serious side effects because of their bodies' reaction to the horse proteins. Fever, chills, and hives are very common. These reactions usually get better with each dose, and go away completely when the ATG is stopped.
After several days of receiving ATG your immune system will have had time to produce new antibodies against it. These antibodies can bind to the ATG proteins and form "immune complexes." If the conditions are right, these complexes of protein can be deposited in different tissues of the body, such as the skin and joints, causing "serum sickness." Serum sickness usually begins about a week after the first dose of ATG, and can continue for several weeks. It can cause a rash, joint pains and muscle aches, and make you feel like you have a bad flu. We give steroids to patients receiving ATG to decrease the chances and the severity of serum sickness. Steroids reduce antibody production by the immune system.
How many times can someone receive ATG?
There is no reason that someone cannot receive ATG more than once. Sometimes a person who did not respond to a first course will respond if ATG is given again, alone or with another immunosuppressive drug, such as cyclosporin. Additional courses of ATG can also be used to treat patients who relapse, especially if they responded to their first course.
People who have received ATG before may have antibodies to the horse proteins. It is especially important they be skin tested and desensitized to protect them from anaphylaxis.
How effective is ATG in aplastic anemia?
If ATG is given alone it works about half the time. When it is used with another drug, such as cyclosporin, the chances of working increase, approaching three-quarters. People who respond to ATG or to other forms of immunosuppression are not usually cured. They no longer need transfusions and they feel well, but their blood counts are still below normal. We haven't been giving ATG long enough to know for certain what the chances of relapse are, but it seems that about a third of patients will need to be treated again.
Does the use of ATG affect the success of a bone marrow transplant?
The choice between ATG and bone marrow transplant as the first treatment for aplastic anemia is difficult. Studies that have followed people treated both ways for many years have similar survival rates. If you do not have a brother or sister who's immune system is perfectly matched to your own (your chances are one in four for each sibling), ATG may be a safer choice. As you get older, your risk of dying or becoming chronically ill as a result of a bone marrow transplant increases, and ATG becomes a more reasonable choice even if you have a matched sibling.
If you've made the choice to be treated with ATG, your chances of dying with a bone marrow transplant if you do not respond to the ATG go up. There are many reasons for this increased risk. If you chose not to have a transplant because you did not have a matched sibling, then any transplant would have to be mismatched, which is a much riskier procedure. Likewise, if you were advised against a transplant because of your age, this risk will only increase with time. Under the best circumstances, by the time you have your transplant you will probably have received more transfusions and you may be sicker, both of which increase the danger of bone marrow transplant.
Does ATG have any long term consequences?
Before successful treatment of aplastic anemia with immunosuppressive drugs like ATG, most people who were afflicted died. Now that we have a successful therapy, people are living many years after they were first found to have aplastic anemia. We are seeing other diseases in some of these patients, but it is very difficult to know if these secondary diseases are caused by their aplastic anemia or by their treatment. Some people develop a condition called paroxysmal nocturnal hemoglobinuria, which is a form of abnormal blood cell production that may or may not produce symptoms. People who have survived aplastic anemia and who were treated with immunosuppressive drugs (but not with bone marrow transplant) seem to be at higher risk for other bone marrow diseases, including leukemia and myelodysplasia. Most patients do not develop any of these complications.