All of the 61 patients in the study were diagnosed with a myelodysplastic syndrome (MDS), a condition in which the bone marrow slowly stops making blood cells and platelets. One-third of patients improved their ability to make blood cells enough to stop blood transfusions after treatment with the immune-suppressing drug antithymocyte globulin (ATG), the researchers report in the Aug. 6 issue of the Annals of Internal Medicine.
"We are able to impact a lot of people's quality of life," says Dr. Molldrem, now an associate professor of medicine and chief of transplantation immunology at M. D. Anderson. "We restored blood counts to normal and they remained normal over a period of five, and now, up to almost seven years.
"With this study, we are the first to demonstrate that MDS has an autoimmune component,"Dr. Molldrem continues. "Now, we can think of this as an autoimmune disease in some patients and tailor treatment accordingly. Our findings have the potential to have a big impact in terms of just becoming a standard of how patients with MDS will get treated."
Currently, unless patients qualify for a bone marrow transplant, there is no effective therapy for MDS, says Dr. Molldrem, and over half the patients die from having low blood counts or they end up having strokes and bleeding to death.
Myelodysplastic syndromes have been particularly troublesome to treat, since the cause of the disorder is not well understood, he adds.
Bone marrow is the factory that produces all blood cells. In some older adults, the bone marrow becomes defective, slowly ceasing production of healthy blood cells, instead making defective blood cells. About 14,000 new cases of myelodysplastic syndromes are diagnosed each year in the U.S., with numbers steadily on the rise, according to the American Cancer Society. These syndromes are considered a precancerous condition, and in about half of cases, patients progress to leukemia, says Dr. Molldrem.
"Myelodysplastic syndromes are more common than leukemia, and they often go under- and un-diagnosed," he says.
Early symptoms of myelodysplastic syndromes, such as weight loss, fever, and loss of appetite, are vague and could be attributed to many other causes. Typically, patients who are diagnosed with bone marrow failure require regular blood transfusions, up to two-to-three times a week, and antibiotics to reduce infection, but little else can be done.
Dr. Molldrem and his then colleague Dr. John Barrett and other scientists at the NIH, sought to understand why the bone marrow stops making blood cells. They reasoned that this disorder may be similar to other bone marrow disorders, such as aplastic anemia, in which the body attacks its own bone marrow. They decided to treat the disorder as if it were an autoimmune disease, rather than a cancerous condition.
"We chose a drug, ATG, because it suppresses the immune system and is used to successfully treat patients with aplastic anemia. There was good evidence that aplastic anemia is probably an immune-mediated effect, so we reasoned that MDS may be similar," says Dr. Molldrem.
From 1994 to 1998, the researchers enrolled patients who were dependent on blood transfusions and studied their response to the drug, as well as long-term outcome. The advantage of the ATG treatment, says Dr. Molldrem, is that it is administered once a day for four days during a hospital stay, and if it works, the effect is long-lasting. In fact, among the patients who responded to ATG, 90 percent were making enough blood cells to be transfusion-free after five years. Perhaps as significant, none had progressed to leukemia, says Dr. Molldrem.
"They got off of transfusions and could then lead a normal life," he says. "In fact, they live longer than the patients who didn't respond to ATG."
The researchers aren't sure why the other two-thirds of patients did not respond to the treatment. Dr. Molldrem suggests that one reason for these findings is that there are five subtypes of the syndrome and that those with the refractory anemia subtype respond best.
M. D. Anderson researchers are currently following-up these results with a study using other immune suppressing drugs, such as cyclosporine, and combinations of drugs, including ATG, to improve the response to treatment.
The study was supported by a grant from the National Institutes of Health.
ATG is produced by Pharmacia Corp.