ADULT STEM-CELL TRANSPLANT NEW TREATMENT FOR SICKLE CELL
A modified blood adult stem-cell transplant regimen has effectively reversed sickle cell disease in 9 of 10 adults who had been severely affected by the disease, according to results of a National Institutes of Health study in the Dec. 10 issue of the New England Journal of Medicine and the trial represents a major milestone in developing a therapy aimed at curing sickle cell disease.
Sickle cell disease is caused by an altered gene that produces abnormal hemoglobin, the protein in normal red blood cells that carries oxygen throughout the body. When affected red cells lose oxygen, they collapse into a sickle, or C, shape and become stiff and sticky. Clumps of these cells block blood flow and can cause severe pain, organ damage from lack of oxygen, and stroke. Anemia often develops in people with the disease because sickle cells die off quickly and bone marrow does not make new ones fast enough.
Nearly 200 children with severe sickle cell disease were cured with bone marrow transplants after undergoing a regimen in which their own marrow was completely destroyed with chemotherapy. That regimen, however, had proven too toxic for adults, who have years of accumulated organ damage from the disease and are less able to tolerate complete marrow transplantation.
In contrast to the established method in children, this adult trial sought to reduce toxicity by only partially replacing the bone marrow. The much longer lifespan of normal red blood cells, compared to sickle red blood cells, allows the healthy cells to outlast and completely replace the disease-causing cells.
To achieve this goal, they used a low dose of radiation to the whole body and two drugs, Alemtuzumab and sirolimus, to suppress the immune system. Alemtuzumab depletes immune cells, but does not adversely affect blood stem cells. Sirolimus does not block the activation of immune cells, but inhibits their proliferation, creating a balance that potentially helps prevent rejection of the new stem cells.
The radiation favorably conditions the bone marrow, where donor stem cells move in and begin producing new, healthy red blood cells. After a median two and one half years follow-up, all 10 recipients were alive and sickle cell disease was eliminated in nine.
“Our patients have had a remarkable change in their lives,” said John F. Tisdale, M.D., the trial’s principal investigator in the NIH Molecular and Clinical Hematology Branch. “They are no longer being admitted to the hospital for frequent pain crises, they have been able to stop chronic pain medications, go back to school and work, get married and have children. Given these results, our regimen will likely have broad application to other nonmalignant diseases and can be performed at most transplant centers.”
Transplanted cells or tissue are known as grafts. To reduce the possibility of the immune system’s rejection of the graft or development of graft-versus-host disease, in which immune cells from the donor attack the recipient’s tissues, investigators tested the patient and the potential donor to determine if they are a good immunological match. This is called human leukocyte antigen (HLA) typing.
The investigators performed HLA typing on 112 people with severe sickle cell disease and 169 healthy siblings. Of these, 10 patient-sibling identical matches were found. Blood stem cells collected from the blood of healthy donors were then infused into their siblings, ages 16 to 45 years.
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