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NHLBI stops sickle cell anemia transfusion study

December 4-7, 2004. San Diego, California.

 
The American Society of Hematology is the world's largest professional society concerned with the management of blood disorders.
 

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San Diego, CA, Dec. 5, 2004 ? The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) has stopped early a clinical trial studying whether children with sickle cell anemia at high risk for stroke could at some point after a minimum of 30 months (range 30-91 months) safely stop receiving the periodic blood transfusions that prevent strokes.

The study found a return to high risk of stroke in children who stopped receiving the transfusions. The National Heart, Lung and Blood Institute of the National Institutes of Health, which funded the $11 million study headquartered at the Medical College of Georgia in Augusta, issued a clinical alert to coincide with the Dec. 5 announcement of study findings at the American Society of Hematology meeting in San Diego.

"Whatever process puts these children at risk is fairly durable," says Dr. Robert J. Adams, neurologist and stroke specialist at MCG and principal investigator on the Optimizing Primary Stroke Prevention in Children with Sickle Cell Anemia, or STOP II, study. "We believed that we had identified a group that might tolerate coming off transfusion but the results did not confirm this. Too many of those taken off had return of abnormal transcranial Doppler, the best indicator we have of stroke risk, and there were two strokes in this group. We need more research to come up with a better way to limit the use of transfusion while still preventing strokes."

"This important study shows the value of continuing periodic blood transfusions in preventing the serious and debilitating consequences of stroke," says NHLBI Acting Director Barbara Alving. "At the same time, there are risks of chronic transfusions and the decision to continue with this treatment must be made on a case-by-case basis."

The STOP II study tested whether regular transfusions could be safely stopped after at least 30 months in a group of children who reverted to low stroke risk based on normal transcranial Doppler and magnetic resonance angiography after treatment.

The study was to have enrolled 100 children. However, the NHLBI-appointed Data and Safety Monitoring Board recommended early closure of the study after 79 children were enrolled and randomized ? half continued transfusion, half did not ?because too many of the children who did not receive transfusions were reverting to high-risk status.

Of the 41 children who came off transfusions, 14 reverted to high-risk status within 10 months and two others had strokes shortly after their first abnormal study but before a confirmatory test could be performed and transfusions resumed. No reversions or strokes were seen in children who continued to receive transfusions. Thirteen of the 14 children who reverted to high-risk status resumed transfusions; one patient opted against resumption.

"Some reversion to high risk was expected with discontinuing transfusion, but the number was too high," Dr. Adams says. "Even with the strict TCD monitoring required in the study protocol, which is probably more rigorous than you can expect in clinical practice, we still had two children experience strokes. Although TCD indicated that stroke risk had returned, there was not much time after the first abnormal TCD in these children to respond and restart treatment."

Dr. Adams and Dr. Virgil C. McKie, the now-retired chief of pediatric hematology/oncology at MCG, published a paper in the New England Journal of Medicine in 1992 identifying the painless transcranial Doppler as the first non-invasive method for identifying these children before their first stroke.

The finding led to the original STOP study, which found that monthly blood transfusions that raise the amount of healthy, oxygen-carrying red blood cells in these at-risk children reduced stroke risk by 90 percent. That study, which began in early 1995 and followed 130 at-risk children with sickle cell disease age 2-16 at 14 sites in the United States and Canada, also was halted early in September 1997 by the NHLBI because of the obvious transfusion benefit. The institute issued a physician advisory recommending regular transcranial Doppler studies in children age 2-16 with sickle cell disease and consideration of transfusions in children at risk.

STOP II sought to determine whether the normalizing benefits of 30-plus months of transfusions would hold up if therapy stopped.

"While some children seemed to tolerate coming off transfusion, in most others, the need for ongoing treatment was clear within a few months. Some of those who halted transfusions restarted for other reasons such as pain," Dr. Adams says of the still poorly understood events that lead to narrowed arteries and stroke risk in these children. The idea of regularly transfusing children has understandably met with some resistance from clinicians and parents because of concerns such as iron buildup and blood-borne infections, Dr. Adams says. "Now, we need to work on other ways to provide some kind of maintenance therapy that is safer long term and that holds onto the large gains in stroke prevention we have made. We know that for the stroke-prevention strategy based on STOP to be fully accepted, we have to find a stopping point for transfusions."

One approach might be comparing transfusion therapy to hydroxyurea, the first Food and Drug Administration-approved drug for adults with sickle cell disease, which is still under study in children. The drug raises the level of fetal hemoglobin, which cannot sickle. Another approach is modifying the transfusion program to deliver less iron.

Dr. McKie, Professor Emeritus of Pediatrics and STOP II co-investigator, concurs that STOP 2 is not the end of the story. "Now it's time to step back and see if we can figure out what it is about the 10 percent that makes them at risk," he says. "The other issue is how transfusions work to prevent strokes."

They are joining forces with Dr. Jin-Xiong She, director of the MCG Center for Biotechnology and Genomic Medicine, to look for clues about how the stroke risk happens and possibly for better ways to avoid stroke. "We can compare the serum of children who continued transfusion therapy and those who did not to look for differences," Dr. Adams says. The difference could be proteins that damage blood vessel walls or enhance cells sticking to those walls, he says.

"Although we have a very effective primary prevention strategy, we have not made substantial progress in understanding what is driving the process," so Dr. Adams also wants to study why blood vessel walls thicken and passageways narrow.

The mounting evidence makes him certain that all children with sickle cell disease should get transcranial Doppler screening at age 2 with a follow-up within a year. If the studies are normal, parents and physicians should work out individualized follow-up, with the general guideline that those who need closest follow-up are the youngest children whose studies are closest to abnormal.

In the meantime, Dr. McKie is glad to have better information he can present to parents to help them make better choices for their children.

Legal Disclaimer

The materials presented here were prepared by independent authors under the editorial supervision of The Doctors Lounge, and do not represent a publication of the American Society of Hematology. These materials and the related activity are not sanctioned by the American Society of Hematology or the commercial supporter of the conference, and do not constitute an official part of that conference.

The material presented here does not reflect the views of The Doctors Lounge or the companies providing unrestricted educational grants. These materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified health care professional should be consulted before using any therapeutic product discussed. All readers or continuing education participants should verify all information and data before treating patients or employing any therapies described in this educational activity.

Copyright ? 2004 The Doctors Lounge.

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