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NHLBI stops sickle cell anemia transfusion study
December 4-7, 2004. San Diego, California.
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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.
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