? ? Stroke occurs in 10% of children with sickle cell anemia (SCA) and has a very high risk of recurrence without therapy. Affected children receive chronic erythrocyte transfusions to prevent a secondary stroke, which are effective but have limited long-term utility due to transmission of infectious agents, erythrocyte alloantibody and autoantibody formation, and iron overload. Transfusion acquired iron overload has morbidity and mortality for young patients with SCA and stroke, including chronic organ damage with hepatic fibrosis and cirrhosis, poor growth and development, cardiac arrhythmias, and early sudden death. Deferoxamine (Desferal(r)) chelation therapy is difficult to tolerate and leads to non-compliance an alternative to transfusions for secondary stroke prevention is clearly needed, which also addresses the issue of transfusion acquired iron overload. Hydroxyurea can prevent acute vaso-occlusive events in SCA, but its utility for cerebrovascular disease and specifically for the prevention of secondary stroke in SCA, is not proven. Our pilot data indicate hydroxyurea can prevent stroke recurrence in children with SCA, and after transfusions are discontinued, serial phlebotomy reduces iron burden. We propose a Phase III randomized clinical trial for children with SCA termed Stroke with Transfusions Changing to Hydroxyurea (SWiTCH). We hypothesize that hydroxyurea and phlebotomy can maintain an acceptable stroke recurrence and significantly reduce the hepatic iron burden. The primary aim is to compare standard therapy (transfusions and chelation) with alternative therapy (hydroxyurea and phlebotomy) for the prevention of secondary stroke and management of iron overload. Additional aims include comparisons of growth and development, frequency of non-stroke neurological and other sickle-related events, and quality of life. The use of hydroxyurea for secondary stroke prevention, coupled with removal of excess iron by phlebotomy, would represent a significant improvement in the management of patients with SCA and stroke. If hydroxyurea has efficacy for prevention of secondary stroke, it may also be beneficial for other children with SCA and cerebrovascular disease including those at risk for primary stroke. ? ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HL078787-04
Application #
7479269
Study Section
Clinical Trials Review Committee (CLTR)
Program Officer
Luksenburg, Harvey
Project Start
2005-08-05
Project End
2010-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
4
Fiscal Year
2008
Total Cost
$3,101,582
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
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Schaefer, Beverly A; Flanagan, Jonathan M; Alvarez, Ofelia A et al. (2016) Genetic Modifiers of White Blood Cell Count, Albuminuria and Glomerular Filtration Rate in Children with Sickle Cell Anemia. PLoS One 11:e0164364
Aygun, Banu; Mortier, Nicole A; Kesler, Karen et al. (2015) Therapeutic phlebotomy is safe in children with sickle cell anaemia and can be effective treatment for transfusional iron overload. Br J Haematol 169:262-6
Sheehan, Vivien A; Crosby, Jacy R; Sabo, Aniko et al. (2014) Whole exome sequencing identifies novel genes for fetal hemoglobin response to hydroxyurea in children with sickle cell anemia. PLoS One 9:e110740
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Flanagan, Jonathan M; Sheehan, Vivien; Linder, Heidi et al. (2013) Genetic mapping and exome sequencing identify 2 mutations associated with stroke protection in pediatric patients with sickle cell anemia. Blood 121:3237-45
McCarville, Mary Beth; Rogers, Zora R; Sarnaik, Sharada et al. (2012) Effects of chronic transfusions on abdominal sonographic abnormalities in children with sickle cell anemia. J Pediatr 160:281-285.e1
Ware, Russell E; Helms, Ronald W; SWiTCH Investigators (2012) Stroke With Transfusions Changing to Hydroxyurea (SWiTCH). Blood 119:3925-32

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