BACKGROUND: 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. Pilot data indicate hydroxyurea can prevent stroke recurrence in children with SCA, and after transfusions are discontinued, serial phlebotomy reduces iron burden.

DESIGN NARRATIVE: This is a Phase III randomized clinical trial for children with sickle cell anemia (SCA). The study tests that hypothesis 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.

The trial includes approximately 130 children (5.0-15.9 years of age with 65 subjects per treatment arm) with sickle cell anemia who have had symptomatic cerebral infarctions and have been treated with monthly red cell transfusion and iron chelation. The plan is that after 30 months or more of transfusion/chelation therapy, half the patients will be switched to a therapeutic program of hydroxyurea and phlebotomy. Half will remain on transfusion/desferoxamine chelation. The composite primary endpoint in this study is to compare two modalities of treatment for prevention of secondary stroke and iron overload. The impetus for this trial is the fact that long term transfusion/chelation therapy in children is difficult, is frequently unsuccessful, often complicated by severe symptomatic iron overload particularly of the heart, lungs and liver.