PEDIATRIC HYDROXYUREA STUDY GROUP

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Hydroxyurea (HU) is an antineoplastic agent that has been shown to increase fetal hemoglobin production in a small experimental group of adult subjects with sickle cell disease (SCD). Because these studies have revealed a hemoglobin F response with minimal toxicity in adults, a larger-scale, placebo controlled study of efficacy in adults is underway. Until the efficacy of HU therapy for SCD is demonstrated in the adult trial, there is no rationale for doing a large scale efficacy trial in pediatric sickle cell patients. However, there are a small number of children and adolescents around the country for whom there is currently no treatment option available. These are atypical children with exceptionally high rates of painful "crises", severe recurrent episodes of chest syndrome, or stroke, and the inability to be transfused because of alloimmunization. In most large pediatric centers, a trial of hydroxyurea will be considered for such patients on a "compassionate" individual basis. We are concerned that although these individual ad hoc protocols may prove beneficial to treat individual patients, there will be no collective knowledge gained, no organized body of data to draw from if and when it comes time to design a large prospective trial assessing clinical efficacy in children. In this proposal, we organize a consortium of pediatric clinical investigators who will agree not to use a variety of ad hoc protocols to treat their patients, but will instead follow a common protocol and pool their individual experiences. We do not intend to increase the number of pediatric patients who would receive hydroxyurea, but rather to have all of these patients treated in a uniform manner. Entry and exclusion criteria have been defined. A series of standard data collection forms have been developed. The data coordinating center will be based at Duke-UNC Sickle Cell Center. The dosing schedule and toxicity criteria are based on the results of the adult experience. Patients will start on 15 mg/kg/day and be advanced in 5 mg/kg increments every 12 weeks, following strict toxicity criteria. The maximal dose will be 30 mg/kg/day. Patients will be monitored every two weeks. F cell counts will be determined centrally at the Johns Hopkins Medical School by George Dover, M.D. Once the "maximal tolerated dose" is achieved, patients will be continued on that dose for 12 months. Our goal is to obtain preliminary data on the following questions: (1) is hydroxyurea effective in increasing fetal hemoglobin levels in children, (2) are there serious toxicities in children that were not seen in adults, and (3) what is the impact of hydroxyurea therapy on growth? The overall strategy would be to develop a common dosing schedule, exclusion criteria, and monitoring protocol.