EXTEND EXpanding Treatment for Existing Neurological Disease

Hydroxyurea treatment: Participants will be treated with open-label hydroxyurea, available as 500 mg capsules or liquid (100 mg/mL). Hydroxyurea will be administered once daily by mouth. Participants will be monitored monthly to maximum tolerated dose and quarterly thereafter with periodic clinical evaluations, laboratory tests, and transcranial doppler examinations every 6 months. Hydroxyurea will be titrated to the maximum tolerated dose as defined by mild marrow suppression, even if the participant has clinical well-being at a lower hydroxyurea dose. The target absolute neutrophil count (ANC)on hydroxyurea therapy will be \< 3.0 x 109/L, but the marrow suppression should also include reduction of the reticulocyte count. Hydroxyurea dosing will commence at 20 mg/kg/day. Dose escalation will occur in 5 mg/kg/day increments, adjusting every 8 weeks unless dose-limiting hematological toxicity occurs (defined as ANC \< 1.0 x 109/L, hemoglobin concentration \< 5 gm/dL or 20% below baseline, absolute reticulocyte count \< 80 x 109/L unless hemoglobin concentration \>9.0 gm/dL, or platelet count \< 80 x 109/L) or the target neutropenia (ANC \< 3.0 x 109/L) is achieved. Based on pilot data and experience in other clinical trials, most pediatric participants require hydroxyurea doses of 20-30 mg/kg/day to reach this target absolute neutrophil count . After reaching maximum tolerated dose, minor hydroxyurea dose adjustments can be made periodically, as necessary based on weight changes and blood counts, to maintain the optimal laboratory response and to prevent dose-related toxicity. If the absolute neutrophil count (ANC) rises above the target range on 2 consecutive visits, compliance will be reinforced and the dose may be adjusted by 2.5 mg/kg/day at eight week intervals to a maximum of 35 mg/kg/day or 2000 mg/day. For hydroxyurea dosing, the current body weight will be used, with dose escalations guided by hematological toxicity. Hydroxyurea will be reduced or even temporarily discontinued for hematological toxicities, e.g., ANC \< 1.0 x 109/L, hemoglobin \< 5.0 gm/dL, or 20% below baseline, absolute reticulocyte count \< 80 x 109/L unless hemoglobin concentration \> 9.0 gm/dL, or platelets \< 80 x 109/L.