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.

Inclusion criteria

• Pediatric participants with a severe form of sickle cell anemia (HbSS, HbSβ0 thalassemia, HbSD, HbSOArab)
• Age: ≥ 2 and ≤ 17 years of age, at the time of enrollment
• Time-averaged maximum velocity (TAMV) TCD Velocity in the conditional (170 - 199 cm/sec) or abnormal (≥200 cm/sec) range by Transcranial Doppler ultrasonography examination within 6 months of enrollment, abnormal or conditional TCD velocity and currently on commercial hydroxyurea for primary stroke prevention, or previously enrolled in SCATE, a previous stroke with abnormal or conditional TCD prior to stroke event.
• Parent or guardian willing and able to provide informed consent and child gives assent
• Ability to comply with study related treatments, evaluations, and follow- up visits

Exclusion criteria

• Inability to take or tolerate daily oral hydroxyurea, including

• Known allergy to hydroxyurea therapy
• Known positive serology to HIV infection
• Known malignancy
• Current lactation
• Abnormal historical laboratory values (most recent pre-enrollment values unless previously enrolled in SCATE):

• Hemoglobin concentration < 6.0 gm/dL
• Absolute reticulocyte count < 100 x 109/L with a hemoglobin concentration < 8.0 gm/dL
• White Blood Cell (WBC) count < 3.0 x 109/L
• Absolute neutrophil count (ANC) < 1.0 x 109/L
• Platelet count < 100 x 109/L
• Use of therapeutic agents for sickle cell disease (e.g., hydroxyurea, arginine, decitabine, magnesium, chronic transfusions) within 3 months of enrollment unless they have an abnormal TCD velocity and receive commercial hydroxyurea for primary stroke prevention or were previously enrolled in the SCATE study or for secondary stroke prevention in a child with a previous stroke.
• Current participation in other therapeutic clinical trials, except SCATE
• Known serum creatinine more than twice the upper limit for age AND

• 1.0 mg/dL
• Any condition or chronic illness, which in the opinion of the clinical investigator makes participation ill-advised
• Pregnancy (for post-menarchal females only)
• Erythrocyte transfusion within the past 2 months
• Previous stem cell transplant or other myelosuppressive therapy (unless they have an abnormal TCD velocity and receive commercial hydroxyurea for primary stroke prevention or for secondary stroke prevention in a child with a previous stroke or were previously enrolled in SCATE)