Pharmacokinetic-Guided Hydroxyurea to Reduce Transfusion Requirements in Ugandan Children with Sickle Cell Anemia: Baseline Data from the Alternative Dosing and Prevention of Transfusions (ADAPT) Trial

Background: Children are the primary recipients of blood transfusions in sub-Saharan Africa where the demand for safe blood far exceeds the supply. Without disease-modifying therapy, sickle cell anemia (SCA) causes excess morbidity, mortality, and healthcare resource utilization, specifically requiring a high reliance on blood transfusions. Hydroxyurea is a safe and effective medication for the treatment of SCA that decreases blood transfusion use in this population, which may offset the costs of improving hydroxyurea access. The widespread use of hydroxyurea in Africa is limited in part by challenges determining an individual's optimal dose; pharmacokinetic (PK) dosing of hydroxyurea may streamline the dosing process, maximizing the clinical benefits and minimizing toxicities. We designed the Alternative Dosing And Prevention of Transfusions (ADAPT) trial to analyze the reduction in transfusion use with hydroxyurea and as a pilot evaluation of the feasibility of PK-guided hydroxyurea dosing in Uganda.

Methods: ADAPT (NCT05662098) is a prospective, single-center, open-label cohort study at Jinja Regional Referral Hospital in Uganda. Children 1-10 years old with HbSS were eligible to enroll; those already receiving hydroxyurea or scheduled blood transfusions, or with malignancy, HIV, tuberculosis, or other chronic illnesses were excluded, and those who received a transfusion within 30 days were temporarily excluded. All participants completed a 3-month screening period during which they underwent baseline evaluations and hydroxyurea PK testing. For PK testing, a 500 mg hydroxyurea test dose was administered, and serum was collected 30, 60, and 180 minutes after the dose. Hydroxyurea concentrations were determined via chemical derivatization and high-performance liquid chromatography in Uganda. Area-under-time-concentration-curves (AUC) and Bayesian estimation were then used to calculate the optimal hydroxyurea dose based on target medication exposure. Those for whom hydroxyurea PK evaluation was completed successfully with a dose recommendation between 15-35 mg/kg/day started on their PK-guided hydroxyurea dose; otherwise, participants started on the default dose of 20 mg/kg/day. All participants will be treated on hydroxyurea for a minimum of 12 months during which time both treatment groups will follow the same laboratory monitoring and dose adjustment protocol to achieve the maximum tolerated dose. The primary study endpoint is the incidence rate ratio of blood transfusion use during screening versus treatment. Secondary endpoints include characterization of blood transfusions (indications, risk factors, adverse reactions), feasibility of PK testing, and laboratory and clinical adverse events comparing children started on PK-guided versus default dosing.

Results: From June 2022 to January 2023, 106 participants were enrolled, exceeding the projected enrollment pace and goal. The average age (mean ± SD) at enrollment was 4.6 ± 2.3 years, and 50% were female. Per family-reported history, most participants had previously received a blood transfusion (78%) with 15% reporting at least 6 lifetime transfusions. Five percent had a prior stroke. A majority also had a history of pain events (86%), malaria (79%), and dactylitis (74%). Only 2% had previously used hydroxyurea. At enrollment, the median weight-for-height z-score was -0.19 (interquartile range -1.03-0.32), and baseline exam demonstrated a palpable spleen in 20%. Abdominal ultrasonography was completed on all participants, and the spleen was identified in 75% of participants with a mean volume of 132 ± 99 mL. Transcranial Doppler exams were completed on 105 participants (99%) during screening with 13% conditional and 6% abnormal results. Baseline labs (mean ± SD) documented hemoglobin = 7.7 ± 1.3 g/dL and HbF = 10.3 ± 7.1 %. Of 106 children enrolled, 1 died from acute chest syndrome in screening and 2 were withdrawn after moving away from the clinic; 103 successfully initiated hydroxyurea treatment.

Conclusion: ADAPT has fully completed enrollment and will prospectively evaluate the effectiveness of hydroxyurea treatment on reducing transfusion use in Ugandan children with SCA, a finding with both individual and public health implications. ADAPT will also provide pilot data regarding the feasibility of PK-guided dosing of hydroxyurea to facilitate safe, effective hydroxyurea use in Africa.