P-039: Alternative Dosing and Prevention of Transfusions (Adapt): A Prospective Trial Evaluating Transfusion Utilization and the Feasibility of Pharmacokinetic Hydroxyurea Dosing in Children with Sickle Cell Anemia in Uganda

Abstract

Purpose: Blood transfusions are a scarce resource globally and particularly in sub-Saharan Africa. Without disease-modifying therapy, in sub-Saharan Africa sickle cell anemia (SCA) has excess morbidity, mortality, and healthcare resource utilization, specifically requiring a high reliance on blood transfusions. Hydroxyurea is a safe medication for the treatment of SCA that can decrease rates of blood transfusions. The widespread use of hydroxyurea in sub-Saharan Africa is limited in part, however, by logistical challenges in determining an individual patient’s optimal dose. Pharmacokinetic (PK) dosing of hydroxyurea may streamline the dosing process, maximizing the clinical benefits and minimizing toxicities, while reducing the time and resources needed to determine the optimal dose. We hypothesize that hydroxyurea treatment will be associated with a 50% reduction in blood transfusion rate in children with SCA, compared to pre-treatment utilization, and that determining a PK-based hydroxyurea starting dose will be feasible in 80% of participants. Materials and methods: To test this hypothesis, we will conduct the Alternative Dosing and Prevention of Transfusions (ADAPT) trial, a prospective cohort study of children with SCA in Jinja, Uganda (Figure). Transfusion rates and indications will be prospectively recorded during a 3-month pre-treatment period and compared to a 12-month treatment period. Every participant will undergo baseline hydroxyurea PK testing using timed serum collections based on our published sparse-sampling method and HPLC analysis. If generated, the participant will start on their PK-guided dose; when PK testing is not feasible, the participant will be started on 20 mg/kg/day per Ugandan guidelines. Regardless of starting dose (PK or default), all participants will undergo the same laboratory monitoring schedule with dose escalation and adjustments as necessary. Hydroxyurea will be purchased from a local commercial source using 500mg capsules. Results: The primary endpoint will be incidence rate ratio of transfusions per 100-patient years during hydroxyurea treatment as compared with the pre-treatment period. Based on sample size analysis, a total of 100 children with SCA (HbSS genotype), aged 1 to 10 years, will be enrolled in ADAPT. A student’s t-test will be performed to compare the rate of transfusions per 100 patient-years prior to and during hydroxyurea treatment. The secondary endpoints include feasibility of determining a PK-based starting dose and the rates of transfusions, clinical events, dose-limiting toxicities, and dose adjustments in participants on PK-based versus default start dose. Conclusion: Overall, the potential for hydroxyurea to reduce the rate of blood transfusions in children with SCA will have important individual and public health implications. Determining the feasibility and accuracy of PK-dosing of hydroxyurea could simplify the safe and effective treatment of SCA. ADAPT is a collaborative research partnership that will provide important data toward increasing the use of hydroxyurea in Uganda and potentially across sub-Saharan Africa.