Hydroxyurea Decreases Transfusion Utilization in Ugandan Children with Sickle Cell Anemia: Main Results from the Alternative Dosing and Prevention of Transfusions (ADAPT) Trial

Introduction: Over 75% of people with sickle cell anemia (SCA) live in Africa where limited access to disease-modifying treatment leads to over-reliance on scarce blood transfusions to treat acute SCA complications. Hydroxyurea may be an important individual and public health strategy to decrease transfusion use in Africa. Hydroxyurea provides the most benefits at maximum tolerated dose (MTD), which varies due to individual pharmacokinetic (PK) differences.

Methods: Alternative Dosing And Prevention of Transfusions (ADAPT, NCT05662098) is a prospective, open-label trial to evaluate the impact of hydroxyurea on transfusion rates and clinical indications for children with SCA in Jinja, Uganda. A key secondary aim is to evaluate the feasibility of PK-guided hydroxyurea dosing in this setting. Children 1-10 years old with HbSS were included; those receiving hydroxyurea or monthly blood transfusions were excluded. The primary study endpoint was the transfusion incidence rate ratio (IRR) between the 3-month screening period and the 12-month treatment period. The decision to transfuse was made by local clinicians based on national guidelines. Transfusion indications, volumes, adverse reactions, and peri-transfusion vital signs, physical exam, and lab parameters were recorded. All participants underwent first-dose PK testing with sparse sample collection, local portable high performance liquid chromatography (SmartLife, HPLC), and PK-dose generation with web-based software (HdxSim). Participants for whom a PK dose was generated within 15-35 mg/kg/day started on their individualized dose; those for whom a dose was not generated or if the dose was outside of the predefined range started at a default dose (20 mg/kg/day) per national guidelines. All children had equivalent laboratory monitoring and dose adjustment criteria to reach MTD.

Results: ADAPT enrolled 106 children (50% female, mean ± standard deviation (SD) age 4.3 ± 2.3 years). Most (83, 78%) had ≥1 transfusion prior to enrollment, and 37 (35%) reported ≥3 lifetime transfusions. At baseline, the average hemoglobin (Hb) =7.7 ± 1.3 g/dL and fetal Hb (HbF) = 10.3 ± 7.3%. The transfusion rate during screening was 2.40 per person-year and decreased to 1.36 on hydroxyurea (IRR 0.57, 95% CI 0.37-0.88, p=0.011). During both screening and treatment, anemia was the primary transfusion indication followed by malaria. A total of 29 (28.2%) participants started on an individualized, PK-guided dose (28.3 ± 5.3 mg/kg/day) and after 12 months of treatment were receiving 29.5 ± 2.9 mg/kg/day. Children started on the default dose (20 mg/kg/day) escalated to 26.5 ± 5.3 mg/kg/day, p=0.005 comparing PK-guided to standard dosing. After 12 months of treatment, children started on the PK dose had higher HbF responses than those started on the default dose (34.2 ± 14.7% vs 27.6 ± 11.4%, p=0.018). The rate of dose-limiting toxicities between children started on PK-guided vs default dosing was equivalent (0.2 vs 0.3 per patient year, p=0.16). The transfusion rates for those started on the default vs PK-guided dose were also similar (1.36 vs 1.39 per person-year, p=0.9).

Conclusion: In ADAPT, a significant 43% reduction in transfusion use was observed in children with SCA during 12 months of hydroxyurea treatment. Prior studies have demonstrated that hydroxyurea reduces transfusion needs in children with SCA, but ADAPT is the first prospective trial to evaluate this individual and public health benefit as a primary study endpoint. ADAPT has also evaluated the feasibility and benefits of prospective PK-guided medication dosing in Africa. Although the PK process needs improvement, the PK-guided starting doses were remarkably close to MTD, achieving HbF>30% safely without stepwise escalation or increased toxicity.