Effectiveness of Nontraditional Hydroxyurea Algorithms: Novel and Clinical Evaluations (ENHANCE)

The EHANCE study will address key knowledge gaps about hydroxyurea for young children with SCA in nine innovative ways:

• Novel functional assessments of brain, heart, kidneys, spleen, and eyes to assess organ protection in young children who receive hydroxyurea at MTD;
• State-of-the-art assays to assess the benefits of hydroxyurea on growth, development, and reproductive health into puberty including serial measurements of pubertal development and sex hormones;
• A simplified PK-guided strategy to optimize hydroxyurea initiation and dosing, with a long-term goal of validating pharmacogenomic approaches to expand treatment and achieve sustained HbF induction;
• A novel single-cell quantitative HbF/F-cell assay, developed utilizing imaging flow cytometry, will determine the distribution of HbF/F-cell across all F-cells, rather than simply estimating the mean value of HbF/F-cell;
• Collection of genomic DNA samples to allow serial quantitation of clonal hematopoiesis in treated children, to evaluate the possibility for potential emergence of clones with an increased risk of leukemic transformation;
• Studies on primary erythroblasts freshly isolated from patients and control subjects with single cell multiome analysis to evaluate in vivo cis and trans-acting elements that regulate HbF and how they are affected by hydroxyurea;
• Evaluation of cellular mechanisms by which hydroxyurea at MTD can regularly achieve >30% HbF with near-pancellular distribution, similar to levels currently touted with 'curative' gene therapy regimens;
• Exploration of the benefits of early hydroxyurea treatment initiation, in terms of γ-globin de-repression to optimize HbF induction, through unknown cellular mechanisms that may be developmentally regulated.

• SPECIFIC AIMS Aim 1: Document the long-term benefits and risks of long-term hydroxyurea treatment at MTD.

Aim 2: Perform pharmacokinetic (PK) and pharmacodynamic (PD) assessment of hydroxyurea at MTD.

Aim 3: Investigate the cellular mechanisms by which hydroxyurea leads to induction of protective HbF and how timing of treatment initiation and dose optimization affect the efficacy of this process.

Inclusion criteria

• Diagnosis of sickle cell anemia (HbSS) or sickle-β0-thalassemia (HbSβ0)
• Age 6 months at the time of enrollment
• Clinical decision by patient, family, and healthcare provider to initiate hydroxyurea therapy

Exclusion criteria

• Current treatment with regularly scheduled blood transfusions
• Sickle-hemoglobin C disease (HbSC), sickle-β+-thalassemia (HbSβ+)