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

Overview

The main reason for this research study is to learn more about hydroxyurea and the treatment of sickle cell anemia (SCA). Hydroxyurea is a medication that has been studied for many years and has been shown to provide benefits for people with SCA. In this research study, the investigators hope to learn more about how to improve the dosing and monitoring of hydroxyurea and learn more about the long-term effects of hydroxyurea over time. Hydroxyurea is usually dosed based only on your weight. Our study will use a new way to select a starting dose that is based on how each patient absorbs hydroxyurea.

Detailed description

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.

3\. 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.

Interventions

• Drug PK-optimized oral hydroxyurea at MTD until 15 years of age.
  Because people are different, we will measure how each participant's body absorbs and eliminates the medicine, hydroxyurea, using blood tests. This information will be used to determine the best dose for each participant (rather than using the same weight-based dose for everyone).

Primary outcome measures

• Composite Organ Injury [Time frame: Through study completion, an average of 10 years]

Secondary outcome measures (7)

• longitudinal change in fetal hemoglobin percentage (HbF%) [Time frame: Through study completion, an average of 10 years]
• Longitudinal change in hemoglobin concentration (g/dL) [Time frame: Through study completion, an average of 10 years.]
• Longitudinal change in reticulocyte count (10^9/L) [Time frame: Through study completion, an average of 10 years.]
• Longitudinal change in absolute neutrophil count (10^9/L) [Time frame: Through study completion, an average of 10 years.]
• Longitudinal change in mean cell volume (fL) [Time frame: Through study completion, an average of 10 years.]
• F-cell fraction (%) [Time frame: Through study completion, an average of 10 years.]
• Adverse events [Time frame: Through study completion, an average of 10 years.]

Eligibility criteria

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+)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• Cincinnati Children's Hospital Medical Center — Cincinnati

Publications

• Hay SB, Ferchen K, Chetal K, Grimes HL, Salomonis N. The Human Cell Atlas bone marrow single-cell interactive web portal. Exp Hematol. 2018 Dec;68:51-61. doi: 10.1016/j.exphem.2018.09.004. Epub 2018 Sep 21. PMID 30243574
• Marahatta A, Megaraj V, McGann PT, Ware RE, Setchell KD. Stable-Isotope Dilution HPLC-Electrospray Ionization Tandem Mass Spectrometry Method for Quantifying Hydroxyurea in Dried Blood Samples. Clin Chem. 2016 Dec;62(12):1593-1601. doi: 10.1373/clinchem.2016.263715. Epub 2016 Sep 30. PMID 27694393
• Vassiliou G. Telomere Length and Clonal Hematopoiesis. N Engl J Med. 2023 Jun 29;388(26):2481-2484. doi: 10.1056/NEJMe2303022. Epub 2023 May 4. No abstract available. PMID 37140164
• Bowman RL, Busque L, Levine RL. Clonal Hematopoiesis and Evolution to Hematopoietic Malignancies. Cell Stem Cell. 2018 Feb 1;22(2):157-170. doi: 10.1016/j.stem.2018.01.011. PMID 29395053
• Sankaran VG, Xu J, Orkin SH. Advances in the understanding of haemoglobin switching. Br J Haematol. 2010 Apr;149(2):181-94. doi: 10.1111/j.1365-2141.2010.08105.x. Epub 2010 Mar 1. PMID 20201948
• Ware RE, Davis BR, Schultz WH, Brown RC, Aygun B, Sarnaik S, Odame I, Fuh B, George A, Owen W, Luchtman-Jones L, Rogers ZR, Hilliard L, Gauger C, Piccone C, Lee MT, Kwiatkowski JL, Jackson S, Miller ST, Roberts C, Heeney MM, Kalfa TA, Nelson S, Imran H, Nottage K, Alvarez O, Rhodes M, Thompson AA, Rothman JA, Helton KJ, Roberts D, Coleman J, Bonner MJ, Kutlar A, Patel N, Wood J, Piller L, Wei P, L PMID 26670617
• Hankins JS, Helton KJ, McCarville MB, Li CS, Wang WC, Ware RE. Preservation of spleen and brain function in children with sickle cell anemia treated with hydroxyurea. Pediatr Blood Cancer. 2008 Feb;50(2):293-7. doi: 10.1002/pbc.21271. PMID 17554794
• Letvin NL, Linch DC, Beardsley GP, McIntyre KW, Nathan DG. Augmentation of fetal-hemoglobin production in anemic monkeys by hydroxyurea. N Engl J Med. 1984 Apr 5;310(14):869-73. doi: 10.1056/NEJM198404053101401. PMID 6199670

Identifiers

NCT: NCT07177300 · ENHANCE · GCF_Quinn

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗