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Updated: Feb 22, 2026
A Precision Medicine Tool for Measurement and Monitoring of Hemoglobin S in Sickle Cell Disease Patients Receiving Transfusion Therapy
A clinically meaningful fetal hemoglobin threshold for children with sickle cell anemia during hydroxyurea therapy
Jeremie H Estepp1,2, Matthew P Smeltzer3, Guolian Kang4
1Department of Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee.
Insights
Hydroxyurea treatment for sickle cell anemia (SCA) in children is effective. Achieving fetal hemoglobin (HbF) levels above 20% significantly reduces hospitalizations without increasing toxicity, supporting higher dosing strategies.
Area of Science:
- Pediatric Hematology
- Sickle Cell Disease Management
- Pharmacological Interventions
Background:
- Hydroxyurea is recommended for all children with sickle cell anemia (SCA).
- Optimal dosing for hydroxyurea in pediatric SCA remains debated.
- The relationship between fetal hemoglobin (HbF) levels and clinical outcomes needs further clarification.
Purpose of the Study:
- To describe the long-term clinical effects of escalating hydroxyurea to its maximal tolerated dose (MTD) in children with SCA.
- To investigate the association between HbF levels and clinical outcomes in pediatric SCA patients on hydroxyurea therapy.
Main Methods:
- Prospective observational study (HUSTLE, NCT00305175).
- Followed 230 children with SCA for 610 patient-years.
- Monitored HbF levels and clinical outcomes, including hospitalizations and adverse events.
Main Results:
- Mean HbF levels exceeded 20% at MTD for up to 4 years.
- HbF ≤20% was associated with doubled odds of hospitalization (any reason, vaso-occlusive pain, acute chest syndrome) and quadrupled odds of fever-related admission.
- Neutropenia was rare, transient, and benign.
Conclusions:
- Attaining HbF >20% is linked to reduced hospitalizations in pediatric SCA patients.
- Higher hydroxyurea dosing targeting HbF >20% appears safe and effective.
- These findings support utilizing hydroxyurea dosing strategies aimed at achieving HbF levels above 20% in children with SCA.
Abstract:
Hydroxyurea has proven clinical benefits and is recommended to be offered to all children with sickle cell anemia (SCA), but the optimal dosing regimen remains controversial. Induction of red blood cell fetal hemoglobin (HbF) by hydroxyurea appears to be dose-dependent. However, it is unknown whether maximizing HbF% improves clinical outcomes. HUSTLE (NCT00305175) is a prospective observational study with a primary goal of describing the long-term clinical effects of hydroxyurea escalated to maximal tolerated dose (MTD) in children with SCA. In 230 children, providing 610 patient-years of follow up, the mean attained HbF% at MTD was >20% for up to 4 years of follow-up. When HbF% values were ≤20%, children had twice the odds of hospitalization for any reason (P < .0001), including vaso-occlusive pain (P < .01) and acute chest syndrome (ACS) (P < .01), and more than four times the odds of admission for fever (P < .001). Thirty day readmission rates were not affected by HbF%. Neutropenia (ANC <1000 × 106 /L) was rare (2.3% of all laboratory monitoring), transient, and benign. Therefore, attaining HbF >20% was associated with fewer hospitalizations without significant toxicity. These data support the use of hydroxyurea in children, and suggest that the preferred dosing strategy is one that targets a HbF endpoint >20%.
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