Maximal Tolerated Dose of Hydroxyurea Supported in Children With Sickle Cell Anemia

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Recently reported results from Hydroxyurea Study of Long-Term Effects (HUSTLE) support the use of hydroxyurea in children, and indicate that a preferred dosing strategy should target an HbF endpoint of greater than 20%.

Hydroxyurea is recommended for the treatment of children who have sickle cell anemia (SCA), but optimal dosing of the drug has been a matter of controversy. Recently reported results from the Hydroxyurea Study of Long-Term Effects (HUSTLE) support the use of hydroxyurea in children, and indicate that a preferred dosing strategy should target a fetal hemoglobin (HbF) endpoint of greater than 20%.

The HUSTLE study was a prospective, observational study with primary goal of identifying the long-term clinical effects of hydroxyurea escalated to a maximal tolerated dose (MTD). Hydroxyurea is currently recommended to treat all children with SCA from an age of 9 months, independent of disease severity, as natural history studies and murine models have shown higher percentages of HbF (greater than 20%) to be associated with reduced morbidity and mortality from SCA.


The study included children with SCA (n = 230) who ranged in age from 6 months to 17.9 years (median, 7.4 years) who were treated at St. Jude Children's Research Hospital. Patients had either already initiated hydroxyurea therapy, or began therapy at the study’s outset at a dose of 20 mg per kg per day and (increased by 5 mg per kg every 8 to 12 weeks to MTD). The maximum absolute dose was 35 mg per kg per day or 2000 mg per day, whichever was achieved first. The patients were evaluated every 4 to 6 weeks during initiation, and every 8 to 12 weeks after having achieved MTD, for up to 4 years of follow-up.

The researchers found the following:

  • Hydroxyurea therapy escalated to MTD resulted in a median HbF of 21.7% (range, 16.2 to 27.8%).
  • Compared to laboratory parameters when patients reached MTD, HbF, hemoglobin, mean corpuscular volume, absolute reticulocyte count, absolute neutrophil count, and platelet counts were maintained and were not significantly altered following 1, 2, 3, and 4 years of therapy.
  • Patients experienced a median 1 (range, 0 to 43) hospitalization during the study period, with the most common reason for sickle cell-related admission being vaso-occlusive pain. Statistical modeling showed that a patients’ odds of being hospitalized ranged from 2- to 4-fold higher when the patient’s HbF was at or below 20%.
  • Moderate neutropenia occurred in 14% of participants and in 2% of all evaluable time intervals. All episodes were transient, and none led to hospitalization. The primary side effect of hydroxyurea is a suppression of white blood cell counts, which causes neutropenia.

The researchers concluded that most children with SCA treated with hydroxyurea can safely achieve and maintain HbF levels above 20% when they are escalated to MTD, and children who maintain these levels have fewer SCA-related complications that require hospital admission.

“These data support a dosing strategy for hydroxyurea that produces HbF levels above 20% to decrease hospitalizations in children with SCA, with this value serving as clinically meaningful endpoint for future trials and clinical practice,” the authors wrote.