Meghna Dua, MD, Department of Global Pediatric Medicine, St. Jude Children’s Research Hospital, presented data from her team’s findings regarding hydroxyurea dosing in very young children with sickle cell disease (SCA) during the American Society of Hematology (ASH) Annual Meeting and Exposition.
With little published research on infants’ tolerance to hydroxyurea dose escalation, Dua and investigators began “Hydroxyurea Management in Kids: Intensive versus Stable Dosage Strategies” (HUGKISS) to determine the feasibility of recruitment, randomization and treatment of very young children with sickle cell disease. anemia, with a fixed or intensified dose of hydroxyurea.
While the initial trial (BABY HUG) showed a fixed dose of 20 mg/kg/day hydroxyurea to be safe and effective in improving complications of sickle cell disease in children aged 9-18 months, children who received the treatment continued to suffer from vaso-occlusive effects. episodes (VOE) and symptoms as well as organ damage.
However, older children and adults with CSA benefit from intensification of hydroxyurea to a maximum tolerated dose, defined as mild to moderate myelosuppression. Laboratory parameters and clinical benefits over a fixed lower dose have been demonstrated in association with the maximum tolerated dose.
Standard vs Intensive Hydroxyurea in Infants and Young Children
This study (HUGKISS) was a multicenter, randomized, single-blind pilot trial of hydroxyurea in infants and toddlers aged 9 to 36 months with sickle cell anemia. This population was then compared to the “standard” dose of treatment (20 mg/kg/day) to see how their “intensive” treatment would compare, as defined by an absolute neutrophil count (ANC) goal of 1,500 at 3000 cells/µL. .
A 1:1 ratio for randomization was used for the standard or intensive treatment group, stratified by center and age (9-24; 24-36 months). Both groups started treatment at the standard dose of 20 mg/kg/day, although the standard group maintained this dose while the intensive group increased.
Patients in the intensive group increased in 5 mg/kg/day increments, depending on tolerance. The maximum dose, adjusted every 8 weeks, was 35 mg/kg/day in order to maintain NAPs.
Clinical, laboratory, and medication adherence assessments occurred every 4 (±2) weeks of the trial duration. The principal investigator and medical center staff were not informed of treatment assignment, although the volume of hydroxyurea was not blinded to patients or caregivers.
Benefits of increasing hydroxyurea in very young patients
The results of this study included 26 young children randomized to receive standard treatment and 25 young children randomized to receive intensive treatment. No statistically significant difference was noted for their age or their laboratory values at the time of randomisation. One year after the start, 19 and 23 patients could be evaluated in the standard and intensive groups respectively.
The mean doses of hydroxyurea were 27.2 mg/kg/day in the intensive group and 18.8 mg/kg/day in the standard group at the end of the study. The intensive group demonstrated significantly greater increases (38.8%) in fetal hemoglobin (HbF) compared to the standard group (26.1%), with a median increase in hemoglobin (Hb) of 1. 2g versus 0.4g, respectively.
“Intensive treatment with hydroxyurea induced greater increases in HbF and Hb than standard dosing without significant toxicity in very young children with ACS, and may attenuate or delay the fall in HbF observed after 6 months of treatment with lower doses,” the researchers concluded. “HUGKISS has demonstrated the feasibility of treating very young children with ACS with high-dose hydroxyurea.”
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