For Hydroxyurea in Pediatric Patients With Sickle Cell Anemia, the Earlier the Better?

Intensifying hydroxyurea (HU) therapy is safe and effective in pediatric patients with sickle cell anemia (SCA), but starting HU at an earlier age appeared to only offer short-term benefits in hemoglobin levels, according to results from the prospective, observational HUSTLE (Hydroxyurea Study of Long-Term Effects) trial.

Christina Abrams, MD, of the Le Bonheur Children’s Hospital at the University of Tennessee, and colleagues collected data from 151 children with SCA who had not yet completed the physiologic decline of fetal hemoglobin (HbF) and replacement with sickle hemoglobin. Researchers compared hematologic parameters between children who began HU before 5 years of age (n=49) and those who began treatment at ≥5 years of age (n=102). All patients received a standard dose of 20 mg/kg per day, which was escalated over time.

On average, younger patients began treatment at  2.6 years and older patients began treatment at  11.1 years. Compared with older patients, younger patients had higher baseline levels of HbF (14.9% vs. 7.5%; p<0.001), absolute reticulocyte count (300 vs. 270 x103/μL; p=0.02), and white blood cell count (15.6 vs. 12.6 x103/μL; p<0.001).

“Similar relationships were observed [after patients received] the maximal tolerated dose of HU (28.8 mg/kg per day in younger patients and 24.7 mg/kg per day in older patients),” the authors reported.

Though treatment with HU led to long-term improvements in hematologic parameters (TABLE), there were no differences between the two age groups, even after escalation of HU. “For example, the young group had an average increase of 13.3 percent in HbF, compared [with] 13.4 percent in the older group (p=0.87),” they wrote.

After 5 years of therapy, hemoglobin levels were slightly higher in the older patients (9.5 g/dL vs. 8.7 g/dL; p=0.03), but HbF levels were similar between groups, as HbF declined at comparable levels with age in both groups (19.2% vs. 19.3%; p=0.7).

“Intensifying HU to the maximum tolerated dose in young children with SCA is safe and efficacious, providing stable long-term improvement in numerous hematologic parameters,” Dr. Abrams and co-authors concluded. “At young ages, there appears to be a short-term additive effect of HU to the elevated baseline HbF, but this is not sustained.”

The study’s findings are limited by the small patient population and the authors noted that future research should evaluate the clinical effect of intensifying HU in very young patients.

Source: Abrams C, Moen J, King G, et al. Hydroxyurea at maximal tolerated dose (MTD) prior to completion of the β-globin switch has additive but not sustained benefits in fetal hemoglobin production. Abstract #125. Presented at the 2016 ASH Annual Meeting, December 3, 2016; San Diego, California.

TABLE. Laboratory Characteristics in MTD, Following 5 Years of Therapy at MTD, and Mean Change from Baseline in Children ≥ and <5 years of age at Initiation of Therapy
Parameter, mean (mean change) ≥5 years (n=102) <5 years (n=49) P Value* P Value**
White blood cells (x103/µL) 7.9 (-4.8) 9.4 (-6.3) 0.04 0.07
Absolute neutrophil (x106/µL) 3800 (-3000) 3800 (-2000) 0.7 0.17
Hemoglobin (g/dL) 9.5 (+1.3) 9.6 (+1.5) 0.6 0.28
Fetal hemoglobin (%) 21.0 (+13.4) 27.9 (+13.3) <0.001 0.87
Mean corpuscular volume (fL) 105.5 (+21) 102.2 (+16.5) 0.06 0.006
Absolute reticulocyte ((x103) 130 (-130) 160 (-150) 0.03 0.36
Platelet (x103/µL) 370 (-92.8) 340 (-99) 0.5 0.55
After 5 years of Therapy
White blood cells (x103/µL) 8.4 (-4) 8.3 (-6.8) 0.9 0.12
Absolute neutrophil (x106/µL) 4200 (-2500) 3900 (-1700) 0.8 0.54
Hemoglobin (g/dL) 9.5 (+1.3) 8.7 (+0.7) 0.03 0.12
Fetal hemoglobin (%) 19.2 (+10.0) 19.3 (+5.6) 0.7 0.15
Mean corpuscular volume (fL) 103.5 (+19.1) 101.4 (+16.7) 0.6 0.43
Absolute reticulocyte (x103) 160 (-90) 170 (-110) 0.3 0.69
Platelet (x103/µL) 350 (-151.4) 345 (-113.2) 0.9 0.76
MTD = maximal tolerated dose
P values * comparing mean laboratory values
** comparing mean laboratory value changes in participants ≥ and <5 years of age