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Published on: November 5, 2019
Predictors of fetal hemoglobin response in children with sickle cell anemia receiving hydroxyurea therapy
Russell E Ware1, Barry Eggleston, Rupa Redding-Lallinger
1Duke University Medical Center, Durham, NC 27710, USA. ware005@mc.duke.edu
Insights
Predictors of fetal hemoglobin increase in children with sickle cell anemia receiving hydroxyurea therapy were identified. Baseline fetal hemoglobin, hemoglobin concentration, MTD dose, and compliance are key factors influencing response.
Area of Science:
- Pediatric Hematology
- Pharmacogenomics
- Sickle Cell Disease Research
Background:
- Sickle cell anemia (SCA) is a genetic blood disorder with significant morbidity.
- Hydroxyurea therapy increases fetal hemoglobin (%HbF) levels, offering clinical benefits in SCA.
- The response to hydroxyurea in children with SCA is highly variable.
Purpose of the Study:
- To identify predictors of fetal hemoglobin (%HbF) response to hydroxyurea therapy in children with SCA.
- To analyze baseline clinical and laboratory values, and treatment variables associated with %HbF increase.
Main Methods:
- Analysis of data from 53 children in the HUG-KIDS trial who achieved maximally tolerated dose (MTD) of hydroxyurea.
- Statistical analysis of baseline parameters (age, sex, hemoglobin, %HbF, reticulocytes, WBC, platelets) and treatment variables (toxicities, compliance, MTD dose, MTD blood counts).
- Regression analysis to identify significant associations with %HbF at MTD, adjusting for baseline %HbF.
Main Results:
- Higher baseline %HbF, baseline hemoglobin concentration, MTD dose, and compliance were significantly associated with higher %HbF at MTD.
- Baseline reticulocyte count and baseline WBC count were also associated with higher %HbF at MTD after adjustment.
- Hydroxyurea-induced increases in hemoglobin and MCV, and decreases in reticulocytes and WBC, correlated with higher %HbF.
Conclusions:
- Baseline laboratory parameters, higher MTD dose with good compliance, and significant therapy-related blood count changes predict hydroxyurea response in pediatric SCA.
- The %HbF response to hydroxyurea is complex and variable, with potential for substantial increases even in patients with low baseline %HbF.
Abstract:
In the phase I/II pediatric hydroxyurea safety trial (HUG-KIDS), school-aged children with sickle cell anemia receiving hydroxyurea at the maximally tolerated dose (MTD) had variable increases in the percentage of fetal hemoglobin (%HbF). To identify predictors of the HbF response to hydroxyurea therapy, baseline clinical and laboratory values (age, sex, hemoglobin concentration, %HbF, reticulocytes, white blood cell [WBC], platelets, and serum chemistries), as well as treatment variables (number of toxicities, noncompliance, MTD dose, and MTD blood counts) were analyzed in 53 HUG-KIDS children who achieved MTD. Baseline %HbF values (P =.001), baseline hemoglobin concentration (P =.01), MTD dose (P =.02), and compliance (P =.02) were significantly associated with a higher %HbF at MTD; in contrast, age, sex, number of toxicities, and other baseline hematologic parameters were not. After adjusting for variations in baseline %HbF, the baseline reticulocyte count (P =.05) and baseline WBC count (P =.05) were also significantly associated with a higher %HbF at MTD. Hydroxyurea-induced increases in the hemoglobin concentration and mean corpuscular volume (both higher absolute values at MTD and larger positive changes from baseline values), as well as hydroxyurea-induced decreases in reticulocytes and WBC count, were significantly associated with a higher %HbF at MTD. These data suggest that selected baseline laboratory parameters, a higher MTD dose with attention to compliance, and greater therapy-related changes in blood counts may predict the HbF response to hydroxyurea therapy for children with sickle cell anemia. The HbF response to hydroxyurea is variable and complex, however, and even children with low baseline %HbF values can develop substantial increases in %HbF at MTD.
