Abstract
Background. Hydroxyurea has proven laboratory and clinical benefits for children with sickle cell anemia (SCA); however, the benefits of escalation to a maximum tolerated dosage (MTD) over a fixed or low-dose approach to therapy, remains controversial. Clinical trials utilizing hydroxyurea at MTD reported higher fetal hemoglobin (HbF) levels (~20% versus ~15%) compared to those with a fixed lower-dose (Ware, Blood 2010). The clinical benefits gained, if any, from increasing HbF levels from 15% to 20% has not been described. The Hydroxyurea Study of Long-Term Effects (HUSTLE) provides the opportunity to examine the relationship between the magnitude and duration of pharmacologically induced HbF and clinical outcomes, specifically the number of hospitalizations for vaso-occlusive complications such as acute chest syndrome (ACS) and vaso-occlusive events (VOE).
Methods. The Hydroxyurea Study of Long-Term Effects (HUSTLE) is a prospective observational study (NCT00305175) with a primary goal of describing the long-term effects of HU therapy in children with SCA, using serial and longitudinal collection of laboratory and clinical data. All children (≤18 years of age) who enrolled in HUSTLE and did not receive chronic blood transfusions are included in this analysis. All participants received hydroxyurea therapy escalated to a stable MTD, which was defined by moderate myelosuppression (typically ANC of 2,000-4,000 x 106/L) and no dose-limiting toxicities. Children were initially evaluated monthly but then every 2-3 months after achieving MTD. Neutropenia was defined as an ANC of <1,000 x 106/L. For this analysis, laboratory and clinical data were abstracted over twenty-seven months following enrollment onto HUSTLE, which constituted nine consecutive three month intervals. Hospitalizations for VOE and ACS were evaluated categorically for each three month time period, and %HbF levels at the beginning of each interval were used as the representative value for that period. To account for the correlated nature of the data, with potentially multiple hospitalizations per patient and time, a generalized estimating equation model was utilized.
Results. A total of 162 children with SCA (148 HbSS, 14 HbSβ0thalassemia) at a mean (SD) age of 10.7 (4.3) years were analyzed. Children were hospitalized a total of 253 (52 ACS, 201 VOE) times during the first twenty-seven months following enrollment. The Figure illustrates the number of individuals hospitalized (yes versus no), stratified by HbF category, for each consecutive 3-month interval following HUSTLE enrollment. Compared to intervals when HbF levels were >20%, those with HbF levels of ≤20% had 2.2 (95% CI: 1.2-4.0; p=0.013) higher chance of hospitalization, and intervals with HbF levels <15% had 2.6 (95% CI: 1.3-5.1; p=0.021) times higher odds of hospitalization. For every 5% decrease in HbF, the odds of hospitalization due to VOE/ACS increased by 1.3 (95% CI: 1.1-1.5; p=0.014), correlating to a 30% increase. There was no statistically significant association between hydroxyurea dose (mg/kg) and hospitalization over time. Neutropenia occurred 39 times in 22 (13.6%) children; no episodes were associated with an invasive bacterial infection.
Figure Children hospitalized versus not during three month intervals following HUSTLE enrollment, stratified by fetal hemoglobin percentage. Figure. Children hospitalized versus not during three month intervals following HUSTLE enrollment, stratified by fetal hemoglobin percentage.
Discussion. In this pediatric cohort receiving hydroxyurea therapy escalated to MTD, higher %HbF levels conferred greater protection against hospitalization for severe vaso-occlusive pain or ACS. Escalation of hydroxyurea to MTD was rarely associated with neutropenia and had no clinical implications. These prospectively collected data from HUSTLE suggest that hydroxyurea dose escalation to MTD, designed to maximize %HbF levels, provides additional clinical benefit by reducing vaso-occlusive complications in children with SCA.
Disclosures
Estepp: Ely Lily: Research Funding; NIH: Research Funding. Off Label Use: Hydroxyurea in children with sickle cell anemia.
Hydroxyurea for treatment of severe sickle cell anemia: a pediatric clinical trial
