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 Background: Serious morbidity and mortality in sickle cell anemia (SCA) begins early in life during the physiologic decline of fetal hemoglobin (HbF) and its replacement with sickle hemoglobin (HbSS). In older children (>5 years), hydroxyurea (HU) is safe and provides similar laboratory benefits as in adults when escalated to a mean (standard deviation, SD) maximal tolerated dose (MTD) of 25.6 ± 6.2 mg/kg/day (Kinney, Blood 1999). In infants, a fixed-dose of 20 mg/kg/day is safe, improves hematologic parameters and provides substantial clinical benefits (Wang, Lancet 2011). However, the hematologic benefits of intensifying HU to MTD in young children have not been evaluated. We aimed to describe the initial and long-term hematologic changes provided by initiation of HU and escalation to MTD in young children ( Methods: The Hydroxyurea Study of Long-Term Effects (HUSTLE, NCT00305175) is a prospective observational evaluation of HU in children with SCA. After enrollment, all children were escalated to MTD, defined by an absolute neutrophil count goal of 2,000-4,000x106/L or other hematologic toxicity. Medication possession ratios (MPR) were calculated as [(days medication in family’s possession ÷ days for which medication was prescribed) x 100] and MPR values >80% were used as a surrogate for good adherence (Estepp, Pediatr Blood Cancer 2014). Children who initiated HU prior to 5 years of age (younger group) were compared to those who initiated at ≥5 years of age (older group) at three time points: prior to initiation of HU (baseline), when MTD was established, and 5 years after MTD was reached. Laboratory parameters for the two groups (means and SD) were compared using the two sample t-test or Wilcoxon Rank Sum test based on the normality of the data. Correlation between changes in HbF and age at baseline was tested using Spearman correlation test. P-values Results: In total, 151 children provided nearly 700 patient-years of follow up with a mean MPR of 106% (0.9) (median [IQR]; 100% [84.8-107.1%]). The young group (n=49) initiated HU at a mean (SD) of 2.6 (1.1) years old, and the old group (n=102) at 11.1 (3.7) years (p Figure 1. Increase in fetal hemoglobin (HbF) at maximal tolerated dose (MTD) from baseline versus age (years) at the time hydroxyurea was initiated. The solid green line stands for linear regression line; the solid and dash read lines stand for nonparametric regression and its smoothed conditional spread lines, respectively. Conclusions: Intensifying HU to MTD in young children with SCA is safe and efficacious, providing stable long-term improvement in numerous hematologic parameters. At young ages, there appears to be a short-term additive effect of HU to the elevated baseline HbF, but this is not sustained. Thus, initiating HU at an early age does not prevent the normal physiological decline of HbF. The clinical impact of intensifying HU to MTD in very young children warrants further exploration and is to be addressed by the recently NHLBI-funded pilot HUGKISS trial (hydroxyurea management in kids: intensive versus stable dosage strategies trial). Download : Download high-res image (222KB) Download : Download full-size image Download : Download high-res image (127KB) Download : Download full-size image Disclosures Hankins: Novartis: Research Funding. Estepp: Pfizer: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Research Funding; National Institute of Health: Research Funding.