Emerging science of hydroxyurea therapy for pediatric sickle cell disease

Abstract

Hydroxyurea (HU) is the sole approved pharmacological therapy for sickle cell disease (SCD). Higher levels of fetal hemoglobin (HbF) diminish deoxygenated sickle globin polymerization in vitro and clinically reduce the incidence of disease morbidities. Clinical and laboratory effects of HU largely result from induction of HbF expression, though to a highly variable extent. Baseline and HU-induced HbF expression are both inherited complex traits. In children with SCD, baseline HbF remains the best predictor of drug-induced levels, but this accounts for only a portion of the induction. A limited number of validated genetic loci are strongly associated with higher baseline HbF levels in SCD. For induced HbF levels, genetic approaches using candidate single-nucleotide polymorphisms (SNPs) have identified some of these same loci as being also associated with induction. However, SNP associations with induced HbF are only partially independent of baseline levels. Additional approaches to understanding the impact of HU on HbF and its other therapeutic effects on SCD include pharmacokinetic, gene expression-based, and epigenetic analyses in patients and through studies in existing murine models for SCD. Understanding the genetic and other factors underlying the variability in therapeutic effects of HU for pediatric SCD is critical for prospectively predicting good responders and for designing other effective therapies.

Figure 1

Physiologic Effects of Hydroxyurea on Sickle Cell Disease. Hydroxyurea has pleiotropic effects on ameliorating sickle cell disease, with complex and interacting vascular and red blood cell effects.

Figure 2

HbF Levels of a Teenager with HbSS on Hydroxyurea. Prior to hydroxyurea, this teenager had 2-3 hospitalizations for pain each year. She had no admissions for 1.7 years after beginning hydroxyurea. Her HbF baseline was 2.4% and HbF maximum recorded level was 16.9%. She acknowledged intermittent adherence in years 2–3, during which time she had 2 admissions for acute pain episodes. (Blue diamonds refer to HbF data points.)

Figure 3

Phenotypic Variability in Hydroxyurea Response. A diagram synthesizes the varying clinical and genetic effects of hydroxyurea in sickle cell disease. The beta globin locus is shown below.