Determinants of fetal hemoglobin response to hydroxyurea

Fetal hemoglobin (HbF) modulates the phenotypic diversity of sickle cell anemia (HbSS), and the prevalence of many disease complications is related to the level of HbF. Hydroxyurea (HU) increases HbF levels in many patients. Adults with HbSS have HbF levels that may differ by two orders of magnitude, suggesting the possibility of genetic modulation of gamma-globin gene expression. In HbSS, the beta-globin gene haplotype is associated with HbF. Polymorphisms present in cis-acting elements are usually linked to the haplotype, suggesting that within a haplotype, mutations in these areas are uncommon mechanisms of HbF modulation in patients with untreated HbSS. In a multicenter trial of HU in HbSS, we examined genetic elements, patient characteristics, and follow-up features to determine their association with changes in HbF. Following treatment, F cells increased in HU-treated patients compared with controls. The increases in the HbF level at 2 years were greatest in patients who had the highest baseline counts of reticulocytes and neutrophils, two or more episodes of study-defined myelotoxicity, and absence of a Bantu haplotype. However, after 2 years, half of the patients had no or only trivial increments in HbF. The ability to respond to HU may depend on bone marrow reserve, or the capacity of the marrow to withstand moderate doses of HU with acceptable myelotoxicity. Baseline reticulocyte and neutrophil counts may be a measure of this marrow reserve. Sustained HbF increases during HU treatment can occur in individuals with bone marrow reserve sufficient to respond to the myelotoxicity of this agent with the evolution of a population of high HbF-producing erythroblasts.