Fetal hemoglobin (Hb F) in sickle cell anemia (HbSS): Determinants of response to hydroxyurea (HU)

HU can increase Hb F in HbSS and temper the course of disease. In a trial of HU in 295 adult HbSS patients, we studied genetic elements that could mark regions that regulate γ-globin gene expression (X-linked F-cell production (FCP) locus and β-globin gene haplotype), and other factors that might predict the response to HU. Patients were treated for a mean of 28 months (range 21-36) and HU dose escalated according to the blood cell counts. At baseline, Hb F levels and associated measurements were higher in females than in males. Highest baseline Hb F measures were associated with the high FCP allele. Hb F rose from 5.1% at baseline to 8.4% in patients assigned to HU - 9.7% in females, 7.0% in males - and was not appreciably changed in patients given placebo. We classified the Hb F response to HU into 4 groups; very high (8% of 150 patients), high (30%), moderate (37%) and low (26%). Baseline Hb F was about 5% in all 4 groups. Hb F increased to 19% in the very high and to 13% in the high group, but was nearly unchanged in other two. Benin haplotype homozygosity, the capacity to be titrated to toxic doses of HU and an HU dose of 15-22.5 mg/kg contributed to the response, but gender and FCP locus did not. Responses of Hb F to HU were strongly related to the baseline measurements and were blunted by the Bantu haplotype. Bone marrow activity, estimated by baseline reticulocyte and leukocyte counts, was a key element in the Hb F response. Patients with the most active bone marrows, that is, the highest leukocyte and reticulocyte counts, had the greatest decrements in these counts, required only modest doses of HU and had the most sizable increments of Hb F. In 26% of our patients, insufficient "bone marrow reserve" precluded achieving a safe marrow-suppressive dose of HU and as a result, no Hb F response occurred. However, about 40% of these severely affected HbSS patients had Hb F responses to HU that are likely to be clinically important. "Bone marrow reserve" is a major predictor of the Hb F response to HU.