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Determinants of fetal hemoglobin response to hydroxyurea.
Semin Hematol 1997; 34(3 Suppl 3):8-14SH

Abstract

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.

Authors+Show Affiliations

Veterans Affairs Medical Center and the Department of Medicine, University of Mississippi, Jackson 39216, USA.

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.
Review

Language

eng

PubMed ID

9317196

Citation

Steinberg, M H.. "Determinants of Fetal Hemoglobin Response to Hydroxyurea." Seminars in Hematology, vol. 34, no. 3 Suppl 3, 1997, pp. 8-14.
Steinberg MH. Determinants of fetal hemoglobin response to hydroxyurea. Semin Hematol. 1997;34(3 Suppl 3):8-14.
Steinberg, M. H. (1997). Determinants of fetal hemoglobin response to hydroxyurea. Seminars in Hematology, 34(3 Suppl 3), pp. 8-14.
Steinberg MH. Determinants of Fetal Hemoglobin Response to Hydroxyurea. Semin Hematol. 1997;34(3 Suppl 3):8-14. PubMed PMID: 9317196.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Determinants of fetal hemoglobin response to hydroxyurea. A1 - Steinberg,M H, PY - 1997/7/1/pubmed PY - 1997/10/8/medline PY - 1997/7/1/entrez SP - 8 EP - 14 JF - Seminars in hematology JO - Semin. Hematol. VL - 34 IS - 3 Suppl 3 N2 - 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. SN - 0037-1963 UR - https://www.unboundmedicine.com/medline/citation/9317196/Determinants_of_fetal_hemoglobin_response_to_hydroxyurea_ DB - PRIME DP - Unbound Medicine ER -