Hydroxyurea increases hemoglobin F levels and improves the effectiveness of erythropoiesis in beta-thalassemia/hemoglobin E disease

Heterozygotes and homozygotes for HbE (beta 26, GAG-AAG, Glu-Lys) are microcytic, minimally anemic, and asymptomatic. The microcytosis is attributed to the beta thalassemic nature of the beta E gene, whereas the in vitro instability of HbE does not contribute to the phenotype. However, the compound heterozygote state HbE/beta thalassemia results in a variable, and often severe anemia, with the phenotype ranging from transfusion dependence to a complete lack of symptoms. This has been well documented in Thailand, but the basis of the interaction and the cause of the variability remains unexplained. We have studied 50 HbE/beta thalassemics from the UK and 16 from Oakland, CA and assessed the role of HbE instability. Time-course globin chain synthesis experiments have shown that instability is not an important factor in the steady state, but that at 41 degrees C newly synthesized Hb molecules are unstable. We have identified one family in which HbE interacts with pyrimidine 5' nucleotidase deficiency to cause severe anemia with Hb instability. The UK individuals, mostly of Bengali origin, have Hb's from 4.5-11 g/dl. The beta thalassemia mutation, alpha thalassemia and the Xmn 1 G gamma polymorphism do not explain this variability, but the relative and absolute amounts of HbF correlate significantly with total Hb. The Oakland individuals, mostly from Southeast Asia, show similar variation in Hb, which again is largely unexplained.

Section: Discussionmentioning

confidence: 99%

The Hemoglobin E Syndromes

Rees¹,

Styles²,

Vichinsky³

et al. 1998

“…Chemotherapeutic agents that stimulate fetal globin production, such as 5-azacytidine, decitabine, and hydroxyurea, all inhibit cell proliferation and cause cell growth arrest, which is known to promote irreversible apoptosis in cancer cells. [9][10][11][12][13][14][15][16][17] The chemotherapy agents are also mutagenic, a drawback for conditions requiring long-term treatment. 18,19 Several short-chain fatty acids (SCFAs) specifically induce transcription from the γ-globin gene promoter and in some patients can increase the efficiency of γ-globin mRNA translation.…”

Section: Introductionmentioning

confidence: 99%

Induction of Fetal Globin in β‐Thalassemia: Cellular Obstacles and Molecular Progress

Perrine

Castañeda

Boosalis

et al. 2005

Accelerated apoptosis of erythroid progenitors in β-thalassemia is a significant barrier to definitive therapy because the beneficial effects of fetal globin-inducing agents on globin chain balance may not be inducible in cells in which programmed cell death is established early. Accordingly, our objectives have been to identify methods to decrease cellular apoptosis and to identify orally tolerable fetal globin gene inducers. A pilot clinical trial was conducted to determine whether combined use of a fetal globin gene inducer (butyrate) and rhu-erythropoietin (EPO), the hematopoietic growth factor that prolongs erythroid cell survival and stimulates erythroid proliferation, would produce additive hematologic responses in any thalassemia subjects. Butyrate and EPO were administered in 10 patients. Novel fetal globin gene inducers that also stimulate erythroid proliferation were evaluated for pharmacokinetic profiles. Patients with β + -thalassemia had relatively low levels of endogenous EPO (<145 mU/mL) and had additive responses to administered EPO and butyrate. Patients with at least one β 0 -globin mutation had higher baseline HbF levels (>60%) and EPO levels (>160 mU/mL), and three-fourths of these subjects responded to the fetal globin gene inducer alone. A few select fetal globin-inducing short-chain fatty acid derivatives that stimulated cell proliferation also had favorable pharmacokinetics. These studies identify a significant subset of thalassemia patients who appear to require exogenous EPO to respond optimally to any HbF inducer, as well as new therapeutic candidates that act on both cellular and molecular pathologies of β-thalassemia. Both approaches now offer excellent potential for tolerable, definitive treatment of β-thalassemia.

“…6 Increases in hemoglobin concentration during hydroxyurea treatment have been described in a non-transfusion-dependent patient 7 and more recently in a transfusion-dependent patient 8 with homozygous β thalassemia, and in a series of patients with hemoglobin E/β thalassemia. 9 The butyrate compounds, derivatives of natural short-chain fatty acids, have offered potential therapy for Cooley's anemia following the observation that elevated plasma concentrations of α amino-n-butyric acid in infants of diabetic mothers delayed the normal switch from γ to β globin. 10,11 The observation that sodium phenylbutyrate, used for years as treatment for children with inherited urea-cycle disorders, 12 resulted in increased fetal hemoglobin production in K562 cells 13 led to early trials of this compound in patients with sickle cell disease 14 and Cooley's anemia.…”

mentioning

confidence: 99%

Elimination of Transfusions Through Induction of Fetal Hemoglobin Synthesis in Cooley's Anemia^a

Olivieri

Rees

Ginder

et al. 1998

Pharmacological stimulation of fetal hemoglobin production is of considerable interest as an alternative approach to therapy for Cooley's anemia. While intravenous compounds have been effective in inducing short-term increases in fetal hemoglobin in a few patients, long-term elimination of transfusion requirement has not been reported. In patients with Cooley's anemia, treatment with oral sodium phenylbutyrate alone, sodium phenylbytyrate combined with hydroxyurea, and hydroxyurea alone, has augmented fetal hemoglobin production and increased total hemoglobin concentration as much as 5 g/dl over baseline eliminating transfusion requirement in two patients. Parallel declines in circulating nucleated red cell count, and concentrations of serum transform receptor and erythropoietin, are consistent with more effective erythropoiesis. Over extended periods of treatment, no induction of other fetal proteins and no adverse effects were observed. Particular disease mutations and other genetic factors may be of prime importance in determining the response to agents that induce production of fetal hemoglobin.