Augmentation by Erythropoietin of the Fetal-Hemoglobin Response to Hydroxyurea in Sickle Cell Disease

Background: Hydroxyurea increases the production of fetal hemoglobin in patients with sickle cell anemia, inhibiting the polymerization of hemoglobin S and potentially improving vaso-occlusive manifestations and hemolysis. Recombinant erythropoietin increases the number of reticulocytes containing fetal hemoglobin in laboratory animals and in humans. We studied whether hydroxyurea and erythropoietin might have a potentiating effect on the production of fetal hemoglobin in patients with sickle cell disease. Methods: We treated four patients who were receiving hydroxyurea for sickle cell disease (three who were homozygous for sickle cell anemia and one with sickle β⁰-thalassemia) with escalating doses of intravenous erythropoietin for seven weeks, along with oral iron sulfate. Doses of hydroxyurea on four consecutive days were alternated with doses of erythropoietin on three consecutive days. Results: There was a 28 percent increase in the number of reticulocytes containing fetal hemoglobin and a 48 percent increase in the percentage of fetal hemoglobin, as compared with the maximal values obtained with hydroxyurea alone. The percentage of erythrocytes containing fetal hemoglobin (F cells) increased from 64 to 78 percent. As compared with hydroxyurea alone, treatment with hydroxyurea and erythropoietin decreased the mean (±SD) serum indirect bilirubin level from 0.8 ±0.2 to 0.5 ±0.1 mg per deciliter (13.3 ±2.9 to 8.9 ±2.2 μmol per liter) (P = 0.02), suggesting a further decrease in hemolysis. Red-cell filterability improved. Conclusions: Intravenous recombinant erythropoietin with iron supplementation alternating with hydroxyurea elevates fetal-hemoglobin and F-cell levels more than hydroxyurea alone. Such increases decrease intracellular polymerization of hemoglobin S and improve the overall rheologic characteristics of erythrocytes. A reduced dosage of hydroxyurea alternating with erythropoietin may prove less myelotoxic than hydroxyurea given daily or in pulsed-dose regimens. It may also increase levels of fetal hemoglobin in patients with sickle cell disease who have not been helped by hydroxyurea alone., Stimulating fetal hemoglobin by increasing γ-globin synthesis in patients with sickle cell disease would, if the production of βS-globin decreased concomitantly, have a large “sparing” effect on the formation of intracellular hemoglobin S polymer¹–³ and would be expected to improve the acute and chronic hemolytic and vaso-occlusive complications of the disease. Azacytidine and hydroxyurea have been shown to increase fetal-hemoglobin levels in some patients with sickle cell disease⁴–⁹. When hydroxyurea is used to induce the production of fetal hemoglobin in sickle cell anemia, the responses of individual patients are variable, and prolonged treatment is required for…