Our group has focused on pharmacologic manipulation of fetal hemoglobin levels in patients with genetic defects of hemoglobin. We have previously shown that hydroxyurea treatment of severely affected sickle cell patients results in about a 70 to 75% response rate defined by at least a two fold increase in F-reticulocytes and a concommitant two fold rise in percent in hemoglobin F. Among the responders, hemoglobin F levels increased two to ten fold, generally after a lag period of about 40 to 50 days. Three patients achieved levels of fetal hemoglobin of 10 to 15%. There were no biochemical, cellular or molecular predictive factors which were associated with response to hydroxyurea. In an effort to achieve higher levels of hemoglobin F, in a more pancellular distribution, we have recently treated four patients with sickle cell disease who were receiving hydroxyurea for periods of 5-15 months on four consecutive days with escalating dose of recombinant erythropoietin (EPO) for 7 weeks, given on the alternate three days along with oral iron sulfate. Treatment with EPO in combination with chronic hydroxyurea therapy had a significant effect on the percentage of hemoglobin F containing reticulocytes (F-reticulocytes), on red cells (F- cells) and on the total hemoglobin F level. In these four patients such combination therapy was associated with a 1.4 to 3 fold increase in F- reticulocytes, a 1.3 to 2 fold increase in F-cells and a 1.4 to 2 fold increase in the percentage of hemoglobin F when compared to the maximal values previously achieved on hydroxyurea alone. In addition, in contrast to the results on hydroxyurea alone, treatment with combination HU/EPO resulted in maximal stimulatory effects within ten to twelve days of therapy. This additional augmentation resulted in a further decrease in serum bilirubin and lactate dehydrogenase as well as a further decline in intracellular hemoglobin S polymerization tendency at physiologic oxygen saturation in cells containing fetal hemoglobin. In three patients in whom it was measured, there was a concomitant improvement in red-cell filterability as measured with a nickel mesh network of uniform 3 micron pore size. Changes in filterability closely parallel hydroxyurea/recombinant erythropoietin induce changes in fetal hemoglobin level. We conclude that recombinant erythropoietin when given in an alternating fashion with erythropoietin in addition to iron supplementation tends to augment the fetal hemoglobin responses seen with hydroxyurea alone. This observation indicates that Epo may offer a hydroxyurea sparing effect which would be of particular importance in individuals who are likely to require hydroxyurea therapy for extended periods of time.
