Patients with severe beta thalassemia or sickle cell anemia would benefit significantly if HbF production could be consistently augmented. The imbalance of globin synthesis characteristic of thalassemia could be partially corrected by increased gamma globin synthesis. Reduction of intracellular HbS concentration by replacement with HbF reduces the polymerization potential of intracellular sickle hemoglobin decreasing the sickling """"""""propensity"""""""" of red cells from such individuals. Several classes of substances stimulate HbF synthesis including cytotoxic agents (e.g. hydroxyurea), hematopoietic growth factors (erythropoietin) and agents that modify DNA or chromatin structure (e.g. 5azacytidine or sodium butyrate, respectively). Our studies have shown a high frequency of response to hydroxyurea in patients with sickle cell disease. This increment in HbF synthesis is accompanied by macrocytosis, an enrichment in HbF containing cells during maturation and a significant reduction in polymer fraction within circulating red cells. We are currently testing the combination of hydroxyurea and erythropoietin. One patient has completed this study and has shown an approximately two-fold increase in HbF synthesis to approximately twenty percent, the threshold level thought to be necessary to significantly reduce sickling complications. A similar trial of hydroxyurea in patients with thalassemia has documented a low incidence of response. Untransfused patients with thalassemia intermedia have shown an increase in Hb concentration and one transfusion dependent patient has experienced a lengthening of her transfusion interval. Three patients with severe beta thalassemia with end-stage disease have begun a trial of intravenous 5-Azacytidine given at two or three week intervals. Significant increases in hemoglobin concentration have been experienced and the transfusion requirement eliminated. Our experience with pharmacological agents demonstrate the potential for modification of HbF synthesis with significant therapeutic benefit.
