The beta thalassemias are characterized by a deficiency of adult (beta) globin chains of adult hemoglobin (Hb), an excess of toxic, unmatched alpha globin chains, and intramedullary hemolysis. The resulting anemia develops only after fetal (gamma) globin synthesis and Hb F is suppressed in infancy. Induction of fetal (gamma) globin to levels which improve globin chain balance by even 10 percent can prolong red blood cell survival and diminish clinical morbidity. 5-Azacytidine has increased hemoglobin (Hb) levels by 1.8-3 gmd/d1 in thalassemia, but also causes general cytopenias and carries carcinogenicity risks. Fatty acids induce (gamma) globin experimentally. Arginine Butyrate, a prototype fatty acid, has been most effective when given intermittently or Pulsed, inducing Hb F to a mean level of 22 percent in 7/9 adults with sickle cell disease and increasing total hemoglobin by 3 gm/dl over baseline levels in 5/6 beta thalassemia patients. Two clinical pilot studies are proposed to test the hypotheses that therapy with Pulsed Butyrate, or rhu-EP0 + Pulsed Butyrate, will induce gamma globin chain synthesis sufficiently to improve non alpha: alpha globin chain balance and red blood cell survival, and increase total Hb in a significant proportion of patients with beta thalassemia intermedia. Baseline hematologic levels will be assayed four times over a two-month period. Butyrate will then be administered during an Induction Phase, to determine a patient's optimal dose, followed by a """"""""Maintenance Phase"""""""" of therapy for 3 months. Pulsed Butyrate will also be tested with rhu-EPO. The proportions of patients on each study in whom the following endpoints are achieved, compared to baseline levels, will be analyzed: 1) an increase in total Hb of at least 2.0 grams/dl, 2) an increase in hematocrit of at least 5 percent, 3) a decrease in hemolysis, measured by LDH and bilirubin, 4) improvement in globin chain synthesis by 10 percent. Whether specific genotypes and in vitro response to Butyrate correlate with clinical responses will also be analyzed. These studies should determine the proportion and some genotypes of beta thalassemia patients which can benefit from Pulsed Butyrate plus/minus rhu-EP0 therapy.
