PULSE BUTYRATE AND ERYTHROPOIETIN IN BETA THALASSEMIA

$0M01FY2000RRNIH

Boston University Medical Campus, Boston MA

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Abstract

The beta thalassemias are characterized by deficiency of adult (b) globin chains of adult hemoglobin (Hb), an excess of toxic, unmatched a globin chains, and intramedullary hemolysis. The resulting anemia only after fetal (g) globin synthesis and Hb F is suppressed in infancy. Induction of fetal (g) globin synthesis and Hb F is suppressed in infancy. Induction of fetal (g) globin to levels which improve globin chain balance by even 10% can prolong red blood cell survival and diminish clinical morbidity. Arginine Butyrate, a prototype fatty acid, has been effective when given intermittently or Pulsed, inducing Hb F and increasing total hemoglobin by 3 gm/dl over baseline levels in 5/6 beta thalassemia patients. EPO-rhu can prolong red cell survival but does not correct underlying globin chain imbalance. We hypothesize that these two agents should have additive therapeutic benefit. A clinical pilot study is proposed to test the hypothesis that therapy with Pulsed Butyrate, or rhu-EOP + Pulsed Butyrate, will induce g globin chain synthesis sufficiently to improve non a: a 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 arm of the study in whom the following endpoints are achieved, compared to baseline levels, will be analyzed: 1) an increase in total of Hb in at least 2.0 grams/dl, 2) an increase in hematocrit of at least 5%, 3) a decrease in hemolysis, measured by LDH and bilirubin, 4) improvement in globin chain synthesis by 10%. Whether specific genotypes and in vitro response to Butyrate correlate with clinical responses will also be analyzed. These studies should determine he proportion and some genotypes of beta thalassemia patients which can benefit from Pulsed Butyrate +/- rhu-EPO therapy.

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