Oral Sodium Phenylbutyrate Therapy in Homozygous p Thalassemia: A Clinical Trial

Butyrate analogues have been shown to increase fetal he- moglobin (HbF) production in vitro and in vivo. Sodium phe- nylbutyrate (SPB), an oral agent used to treat individuals with urea-cycla disorders, has been shown to increase HbF in nonanemic individuals and in individuals with sickle cell disease. We have treated eleven patients with homozygous /3 thalassemia (three transfusion dependent) and one sickle- &thalassemia patient with 20 g/d (forty 500-mg tablets! of SPB for 41 to 460 days. All patients showed an increase in the percent of F reticulocytes associated with treatment, but only four patients responded by increasing their Hb levels by greater than 1 g/dL (mean increase, 2.1 g/dL; range, 1.2 to 2.8 g/dL). None of the transfusion-dependent thalassemia subjects reapondod. Increase in Hb was associated with an increase in red blood cell number (mean increase, 0.62 x 10'z/L), and mean corpuscular volume (mean increase, 6 fL). Changes in percent HbF, absolute HbF levels, or Q- to non- OMOZYGOUS 0 THALASSEMIA, a disease in which there is inadequate production of 0 globin leading to severe anemia, affects thousands of individuals worldwide. Current management of this condition includes the use of regular red blood cell (RBC) transfusions and iron chelation therapy. The development of an effective therapy to increase hemoglobin (Hb) levels in homozygous fJ thalassemia with- out the use of RBC transfusions could allow normal growth and development, whereas decreasing or eliminating transfu- sional iron overload, which remains the major cause of death, reduced life expectancy and morbidity in individuals with this disease.' Although bone marrow transplantation can achieve these aims: it is not a therapeutic option for the majority of patients. For some years, there has been interest in increasing y- globin transcription and fetal Hb (HbF) production in pa- tients with ,B hemogl~binopathies.~.~ For patients with homo- zygous fJ thalassemia, increased y-globin production and a reduction in the ratio of a- to non-a-globin could reasonably be expected to ameliorate the seventy of the anemia. To this end, trials of chemotherapeutic agents including 5-azacyti- elotoxicity, fears of long-term carcinogenesis, and only mod- est responses to treatment have limited the clinical usefulness of these agents. Erythropoietin has also been used, but re- sponses to this therapy have been variable.L'*L1 There is considerable evidence that butyrate analogues induce erythroid differentiati~n""~ and stimulate HbF pro- duction in human erythroid progenitors in vitr~.~~"~ In vivo, these agents have also been shown to reactivate embryonic globin production in an avian model," delay the switch from fetal to adult globin in ovine fetuses," and to increase HbF production in adult primates.17.20-22 In humans, several fatty acids including a amino-butyric acid?' arginine isob~tyramide,~~~" sodium phe- nylb~tyrate,~~.~ ~ propionic acid:' and 2-propylpentanoic (di- propylacetic) acid (unpublished data) have now been shown to stimulate HbF production, suggesting that they may play a role in the treatment of the p-globin disorders. However, previous clinical trials of these agents in &thalassemia have H been limited to relatively short-term trials of the intravenous agent, arginine b~tyrate,".~~.~' and oral i~obutyramide.~. ~~ Sodium phenylbutyrate is an orally administered agent originally developed to promote waste nitrogen excretion in the treatment of urea-cycle disorders3' and is currently used for this purpose in an Federal Drug Administration-approved phase I11 trial. Over 100 patient-years experience with this drug has now accumulated with no untoward effects being found. The finding of increased HbF levels in these patients2* stimulated clinical trials of sodium phenylbutyrate in patients with P-hemoglobinopathies. We report here the first long-term clinical trial of an orally administered fatty acid, sodium phenylbutyrate, in patients with homozygous p thalassemia. This represents the largest clinical trial of any Hb switching agent used in thalassemic patients to date.