Sustained induction of fetal hemoglobin by pulse butyrate therapy in sickle cell disease

High levels of fetal hemoglobin (Hb F) protect from many of the complicatio ns of sickle cell disease and lead to improved survival. Butyrate and other short chain fatty acids were previously shown to increase Hb F production in erythroid cells in vitro and in animal models in vivo. However, butyrate s are also known to inhibit the proliferation of many cell types, including erythroid cells. Experience with the use of butyrate in animal models and in early clinical trials demonstrated that the Hb F response may be lost af ter prolonged administration of high doses of butyrate. We hypothesized tha t this loss of response may be a result of the antiproliferative effects of butyrate. We designed a regimen consisting of intermittent or pulse therap y in which butyrate was administered for 4 days followed by 10 to 24 days w ith no drug exposure, This pulse regimen induced fetal globin gene expressi on in 9 of 11 patients. The mean Hb F in this group increased from 7.2% to 21.0% (P <.002) after intermittent butyrate therapy for a mean duration of 29.9 weeks. This was associated with a parallel increase in the number of F cells and F reticulocytes. The total hemoglobin levels also increased from a mean of 7.8 g/dL to a mean of 8.8 g/dL (P <.006). The increased levels o f Hb F were sustained in all responders, including 1 patient who has been o n pulse butyrate therapy for more than 28 months. This regimen, which resul ted in a marked and sustained increase in Hb F levels in more than two thir ds of the adult sickle cell patients enrolled in this study, was well toler ated without adverse side effects. These encouraging results require confir mation along with an appropriate evaluation of clinical outcomes in a large r number of patients with sickle cell disease. (C) 1999 by The American Soc iety of Hematology.