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

Abstract

High levels of fetal hemoglobin (Hb F) protect from many of the complications 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, butyrates 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 after prolonged administration of high doses of butyrate. We hypothesized that this loss of response may be a result of the antiproliferative effects of butyrate. We designed a regimen consisting of intermittent or pulse therapy in which butyrate was administered for 4 days followed by 10 to 24 days with no drug exposure. This pulse regimen induced fetal globin gene expression 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 of Hb F were sustained in all responders, including 1 patient who has been on pulse butyrate therapy for more than 28 months. This regimen, which resulted in a marked and sustained increase in Hb F levels in more than two thirds of the adult sickle cell patients enrolled in this study, was well tolerated without adverse side effects. These encouraging results require confirmation along with an appropriate evaluation of clinical outcomes in a larger number of patients with sickle cell disease.

Fig 1

A bar graph that shows the initial Hb F levels (▨) and the increment in Hb F during therapy (■) in the 6 patients enrolled on the weekly butyrate regimen.

Fig 2

Bar graph illustrating the Hb F response in a patient receiving weekly butyrate therapy. Each vertical bar represents the average of approximately eight determinations of hemoglobin F per month. The periods of butyrate therapy are depicted as solid horizontal bars below the vertical bar graph and the periods of interruption of therapy are depicted as open horizontal bars.

Fig 3

A bar graph that shows the initial Hb F levels (▨) and the increment in Hb F during therapy (■) in the 11 patients enrolled on the pulse butyrate regimen.

Fig 4

Detailed representation of the Hb F responses to pulse butyrate therapy in 3 adult patients with sickle cell disease. Each bar represents the average of two fetal hemoglobin levels obtained during the week of therapy.

Fig 5

A bar graph that shows the initial Hb F levels (▨) and the increment in Hb F during therapy (■) in the 3 butyrate nonresponsive patients who were treated with hydroxyurea either before or after the end of their butyrate therapy.