Correspondence

Butyrate Treatment in β-Hemoglobinopathies

N Engl J Med 1995; 333:1287-1288November 9, 1995

Article

To the Editor:

Sher et al. (June 15 issue)1 may have drawn premature conclusions about the potential efficacy of butyrate in treating the β-hemoglobinopathies, for several reasons. The patients in the study did not receive any iron supplements, according to the report and other presentations by the authors. Iron has been shown to be required for responses to other agents that stimulate fetal hemoglobin.2 We observe moderate responses to butyrate, even in iron-overloaded patients, with a low level of iron supplementation, whereas twofold greater responses occur with increased supplementation.

More important, the regimen of butyrate used in the study by Sher et al. — a high dose administered continuously for prolonged periods — produces plasma concentrations of 0.5 mM or higher,3 which are well known to suppress both reticulocytosis and the fetal-hemoglobin response to butyrate in baboons.4 This regimen may be more suitable to elicit the antineoplastic, antiproliferative effects of butyrate (through its activity in arresting growth in the G1 phase of the cell cycle) than to induce hematopoietic activity, which requires cell proliferation.3,5

The threshold Sher et al. used for a hematologic response (an increase of 2.0 g of hemoglobin per deciliter) differs from standard criteria used in studies of other fetal-hemoglobin stimulants, such as hydroxyurea, which produces a mean increase of 0.8 g of hemoglobin per deciliter.2 Greater increases in the hemoglobin concentration and hematocrit are potentially harmful in patients with sickle cell disease, increasing the blood viscosity and precipitating painful crises.

The study by Sher et al. is useful in demonstrating that a cytostatic dosing regimen of butyrate should be avoided in the β-hemoglobin disorders and is probably not indicated after the induction of fetal hemoglobin occurs, as it did in all five of the patients with sickle cell disease. Conclusions regarding the efficacy of any potential therapy in these disorders, however, requires an evaluation of rational dosing regimens in patients receiving appropriate iron supplementation.

Mark Brauer, M.D.
Boston City Hospital, Boston, MA 02118

Abdul-Kareem Al-Momen, M.D.
King Khalid University Hospital, Riyadh, Saudi Arabia

Douglas V. Faller, Ph.D., M.D.
Boston University School of Medicine, Boston, MA 02118

5 References

1. 1

   Sher GD, Ginder GD, Little J, Yang S, Dover GJ, Olivieri NF. Extended therapy with intravenous arginine butyrate in patients with β-hemoglobinopathies. N Engl J Med 1995;332:1606-1610
   Full Text | Web of Science | Medline

2. 2

   Rodgers GP, Dover GJ, Uyesaka N, Noguchi CT, Schechter AN, Nienhuis AW. Augmentation by erythropoietin of the fetal-hemoglobin response to hydroxyurea in sickle cell disease. N Engl J Med 1993;328:73-80
   Full Text | Web of Science | Medline

3. 3

   Sanders D, Tansan S, Arthur V, Faller D, McCaffrey R, Foss F. Phase I clinical trial of arginine butyrate in patients with refractory neoplasms. Prog Proc Am Soc Clin Oncol 1995;14:476-476 abstract.
   

4. 4

   Faller DV, Perrine SP. Butyrate in the therapy of sickle cell disease and beta thalassemia. Curr Opin Hematol 1995;2:109-117
   CrossRef | Medline

5. 5

   Toscani A, Soprano DR, Soprano KJ. Molecular analysis of sodium butyrate-induced growth arrest. Oncogene Res 1988;3:223-238
   Medline

Author/Editor Response

Dr. Olivieri replies:

To the Editor: Brauer et al. state that the “high dose” of butyrate administered to our patients is associated with plasma concentrations “well known to suppress both reticulocytosis and the fetal-hemoglobin response to butyrate in baboons.” In support of this statement, the authors cite a review of butyrate treatment that one of them cowrote. These “cytostatic” doses were identical to those administered to the first patient with thalassemia, in whom an increase of 6 g per deciliter in the total hemoglobin concentration was observed during a period of seven weeks. This response, noted in a report1 coauthored by one author of the letter by Brauer et al., is the only hematologic response to arginine butyrate — or in fact to any butyric acid compound — reported to date in a patient with thalassemia major. It should be added that this response was observed without the use of supplemental iron in a patient whose body iron burden was normal. Furthermore, we have continued to observe a sustained response to butyric acid in this patient during the past three years, despite a “cytostatic” regimen of butyrate and in the absence of iron supplementation (unpublished data). These findings are consistent with the observations that supplemental iron is not required for the increase in fetal-hemoglobin synthesis observed during treatment with hydroxyurea2 and is not required for increases in the total hemoglobin concentration in patients with thalassemia intermedia receiving long-term treatment with high-dose recombinant erythropoietin.3

Finally, Brauer et al. have confused the criteria for a response used in our study. We clearly stated that “a clinical response was defined as an increase in the hemoglobin concentration of at least 2 g per deciliter in patients with thalassemia and as a twofold increase in the percentage of fetal hemoglobin in patients with sickle cell disease.” Although we do not disagree that a precipitous rise in the hemoglobin concentration may be associated with problems in patients with sickle cell disease, this risk appears to be acceptably low; indeed, to our knowledge, there has been no reported increase in the hemoglobin concentration in a patient with sickle cell disease treated with arginine butyrate. The pathophysiology of thalassemia is different from that of sickle cell disease,4 and affected patients should benefit — without risk, to our knowledge — from an increase of 2 g per deciliter or more in the total hemoglobin concentration.

When new therapies are introduced, it is important to confirm promising initial findings5 in a timely fashion, so that false hope and expectation on the part of patients with chronic disease can be avoided. For this reason, almost three years after our first observations were made,1 we continue to await publication of the results of “rational dosing regimens” of butyrate therapy.

Nancy F. Olivieri, M.D.
Hospital for Sick Children, Toronto, ON M5G 1X8, Canada

5 References

1. 1

   Perrine SP, Ginder GD, Faller DV, et al. A short-term trial of butyrate to stimulate fetal-globin-gene expression in the β-globin disorders. N Engl J Med 1993;328:81-86
   Full Text | Web of Science | Medline

2. 2

   Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. N Engl J Med 1995;332:1317-1322
   Full Text | Web of Science | Medline

3. 3

   Olivieri NF. Erythropoietin therapy in inherited anemias. In: Biology of hematopoietic growth factors and their use in children. Int J Pediatr Hematol Oncol 1995;2:105-116
   

4. 4

   Weatherall DJ, Clegg JB. The thalassaemia syndromes. 3rd ed. Oxford, England: Blackwell Science, 1981:148-319.
   

5. 5

   Desforges JF. My life at the Journal, 1961-1993. N Engl J Med 1993;329:1038-1039
   Full Text | Web of Science | Medline

Citing Articles (1)

Citing Articles

1. 1

   Lillian McMahon, Hannah Tamary, Melissa Askin, Patricia Adams-Graves, Robert T. Eberhardt, Millicent Sutton, Elizabeth C. Wright, Serguei A. Castaneda, Douglas V. Faller, Susan P. Perrine. (2010) A randomized phase II trial of Arginine Butyrate with standard local therapy in refractory sickle cell leg ulcers. British Journal of Haematology 151:5, 516-524
   CrossRef