Oral Iron Chelation Therapy—Where Do We Stand?

Abstract & Commentary

Synopsis: Iron chelation therapy with deferoxamine has become standard for children with transfusional hemosiderosis but requires 10-12-hour, daily subcutaneous or intravenous infusions, which makes compliance difficult. An oral iron chelating agent, deferiprone, did not control the body iron burden and may have worsened hepatic fibrosis.

Source: Olivieri NF, et al. Long-term safety and effectiveness of iron-chelation therapy with deferiprone for thalassemia major. N Engl J Med 1998;339:417-423.

Nancy olivieri, md, from the hospital for sick children in Toronto and coinvestigators from several North American and U.K. hospitals studied 18 patients with thalassemia major who had developed transfusional hemosiderosis. These patents were treated for an average of 4.6 years with oral deferiprone. Hepatic iron stores were measured by chemical analysis of yearly liver biopsies, magnetic susceptometry, or both. Fourteen of these patients had multiple liver biopsies that were examined histologically for progression of fibrosis by three hepatopathologists; these were then compared to the liver biopsies of 12 patients who were treated with deferoxamine (DF).

At the final analysis, seven of 18 patients had liver iron levels that are associated with risk of cardiac disease and early death. Five of 14 patients treated with deferiprone had progression of hepatic fibrosis, compared to none of the 12 patients in the DF group (P = 0.04). Olivieri et al conclude that deferiprone does not adequately control body iron burden in patients with thalassemia and may, in fact, worsen hepatic fibrosis.

Comment by Howard A. Pearson, MD, FAAP

Chronically transfused patients inevitably develop iron overload. Each unit of transfused RBC delivers about 250 mg of iron into the body, and there is no physiologic mechanism for iron excretion. After a decade or more of transfusions, the buildup of iron in the body results in damage to many organs (especially in the liver, pancreas, and heart), and this damage results in early death.

DF, the only drug that has proven effectiveness in thalassemia major patients, has been widely used for about 20 years. When begun early and used sufficiently, it reduces body iron, prevents organ damage, and extends life. However, the drug is not orally effective. It is expensive and must be administered as a 9-12 hour subcutaneous or I.V. infusion with a battery-driven pump, 5-6 days per week. Side reactions, especially painful lumps at the injection site, are common. Not surprisingly, noncompliance with the DF regime is frequent. An oral chelator has been desired for these patients for a long time.

The only oral iron chelating drug that has been extensively studied is deferiprone, the focus of the study by Olivieri et al. Three previous studies resulted in conflicting conclusions about efficacy. The Olivieri study showed that deferiprone was certainly less effective than DF, but even more disturbing was their finding that it may have accelerated hepatic fibrosis. Similar hepatic toxicity as well as cardiac toxicity have been described associated with a drug similar to deferiprone in an animal model of hemosiderosis (Carethew T, et al. Biometals 1994;7:267-271).

In an accompanying editorial, Kowdley and Kaplan (N Engl J Med 1998;339:468-469) do not seriously challenge the observation that deferiprone may not be effective in reducing hepatic iron. However, they believe that the reported acceleration of hepatic fibrosis might be more related to differences in the DF and deferiprone groups of patients and, perhaps, to technical reasons.

Nevertheless, I believe that it is unlikely that deferiprone will be licensed for use in the United States. The FDA is unlikely to approve a drug that is less effective and possibly more toxic than DF, an already approved, effective, and remarkably safe drug. So the long-awaited effective, safe oral chelator is not yet with us. The most promising avenue of research now emerging is modification of DF by complexing it with large molecules to create a long-acting form that can be administered only once or twice a week.