Clinical Pearls & Morning Reports
Published November 28, 2018
Deferiprone is now licensed worldwide for the treatment of iron overload in patients with thalassemia major in cases in which deferoxamine therapy is contraindicated or inadequate. Read the latest NEJM Review Article here.
Q: How is deferiprone administered?
A: Deferiprone is an oral iron chelator. Early clinical trials of deferiprone showed that the drug caused urinary iron excretion that increased with increasing doses and iron load, with the latter assessed on the basis of the number of transfusions received. Treatment with deferiprone at a total dose of up to 100 mg daily, divided into three doses, was widely adopted. Iron excretion of up to 0.60 mg per kilogram of body weight per day could be achieved, as compared with an estimated mean daily iron intake of 0.3 to 0.5 mg per kilogram per day from blood transfusions in patients with thalassemia major.
Q: What is the most serious side effect associated with deferiprone?
A: Agranulocytosis is the most serious side effect. An analysis of 161 episodes, defined as a neutrophil count of less than 0.5×109 per liter, showed that agranulocytosis was three times as frequent in females as in males (2.4% vs. 0.8%). The incidence was unrelated to the dose, and about 80% of episodes occurred in the first year of therapy, with a median interval of 5 months between the initiation of treatment and the onset of symptoms. Neutropenia (neutrophil count, 0.5×109 to 1.5×109 per liter) is four times as frequent as agranulocytosis. Most cases of neutropenia do not progress to agranulocytosis, even when the drug is continued.
A: Retrospective and prospective studies have shown the superiority of daily deferiprone, as compared with subcutaneous deferoxamine 5 to 7 days a week, for reducing cardiac iron levels and improving cardiac function. A meta-analysis of 15 randomized, controlled trials involving 1003 participants showed that deferiprone was more efficacious than deferoxamine for improving the cardiac ejection fraction and also endocrine dysfunction. A large multicenter survey in Italy showed that cardiac morbidity and mortality were substantially lower among patients treated with deferiprone than among those receiving deferoxamine. Using T2*-weighted MRI in a retrospective study, Anderson et al. reported that deferoxamine and deferiprone were equivalent in controlling liver iron, whereas Pennell et al. found that deferiprone, at a dose of 100 mg per kilogram per day, was marginally less effective than deferoxamine, at a mean dose of 43 mg per kilogram per day for 5 days a week.
A: Wonke et al. initiated the practice of administering deferiprone and deferoxamine on the same day for patients in whom chelation was inadequate with either drug alone. The observed response in urinary iron excretion was either additive or synergistic. Deferiprone can enter cells, chelate iron, and exit as an iron complex, which can then transfer iron to apotransferrin or to deferoxamine. The transfer of iron to deferoxamine releases free deferiprone, which can re-enter cells and bind more iron. Intermittent administration of deferoxamine extracts about 1 to 2% of cardiac iron each month, whereas deferoxamine combined with daily deferiprone increases the extraction to 3 to 4%. The drug combination can also reverse endocrine complications, including diabetes. Intensive combined therapy is superior to deferoxamine alone in preventing death and in reversing cardiac damage in patients with thalassemia major and cardiac disease.