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Long-Term Safety And Efficacy Of Deferiprone Defined

Results from a multi-centre clinical trial of deferiprone, an oral iron chelator, have further defined the treatment's safety and efficacy in the treatment of iron overload in patients with thalassaemia major.

The 4-year trial, originally designed as a prospective 1-year study of 187 patients, was extended based on the first year's results (see reference below).

The study, led by Dr Alan Cohen of the Children's Hospital of Philadelphia, Pennsylvania, United States, was sponsored by Apotex and Novartis Pharma (Switzerland). Primary objective was to measure the incidence of serious adverse events, particularly agranulocytosis, which was defined as a confirmed neutrophil count of <0.5x109/litre. Secondary objective was to assess the efficacy of deferiprone in limiting iron overload, as assessed by serum ferritin levels.

Eighty four patients completed treatment with deferiprone, 25 mg/kg body weight, 3 times daily for the full 4 years. This compared with 162 patients completing the first year.

Generally, adverse events were only seen in the first year, lessening in frequency in the second and subsequent years. Twenty nine patients withdrew from the study due to adverse events - 21 in the first year and 8 in the second. The most common adverse events were gastrointestinal but these only resulted in 3 patients discontinuing treatment in the first year.

There was only 1 incidence of agranulocytosis and a total of 16 cases of less severe neutropaenia. The researchers noted that the 0.5% incidence of agranulocytosis was less than previous estimates from smaller studies. "The lower rate of agranulocytosis and the higher rate of milder neutropaenia found in this study may be a result of rigid adherence to the protocol's requirements for weekly monitoring of blood counts and the strict guidelines for interrupting or discontinuing therapy," they said.

The study revealed that those who completed the full 4 years were significantly more likely to have had splenectomy and to have had lower serum ferritin levels at study entry. "These findings indicate that milder forms of neutropaenia may often be due to hypersplenism rather than chelation therapy with deferiprone," the researchers said. There was no significant difference in age between those who completed 4 year's treatment and those who did not.

Questions being raised as to the efficacy of deferiprone led to the withdrawal of a further 47 patients from the study. In 28 patients, the decision to discontinue was based on increasing serum ferritin levels, and in the remaining 19, liver iron concentrations and/or serum ferritin levels prompted withdrawal.

However, in the 84 patients who completed the full study, mean serum ferritin levels were 2087 µg/L after 4 years, compared with 2268 µg/L at baseline. For patients with initial ferritin levels greater than 2500 µg/L, the ferritin level declined from an average of 3661 µg/L to 2630 µg/L at the end of 4 years. There was no significant change in mean ferritin levels in patients with initial values less than 2500 µg/L.

In addition to the withdrawals because of adverse events and questionable efficacy of deferiprone, 12 patients withdrew voluntarily, 2 because of protocol violations and 13 withdrew because of exposure to deferoxamine, an injectable iron chelator, for reasons unrelated to iron stores.

Commenting on the possible reasons for the study's high attrition rate, the researchers said: "First, the protocol did not allow an adjustment in the dose of deferiprone in order to optimise therapy according to the patient's needs, and second the protocol did not permit the use of deferoxamine. The former may have contributed to the loss of 47 patients who received deferoxamine because of increased iron stores, and the latter was responsible for the loss of 13 patients who used deferoxamine for other reasons such as prolonged vacations during which monitoring of blood counts was not possible."

Related link: A multi-center safety trial of the oral iron chelator deferiprone. Annals of the New York Academy of Sciences. 1998;850:223-226 (Authors: Cohen et al).
Blood 2003 May 22; (epub ahead of print). "Safety and effectiveness of long-term therapy with the oral iron chelator deferiprone"

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