Deferiprone(L1)-induced agranulocytosis: A possible mechanism

The most serious adverse effect of L1, the first orally active iron chelator agent, is agranulocytosis (agran.) inflicting 1.6% of patients. Among the 13 reported cases of L1-induced agran. 5 were rechallenged. All 5 developed agran. with a significant shorter lag period after re-exposure: 13.2±21.7 weeks compared to 51.2±24.4 weeks in the first episode (P<0.05) suggesting a possible immune mechanism. There was no trend of dose-dependency as of all patients who had experienced L1-induced agran. 23% were treated with 50 mg/kg/d, 46% with 75-90 mg/kg/d and 31% with >90 mg/kg/d. We found that a chemically reactive species was formed on oxidation of L1 with hypochlorous acid, the major neutrophil oxidant. This reactive species demonstrated neutrophil toxicity and dose dependent lympho-toxic curve as 62.5% of lymphocytes were killed when incubated with 100 μmol of this metabolite, 89.7% with 500 μmol and 95.8% with 1000 μmol. However we found no differences in the toxicity of this reactive species to neutrophils or lymphocytes from 2 patients with a history of L1-induced agran. when compared to controls. Although the reactive species does not appear to cause agran. by direct toxicity, the clinical characteristics suggest a reactive metabolite-induced immune-mediated reaction.