Deferiprone-induced agranulocytosis. A critical review of five rechallenged cases

The most serious adverse effect of deferiprone, the first orally active iron chelator, is agranulocytosis afflicting an estimated 1.6% of patients. Among the 13 reported patients who had experienced deferiprone-induced agranulocytosis or severe neutropenia, 5 were rechallenged. We studied the onset, clinical and rechallenge course of all 5 patients in an attempt to characterise the mechanisms involved in deferiprone-induced agranulocytosis, to verify whether rechallenge in future patients is ethically justified. Deferiprone-induced agranulocytosis showed no trend of dose dependency: of all patients who had experienced agranulocytosis 23% were treated with 50 mg/kg/day, 46% with 75 to 90 mg/kg/day, and 31% with > 90 mg/kg/day. Available data including bone marrow aspiration in some patients support the hypothesis that an early myeloid precursor is the target cell affected by deferiprone. All 5 rechallenged patients re-experienced agranulocytosis/neutropenia. The lag period to agranulocytosis/neutropenia following reinduction was significantly shorter (13.2 ± 21.7 weeks compared with 46.4 ± 14.2 weeks in the first episode; p < 0.05). All but one of the rechallenged patients re-experienced agranulocytosis or neutropenia 2 to 4 weeks following re-exposure to deferiprone, suggesting a possible immune mechanism. We found that deferiprone was oxidised in vitro by hypochlorous acid, the major neutrophil oxidant to produce a myelotoxic metabolite. This reactive species demonstrated neutrophil toxicity and a dose-dependent lymphotoxic curve. However, we found no differences in the toxicity of this reactive species to neutrophils from 2 patients with a history of deferiprone-induced agranulocytosis when compared with controls. In combination with the clinical characteristics, these results suggest a reactive metabolite-induced immune-mediated reaction. These 5 rechallenged cases ethically preclude the rechallenge of additional cases.