DEFERIPRONE-INDUCED AGRANULOCYTOSIS - A CRITICAL-REVIEW OF 5 RECHALLENGED CASES

The most serious adverse effect of deferiprone, the first orally activ e iron chelator, is agranulocytosis afflicting an estimated 1.6% of pa tients. Among the 13 reported patients who had experienced deferiprone -induced agranulocytosis or severe neutropenia, 5 were rechallenged. W e 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 patie nts is ethically justified. Deferiprone-induced agranulocytosis showed no trend of dose dependency: of all patients who had experienced agra nulocytosis 23% were treated with 50 mg/kg/day, 46% with 75 to 90 mg/k g/day, and 31% with > 90 mg/kg/day. Available data including bone marr ow aspiration in some patients support the hypothesis that an early my eloid precursor is the target cell affected by deferiprone. All 5 rech allenged patients re-experienced agranulocytosis/neutropenia. The lag period to agranulocytosis/neutropenia following reinduction was signif icantly 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 patie nts re-experienced agranulocytosis or neutropenia 2 to 4 weeks followi ng 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-dependen t 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. I n combination with the clinical characteristics, these results suggest a reactive metabolite-induced immune-mediated reaction. These 5 recha llenged cases ethically preclude the rechallenge of additional cases.