ORAL IRON CHELATION WITH 1,2-DIMETHYL-3-HYDROXYPYRID-4-ONE (L1) IN IRON-LOADED THALASSEMIA PATIENTS

Despite the successes of deferoxamine (DFO) in the treatment and preve ntion of iron overload, an effective orally available iron chelating d rug is needed, since erratic compliance with irritating, cumbersome pa renteral infusions still results in fatal iron accumulation in many pa tients. Disorders of increased iron absorption should also benefit fro m the development of safe and effective iron chelating agents. Individ uals with non-transfusion-dependent thalassemia (thalassemia 'intermed ia''), exhibit excessive dietary iron absorption that can lead to seri ous iron loading by the second or third decade of life. An orally effe ctive iron-chelating drug would have major therapeutic advantages for all these patients. The oral chelating agent 1,2-dimethyl-3-hydroxypyr id-4-one (L1; CP20; DMBP) has been demonstrated by several groups to b e well-tolerated in patients with iron overload. We administered L1 75 -100 mg/kg/day over a mean (+/- SD) period of 20 +/- 8 months (range, 9-30 months) to 16 iron-loaded thalassemia patients, who were non-comp liant with subcutaneous DFO or had DFO-related neurotoxicity. While 24 -hour iron excretions induced by L1 was highly variable, serum ferriti n concentrations as declined or stabilized in all transfusion-dependen t L1-treated patients. Excellent compliance with L1 was recorded. No c hanges in hematologic or biochemical parameters were noted in patients receiving L1. Three patients complained of bilateral knee pain associ ated with small effusions, without evidence of associated drug-induced systemic lupus, or of active inflammation as demonstrated by synovial aspiration and biopsy. In one patient with non-transfusion dependent beta-thalassemia, normalization of serum ferritin concentration and re duction of tissue iron in the liver and heart was demonstrated followi ng nine months of therapy with L1. These data demonstrate that oral L1 is safe and effective in reducing serum and tissue iron concentration s in thalassemia patients with iron overload, and is associated with e xcellent patient compliance. Larger trials may now determine the effec tiveness of L1 as a replacement for deferoxamine in iron-loaded patien ts.