Probing the Origin of Chelatable Iron During Deferiprone and Combination Therapies: Insights From Plasma NTBI and LPI Determinations

Classic clinical and animal studies with deferoxamine (DFO) showed that two major chelatable pools exist in thalassemia major (TM), the first derived from hepatocytes and the second from red cell catabolism. Knowledge about the origin of chelatable iron with deferiprone (DFP) treatment, alone or when combined with DFO, is relatively limited. We hypothesized that changes in plasma iron species during chelation therapy may be proportional to the magnitude of chelatable iron pools. In this study, we have examined the relationship between urinary iron excretion (UIE), transfusional iron loading rates (ILR), liver iron concentration (LIC) and plasma concentrations of non-transferrin bound iron (NTBI) and labile plasma iron (LPI) before and after DFP therapies.

12 TM patients were randomized to one year of DFP monotherapy (25mg/kg tds) or 9 to DFP at the same dose with the addition of subcutaneous DFO (40-50mg/kg), 2 nights a week (COMB). Plasma samples were taken for NTBI and LPI measurements, at baseline, at 1 week and at 52 weeks. These were obtained at 9am, which was 10hrs following the previous DFP dose, and 24h after the second of two weekly DFO doses for COMB patients. A 24h urine iron was collected at baseline, 1 week and 52 weeks of treatment. The ILR, expressed in mg/kg/day, was calculated from the blood volume transfused during the 1 year study.

After 1 week of treatment, there was a significant increase in NTBI from baseline in DFP and in COMB patients. A significant increase in LPI was also seen in DFP patients at this time (p=0.039). In all patients, absolute LPI levels at 1 week correlated with those of NTBI and increments in LPI also correlated with increments in NTBI from baseline to 1 week (r=0.52, p=0.002). Plasma NTBI levels at 1 week were proportional to UIE mg/kg/day)(r=0.51, p= 0.02), to LIC mg/g dry wt (r=0.54, p=0.01) and inversely proportional to the ILR (r=0.74, p=0.0001). By weighting the LIC and ILR pools equally, a combined chelatable pool index was derived: this was significantly proportional to both absolute NTBI at 1 week (r=0.72, p=0.003) and increments in NTBI from baseline. This index was also significantly correlated with UIE (p=0.66, p=0.0017) and with LPI at 1 week.

Urinary iron excretion with DFP (the predominant route of iron excretion with DFP) and COMB therapy is directly proportional to the LIC, as well as to plasma NTBI and LPI and is inversely proportional to the ILR. This is consistent with the existence of two major chelatable iron pools; the first being liver derived and the second derived from red cell catabolism. This latter pool appears to be larger for those patients who require less blood transfusion and who presumably have greater rates of ineffective eryrthropoiesis. The origin of chelatable iron with this form of COMB therapy, with DFO only two days a week, appears is similar to that of DFP monotherapy.

Aydinok:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: Deferiprone and desferrioxamine are indicated and approved for the chelation therapy of iron-overloaded patients with beta thalassemia. The combination of both agents as treatment regimen for patients with beta thalassemia is part of the investigation described in the abstract and is not approved for use. Manz:Lipomed AG: Employment. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.