Timed non-transferrin bound iron determinations probe the origin of chelatable iron pools during deferiprone regimens and predict chelation response

Abstract

Background: Plasma non-transferrin bound iron refers to heterogeneous plasma iron species, not bound to transferrin, which appear in conditions of iron overload and ineffective erythropoiesis. The clinical utility of non-transferrin bound iron in predicting complications from iron overload, or response to chelation therapy remains unproven. We undertook carefully timed measurements of non-transferrin bound iron to explore the origin of chelatable iron and to predict clinical response to deferiprone.

Design and methods: Non-transferrin bound iron levels were determined at baseline and after 1 week of chelation in 32 patients with thalassemia major receiving deferiprone alone, desferrioxamine alone, or a combination of the two chelators. Samples were taken at baseline, following a 2-week washout without chelation, and after 1 week of chelation, this last sample being taken 10 hours after the previous evening dose of deferiprone and, in those receiving desferrioxamine, 24 hours after cessation of the overnight subcutaneous infusion. Absolute or relative non-transferrin bound iron levels were related to transfusional iron loading rates, liver iron concentration, 24-hour urine iron and response to chelation therapy over the subsequent year.

Results: Changes in non-transferrin bound iron at week 1 were correlated positively with baseline liver iron, and inversely with transfusional iron loading rates, with deferiprone-containing regimens but not with desferrioxamine monotherapy. Changes in week 1 non-transferrin bound iron were also directly proportional to the plasma concentration of deferiprone-iron complexes and correlated significantly with urine iron excretion and with changes in liver iron concentration over the next 12 months.

Conclusions: The widely used assay chosen for this study detects both endogenous non-transferrin bound iron and the iron complexes of deferiprone. The week 1 increments reflect chelatable iron derived both from liver stores and from red cell catabolism. These increments correlate with urinary iron excretion and the change in liver iron concentration over the subsequent year thus predicting response to deferiprone-containing chelation regimes. This clinical study was registered at clinical.trials.gov with the number NCT00350662.

Figure 1.

(A) The NTBI at week 1 is shown in relation to baseline as mean SEM. The change in NTBI at week 1 is shown in relation to; (B) baseline LIC and (C) 1/transfusional iron loading rate (1/TILR) for patients receiving DFP regimens. Patients receiving DFP monotherapy are represented by circles and those receiving DFP in combination with DFO by triangles. The correlations shown are those for all patients.

Figure 2.

The relationship of the 24 h UIE measured after 1 week of therapy to: (A) week 1 change in NTBI, (B) baseline LIC and (C) 1/transfusional iron loading rate (1/TIRL) are shown for patients receiving DFP. Patients receiving DFP monotherapy are represented by circles and those receiving DFP in combination with DFO by triangles. The correlations shown are for all patients.

Figure 3.

Change in NTBI relative to baseline is proportional to the plasma DFP-iron complex concentration at week 1. Patients receiving DFP monotherapy are represented by circles and those receiving DFP in combination with DFO by triangles. The correlations shown are those for all patients.

Figure 4.

The change in LIC after 1 year of treatment is compared with the change in NTBI after 1 week of treatment (A) or with UIE at week 1 (B). Patients receiving DFP monotherapy are represented by circles and those receiving combination therapy by triangles. The correlations shown are for all patients.