Evaluating Toxic Free Iron and Options for Keeping It At Bay in Iron Overloaded Patients.

Abstract

AbstractAbstract 2110An important goal in iron chelation is preventing tissue iron overload by maintaining low levels of plasma non-transferrin bound iron (NTBI). This is important in periods between chelator administration, when the plasma iron might surpass not only transferrin- but also chelator-iron binding capacities, thereby raising plasma NTBI and exposing cells to infiltrating forms of iron. We aimed to assess the ability of different chelation protocols to maintain patients free of the redox active and chelatable component of NTBI referred to as labile plasma iron (LPI) and the correlation between LPI and eLPI (equivalent to NTBI including mobilizable and chelated iron) with respect to compliance. Patients & Methods:49 TMps (23 M, 26 F, mean age 35.5±11 years were included. Patients received deferoxamine (DFO)=8–40 (mg/kg) and/or deferiprone (DFP)=74–100 and/or deferasirox (DFX)=7.6–25 for >3 years. Blood samples were drawn at trough levels (12 hr for DFP & 24 hr for DFO and/or DFX) and at peak plasma levels of chelator (2 hrs post DFP and/or DFX p/o). LPI and eLPI were determined with the FeROS™ assay (Aferrix, Israel). Stata 11.0 was used for statistical analysis. The numbers of patients receiving a particular regime were adequate for comparison in the two combination regimes that included deferiprone. Results:28/49 (57%) of TMps had normal basal LPI (<0.45μM/l) and 90% (19/21) normalized within 2 h of chelation. Baseline eLPI and LPI were negatively related to compliance (Spearman’s rho: −0.28, p=0.05 and Spearman’s rho: −0.38, p=0.007, respectively). A total of 34 TM patients (23 on DFP+DFO, 11 on DFX+DFO) were included in the comparison analysis based on measurements presented in Table 1.Table 1Summary statisticsOverall (34)DFP & DFO (23)DFP & DFX (11)Age†35.1 ± 11.635.4 ± 10.034.4 ± 15.1Gender, females, n (%)16/34 (47.1%)11/23 (47.8%)5/11 (45.5%)LPI_BF†0.71 ± 0.770.85 ± 0.830.40 ± 0.56LPI_AF†0.09 ± 0.230.04 ± 0.10.20 ± 0.36eLPI_BF†1.52 ± 1.311.66 ± 1.421.21 ± 1.03eLPI_AF†1.53 ± 1.151.64 ± 1.171.30 ± 1.13LPI change†−0.61 ± 0.74−0.80 ± 0.79−0.20 ± 0.42eLPI change†0.01 ± 0.98−0.02 ± 1.170.08 ± 0.36probability of reducing LPI, n (%)19/23 (82.6%)15/15 (100%)4/8 (50.0%)probability of increasing eLPI, n (%)15/34 (44.1%)11/23 (47.8%)4/11 (36.4%)probability of normalizing LPI, n (%)14/16 (87.5%)13/13 (100%)1/3 (33.3%)Compliance†78.1 ± 18.272.9 ± 17.988.7 ± 14.1None of the two LPI and two eLPI measurements differed between the two treatment groups (all p-values >0.05). Reduction of LPI was significantly higher in DFP+DFO compared to DFP+DFX (p=0.004). Linear regression estimated that DFP+DFO achieved 0.32 μM higher reduction compared to DFP+DFX (results adjusted for baseline LPI). Detailed regression results: DFP+DFO vs DFP+DFX: b-coefficient=0.32 (95% ci: 0.06–0.59, p=0/019), LPI-bf: b-coefficient=0.85 (95% ci: 0.67–1.03, p<0.001). The R2 of 0.896 shows 89.6% of the variation of LPI decrease can be explained by the model, indicating a good fit.†mean ± SD. [Display omitted] The same trends were confirmed by analysis of the probability of increasing eLPI, reducing LPI and normalizing LPI. No differences were observed in the proportion of patients who increased their baseline eLPI between the two regimes (p>0.05). In contrast, patients on DFP+DFO were 11.0 times more likely to reduce their baseline LPI levels compared to DFP+DFX (exact logistic regression, odds ratio (OR)=11.0, 95% ci: 1.05 - +∞, p=0.045). Similarly, patients treated with DFP+DFO were 14.7 times more likely to normalize their baseline LPI levels compared to DFP+DFX (exact logistic regression, OR =14.7, 95% ci: 1.0 - +∞, p=0.05). Discussion:The DFP+DFO combination seems to be superior to DFP+DFX in reducing LPI despite the lower compliance with the former. As the DFP is in both regimes our results indicate that the DFP is more efficient in combination with DFO than with DFX. The concept of having chelator present in the circulation at all times is logical as it would protect from the infiltrating forms of iron and is attainable with the present repertoire of chelators. This preliminary study suggests that the measurement of LPI provides a convenient and immediate index of chelation efficacy, adequacy of doses of chelator prescribed, and patient compliance. Repeating such measurements every 3 months should be useful in guiding patient management. Disclosures:Berdoukas:Apopharma: Consultancy. Cabantchik:Aferrix: Consultancy.