Vitamin C Status in Transfusionally Iron-Overloaded Patients On Long-Term Deferasirox and Its Relationship to Myocardial Iron Removal.
Authors: Garbowski Maciej W , Fabre Margarete , Evans Patricia , Porter John B 
Published: October 2019

Abstract
Abstract 2005
Poster Board I-1027

Background
Although the benefits to iron balance of supplementing deferoxamine therapy with ascorbic acid (AA, 2-3mg/kg/day) are well established, the role of this approach with deferasirox (DFX) chelation is unknown. We have previously reported that fasting plasma ascorbate (FPA) was significantly lower in patients on long-term DFX without AA supplementation (30.3 ± 20.8 mM) than in healthy controls (60.3 ± 12.6 mM, P<0.0001), with deficiency (defined as >2 SDs from the adult control mean) present in 72% of patients not receiving AA supplementation (Sarantos et all, Blood 112, Abstract 1858, 2008). It is therefore important to establish prospectively the relevance of ascorbate status to iron balance and also to myocardial iron loading in DFX-treated patients. Here we examine changes in FPA and markers of iron overload in the same patients over at least one year follow-up and examine the impact of AA supplementation in selected patients.

Patients and Methods:
21 adult patients with a range of transfusional iron overload conditions excluding Sickle Cell Disease (17 with b-Thalassaemia Major, 2 with Congenital Syderoblastic Anaemia, 1 with Red Cell Aplasia, 1 with Diamond-Blackfan Anaemia) on long-term DFX chelation (duration of treatment 3-6 years, mean dose 27.1mg/kg/day) had measurements of FPA, ferritin, cardiac and hepatic T2* on two occasions, separated by a period of approximately one year (median 419 days). Of these, 10 received AA supplementation (2-3mg/kg/day) and 11 did not. The decision to prescribe AA was based on clinical criteria and patient preference rather than by randomisation. FPA was measured under controlled conditions: a 4 ml fasting heparinised blood sample was taken, placed immediately on ice and centrifuged at 4oC at 2000g for 10 minutes. An equal volume of 10% trichloroacetic acid (TCA) was added, the sample re-spun, and stored at —80oC until measurement of vitamin C fluorimetrically as previously described (Speek et al, 305, J Chromatogr, 1984).

Results:
In 10 patients who received AA supplementation for 1y (432 ± 96 (SD) days) , the FPA increased significantly from mean baseline of 35.99 ± 21.02 mM to 46.94 ± 14.69 mM at follow up (p=0.03) correcting the deficiency in 3 of the 5 scorbutic patients. FPA increased slightly but not significantly (p=0.3) in 11 patients without supplementation rising from 27.4 ± 15.8 mM to 34.0 ± 12.37 mM where deficiency was corrected in 2 of the 8 scorbutic patients. The increment in FPA levels in un-supplemented patients correlated with decrements in liver iron (LIC, r=-0.64, p=0.04), with mean liver R2* decreasing from 209.24 to 178.07 Hz (i.e. estimated LIC from 7.01 to 6.08 mg Fe/g dry weight (dw)), consistent with previous observations that iron overload accelerates oxidation of AA.
Significant improvements in myocardial iron (shown as decreasing myocardial R2*) were seen in ascorbate replete patients at 1y (n=13, mean FPA 48.73 ± 10.61 mM) from a mean myocardial R2* of 61.4 to 52.5Hz p=0.008, i.e. T2* of 16.2ms to 19ms). By contrast, in patients who remained AA deficient (mean FPA 26.28 ± 8.44uM, n=8), the improvement in myocardial R2* was less marked (from 50.41 to 46.65Hz, i.e. T2* 19.8 to 21.4 ms) and did not reach significance.

Conclusions:
AA deficiency is a significant risk in transfusionally iron loaded patients on long term DFX without AA supplementation, particularly in patients with high levels of body iron loading. Our findings suggest that improvement in myocardial and liver iron with DFX therapy is more likely in AA replete than AA deficient patients. A prospective randomised study of the effects of AA supplementation on iron overload and myocardial iron in DFX treated patients is indicated but until such data are available, we recommend that patients on long term chelation with DFX have FPA levels assessed and consideration is given to supplementing deficient patients.

Disclosures:
Garbowski: Novartis: Research Funding. Evans:Novartis: Research Funding. Porter:Novartis: Consultancy, Research Funding.