Introduction Chronic transfusion therapy represents the standard of care for sickle cell anemia (SCA) patients with abnormal transcranial Doppler (TCD) ultrasound or prior stroke. While effective, monthly transfusions produce iron overload and toxicity if not controlled with chelation therapies. Liver iron concentration (LIC) is a powerful surrogate for total body iron stores. Unfortunately, liver biopsy is not suited for longitudinal analysis because it is invasive, expensive, and prone to sampling variability. MRI transverse relaxation rates, R2 and R2*, are highly correlated with LIC and have mostly supplanted liver biopsy for iron quantification in clinical practice and clinical trials. Since R2 and R2* have different sensitivity to the size and scale of tissue iron distribution, we compared the agreement of LIC values predicted by R2 and R2* in children with SCA and transfusional iron overload from the prospective multicenter TCD with Transfusions Changing to Hydroxyurea (TWiTCH) trial (ClinicalTrials.gov; NCT01425307). Methods 133 patients underwent LIC assessment using both R2 and R2* techniques at 22 MRI sites. All sites used 1.5 Tesla magnets and torso phased array coils. Images for R2 measurements were collected on validated scanners and analyzed centrally according to the FerriScan” protocol (Resonance Health, Western Australia, see St Pierre, T.G., et al. Blood,105, 855-861, 2005). Images for R2* assessment were collected using multiple-echo gradient echo sequences (see Wood, J.C., et al. Blood,106, 1460-1465, 2005). Images were analyzed centrally at Children's Hospital Los Angeles, using an exponential-plus-constant fit to the signal decay. Bland-Altman analysis on log-transformed LIC values was used to test agreement between LICR2 and LICR2*; the residuals of this relationship were probed for association with transfusion/chelation history, markers of inflammation, and markers of hemolysis. Results Figure 1A illustrates the scattergram between LICR2* and LICR2. The variance of the disagreement between the two techniques increases with LIC, so log-transformation was performed prior to Bland Altman analysis. LICR2* was systematically higher than LICR2 below about 5 mg Fe/g dw and systematically lower above 5 mg Fe/g dw. Bland Altman comparison of the log-transformed data (Figure 1B) reveals a downward trend (r2 of 0.203, p<0.0001). After correcting for the trend, 95% limits of agreement were -0.42 to 0.42, translating to 95% limits of agreement of the ratio of the two LIC measurements of 0.66 to 1.52. After controlling for mean log LIC, differences in log LIC values were not associated with transfusion or chelation history, markers of inflammation, or markers of hemolysis. Discussion Systematic bias is present between LICR2 and LICR2* in a cohort of children with SCA and transfusional iron overload. Even after correcting these differences, LICR2 and LICR2* also demonstrate significant intrasubject variability, comparable to the error both techniques displayed with respect to biopsy, precluding use of these metrics interchangeably. This implies that LICR2 and LICR2* have potentially clinically significant deviations from true LIC. Rather than sampling or MRI measurement errors, which are consistently < 10% in multiple studies, these disparities likely reflect calibration bias introduced by intersubject differences in tissue iron distribution. Longitudinal LIC determination should lessen their impact, however, and the changes in LIC predicted by R2 and R2* will be compared using one and two year data from the TWiTCH trial. Disclosures: Wood: Novartis: Honoraria; Apopharma: Honoraria, Patents & Royalties; Shire: Consultancy, Research Funding. Off Label Use: Hydroxyurea is FDA-approved for use in adults but not children. Kwiatkowski:Shire: Consultancy; Resonance Health: Research Funding. St. Pierre:Resonance Health Ltd: Consultancy, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau.
5147 In patients with Hemoglobin (Hb) E thalassemia, the most common form of severe thalassemia worldwide (Weatherall DJ. Blood 2010;4331-6), early reports suggest that this disorder is associated with variable iron loading in the absence of frequent transfusions (Olivieri NF et al. Int J Ped Hem Onc 2000; 22:593-7), possibly related to the phenotypic variability of the disorder. At the National Thalassaemia Centre, Kurunegala, Sri Lanka, we have studied two groups of patients with Hb E thalassemia using spin density projection assisted R2-MRI (R2-MRI; FerriScan) (St Pierre TG et al. Blood 2005; 105:855-61). Group 1 (n=23) had received ≤ 20 transfusions (median = 9) lifelong, despite a relatively advanced age (mean ± SD, 27.5 ± 16.2 [range 7.8–57.4] years). Group 2 (n=47) had received > 20 transfusions lifelong. In Group 1, liver iron concentration (LIC) was strikingly variable (geometric mean 5.6 [range 1.0–33.0] mg Fe/g dw). LIC exceeded 7 mg Fe/g dw in 11 patients and 15 mg Fe/g dw in 4 patients. Values of serum ferritin (SF) (mean ± SD, 827 ± 611 [range 254–2484] ug/L) and serum ALT (37.6 ± 19.7 [range 12–86] U/L) did not reliably reflect the degree of elevation in LIC (R2 = 0.38, P = 0.0017 for SF; R2 = 0.12, P = 0.10 for ALT). These elevations of body iron burden were associated with evidence of organ dysfunction, with abnormal ALT (observed in 11 patients), hypothyroidism (6 patients), final adult height <3rd percentile (2 patients), and no evidence of glucose intolerance. In 15 of the 23 Group 1 patients, LIC had been determined in a previous biopsy, and 9 of these 15 patients had received <1 transfusion/year since that biopsy. None of these 9 patients had significant deferoxamine (DFO) exposure between biopsy and R2-MRI. Hence, rates of non-transfusional iron accumulation (NTIA) could be estimated (over a period of 8.4 ± 2.6 [range 2.6–11.4] years between biopsy and R2-MRI). NTIA in these 9 patients was 0.40 ± 0.39 [range -0.10 to 0.96] mg Fe/g dw liver per year. In the 47 Group 2 patients, regular transfusions had been administered for years and subsequently withdrawn, as described previously (Premawardhena A et al. Lancet 2005;366:1467-70). In 37 of these 47 patients, LIC had been determined by biopsy following the period of regular transfusions. Of these 37 patients, 25 patients had had <1 transfusion/year since biopsy. Of these 25 patients, 9 had had no significant DFO exposure between biopsy and R2-MRI, and the rate of NTIA could therefore be estimated between these two LIC measurements (over a period of 9.1 ± 1.4 [range 7.3–11.8] years). NTIA in these 9 patients was 0.12 ± 0.21 [range -0.15 to 0.41] mg Fe/g dw liver per year. The other 16 of the 25 patients had had significant DFO exposure between biopsy and R2-MRI. Of the 18 patients (9 in Group 1 and 9 in Group 2) for whom rates of NTIA could be estimated, the mean age was 32.0 ± 13.6 [range 14.0–60.3] years. Time between LIC assessments was 8.8 ± 2.1 [2.6-11.9] years. Initial and final LIC were 4.6 ± 1.9 [1.8-8.3] mg Fe/g dw liver, and 6.7 ± 3.4 [0.7-12.7] mg Fe/g dw liver, respectively. Mean NTIA (Figure; see A) was 0.26 ± 0.33 [-0.15 to +0.96] mg Fe/g dw per year. Rates of change of LIC in patients receiving < 1 transfusion per year (A) with no significant exposure to DFO; and (B) with significant exposure to DFO. In the 16 patients in Group 2 who had received < 1 transfusion per year and significant DFO exposure between LIC measurements, the rate of NTIA was -0.34 ± 0.66 [range -1.70 to +1.02] mg Fe/g dw liver per year (Figure; see B). These data suggest variable rates of NTIA in Hb E thalassemia, with evidence in some patients of rates up to approximately 1 mg Fe/g dw liver per year. This rate of NTIA may be associated with risk of organ dysfunction in the second decade of life. The data also suggest that DFO, administered in low doses and over short periods relative to those used in thalassemia major, may be effective in reducing body iron in Hb E thalassemia. The etiology of the observed variation in NTIA in these patients is being explored. Although hereditary hemochromatosis in Asia was believed to be rare and may often be masked by iron deficiency, recent studies (Lok CY et al. Blood 2009; 114:20-5) suggest that primary iron overload is not as rare in the Indian subcontinent and Southeast Asia as believed previously. Genetic studies, in parallel with evaluation of body iron burden, using techniques with known accuracy and precision, may elucidate the origins of the variable NTIA observed in patients with Hb E thalassemia. Disclosures: St. Pierre: Resonance Health Ltd: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis Pharmaceuticals Inc: Consultancy, Research Funding, Speakers Bureau.
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