Liver Iron Concentration Levels Research Articles

Increased Liver Iron Concentration (LIC) in Adults with Non-Transfusion Dependent Sickle Cell Disease (NTD-SCD): Correlation with Serum Ferritin Concentrations

Introduction:Hepatic iron concentration (HIC) is used as a surrogate for total iron balance to guide chelation therapy in transfusion-dependent and independent patients. Unfortunately, liver biopsy is invasive and provides only indirect information regarding other organ systems. FerriScanprovides an accurate validated measurement of liver iron concentration (LIC) through a non-invasive, using patented R2-MRI imaging technology.Aim:To determine the iron status of 11 patients with non-transfusion dependent (NT) patients with sickle cell disease (SCD).Patients and methods:FerriScan (a quick, easy and painless, with an MRI scan time of only two minutes) is used to determine LIC in eleven adults with NT-SCD. Serum ferritin, iron concentrations and hepatic enzymes (ALT and AST) concentrations and total iron binding capacity (TIBC) were measured.Results:11 adults with NT-SCD were studied. Three had serum ferritin > 500 umol/L , 2 out of the three (ferritin level 1138 and 531 ug/L) had high liver iron measured by ferriScan (> 30 mmol/kg dry tissue). One patient had high liver iron content despite a concomitant serum ferritin concentration = 237 ug/L. On the other hand a patient had serum ferritin = 1117 ug/L while his liver iron was still (27 mmol/kg dry tissue) in the normal range. Serum ferritin concentrations were correlated significantly with liver iron content measured by ferriScan (r = 0.47, p = 0.05). (fig) Three patients had elevated liver enzymes (ALT and AST). Neither serum ferritin, nor LIC was correlated significantly with hepatic function.Discussion:In this study significant number of patients with ND-SCD had high LIC and high serum ferritin and hepatic enzymes (ALT and AST). Elevated levels of LIC and ferritin impose high risk for hepatic disease and cardiac toxicity in these patients. Evidence suggests that patients with high LIC have higher risk of liver fibrosis and cirrhosis as a result of iron overload. In addition, Liver iron concentration (LIC) over 15.0 mg Fe/g dry weight is associated with increased risk of cardiac diseases. Moreover, the liver is considered the early warning system against later endocrine complications, due to iron overload. For NT-SCD, with increased LIC, effective management of liver iron concentration is critical to ensure risk of morbidity due to iron overload is minimizedSummary: This is the first study that document increased iron overload in NT-SCD patients. Therefore, we recommend measuring serum ferritin and LIC in NT-SCD patients. Those with increased LIC and/or ferritin should be chelated to prevent long term complications of iron overload. TableAgeserum FeTIBCFerritinliver ironALTASTyrumol/Lumol/Lug/Lmmol/kgU/LU/L32.323.755.7361.731.024.236.114.217.78.4405.717.716.422.3 DisclosuresNashwan:HMC MRC: Research Funding. Moustafa:HMC MRC: Research Funding. Elomry:HMC MRC: Research Funding.

MRI for assessment of iron overload in patients with hematologic disease

目的比较磁共振成像（MRI）肝横向弛豫时间（T2*）、心T2*检测和血清铁蛋白（SF）评估铁过载的特征。方法对2011年11月至2014年6月69例患者进行肝脏、心脏MRI检查，并采集其各项临床数据进行分析。结果肝T2*与调整后铁蛋白（ASF）水平明显相关（P=0.003）。心T2*与肝T2*、ASF水平均无明显相关性。69例患者中，62例肝T2*诊断为铁过载，其中重度铁过载20例（32.26%）；47例ASF诊断为铁过载，其中重度14例（29.79%）；25例心T2*诊断为铁过载，无一例为重度铁过载。结论SF易受其他因素影响而无法完全客观地反映机体铁沉积水平；肝T2*检测可信度强、重复性好。心T2*不能正确评估全身铁过载的情况，仅仅是检测心脏铁沉积的一种手段。

Pulmonary hypertension in non-transfusion-dependent thalassemia: Correlation with clinical parameters, liver iron concentration, and non-transferrin-bound iron

BackgroundPulmonary hypertension is a major cardiac complication in non-transfusion-dependent thalassemia (NTDT). Several clinical and laboratory parameters, including iron overload, have been shown to have a positive correlation with the incidence of pulmonary hypertension. Non-transferrin-bound iron (NTBI) is a form of free-plasma iron that is a good indicator of iron overload.ObjectivesThe aim of this study was to determine the prevalence of pulmonary hypertension in patients with NTDT and to investigate its correlation with the clinical parameters, liver iron concentration (LIC) and NTBI.MethodsPatients with NTDT were evaluated using echocardiography, and magnetic resonance imaging for cardiac T2* and LIC. Pulmonary hypertension was defined as peak tricuspid regurgitation velocity ≥2.9 m/s measured using trans-thoracic echocardiography. Clinical parameters and the status of iron overload as determined by LIC, serum ferritin, and NTBI level were evaluated for their association with pulmonary hypertension.ResultsOf 76 NTDT patients, mean age 23.7 ± 8.5 years, seven patients (9.2%) had pulmonary hypertension. Previous splenectomy (71.4 vs. 24.6%, P-value 0.019), higher cumulative red blood cell (RBC) transfusions (received ≥10 RBC transfusions 85.7 vs. 33.3%, P-value 0.011), higher nucleated RBCs (353 ± 287 vs. 63 ± 160/100 white blood cells, P-value <0.001), and a high NTBI level (5.7 ± 3.0 vs. 3.3 ± 2.8 µmol/l, P-value 0.034) were associated with pulmonary hypertension. There was no significant correlation between LIC or serum ferritin and pulmonary hypertension.ConclusionPulmonary hypertension in NTDT is common, and is associated with splenectomy and its related factors. NTBI level shows a significant correlation with pulmonary hypertension.

Liver Iron Concentration and Liver Impairment in Relation to Serum IGF-1 Levels in Thalassaemia Major Patients: A Retrospective Study.

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Long Term Erythrocytapheresis Is Associated with Reduced Liver Iron Concentration in Sickle Cell Disease

Background:Observational studies and randomized clinical trials have demonstrated that RBC transfusions can alleviate or prevent many complications of sickle cell disease (SCD). Obligatory iron loading is most problematic for those receiving chronic simple transfusions and is managed with chelation therapy to prevent hepatic, cardiac, and endocrinologic complications. Erythrocytapheresis procedures are increasingly used in SCD as they achieve dilution of hemoglobin S without significantly raising the total hematocrit. Some guidelines for the management of iron overload use serum ferritin levels, but non-invasive measurements of liver iron concentration (LIC) using validated and widely available MRI techniques have been described. There is a paucity of data elucidating the impact of long-term erythrocytapheresis (LTE) on LIC. We evaluated LIC with MRI and serial serum ferritin measurements among a population of SCD patients maintained on LTE at a single institution.Methods:Subjects with SCD maintained on the LTE program included those with elevated TCD, history of stroke, recurrent acute chest syndrome, or frequent pain crises unresponsive to hydroxyurea therapy. Serial serum ferritin measurements were followed and chelation with deferasirox was initiated for consistent ferritin level >1000 ng/mL. MRI of liver and cardiac iron was measured on all LTE subjects with non-contrast MRI techniques. A total of n=31 subjects maintained on LTE were enrolled and stratified into two groups: high LIC, ≥5mg/g of dry tissue (n=4, 12.9%) and low LIC, <5mg/g (n=27, 87.1%). Chi-squared and t-test were used to test for differences between the two groups. Logistic regression was used to test what impacted the odds of having a high LIC, while generalized linear mixed-effects modeling was used to test what impacted LIC.Results:None of the subjects had high cardiac iron concentration. Subjects with high LIC were significantly older (17.8 vs. 13.1, p=0.032) and were more likely to be female (100% vs. 44.4%, p=0.038). The duration of LTE was not associated with high and low levels of LIC (8.25 vs. 6.15, p=0.240, Figure 1), levels of LIC (r=0.247, p=0.188, Figure 2), or serum ferritin (r=0.077, p=0.680). The total number of simple of transfusions was not associated with serum ferritin (r=-0.177, p=0.558) or LIC (r=-0.022, p=0.910). Serum ferritin was not significantly associated with LIC (r=0.296, p=0.112, Figure 3). One of the 4 patients with high LIC required chelation with deferasirox for ferritin >1000 ng/mL. Three of the 31 subjects required iron chelation with deferasirox.Conclusions:There was no significant correlation between duration of LTE and LIC. The impact of cumulative simple transfusions on LIC was obviated by maintenance LTE. These findings are consistent with reports that LTE is associated with reduced transfusional iron overload. The lack of significant association between serum ferritin and LIC suggest that validated MRI measurements of LIC may have greater sensitivity for identifying patients with iron overload and guidelines for iron chelation should consider LIC rather than serum ferritin alone. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Deferasirox improves hematologic and hepatic function with effective reduction of serum ferritin and liver iron concentration in transfusional iron overload patients with myelodysplastic syndrome or aplastic anemia

Transfusional iron overload and its consequences are challenges in chronically transfused patients with myelodysplastic syndromes (MDSs) or aplastic anemia (AA). This was a prospective, multicenter, open-label study to investigate the efficacy of deferasirox (DFX) by serial measurement of serum ferritin (S-ferritin) level, liver iron concentration (LIC) level using relaxation rates magnetic resonance imaging, and other laboratory variables in patients with MDS or AA. A total of 96 patients showing S-ferritin level of at least 1000 ng/mL received daily DFX for up to 1 year. At the end of the study, S-ferritin level was significantly decreased in MDS (p=0.02366) and AA (p=0.0009). LIC level was also significantly reduced by more than 6.7 mg Fe/g dry weight from baseline. Hemoglobin level and platelet counts were significantly increased from baseline (p=0.002 and p=0.025, respectively) for patients showing significant anemia or thrombocytopenia. Elevated alanine aminotransferase was also significantly decreased from baseline. This study shows that DFX is effective in reducing S-ferritin and LIC level in transfusional iron overload patients with MDS or AA and is well tolerated. In addition, positive effects in hematologic and hepatic function can be expected with DFX. Iron chelation treatment should be considered in transfused patients with MDS and AA when transfusion-related iron overload is documented.

MRI Survey In Transfusion-Dependent and Non-Transfusion-Dependent MDS Patients

IntroductionSeveral studies have shown cardiac diseases as causes of death in myelodisplastic (MDS) patients receiving transfusions. So iron overload may be considered an independent negative prognostic factor. There are few and rather contradictory studies using Magnetic Resonance Imaging (MRI) in the evaluation of myelodysplastic syndromes. We report the baseline MRI findings at the end of the recruitment in the MIOMED (Myocardial Iron Overload in MyElodysplastic Diseases) study. In particular, we investigated myocardial iron overload (MIO), hepatic iron overload and biventricular functional parameters in MDS patients, outlying the differences between transfusion dependent and non transfusion dependent patients. MethodsMIOMED is an observational, MRI multicentre study in low and intermediate-1 risk MDS patients who have not received regular iron chelation therapy. Out of the 51 MDS patients enrolled, 48 underwent the baseline MRI exam. Mean age was 71.7±8.5 years and 17 patients were females. Hepatic T2* values were assessed in a homogeneous tissue area and converted into liver iron concentration (LIC). MIO was assessed using a multislice multiecho T2* approach. Biventricular function parameters were quantified by cine sequences. ResultsThe mean global heart T2* was 38.7±8.3 ms while the mean LIC was 7.6±8.8 mg/g/dw. Global heart T2* values were not significantly correlated with LIC or serum ferritin levels while a significant association between LIC and serum ferritin was detected (R=0.689; P<0.0001).Thirty-two (66.6%) patients were non-transfusion dependent while 16 patients were transfusion-dependent. The two groups were homogeneous for age, sex and hemoglobin levels but transfusion-dependent patients had significantly higher serum ferritin levels (1612±864 vs 711±430; P<0.0001). The percentage of patients with detectable hepatic iron (LIC≥3 mg/g/dw) was significantly higher in the transfusion-dependent group (Figure 1, left). Mean LIC was 14.4±11.1 mg/g/dw in the transfusion-dependent group and 4.2±4.6 mg/g/dw in the non-transfusion-dependent group (P<0.0001). A significant heart iron (global heart T2* value <20 ms) was found in two patients, in both patients an heterogeneous pattern (some segments with T2* values >20 ms and other segments with T2* values <20 ms) was detected. Out of two patients with significant heart iron one patient was not transfused and he did not show significant hepatic iron (LIC=2.12 mg/g/dw). The other one patient was regularly transfused and he received sporadically (less than two weeks/month) chelation treatment with deferoxamine in the 2 years before the MRI. The global heart T2* (Figure 1, right), the pattern of iron burden and the number of segments with T2*<20 ms were comparable between the two groups. Biventricular end-diastolic volume index, biventricular ejection fraction and left ventricular (LV) mass index were comparable between the two groups. [Display omitted] ConclusionsAs expected, regularly transfused MDS patients showed significantly higher levels of hepatic iron overload, that, however, was present in almost the 30% of non-transfusion-dependent patients, mainly due to increased intestinal iron and augmented erythropoiesis. MIO is not frequent in MDS patients and it is not correlated with LIC and serum ferritin levels. Conversely, MIO can be present also in non-transfusion dependent patients and in absence of detectable hepatic iron. These data remark the importance to check directly for heart iron with a more sensitive segmental approach avoiding to estimate heart iron burden from indirect indicators such as LIC, serum ferritin or transfusion state. Disclosures:No relevant conflicts of interest to declare.

Deferasirox–Deferoxamine Combination Therapy Reduces Cardiac Iron With Rapid Liver Iron Removal In Patients With Severe Transfusional Iron Overload (HYPERION)

Background Transfusion-dependent patients with severe cardiac siderosis often require intensive iron chelation therapy for a limited time to facilitate rapid removal of iron from the heart, allowing patients to move from a high-risk (cardiac T2*<10 ms) to lower risk (≥10 ms) status for heart failure. Oral deferasirox (DFX) monotherapy has been shown to improve cardiac T2*, but data on the combined use of DFX and deferoxamine (DFO) are limited. Aim To evaluate efficacy and safety of investigational DFX–DFO in combination followed by DFX monotherapy in patients with severe transfusional cardiac siderosis. Methods The prospective, Phase II, open-label, multinational HYPERION study evaluated DFX–DFO in combination followed by DFX monotherapy in transfusion-dependent patients with severe cardiac siderosis ([NCT01254227][1]). Patients enrolled were ≥10 years with CMR-measured cardiac T2* 5–<10 ms, left ventricular ejection fraction (LVEF) ≥56%, R2-MRI liver iron concentration (LIC) ≥7 mg Fe/g dw. Starting dose was DFX 20 mg/kg/d, 7 d/wk, plus DFO 40 mg/kg/d, 5 d/wk for ≥8 hrs/d. DFX dose could be increased to 30 and 40 mg/kg/d after Month 1 and 6, respectively. Patients achieving cardiac T2* ≥10 ms and a relative T2* increase of ≥10% from baseline (BL) any time after 6 months were switched to DFX monotherapy. Combination therapy was resumed if cardiac T2* fell to <10 ms with a relative decrease of ≥10% from previous T2* value. Dose adjustments were based on efficacy and safety parameters. Primary efficacy endpoint was change in geometric mean cardiac T2* at Month 12 divided by that at BL. A key secondary objective was the proportion of patients achieving T2* ≥10 ms and a ≥10% relative increase from BL after 6 and 12 months. Efficacy was analyzed for all evaluable patients in the full analysis set (FAS) who received ≥1 dose of study drug and had a BL and post-BL assessment; cardiac T2* is also reported for patients with T2* at BL and Month 12 (12-month completers). Results 60 patients were enrolled (59 β-thalassemia major, 1 Diamond–Blackfan anemia; mean age 22.8 years; 46.7% male) with severe iron overload (geometric mean [Gmean] cardiac T2* 7.03 ms, mean LIC 33.4 ± 14.5 mg Fe/g dw, median serum ferritin 5551 ng/mL [range 1163, 11,317]). Overall, 20 patients discontinued; 5 consent withdrawals, 4 adverse events (AEs: pruritus, arthritis, abdominal pain, drug rash with eosinophilia and systemic symptoms), 4 abnormal test procedure results (all T2* 33% increase from BL and >upper limit of normal at 2 consecutive visits. ![Figure][3] Discussion Cardiac T2* improved during 12 months of treatment with DFX–DFO in patients with severe transfusional body iron burden. High BL LIC levels decreased considerably with DFX–DFO. Overall, as LIC decreased cardiac T2* increased, most notably after 6 months. The higher DFX dose permitted after Month 6 possibly influenced this trend. Cardiac T2* improvements were observed irrespective of BL LIC value, but were most marked in those with BL LIC <30 mg Fe/g dw, consistent with previous data showing that cardiac iron removal follows liver iron removal (Noetzli Blood 2008). Safety of DFX–DFO was consistent with established monotherapy profiles, with no unexpected findings. 2-year follow-up for HYPERION will evaluate the impact of longer-term DFX–DFO in combination on liver and cardiac iron removal. Disclosures: Aydinok: Shire: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: Deferasirox and deferoxamine are both indicated as a monotherapy for the treatment of chronic iron overload due to frequent blood transfusions. Patients with severe cardiac iron overload are at increased risk of heart failure and are often treated by off-label combination therapy for a limited time to facilitate rapid removal of iron from the heart, allowing patients to move to a lower-risk status. This abstract describes off-label use of the combination of deferasirox and deferoxamine to treat patients with severe transfusional cardiac iron overload. Kattamis: Novartis: Research Funding, Speakers Bureau; ApoPharma: Speakers Bureau. Cappellini: Genzyme: Honoraria; Novartis: Honoraria, Speakers Bureau. Perrotta: Novartis: Research Funding. Karakas: Novartis: Honoraria, Research Funding. Viprakasit: GPO, Thailand: Honoraria, Research Funding; Shire: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Habr: Novartis: Employment. Wegener: Novartis: Employment. Shen: Novartis: Employment. Porter, MD on behalf of the HYPERION investigators: Shire: Consultancy, Honoraria; Celgene: Consultancy; Novartis: Consultancy, Honoraria, Research Funding. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01254227&atom=%2Fbloodjournal%2F122%2F21%2F2257.atom [2]: #F1 [3]: pending:yes

Iron Overload in Non-Transfusion-Dependent Thalassemia

Iron overload due to increased intestinal iron absorption remains a concern in patients with non-transfusion-dependent thalassemia (NTDT). A dynamic regulation between ineffective erythropiesis and iron metabolism in these disorders has been recently elucidated. Although the rate of iron loading in NTDT is slower than that observed in regularly transfused patients, the process is cumulative and patients may reach considerably high liver iron concentration levels. The clinical consequences of iron overload in patients with NTDT are various and include hepatic disease, endocrinopathy, bone disease, and vascular outcomes; while cardiac siderosis is less frequently observed. Although serum ferritin levels correlate with LIC in NTDT, they underestimate iron load when compared with transfusion-dependent patients with equivalent LIC. Therefore, direct measurement of LIC is recommended to identify patients at risk and guide iron chelation decisions.

Effect of Antioxidant Therapy On Hepatic Fibrosis and Liver Iron Concentrations In Beta-Thalassemia Major Patients

Abstract 5292 Objective:Repeated blood transfusion my lead to peroxidative tissue injury in thalassemia ptients due to secondary iron overload. The aim of the study was to assess the effects of antioxidant vitamins on the oxidative stress, antioxidant status, erythrocytes, hemoglobin derivatives. Also to demonstrate their effects on hepatic status in multitransfused beta-thalassemia major patients. Methods:The study was a prospective follow up study. It involved thirty β-thalassemia major patients aged 4–17 years (15 males and 15 females) recruited from Hematology Oncology Department, Ain Shams University. They were compared to a 20 healthy age and sex matched subjects served as controls. Patients were treated with oral dose of vitamin E (400 mg/day if patient weight < 20 kg and 600 mg/day in patient weight at least 20 kg), low dose of vitamin C (100 mg/day) and vitamin A (25000 IU/ week) for twelve months. Investigations were performed before and after 6 and twelve months of therapy: liver transaminases, serum ferrittin, hepatitis status for HBV, HCV, hepatic fibroscan elastography (TE) for assessment of liver fibrosis and hepatic MRI R2* to measure liver iron concentration (LIC). Assessment of the oxidant /antioxidant capacity by measuring: reduced glutathione, malondialdehyde, ascorbic acid, catalase enzyme, superoxide dismutase, glutathione reductase as well as glutathione peroxidase determination. Results:All patients were on iron chelation therapy: 12 patients received deferiprone (DFP) (75 mg/kg per day orally), 8 patients received deferoxamine (DFO) (30–50 mg/kg per day subcutaneously at least 5 times/week), and 10 patients received a combination of DFO (30–50 mg/kg per day, 2–3 days/week) and DFP (75 mg/kg per day, 7 days/week). In the studied thalassemics 40.0% and 54% were HCV RNA and hepatitis B surface antigen positive. The basal levels of vitamin A, E and C were 3.1, 4, and 2.6 times significantly lower in thalassemia patients compared to controls(p<0.001). Malondialdehyde concentration was 3.4 times higher while reduced glutathione level was 3.2 times lower in studied thalassemics compared to controls(p=0.02,p=0.04). Levels of vitamin A, C, E, reduced glutathione and hemoglobin were significantly elevated during the study period on antioxidant therapy(P=0.03, P=0.02, P<0.001)).This was paralleled by a significant decline in the oxidative-stress marker malondialdehyde (7.87±2.2,8.2±3,11.6±4.1nmol/L;at baseline, after 6 and 12 ms therapy respectively, p<0.001) and serum ferritin levels(2887±1009,2456±1122,2114±990 μg/L, p=0.05). After twelve months of vitamins treatment, there were highly significant improvements of enzymatic antioxidants parameters as compared with before treatment in thalassemia patients. Alanine transaminase, aspartate transaminase, superoxide dismutase and glutathione peroxidase were significantly decreased(p<0.001) while catalase and glutathione reductase activities were significantly elevated(p<0.005). The extent of hemolysis of erythrocytes in studied patients decreases markedly after treatment compared to baseline (p<0.001).There was significant improvement of hepatic fibrosis after 12ms of therapy as 20% of patients had high TE values (FibroScan>12kPa) at baseline compared to 16% after 12 ms therapy (P=0.04).And 56% of patients had value of (>6kPa) at baseline compared to 66%, 70% at 6 and 12months therapy respectively(p=0.03). Levels of liver iron concentration were progressively decreased during the study period compared to baseline (22.4±6.7, 19.4±4.8, 14.4±3.6 mg/gm) in MRI R2* at baseline, after 6 and 12 months therapy respectively<0.001. CONCLUSIONS:Antioxidants vitamins are effective in clinical practice for regulation of antioxidant status as well as improvement of liver iron concentration and hepatic fibrosis in multitransfused thalassemia major patients. Disclosures:No relevant conflicts of interest to declare.

Liver Histology, Liver Iron Concentration (LIC), and Serum Ferritin in a Large Cohort of Chronically Transfused Children with Sickle Cell Anemia: Limitations of LIC As a Marker for Hepatic Injury and Ferritin as An Indicator for Chelation Initiation

Abstract▪2142▪This icon denotes a clinically relevant abstractChronic blood transfusion therapy reduces clinical events and prevents recurrent brain injury in children with sickle cell anemia. The benefit of administering chronic transfusion is weighed against the risk of an increased iron burden leading to chronic organ injury. The gold standard technique for evaluating the adverse effect of iron is to perform a liver biopsy for quantification of hepatic iron content and evaluation of liver pathology. Surrogate evaluations for iron overload include monitoring liver enzymes, serum ferritin and performing r2* MRI of the liver. In order to evaluate the role for utilizing surrogate markers to monitor liver injury, we conducted a retrospective review of 262 liver biopsies in 109 children with sickle cell anemia on chronic transfusion therapy over a nine year period at a single center. Ninety one patients had HbSS, 17 had HbSB0 thalassemia, and one patient had HbSD. Chronic transfusion therapy was performed by either simple transfusion (65%) or erythrocytapheresis (35%) primarily for stroke prevention (n=236), with a few for other indications (n=26) including lung injury and acute vascular necrosis. Patients were initiated on chronic transfusion at a mean age of 6.2 ± 3.6 yrs (0.75–17yrs) with initial biopsy obtained at a mean age of 14.6 ± 5.3 yrs (3–34 yrs). Chelation with deferoxamine or deferasirox was determined by the physician with a practice standard of initiation of chelation once ferritin increased to > 1000ng/mL. All patients at the time of liver biopsy were treated with chelation therapy with either deferoxamine (30%) or deferasirox (70%). Two pathologists reviewed the biopsies and utilized a standardized hepatic scoring system to evaluate the degree of portal/periportal and lobular inflammation and hepatic fibrosis (0= none, 1= mild, 2= moderate, 3= severe). Portal/periportal inflammation was scored 0–3 respectively in 132, 89, 38, and 0 patients and lobular inflammation in 29, 226, 4, and 0 patients. Fibrosis was scored 0–3 respectively in 23, 107, 103, and 26 patients. Ferritin and ALT were recorded prior (median of 3 days) to the liver biopsy. Seven biopsies performed as part of a therapeutic clinical trial were excluded from this analysis. Results show that the mean (± SD) serum ferritin, liver iron concentration (LIC), and ALT were 3509 ± 2617ng/mL, 17.12 ± 13.0 mg Fe/gm dry weight, and 40.2 ± 40.2 IU/L. With respect to histology, ferritin and LIC levels were significantly increased with higher periportal inflammation score (F= 21, p<0.001. F= 20, p<0.001) and severe fibrosis (score 3) (F=36, p<0.001, F=10.4, p<0.001), but not for lower fibrosis scores (0–2), or lobular inflammation score (p=0.20). Despite this significant histologic correlation with surrogate markers, individual overlap exists between ferritin, LIC and liver pathology. A strong linear correlation exists between ferritin and LIC (r=0.74, p<0.001) but with a spread in LIC (R2=55%). With respect to ferritin as a predictor of LIC, all patients with ferritin >1000ng/mL, a standard value for initiation of chelation therapy, had abnormally high LICs, and surprisingly 11 patients were identified with an abnormal LIC despite a ferritin <1000ng/ml. Furthermore, patients with a high LIC (≥ 7 mg Fe/gm dry weight) demonstrate a significantly higher ferritin as compared to patients with lower LIC< 7 (p<0.001) and this positive relationship between LIC and ferritin was replicated in a population with a higher LIC (LIC ≥ 30mg Fe/g dry weight vs. <30) (p<0.001). ROC curves demonstrate an AUC of.88 ± 0.02 (p<0.001) utilizing a LIC of ≥7 or <7 and 0.91± 0.02 (p<0.001) utilizing a LIC of ≥30 or <30. A weak association was noted between ferritin and alanine aminotransferase (ALT) (r=0.27, p<0.001, R2=8%). The results show that although strong statistical correlations exist between liver histology and ferritin or LIC, variability exists. Additionally, a ferritin >1000ng/mL always predicts abnormal LIC, but is inadequate as an indicator for initiation of chelation. The results suggest caution when using surrogate markers alone to predict histological changes in the liver and to initiate chelation therapy in individual patients on chronic blood transfusion therapy. Disclosures:Lebensburger:University of Alabama at Birmingham: Employment.

Oxidative Stress and Reproductive Capacity in Iron Overload Thalassemia Major Women

Abstract 2155Despite progress in chelation regimens, excess iron still results in deleterious effect on the reproductive system of thalassemia major (TM) patients; subsequently compromised fertility is common in TM men and women. We have recently assessed the reproductive potential and its relation to iron overload in TM women as measured by the current methods for ovarian reserve testing (ORT) demonstrating a reduced ovarian antral follicle count (AFC) and corresponding low anti mullerian hormone (AMH) levels (Blood PMID 21757620). In the current study we further explored a possible link between iron overload and oxidative stress on fertility potential in thalassemia. Increase in reactive oxygen species (ROS) production and decrease in antioxidant defense mechanisms are thought to be major causes for accelerated follicle aging over time. Excess redox active non-protein bound iron acts as potent catalyst for highly deleterious ROS, causing oxidative damage to plasma lipids, DNA and proteins, and is therefore likely to further accelerate follicle aging and loss of reproductive potential. However, such an effect in TM women has not been demonstrated. Extensive oxidation of intracellular Glutathione (GSH) affects the structural integrity of cells. The ratio of GSH to its oxidized disulfide (GSH/GSSG) has been shown to be a sensitive measure of oxidative stress in biological systems and was noted to be compromised in thalassemia.We studied 26 TM women (median age 28y); obtaining total non-transferrin bound iron (NTBI) and its low-molecular component, labile plasma iron (LPI). Liver iron concentration (LIC) was measured by superconducting quantum interference device (SQUID) biosusceptometer system. Fourteen women had a trans-vaginal ultrasound (TVUS) for assessment of AFC and for ovarian volume measurements. Plasma GSH, GSSG and GSH precursors were obtained from the TM women and from 12 age-matched healthy non-smoking women, all fasting, were assayed by liquid chromatography–electrospray positive ionization–tandem mass spectrometry (LC-MS/MS) as previously described.GSH concentration was ∼25% lower in TM compared to normal controls, mostly due to low concentration of free GSH; 3.88±2.8 (median 2.9) and 5.74±1.4 (median 5.86), respectively. This resulted in a plasma GSH/GSSG ratio drop by 45% from the control ratio of 79.8 to a ratio of 43.4 in the thalassemia cohort (p=0.04). Plasma GSSG levels remained similar in both groups; 0.1±0.07μM in controls and 0.15±0.1μM in thalassemia women. TM women had an increase in precursors of GSH compare to controls (Table 1), suggesting that key metabolic pathways to augment synthesis of GSH may be up-regulated as a compensatory response to increased oxidative stress. GSH/GSSG, an oxidative measure, significantly correlated with AFC and with ovarian volume (R=0.57, p<0.05 and R=0.77, p=0.003, respectively). LIC (mean 14.5±11mg/gr dry wt, range 3.2–42) and GSH levels inversely correlated (R= −0.47 p<0.05). NTBI and LPI were elevated in the TM (as previously shown) but have not correlated with GSH/GSSG ratio. However, AFC (median 6.5, range 0–20) showed a trend of reverse correlation with NTBI and LPI (R=−0.21 and − 0.34, respectively).Although the current finding of lower levels of GSH and GSH/GSSG ratio in TM women does not provide a direct cause-and-effect relationship between GSH redox and fertility in thalassemia, impaired GSH redox homeostasis in the context of iron overload may be a key precipitating factor involved in accelerated follicular aging experienced by female thalassemia patients. Ovarian tissue in TM women is likely vulnerable to the iron-induced oxidative damage and the low antioxidant protection; a direct deleterious effect beyond the ovarian quiescence due to low gonadotropine stimulation. Oxidative stress may have a major effect on the maturation and growth of oocytes, resulting in further shrinking of ovarian tissue. This data suggests a potential role for antioxidants and improved nutritional supplementation as a therapeutic approach for TM women in particular during their reproductive years.Altered Glutathione (GSH) Precursors in Plasma of Thalassemia Patients Compared with Healthy ControlsGSH precursors (mM)Controls (n=15)Thalassemia women (n=23)pGlutamine297 ± 67440 ± 1760.005Cysteine7.4 ± 3.510 ± 3.80.03Cystathionine0.67 ± 0.20.82 ± 0.8ns [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Sobrecarga de ferro transfusional em portadores de anemia falciforme: comparação entre ressonância magnética e ferritina sérica

OBJETIVO: Identificar variáveis preditoras de sobrecarga de ferro em portadores de anemia falciforme e correlacionar indicadores bioquímicos e imaginológicos. MATERIAiS E MÉTODOS: Foi realizado estudo transversal envolvendo 32 portadores de anemia falciforme, que foram submetidos a dosagem sérica de ferro, ferritina e a ressonância magnética do fígado. Foram realizadas cinco sequências gradiente-eco e uma spin-eco. A intensidade de sinal foi obtida em cada sequência pelas médias das regiões de interesse no fígado e musculatura paravertebral para obter a razão da intensidade de sinal (RIS) fígado/músculo. A partir da RIS foi obtida a concentração hepática estimada de ferro (CHEF) pela fórmula: e[5,808 - (0,877 × T2*) - (1,518 × PI)], onde T2* é a RIS na sequência com TE de 13 ms e PI é a RIS da sequência com ponderação intermediária. Os pacientes foram agrupados segundo o regime de transfusão de hemácias (regulares mensais versus esporádicas). RESULTADOS: Os grupos transfusionais foram comparados pelas variáveis clínico-laboratoriais, sendo significativas as diferenças entre RIS, CHEF e ferritina sérica: o grupo que recebeu transfusões regulares apresentou sobrecarga de ferro hepático mais intensa. CONCLUSÃO: A ressonância magnética foi ferramenta eficiente para avaliação de sobrecarga hepática de ferro em portadores de anemia falciforme.

A Multi-Center, Open Label Study Evaluating the Efficacy of Iron Chelation Therapy with Deferasirox In Transfusional Iron Overload Patients with Myelodysplastic Syndromes or Aplastic Anemia Using Quantitative R2 mri.

AbstractAbstract 1125▪Transfusion-related iron overload and its consequences are emerging challenges in chronically transfused patients with myelodysplastic syndromes (MDS) or aplastic anemia (AA). Measurement of liver iron concentration (LIC) is used as a surrogate for total iron burden to guide chelation therapy in transfusion-dependent patients. Although deferasirox (Exjade®, ICL670) is an oral iron chelation agent that is now widely available for the treatment of transfusional hemosiderosis, the clinical data on its specific benefits of iron chelation, including reduction of LIC, in transfusion-related iron overload patients with MDS or AA has been limited. We have prospectively investigated the efficacy of deferasirox for iron chelation by serial measurement of serum ferritin level and LIC, which is measured in vivo using quantitative tissue proton transverse relaxation rates (R2) magnetic resonance imaging (MRI), in transfusional iron overload patients with MDS or AA. Here we report the interim analysis data.A total of 97 patients with de novo MDS (n = 44) or idiopathic AA (n = 53) showing serum ferritin level over 1,000ng/ml were enrolled from 23 institutes. All patients were regularly transfused and received a mean of 28.6 red blood cells (RBC) units in the year prior to the start of the study. Among MDS cases, 3 (8.3%), 25 (69.4%), and 4 cases (11.1%) were categorized as IPSS low-risk, intermediate-1-risk, and intermediate-2-risk group, respectively. In AA cases, 34 (64.2%) were severe form. Mean value of serum ferritin level in enrolled patients was 3,482.6±436.7 ng/ml in MDS, and 3,904.4±399.2 ng/ml in AA at the time of deferasirox initiation. LIC value was measured using quantitative R2 MRI and FerriScan (Resonance Health, Australia) analysis. Mean value of LIC was 20.8 ± 3.5 mg Fe/g dry weight in MDS and 22.6 ± 2.2 mg Fe/g dry weight in AA. Linear regression analysis indicated a close correlation between serum ferritin level and LIC (r=0.55, p<0.001). Deferasirox was given orally at a dose of 20 mg/kg/day for at least 6 months to all patients. If the serum ferritin falls below 500 ng/ml, treatment was withheld. Over the study period, patients with MDS and AA received a mean of 24.2 and 22.0 units RBC per year, respectively. At the end of study (EOS), the serum ferritin levels were significantly decreased to 3,045.1±446.5 ng/ml and 2,614.7±311.9 ng/ml (p=0.005) in MDS and AA, respectively. One-year follow-up R2 MRI could be evaluated in 55 cases, and at the end of study (EOS), the LIC were significantly decreased to 14.3±2.9 mg Fe/g dry weight (p=0.05) and 15.3±2.3 mg Fe/g dry weight (p=0.001) in MDS and AA, respectively. The most common drug-related adverse events (AE) were gastrointestinal disturbances, non-progressive increase in serum creatinine, and skin rash. However, AE were transient and mild-to-moderate in severity. Deferasirox was discontinued in 30.9% cases because of death, patient refusal, and decrease in the serum ferritin level below 500ng/ml. All death was ascribed to disease-related causes. This study clearly shows that deferasirox is effective in reducing LIC and serum ferritin level in transfusional iron overload patients with MDS or AA, even with ongoing transfusion requirement, and well tolerated. Careful assessment of patient's transfusion requirement will be important in making dose adjustment according to purpose of iron chelation. Data from extension phase of this clinical trial may expand our knowledge about the beneficial effects of deferasirox on prolonging survival and improving quality of life in these patients. Disclosures:No relevant conflicts of interest to declare.

Iron Chelation Therapy in Transfusion Dependent Patients with Thalassemia and Minimal Liver Iron Load

AbstractAbstract 4270 Background:Recent advances in the treatment of iron overload in patients with transfusion- dependent thalassemia have dramatically changed iron related morbidity and mortality. Intensive chelation therapy by using combination therapy or monotherapy at high doses had led to total clearing of the iron in many patients. The best approach for chelation treatment in patients with low levels of iron overload is debatable. Patients and MethodsThis study included all the patients with thalassemia major with minimal liver iron overload, followed in our unit. More precisely, to be eligible for this observational study, the patients needed to have liver iron concentration (LIC) <1.5 mg Fe/gram dry weight tissue, defined by MRI, and to have at least a subsequent MRI evaluation after this time. The mean observation time, which was the time between the two MRIs, was 16.9±5.2 months. ResultsFourty five patients (22 females, 30 non-splemectomized, 21 HCV seropositive, mean age: 31±5.6 years) have reached minimal levels of iron overload in any time point after 2004. Thirty one of them have been treated with combined therapy of desferrioxamine (DFO) and deferiprone (DFP) and 5, 6 and 3 with monotherapy of deferasirox (DFX), DFP and DFO, respectively. After reaching these levels, 42% of the patients changed therapy, with the most frequent change being from combined therapy to monotherapy (15 patients).Baseline ferritin levels at the time of the first MRI range from 43 to 4336 ng/ml (median 230 ng/ml) and they were not affected by spleen, gender or HCV status. Baseline LIC (mean 1.2 ± 1.7 mgFe/g.d.w.) correlated well with ferritin levels (Spearman's rho = 0.47, p<0.005), as did ferritin changes to LIC changes (Spearman's rho = 0.67, p<0.005).The results on the follow up evaluation, stratified according to the actual treatment, are shown in the tableDeferiprone was less efficacious in controlling both LIC and ferritin levels compared to combination therapy (p=0.016 and 0.031, respectively). Fifteen out of 17 patients treated with DFP showed an increase in LIC, despite using the recommended dose. Six out of 9 patients treated with DFX, most at a low dose, showed an increase in LIC. There were no differences in changes in the cardiac parameters (LVEF, cardiac T2*) in between treatment groups. The efficiency of DFP and DFX, which represents the ratio of iron excreted to the theoretical maximum of iron that could be bound by the chelators, was calculated at 1.8±0.9 % and 15.2 ± 3.6 %, respectively. ConclusionsCurrent iron chelation therapy regimens are able to render iron load-free many patients with thalassemia major. As iron accumulation from transfusions continues, a fine balance needs to be found in which neither worsening of iron overload nor toxicity from excessive dose of iron chelators will occur. This study showed that at low levels of iron overload both combination therapy and DFX can control iron accumulation, whether monotherapy with DFP may be insufficient to achieve iron balance in many patients. The dose of the chelators needs to be adjusted according to the needs and the clinical course of the patients, which can be predicted by the trend of the ferritin levels. Furthermore, it should be kept in mind that at low levels of iron overload, the iron chelators' efficiency may be lower than previously described. Disclosures:Kattamis:NOVARTIS ONCOLOGY: Honoraria, Research Funding, Speakers Bureau; APOPHARMA: Honoraria. Ladis:NOVARTIS ONCOLOGY: Honoraria, Research Funding; APOPHARMA: Honoraria, Research Funding.

Liver iron concentration quantification by MRI: are recommended protocols accurate enough for clinical practice?

To assess the accuracy of quantification of liver iron concentration (LIC) by MRI using the Rennes University (URennes) algorithm. In the overall study period 1999-2006 the LIC in 171 patients was calculated with the URennes model and the results were compared with LIC measured by liver biopsy. The biopsy showed that 107 patients had no overload, 38 moderate overload and 26 high overload. The correlation between MRI and biopsy was r=0.86. MRI correctly classified 105 patients according to the various levels of LIC. Diagnostic accuracy was 61.4%, with a tendency to overestimate overload: 43% of patients with no overload were diagnosed as having overload, and 44.7% of patients with moderate overload were diagnosed as having high overload. The sensitivity of the URennes method for high overload was 92.3%, and the specificity for the absence of overload was 57.0%. MRI values greater than 170 μmol Fe/g revealed a positive predictive value (PPV) for haemochromatosis of 100% (n=18); concentrations below 60 μmol Fe/g had a negative predictive value (NPV) of 100% for haemochromatosis (n=101). The diagnosis in 44 patients with intermediate values remained uncertain. The assessment of LIC with the URennes method was useful in 74.3% of the patients to rule out or to diagnose high iron overload. The method has a tendency to overestimate overload, which limits its diagnostic performance.

Heightened Sulfur Amino Acid Oxidation in Plasma and Erythrocytes in β-Thalassemia Major.

Abstract 4065Poster Board III-1000 BackgroundOxidative stress in β-thalassemia major is a well documented problem thought in part to be due to transfusional iron overload. Sulfur amino acid (SAA)-derived metabolites, chiefly glutathione (GSH), are critical components of cellular antioxidant defense. Inability to adequately regulate endogenous antioxidant status may lead to further exacerbation of oxidative stress. To characterize whether alteration in SAA metabolism contributes to heightened oxidative stress in thalassemia, we utilized a novel liquid chromatography linked electrospray positive tandem mass spectrometric (LC-MS/MS) technique to simultaneously quantify the redox states of cysteine (Cys) and GSH as well as the concentrations of major amino acid-derived metabolites in plasma and erythrocytes. MethodsAfter institutional review board approval, adult and pediatric subjects with β-thalassemia major were recruited for fasting blood samples drawn immediately prior to the next scheduled blood transfusion. Plasma and red blood cell samples were analyzed using the LC-MS/MS technique (J Chromatogr B 2009;in press) and compared with healthy controls. ResultsTwelve subjects with β-thalassemia major were recruited. The median age of the group was 26.5 years (range 11-41). The median liver iron concentration (LIC) determined by ferritometer was 11.9 mg/g dry-wt (range 1.0-34.8). The median ferritin level for the group was 1980 ng/mL (379-4730). Evidence of myocardial iron overload (T2* <20 msec) was present in 5 of 11 subjects. Plasma SAA redox analysis in these subjects showed significant oxidation of Cys and GSH. Total Cys redox status (Cysteine/2*Cystine ratios) decreased from 0.1 ± 0.01 in healthy controls to 0.08 ± 0.02 in thalassemia (p=0.02). Similarly, the plasma GSH redox state (GSH/2*GSSG ratio) decreased from 38.9 ± 13.7 in healthy controls to 6.7 ± 5.3 in thalassemia subjects (p=0.005). The total GSH and total Cys pools in the plasma did not differ between the two groups. Mirroring the patterns observed in the plasma compartment, the proportion of erythrocyte GSSG was also significantly elevated in thalassemia (0.65% vs. 0.04%, p=0.009), without a concomitant decline in total erythrocyte GSH pool. A significant 3-fold elevation in plasma cystathionine and S-adenosylmethionine levels suggests that key SAA metabolic pathways to augment synthesis of GSH may be up-regulated in thalassemia. In addition to alterations in SAA metabolite profiles, the thalassemia group was >3-fold deficient in plasma valine, spermine and citrulline compared with controls. We found that within this small group, the level of iron overload measured by serum ferritin, liver iron concentration and cardiac MRI T2* showed no correlation with the amount of oxidative stress measured by glutathione redox. DiscussionAssessment of SAA redox states and metabolic pathways has the potential to be a novel important marker in β-thalassemia major. The alterations in both Cys and GSH redox states without concomitant decline in their total concentration suggests either a significant increased rate of SAA oxidation and/or a decline in the capacity for NADPH-dependent reduction of oxidized disulfides. The latter may be supported by the evidence of profound hypocitrullinemia in thalassemia, which has been noted in subjects with inherited mitochondrial disorders (Proc Nat Acad Sci U S A 2009;106:3941-5). Finally, we show that the oxidative environment in the plasma affects the transfused erythrocytes which acquire characteristics of abnormal thiol metabolites observed in the plasma compartment. The demonstration of significant oxidative stress even in subjects with low body iron burden suggests that currently acceptable LIC levels may not be optimal, or that other contributors to the pro-oxidant state should be sought in thalassemia. Disclosures:No relevant conflicts of interest to declare.

Absence of cardiac siderosis by MRI T2* despite transfusion burden, hepatic and serum iron overload in Lebanese patients with sickle cell disease

The use of magnetic resonance imaging (MRI) to detect organ-specific iron overload is becoming increasingly common. Although hepatic iron overload has been recognized in patients with sickle cell disease (SCD), cardiac iron deposition has only been examined in a few reports. This was a cross-sectional study of 23 patients with SCD. Patient charts were reviewed and data collected for drug use, total lifetime transfusions (TLT), transfusion rate (TR), status of the spleen, and comorbid illnesses or infections. Blood samples were obtained for assessment of hemoglobin, serum ferritin, non-transferrin-bound iron (NTBI), and liver enzyme levels. Doppler echocardiography was performed to detect pulmonary hypertension (PHT) and assess left ventricular ejection fraction. Cardiac iron levels were measured by MRI T2*. Direct determination of liver iron concentration (LIC) was performed using R2 MRI. In this study, cardiac T2* >20 ms was considered normal. The mean age was 24.4 +/- 9.7 yr, with a male to female ratio of 15:8. A total of 9 (49.9%) patients were splenectomized. The mean TR was 14.1 +/- 13.2 Units/yr, and the mean hemoglobin level was 9.0 g/dL. PHT was detected in 6 (27.3%) patients, but none had evidence of heart failure. The mean serum ferritin, LIC, and NTBI levels were 997.7 ng/mL, 4.6 mg Fe/g dw, and 1.1 +/- 2.2, respectively. TR was a much better predictor of iron burden (LIC, ferritin, NTBI) than TLT. In fact, TR less than 10 Units/yr did not produce significant iron overload reflecting spontaneous losses as high as 0.11 mg/kg/d. None of the patients had evidence of cardiac iron overload (mean cardiac T2* = 37.3 +/- 6.2 ms; range: 21.9-46.8 ms). There was also no statistically significant correlation between cardiac T2* values and any of the study variables. Our study demonstrates that TR is a stronger predictor of iron overload than TLT. It also confirms cardiac sparing in patients with SCD, even in subjects with significant transfusion burden, systemic and hepatic iron overload.

A Multi-Center, Open Label Study Evaluating the Efficacy of Iron Chelation Therapy with Deferasirox in Transfusional Iron Overload Patients with Myelodysplastic Syndromes or Aplastic Anemia Using Quantitative R2 MRI

Transfusion-related iron overload and its consequences are emerging challenges in chronically transfused patients with myelodysplastic syndromes (MDS) or aplastic anemia (AA). Measurement of liver iron concentration (LIC) is used as a surrogate for total iron burden to guide chelation therapy in transfusion-dependent patients. Although deferasirox (Exjade®, ICL670) is an oral iron chelation agent that is now widely available for the treatment of transfusional hemosiderosis, the clinical data on its specific benefits of iron chelation, including reduction of LIC, in transfusion-related iron overload patients with MDS or AA has been limited. We have prospectively investigated the efficacy of deferasirox for iron chelation by serial measurement of serum ferritin level and LIC, which is measured in vivo using quantitative tissue proton transverse relaxation rates (R2) magnetic resonance imaging (MRI), in transfusional iron overload patients with MDS or AA. Here we report the interim analysis data. A total of 79 patients with de novo MDS (n = 29) or idiopathic AA (n = 50) showing serum ferritin level over 1,000ng/ml were enrolled from 23 institutes. All patients were regularly transfused and received a median of 30 red blood cells (RBC) units in the year prior to the start of the study. Among MDS cases, 3 (10.3%), 20 (69.0%), and 4 cases (13.8%) were categorized as IPSS low-risk, intermediate-1-risk, and intermediate-2-risk group, respectively. In AA cases, 34 (64%) were severe form. Mean value of serum ferritin level in enrolled patients was 4,417 ± 3,378 (4,788 ± 3,996 in MDS, 4,185 ± 2,962 in AA) ng/ml at the time of deferasirox initiation. LIC value was measured using quantitative R2 MRI and FerriScan (Resonance Health, Australia) analysis. Mean value of LIC was 23.9 ± 13.8 (26.1 ± 15.0 in MDS, 22.8 ± 13.2 in AA) mg Fe/g dry weight. Linear regression analysis indicated a close correlation between serum ferritin level and LIC (r=0.55, p<0.001). Deferasirox was given orally at a dose of 20 mg/kg/day for at least 6 months to all patients. If the serum ferritin falls below 500 ng/ml, treatment was withheld. A consistent decrease in the serum ferritin level was demonstrated during the first 6 months in vast majority of patients despite of continued transfusion (209.7 ± 159.9 ng/ml and 324.0 ± 289.4 ng/ml per month in MDS and AA, respectively). Over the study period, patients with MDS or AA received a mean of 3.7 and 2.7 units RBC per month, respectively. After 6 months of medication, a slower decrease in the serum ferritin level was observed in MDS patients. In 30 cases, one-year medication of deferasirox was completed. At the end of study (EOS), the serum ferritin levels were significantly decreased to 3,085 ± 2,150 ng/ml (64.4% of baseline level) and 2,913 ± 2,232 ng/ml (69.6% of baseline level, p<0.01) in MDS and AA, respectively. One-year follow-up R2 MRI could be evaluated in 24 cases, and LIC was significantly decreased to the level of 19.3 ± 13.6 mg Fe/g dry weight (67.4% of baseline value, p=0.01). Decrease in the level of LIC at EOS in MDS (64.3% of baseline) was comparable to that in AA cases (68.5% of baseline). The most common drug-related adverse events (AE) were gastrointestinal disturbances, non-progressive increase in serum creatinine, and skin rash. However, AE were transient and mild-to-moderate in severity. Deferasirox was discontinued in 28 (35.4%) cases because of death (7 in MDS and 6 in AA), patient refusal (11 cases), and decrease in the serum ferritin level below 500ng/ml (4 cases). All death was ascribed to disease-related causes including cytopenia in nine (11.4%) and disease progression in one (1.3%). This study clearly shows that deferasirox is effective in reducing LIC and serum ferritin level in transfusional iron overload patients with MDS or AA, even with ongoing transfusion requirement, and well tolerated. Careful assessment of patient's transfusion requirement will be important in making dose adjustment according to purpose of iron chelation. Data from extension phase of this clinical trial may expand our knowledge about the beneficial effects of deferasirox on prolonging survival and improving quality of life in these patients.

Correlation of Serum Ferritin Levels and Liver Iron Concentration Determined by R2* MRI in Patients with Thalassemia Intermedia.

Background: Unlike patients with thalassemia major (TM), those with thalassemia intermedia (TI) do not require regular blood transfusion therapy but remain susceptible to iron overload due to increased intestinal iron uptake triggered by ineffective erythropoiesis. TI patients can accumulate 1–3.5 g of excess iron per year, and effective monitoring of iron burden is an important element of patient management. Assessment of serum ferritin (SF) levels is a convenient and widely used method, and a correlation between SF and liver iron concentration (LIC) has been demonstrated in patients with TM. SF levels may, however, be a poor indicator of LIC in patients with TI and the limited data available on the SF:LIC correlation prove equivocal; in fact, reports suggest a discrepancy between LIC and SF in patients with TI. This is the largest study to use R2* MRI to evaluate the SF:LIC correlation in patients with TI.Methods: This was a cross-sectional study of randomly selected, infrequently/non-transfused TI patients treated at a chronic care center in Hazmieh, Lebanon. Patient charts were reviewed and a medical history was compiled. Blood samples were taken for SF assessment, and LIC was determined by R2* MRI.Results: Data from 74 TI patients were included in this analysis (33 male, 41 female; mean age 26.5 ± 11.5 years). Of this group, 59 (79.7%) patients were splenectomized, 20 were transfusion-naive, 45 had received several transfusions in their lifetime but none in the past year, and 9 patients were regularly transfused 2–4 times per year. Overall mean SF values were 1023 ± 780 ng/mL (range 15–4140); mean LIC levels were 9.0 ± 7.4 mg Fe/g dry weight [dw] (range 0.5–32.1). In contrast to previous findings, a significant positive correlation between mean LIC and SF values was seen in the whole group (R=0.64; P<0.001), and in a subset of splenectomized patients (R=0.62; P<0.001). In comparison with data obtained from a randomly selected group of patients with TM treated at the center, SF levels in TI were seen to be significantly lower, while the mean LIC values were similar in both groups of TI and TM. For a given LIC, SF values were lower in patients with TI than those with TM (Figure).Conclusions: Evaluation of iron levels shows that many patients with TI have SF and LIC levels above the recommended threshold levels, indicating a risk of significant morbidity/mortality. Similar to TM, a significant correlation between SF and LIC was observed in patients with TI; however, the relationship between SF and LIC was different between TI and TM (for the same LIC, the SF values in TI were lower than those in TM). Therefore, use of the current threshold for iron overload based on SF values in TM will lead to significant underestimation of the severity of iron overload in patients with TI. This may result in delayed chelation therapy, and expose patients to morbidity and mortality risks associated with iron overload. Disease-specific management approaches are therefore required in patients with TI. This includes either regular assessments of LIC, ideally by non-invasive R2* MRI, or lowering the SF threshold for initiating iron chelation in patients with TI. [Display omitted]