Safety and Efficacy of High Dose Intravenous Desferoxamine for Reduction of Iron Overload Due to Chronic Transfusion in Sickle Cell Patients.

Abstract Background: Patients with sickle cell disease (SCD) receiving chronic blood transfusions are at risk of developing iron overload and organ toxicity. Chelation therapy with either subcutaneous (SQ) desferoxamine (DFO) or oral deferasirox is effective in preventing and reducing iron overload but poses significant challenges with patient compliance. Intravenous (IV) infusions of high dose DFO (HDD) have been utilized in non compliant patients with heavy iron overload in small case series. We review our experience of high dose IV DFO in a large cohort of SCD patients with significant iron overload who are non compliant with SQ DFO. Methods: The medical records of SCD patients who received HDD in our center between 1993 and 2004 were reviewed. All of them were on chronic transfusion, had significant iron overload defined by serum ferritin > 1500 and/or liver iron concentration (LIC) more than 10 μg/g of liver tissue and were non-compliant with SQ DFO. All patients underwent annual ophthalmologic, hearing, pulmonary and cardiac evaluation. Demographic data, treatment details, serum ferritin levels, liver iron concentration (LIC), liver enzymes, renal function tests, audiogram and other relevant clinical data were collected. Results: There were 27 patients (19 males, 8 females), 19 patients were on transfusion for history of cerebrovascular accident, 5 for abnormal transcranial Doppler flow velocity, 2 for transient ischemic attack and one for recurrent pain crises. All continued to receive packed red blood cell transfusions aimed to keep HbS levels below 30 or 50% during this time. They were treated in-hospital with DFO 15 mg/kg/hr IV for 48 hrs every 2 weeks (20 patients), 3 weeks (4 patients) and 4 weeks (3 patients). The mean age at start of high dose regimen was 14.6 years (range 9–27 years). The mean duration of HDD treatment was 8.9 months (range 3–49 months). Fourteen patients had LIC determined by liver biopsy. Significant reductions in LIC were observed after HD (table I). This was more pronounced in patients who had higher LIC and received at least 6 months of HDD. Histological examination of liver biopsies revealed a decrease in the grade of liver iron storage. Four patients had portal triaditis initially which resolved after starting HDD therapy. Also there was significant improvement in liver enzymes (ALT, AST) after HDD. There was a trend in decreasing ferritin levels after HDD but this did not achieve statistical significance. All patients tolerated HDD without any major reactions. No audiologic or ophthalmologic toxicity or acute or chronic pulmonary complications were observed. Blood urea nitrogen remained normal in all patients after HDD but there was mild increase in serum creatinine. One patient had high serum creatinine (1.2 mg/dL) after two doses HDD. This patient had focal segmental glomeurosclerosis which was most probably the cause for the rise in creatinine. There was no significant increase in serum creatinine in our series when this patient was excluded. Conclusions: In our cohort of SCD patients we observed a significant decrease in liver iron burden with high dose IV DFO. Our patients tolerated the therapy well without any major toxicity. This regimen is safe and may be an option for poorly compliant patients with significant iron overload. In addition, combination of this regimen with oral iron chelators may be of benefit to patients with significant iron overload and organ dysfunction. Table 1: Laboratory characteristics of sickle cell patients before and after high dose IV DFO Parameter No. of Patients Mean (SD) prior to HDD Mean (SD)after HDD p Value* * Changes in mean levels analyzed using two-tailed Paired T Test with significant p value ≤ 0.05. SD – Standard deviation + See text Liver iron (μg/g of liver tissue ) 14 16864 (10903) 12681 (8298) 0.04 Liver iron min of 6 months of HDD (μg/g of liver tissue ) 8 18677 (8319) 9362 (4521) 0.01 Liver iron >10 mg & minimum 6 months of HDD (μg/g of liver tissue) 7 21181 (7054) 10092 (4443) 0.01 Grade of liver iron storage 14 3.57 (0.9) 3.07 (1) 0.05 Serum Ferritin (ng/mL) 27 3842 (2619) 3238 (1780) 0.06 Serum AST (IU/L) 27 54.1 (27.2) 44.6 (17.6) 0.04 Serum ALT (IU/L) 27 39.2 (36) 27.5 (14.2) 0.01 Blood urea nitrogen (mg/dL) 27 8.9 (2.9) 9.5 (4.3) 0.20 Serum Creatinine (mg/dL)+ 26 0.50 (0.1) 0.55 (0.2) 0.07

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Liver Transient Elastography (FibroScan) Correlates with Liver Iron Concentration and Reflects Liver Fibrosis In Patients with Sickle Cell Disease

Blood ◽

10.1182/blood.v116.21.1646.1646 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1646-1646 ◽

Cited By ~ 3

Author(s):

Ersi Voskaridou ◽

Maria Schina ◽

Eleni Plata ◽

Dimitrios Christoulas ◽

Maria Tsalkani ◽

...

Keyword(s):

Liver Fibrosis ◽

Iron Overload ◽

Hepatic Fibrosis ◽

Sickle Cell ◽

Serum Ferritin ◽

Transient Elastography ◽

Iron Concentration ◽

Liver Stiffness ◽

Cell Disease ◽

Liver Iron

Abstract Abstract 1646 Liver transient elastography (FibroScan) is an interesting new technology that allows estimation of hepatic fibrosis through measurement of liver stiffness. The technique is based on changes in tissue elasticity induced by hepatic fibrosis and is considered as a noninvasive, reproducible and reliable method to assess hepatic fibrosis as well as to diagnose liver cirrhosis. Hepatic iron overload is a severe complication of chronic transfusion therapy in patients with hemoglobinopathies and plays an important role in the development of hepatic fibrosis and cirrhosis. Iron overload is present in several cases of sickle cell disease (SCD) including sickle cell anemia (HbS/HbS) and double heterozygous sickle-cell/beta-thalassemia (HbS/beta-thal). The aim of the study was to evaluate liver fibrosis by measuring the liver rigidity (Liver Stiffness Measurement, LSM, kPascals) using transient elastography (FibroScan, Echosens, Paris, France) in patients with SCD and explore possible correlations with clinical and laboratory characteristics of the patients, including iron overload. We studied 110 consecutive patients with SCD who are followed-up in the Thalassemia Center of Laikon General Hospital in Athens, Greece. Forty-four patients were males and 66 females; their median age was 44 years (range: 21–73 years). Twenty-two patients had HbS/HbS and 88 patients had HbS/beta-thal. On the day of Fibroscan, all patients had a thorough hematology and biochemical evaluation, including hemoglobin, reticulocyte counts, serum ferritin, liver biochemistry, bilirubin, lactate dehydrogenase (LDH) and serology for viral hepatitis. Liver iron concentration was evaluated by magnetic resonance imaging (MRI) T2* in all patients. The median LSM of all patients was 6.1 kPascals (range: 3.4–48.8 kPascals) with no differences between HbS/HbS (6.1 kPascals, 3.5–17.3 kPascals) and HbS/beta-thal (6.1 kPascals, 3.4–48.8 kPascals) patients (p=0.835). LSM values strongly correlated with liver MRI T2* values (r=0.337, p<0.001), serum ferritin (r=0.328, p=0.001), number of transfusions (r=0.332, p=0.001), bilirubin (r=0.299, p=0.003), LDH (r=0.287, p=0.004), Hb (r=-0.275, p=0.006) and reticulocyte counts (r=0.244, p=0.015). LSM values showed also strong positive correlations with biochemical indicators of liver function: gamma-glutamyl transpeptidase (r=0.522, p<0.0001), glutamic oxaloacetic transaminase (r=0.484, p<0.0001), glutamic pyruvic transaminase (r=0.422, p<0.0001), alkaline phosphatase (r=0.334, p=0.001), gamma-globulin (r=0.296, p=0.005) and weak correlation with PT-International Normalized Ratio (r=0.184, p=0.094). The above correlations were similar in patients with HbS/HbS and in patients with HbS/beta-thal. However, in HbS/HbS patients the correlation between LSM and liver T2* values was very strong (r=0.770, p=0.001). Patients who were regularly transfused had higher values of LSM (median: 6.7 kPascals, range: 2.3–48.8 kPascals) compared with patients who were sporadically transfused or were not transfused (4.4 kPascals, 3.6–17.5 kPascals, p=0.003). Patients who were under iron chelation therapy had lower values of LSM (6.3 kPascals, 3.4–15 kPascals) compared with those who did not receive iron chelators (13.9 kPascals, 8.5–17.3 kPascals, p=0.013). We found no correlations between the presence of HBV or HCV positivity and the levels of LSM. In conclusion, FibroScan may constitute a reliable and easy to apply noninvasive method to assess liver fibrosis in patients with SCD; the strong correlations between LSM values with MRI T2* values and serum ferritin supports this observation. Furthermore, FibroScan seems also to reflect the presence of chronic hepatic injury in these patients. If our results are confirmed by other studies, FibroScan may be regularly used in the management of SCD patients in whom liver is the main target organ of the disease. Disclosures: No relevant conflicts of interest to declare.

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Serum Ferritin a Predictor of Iron Overload in Patients with Thalassemia and Sickle Cell Disease?.

Blood ◽

10.1182/blood.v104.11.3789.3789 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3789-3789 ◽

Cited By ~ 1

Author(s):

Zahra Pakbaz ◽

Roland Fischer ◽

Richard Gamino ◽

Ellen B. Fung ◽

Paul Harmatz ◽

...

Keyword(s):

Sickle Cell Disease ◽

Iron Overload ◽

Sickle Cell ◽

Serum Ferritin ◽

Iron Concentration ◽

Cell Disease ◽

Liver Iron Concentration ◽

Liver Iron ◽

Iron Stores ◽

Significant Difference

Abstract Introduction: Monitoring iron overload by serum ferritin in patients with hemosiderosis is still a routine practice although its limitations are widely studied and well known. Using non-invasive liver iron assessment by quantitative MRI or by biomagnetic liver susceptometry (BLS) with SQUID biomagnetometers would be the better alternative, however, these methods are available at only a few centers worldwide. Objective: To determine the relationship between serum ferritin (SF) and liver iron concentration (LIC), measured by BLS at CHRCO, in patients with different types of hemosiderosis. Methods and Patients: A total of 97 patients with thalassemia (TM: 3 to 52 y, 54% females) and 39 patients with sickle cell disease (SCD: 5 to 49 y, 60% female) were prospectively assessed for LIC and SF. Both tests were performed within 2 weeks of each other. Most patients with TM and SCD were chronically transfused, while 10 b-thalassemia intermedia (TI), 5 HbE/β-thalassemia (HbE), and 5 SCD patients were not on transfusion programs. LIC was measured by LTc SQUID biosusceptometer system (Ferritometer®, Model 5700, Tristan Technologies, San Diego, USA) under the standardized Hamburg-Torino-Oakland protocol. A non-parametric test (U-test) was utilized to analyze differences between SF and LIC data. Results: In chronically transfused TM and SCD patients, the median SF and LIC were very similar (Table I). In TI&HbE patients, ferritin results were disproportionately low with respect to LIC. In order to improve prediction of iron stores by SF, the SF/LIC ratio was calculated. There was a significant difference between the median ratios of the two groups of transfused and non- transfused thalassemia patients, 0.82 vs. 0.32 [μg/l]/[μg/gliver], respectively (p < 0.01). In SCD patients the ratio is significantly (p < 0.01) higher. Conclusion: Present data confirm ferritin to be a poor predictor of liver iron stores both in sickle cell disease and thalassemia. Relying only on ferritin to monitor iron overload in patients with hemosiderosis can be misleading, especially, in sickle cell disease and non-transfused thalassemia patients. Taking into account disease specific ferritin-LIC relations, could improve the prediction of iron stores. However, assessment of liver iron stores is the ultimate method to initiate and adjust chelation treatment in order to avoid progressive organ injury. Table I. Median values and ranges ( − ) of serum ferritin (SF) and liver iron concentration (LIC) in transfused (Tx) and non-transfused (non-Tx) hemosiderosis patients. Patient group n SF μg/l] LIC [mg/gliver ] SF:LIC Thalassemia Tx 82 1721 (209–8867) 3424 (364–7570) 0.82 (0.3–1.8) TI &HbE non-Tx 15 766 (52–2681) 2174 (226–5498) 0.32 (0.1–1.4) SCD Tx 34 2757 (400–9138) 1941 (518–6670) 1.2 (0.6–3.3)

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Correlation of Serum Ferritin Levels with Liver Iron Concentration By MRI Measurement in Sickle Cell Patients with Transfusional Iron Overload

Blood ◽

10.1182/blood-2018-99-119597 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4926-4926 ◽

Cited By ~ 1

Author(s):

Germame Ajebo ◽

Abhishek A. Mangaonkar ◽

Imran Ahmad ◽

Nadine Barrett ◽

Leigh Wells ◽

...

Keyword(s):

Liver Function ◽

Iron Overload ◽

Sickle Cell ◽

Serum Ferritin ◽

Iron Concentration ◽

Liver Function Tests ◽

Liver Iron Concentration ◽

Liver Mri ◽

Liver Iron ◽

Positive Correlation

Abstract Background: Recent reports from the thalassemia literature suggest that serum ferritin may be a poor and possibly misleading measure of total iron store in heavily iron overloaded patients. Moreover, the relationship between plasma ferritin and body iron stores is distorted by ascorbate deficiency, fever, infection, inflammation, and hepatic dysfunction, all of which occur in patients with sickle cell disease (SCD). On the other hand, following the results of multiple studies that demonstrated a high correlation of hepatic iron overload determination by magnetic resonance imaging to the values found in specimens from liver biopsy, R2* liver MRI has emerged as the best noninvasive yet highly sensitive and specific method for measuring the level of iron in the liver. The goal of this study was to determine the correlation of liver iron by liver R2* MRI with serum ferritin and by extrapolation assess whether serum ferritin remains to be a useful clinical marker of iron overload in patients with SCD. We also sought to determine the correlation of liver iron concentration with abnormalities in the liver function tests. Methods: We conducted a retrospective analysis of 31 patients with sickle cell disease and transfusional iron overload who are being followed at the Augusta University Comprehensive Sickle Cell Center. Serum ferritin, hepatic R2* MRI liver iron concentration, hepcidin level, and liver function tests (AST, ALT and total bilirubin) were assessed for correlation. We used the Pearson correlation coefficient to determine the relationship between the various variables with hepatic R2* MRI. Results: Serum ferritin levels showed a statistically significant positive correlation with R2* hepatic MRI (r = 0.479 with p = 0.0085) in the patients with SCD and transfusional iron overload . We also saw a positive correlation, although not statistically significant, between hepcidin level and liver iron concentration by liver MRI(r=0.493 with P= 0.399). This may be due to the small sample size of the patients who had hepcidin levels available. On the other hand, no correlation was detected between abnormalities in liver function tests and liver iron concentration. The correlation between liver iron concentration(LIC) and AST was 0.045 with p = 0.816 and the correlation between LIC and ALT was 0.233 with p = 0.224. Conclusion: While R2* MRI is the the most accurate method to diagnose and monitor response to therapy in SCD patients with transfusional iron overload, we have found a statistically significant positive correlation with serum ferritin values. Thus, where R2* liver MRI is unavailable, serum ferritin remains a clinically useful tool that can be used in the diagnosis and monitoring of iron overload in sickle cell patients, despite its limitations. As previously reported, we did not find any correlation between LIC and liver function abnormalities in this population (Harmatz et al, 2000) These findings suggest that patients with SCD may have a different response to iron overload in comparison to patients with thalassemia or hereditary hemochromatosis. Disclosures Kutlar: Bluebird Bio: Other: DSMB Member; Sancilio: Other: DSMB Chair; Novartis: Consultancy, Honoraria, Other: Personal fees, Research Funding.

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Correlation of Serum Ferritin Levels with Liver and Heart Mri T2 and Liver Iron Concentration in Beta Thalassemia Intermediate Patients: A Contemporary Issue

Blood ◽

10.1182/blood.v128.22.4829.4829 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4829-4829 ◽

Cited By ~ 1

Author(s):

Mehran Karimi ◽

Fatemeh Amirmoezi ◽

Sezaneh Haghpanah ◽

Seyed pouria Ostad ◽

Mehrzad Lotfi ◽

...

Keyword(s):

Iron Overload ◽

Serum Ferritin ◽

Iron Concentration ◽

Beta Thalassemia ◽

P Value ◽

Hepatic Iron ◽

Liver Iron Concentration ◽

Liver Iron ◽

Hepatic Iron Overload ◽

T2 Mri

Abstract Background: B-Thalassemia intermediate (B-TI) is a genetic disease that is milder than beta thalassemia major. The accumulation of iron in different organs causes tissue damage. The T2* magnetic resonance imaging (MRI) technique is currently the gold standard for iron load detection. However, it is expensive and needs an expert radiologist to report findings. Therefore, we conducted this study to determine an optimal cut-off value of ferritin in proportion to T2 MRI for early detection of cardiac and hepatic iron overload in patients with beta thalassemia intermediate. Methods: This cross-sectional study was conducted on 108 patients with B-TI who referred to tertiary Hospital, Shiraz University of Medical Sciences, Shiraz, Iran. Serum ferritin, hepatic and cardiac T2 MRI were assessed. The ROC curve was used to determine the sensitivity and specificity of cut-off value. Results: Serum ferritin levels showed a statistically significant negative correlation with T2 hepatic MRI (r= -0.290, P value=0.003) and positive correlation with LIC (r= 0.426, P value ˂ 0.001) in the patients with BTI. However, T2 cardiac MRI was not significantly correlated with serum ferritin levels (P value= 0.073).According to the analysis of ROC curves, the best cut-off value for ferritin to show early diagnosis of liver iron overload was 412 ng/ml. calculated sensitivities and specificities were 0.78 and 0.82 for T2 liver MRI and 0.76 and 0.86 for liver iron concentration (LIC) respectively. Conclusion: Serum ferritin levels of 412 ng/ml might be considered as a cut-off point to evaluate hepatic iron overload before using expensive, not readily available T2 MRI. This level of serum ferritin (around 500 ng/ml) could be considered for starting iron chelation therapy in patients with B-TI in areas where T2 MRI is not available. Disclosures No relevant conflicts of interest to declare.

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Consequences and management of iron overload in sickle cell disease

Hematology ◽

10.1182/asheducation-2013.1.447 ◽

2013 ◽

Vol 2013 (1) ◽

pp. 447-456 ◽

Cited By ~ 57

Author(s):

John Porter ◽

Maciej Garbowski

Keyword(s):

Sickle Cell Disease ◽

Blood Transfusion ◽

Iron Overload ◽

Sickle Cell ◽

Iron Concentration ◽

Thalassemia Major ◽

Iron Loading ◽

Cell Disease ◽

Liver Iron Concentration ◽

Liver Iron

Abstract The aims of this review are to highlight the mechanisms and consequences of iron distribution that are most relevant to transfused sickle cell disease (SCD) patients and to address the particular challenges in the monitoring and treatment of iron overload. In contrast to many inherited anemias, in SCD, iron overload does not occur without blood transfusion. The rate of iron loading in SCD depends on the blood transfusion regime: with simple hypertransfusion regimes, rates approximate to thalassemia major, but iron loading can be minimal with automated erythrocyte apheresis. The consequences of transfusional iron overload largely reflect the distribution of storage iron. In SCD, a lower proportion of transfused iron distributes extrahepatically and occurs later than in thalassemia major, so complications of iron overload to the heart and endocrine system are less common. We discuss the mechanisms by which these differences may be mediated. Treatment with iron chelation and monitoring of transfusional iron overload in SCD aim principally at controlling liver iron, thereby reducing the risk of cirrhosis and hepatocellular carcinoma. Monitoring of liver iron concentration pretreatment and in response to chelation can be estimated using serum ferritin, but noninvasive measurement of liver iron concentration using validated and widely available MRI techniques reduces the risk of under- or overtreatment. The optimal use of chelation regimes to achieve these goals is described.

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Safety and Efficacy of Alternate Desferrioxamine and Deferiprone Compared to Desferrioxamine Alone in the Treatment of Iron Overload in Transfusion-Dependent Thalassemia Patients.

Blood ◽

10.1182/blood.v104.11.3611.3611 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3611-3611 ◽

Cited By ~ 3

Author(s):

Renzo Galanello ◽

Antonios Kattamis ◽

Antonio Piga ◽

Fernando Tricta

Keyword(s):

Adverse Events ◽

Iron Overload ◽

Serum Ferritin ◽

Iron Concentration ◽

Comparable Efficacy ◽

Liver Iron ◽

Safety And Efficacy ◽

Alternate Therapy ◽

Significant Difference ◽

Wet Weight

The safety and efficacy of alternating desferrioxamine and deferiprone for the treatment of iron overload in patients with transfusion-dependent anemias was studied in 60 thalassemia patients regularly treated with desferrioxamine. Patients were randomized to continue desferrioxamine alone (20–60 mg/kg/day, 5–7 days/week) or to alternate desferrioxamine (20–60 mg/kg/day, 2 days/week) with oral deferiprone (25 mg/kg tid, 5 days/week). Both treatment groups were similar for age (19.8 ± 6.1 years for desferrioxamine alone and 18.7 ± 4.8 years for alternate therapy) as was gender distribution and mean standard dose of desferrioxamine at the time of study initiation. Over the following 12 months, all patients were monitored weekly for adverse events and for their white blood cell count. Efficacy of the chelation was evaluated by measurement of the serum ferritin, liver iron concentration (magnetic susceptometry by SQUID), and by Non-Transferrin Bound Iron (NTBI). Compliance was comparable for both arms (96.1 ± 5.0% for alternate therapy vs 95.7 ± 5.7 % for desferrioxamine alone; p=0.7883). There was no significant difference in the proportion of patients with adverse events in the two therapy groups but the chelation regimens were associated with distinct adverse events. The alternate therapy was associated with transient gastrointestinal symptoms, such as vomiting in 5 patients (17%), abdominal pain in 3 patients (10%), or diarrhea in one patient (3%), or transient increase of serum ALT levels in one patient (3%), occurring mainly in the first weeks of therapy and were mild/moderate in severity. Daily infusions of desferrioxamine were associated with abscess at the site of infusion in one patient (3%), and allergic reactions in another patient (3%). Mean serum ALT levels were not significantly different between the two therapies. There were no episodes of agranulocytosis and only one patient, treated with desferrioxamine alone, experienced milder neutropenia. Both therapies resulted in similar decreases of serum ferritin (−349 ± 573 mg/L for the desferrioxamine arm; −248 ± 791 for the alternate arm; p=0.5802), and of liver iron concentrations (−239 ± 474 μg/g wet weight for the desferrioxamine arm; −65 ± 615 μg/g wet weight for the alternate therapy arm; p=0.2263) by the end of the treatment period. No significant changes in NTBI were observed between the two treatment arms (1.10 ± 7.19 μmol/L for the desferrioxamine arm; −0.03 ± 8.13 μmol/L for the alternate arm; p=0.5775). In conclusion, this 12 month study in transfusion-dependent thalassemia demonstrated that the alternating therapy with deferiprone and desferrioxamine is not associated with a significant increase in the incidence of adverse events and that it has comparable efficacy to desferrioxamine alone in controlling iron overload.

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Safety of Deferasirox (Exjade®) in Patients with Transfusion-Dependent Anemias and Iron Overload Who Achieve Serum Ferritin Levels <1000 Ng/Ml during Long-Term Treatment

Blood ◽

10.1182/blood.v112.11.5423.5423 ◽

2008 ◽

Vol 112 (11) ◽

pp. 5423-5423 ◽

Cited By ~ 3

Author(s):

John B Porter ◽

Antonio Piga ◽

Alan Cohen ◽

John M Ford ◽

Janet Bodner ◽

...

Keyword(s):

Clinical Trials ◽

Abdominal Pain ◽

Iron Overload ◽

Serum Ferritin ◽

Safety Profile ◽

Iron Concentration ◽

Thalassemia Major ◽

Liver Iron ◽

Long Term Treatment ◽

Baseline Characteristics

Abstract Background: Maintaining serum ferritin (SF) levels below 1000 ng/mL has been reported to predict longer survival and a reduced risk of complications (eg heart failure) in patients with thalassemia major. Experience with deferoxamine (Desferal®, DFO) has indicated that the toxicity of DFO may increase as SF levels decrease. A target SF value in the deferasirox clinical trials was not specified per protocol, but was determined by the individual investigators. This analysis evaluates the safety of deferasirox (Exjade®) in a cohort of adult and pediatric patients with transfusion-dependent anemias and iron overload from two large clinical trials (107 and 108) who were chelated to SF levels <1000 ng/mL. Methods: In core studies 107 and 108, frequently-transfused patients with chronic anemias ≥2 years old received deferasirox 5–30 mg/kg/day for 1 year. Eligible patients were then enrolled in 4-year extension trials, where initial dosing was based on the end of core study liver iron concentration; dose adjustments were based on SF levels. Patients eligible for this analysis had an initial SF ≥1000 ng/mL. Patients who achieved a SF level <1000 ng/mL on ≥2 consecutive visits, any time after starting deferasirox, were identified. The number of days when SF was <1000 ng/mL was calculated for each patient. AEs in these patients were calculated for the entire period on deferasirox, and for the period following the first SF measurement of <1000 ng/mL, irrespective of future SF levels. Results: 474 patients were included in this analysis: underlying anemias were β-thalassemia (n=379), myelodysplastic syndromes (n=43), Diamond-Blackfan anemia (n=30) and other anemias (n=22). Overall, 13.5% patients achieved SF<1000 ng/mL in year 1, 18.6% in year 2, 25.7% in year 3, 32.5% in year 4 and 36.7% by the time of this analysis. Therefore, overall 174 patients (36.7%) reached a SF level <1000 ng/mL on ≥2 consecutive visits, while in 300 patients SF levels remained ≥1000 ng/mL. The median period for a SF value <1000 ng/mL was 149 days [range 18–1726]. Patient demographics, baseline characteristics and safety profiles of the two groups throughout deferasirox treatment are shown in Table 1. At month 54, median SF levels in the <1000 and >1000 ng/mL groups were 872 and 2118 ng/mL, respectively. The incidence of drug-related AEs (gastrointestinal, renal and liver) did not appear to increase during the periods after SF levels first decreased below 1000 ng/mL (data not shown). Table 1. Demographics, baseline characteristics and safety profile of patients who achieved SF levels <1000 ng/mL and patients who did not Patients who achieved SF <1000 ng/mL Patients who did not achieve SF <1000 ng/mL *Investigator-assessed; SCr, serum creatinine; ULN, upper limit of normal; ALT, alanine aminotransferase n 174 300 Male:female 85:89 145:155 Mean age ± SD, years 23.8 ± 16.7 23.5 ± 18.2 <16, n (%) 65 (37.4) 123 (41.0) ≥16, n (%) 109 (62.6) 177 (59.0) Enrolled from study 107:108 120:54 175:125 Median exposure to deferasirox, months 56.3 45.2 Mean actual deferasirox dose, mg/kg/day 20.3 22.9 Median baseline SF, ng/mL 1791 2883 Drug-related AEs* (≥5% in either group), n (%) Nausea 26 (14.9) 38 (12.7) Diarrhea 17 (9.8) 42 (14.0) Vomiting 14 (8.0) 25 (8.3) Abdominal pain 12 (6.9) 32 (10.7) Upper abdominal pain 6 (3.4) 20 (6.7) Rash 9 (5.2) 16 (5.3) Audiological abnormalities 7 (4.0) 4 (1.3) Ophthalmological abnormalities 4 (2.3) 5 (1.7) Two consecutive SCr increases >33% above baseline and above ULN 26 (14.9) 36 (12.0) Increase in ALT >10×ULN on at least 1 visit 12 (6.9) 20 (6.7) Baseline levels elevated 6 (3.4) 16 (5.3) Conclusions: Over the core and extension phases of these clinical studies, the safety profile of patients achieving SF levels <1000 ng/mL was similar to that observed in patients who did not achieve SF levels <1000 ng/mL. There was also no apparent increase in AEs associated with a decrease in SF levels <1000 ng/mL. In particular, no increase in the proportion of patients with creatinine increases >33% above baseline and ULN or with ALTs >10×ULN were observed in these patients. These findings suggest that ironoverloaded patients can be safely chelated with deferasirox to low SF levels.

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Comparing the Value of Serum Ferritin, Transfusion History and Magnetic Resonance Imaging for the Prediction of Iron Overload In MDS and AML Patients Undergoing Allogeneic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v116.21.3493.3493 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3493-3493

Author(s):

Martin Wermke ◽

Jan Moritz Middeke ◽

Nona Shayegi ◽

Verena Plodeck ◽

Michael Laniado ◽

...

Keyword(s):

Iron Overload ◽

Serum Ferritin ◽

Iron Content ◽

Iron Concentration ◽

Transferrin Saturation ◽

Resonance Imaging ◽

Liver Iron Concentration ◽

Liver Iron ◽

Liver Iron Content ◽

Transfusion History

Abstract Abstract 3493 An increased risk for GvHD, infections and liver toxicity after transplant has been attributed to iron overload (defined by serum ferritin) of MDS and AML patients prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT). Nevertheless, the reason for this observation is not very well defined. Consequently, there is a debate whether to use iron chelators in these patients prior to allo-HSCT. In fact, serum ferritin levels and transfusion history are commonly used to guide iron depletion strategies. Both parameters may inadequately reflect body iron stores in MDS and AML patients prior to allo-HSCT. Recently, quantitative magnetic resonance imaging (MRI) was introduced as a tool for direct measurement of liver iron. We therefore aimed at evaluating the accurateness of different strategies for determining iron overload in MDS and AML patients prior to allo-HSCT. Serologic parameters of iron overload (ferritin, iron, transferrin, transferrin saturation, soluble transferrin receptor) and transfusion history were obtained prospectively in MDS or AML patients prior to allo-SCT. In parallel, liver iron content was measured by MRI according to the method described by Gandon (Lancet 2004) and Rose (Eur J Haematol 2006), respectively. A total of 20 AML and 9 MDS patients (median age 59 years, range: 23–74 years) undergoing allo-HSCT have been evaluated so far. The median ferritin concentration was 2237 μg/l (range 572–6594 μg/l) and patients had received a median of 20 transfusions (range 6–127) before transplantation. Serum ferritin was not significantly correlated with transfusion burden (t = 0.207, p = 0.119) but as expected with the concentration of C-reactive protein (t = 0.385, p = 0.003). Median liver iron concentration measured by MRI was 150 μmol/g (range 40–300 μmol/g, normal: < 36 μmol/g). A weak but significant correlation was found between liver iron concentration and ferritin (t = 0.354; p = 0.008). The strength of the correlation was diminished by the influence of 5 outliers with high ferritin concentrations but rather low liver iron content (Figure 1). The same applied to transfusion history which was also only weakly associated with liver iron content (t = 0.365; p = 0.007). Levels of transferrin, transferrin saturation, total iron and soluble transferrin receptor did not predict for liver iron concentration. Our data suggest that serum ferritin or transfusion history cannot be regarded as robust surrogates for the actual iron overload in MDS or AML patients. Therefore we advocate caution when using one of these parameters as the only trigger for chelation therapy or as a risk-factor to predict outcome after allo-HSCT. Figure 1. Correlation of Liver iron content with Ferritin. Figure 1. Correlation of Liver iron content with Ferritin. Disclosures: No relevant conflicts of interest to declare.

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Exome Sequencing Identifies Genes and Variant Alleles Associated With Severity Of Iron Overload In Hemochromatosis HFE C282Y Homozygotes

Blood ◽

10.1182/blood.v122.21.179.179 ◽

2013 ◽

Vol 122 (21) ◽

pp. 179-179

Author(s):

Christine E. McLaren ◽

Mary J. Emond ◽

Pradyumna D. Phatak ◽

Paul C. Adams ◽

V. Nathan Subramaniam ◽

...

Keyword(s):

Iron Overload ◽

Serum Ferritin ◽

Iron Concentration ◽

Missense Variant ◽

Dry Weight ◽

P Value ◽

Hepatic Iron ◽

Common Variants ◽

Iron Stores ◽

Hepatic Iron Concentration

Abstract Variability in the severity of iron overload among homozygotes for the HFE C282Y polymorphism is one of the major problems extant in our understanding of hereditary hemochromatosis (HH). We conducted exome sequencing of DNA from C282Y homozygotes with markedly increased iron stores (cases) and C282Y homozygotes with normal or mildly increased iron stores (controls) to identify rare and common causal variants associated with variability of disease expression in HH. Criteria for cases included serum ferritin >1000 µg/L at diagnosis, and (a) mobilized body iron >10 g by quantitative phlebotomy, and/or (b) hepatic iron concentration >236 µmol/g dry weight. Criteria for controls included (a) serum ferritin <300 µg/L, or (b) age ≥50 y with ≤3.0 g iron removed by phlebotomy or age ≥40 y with ≤2.5 g iron removed by phlebotomy to achieve serum ferritin <50 µg/L. Deep sequencing of the full exome was performed in 33 cases and 14 controls. After quality control filtering, the dataset included 82,068 SNPs and 1,403 insertions/deletions (indels). Our initial analysis tested for differences in the distribution of variants between groups for each gene separately using the Sequence Kernel Association Test (SKAT) that includes rare and common variants but downweights the contribution of common variants to the test statistic. Only non-synonymous variants were included in the by-gene tests. Principal components were constructed from the exome variants to adjust for possible confounding by ancestry and to confirm no ancestral outliers. All study participants were male, and all clustered closely together within a larger group of Europeans in a principal components analysis of ancestry. Mean (SD) ages at presentation were 54 (11.0) y and 56 (9.4) y for cases and controls, respectively. Median serum ferritin was 2788 µg/L in those with increased iron stores and 309 μg/L in those with normal or mildly increased iron stores. The median transferrin saturation (94%) was greater in cases than in the comparison group (70%). In a preliminary analysis, we found 9 genes associated with case-control status. To separate effects of alcohol use and/or alcohol addiction variants, an analysis was conducted to compare the 13 controls and 22 cases who reported never using alcohol or only very light use. The two most significant genes identified in this comparison were GNPAT (p=7.4x10-6) and CDHR2 (p=2.8x10-4). A quantile-quantile (QQ) plot is shown in the Figure, comparing the observed distribution of –(log10p-values) from 10,337 genes to the expected uniform distribution if there were no variants modifying severity of expression, and gives evidence of the effect of the GNPAT gene.Figure 1Figure 1. Inspection of the two variants contributing to the GNPAT by-gene p-value revealed one missense variant (rs11558492) for which 0/13 controls had a polymorphism, while 16/22 cases had at least one missense variant, and one case was homozygous for this missense variant. The latter case presented at the early age of 26 with a serum ferritin of 1762 µg/L, 4+ hepatocellular iron and hepatic iron concentration of 284.4 µmol/g dry weight. GNPAT (aka DHAPAT) mutations/deletions have been found in peroxisomal disease, a class of diseases in which increased hepatic iron is observed (Biochim Biophys Acta 1801:272-280, 2010). GNPAT rs11558492 is common among people of European descent but might interact with aberrant HFE to increase risk of hepatic iron overload. Three rare variants in CDHR2 accounted for its low p-value, having a cumulative frequency of 4/13 among controls and 0/22 among cases: rs115050587, rs752138, rs143224505 with minor allele frequencies, MAF = 1.4%, 4.7% and 0.06%, respectively. The first two polymorphisms are predicted to be highly damaging by PolyPhen2 and the third probably damaging. Expression levels of CDHR2 recently have been associated with increased hepatocyte iron and elevated serum ferritin in liver allograft patients (J Clin Invest 122:368-382, 2012). These data indicate associations between iron status in HFE C282Y homozygotes and genes with previous links to iron overload that may modify severity of disease expression. Of note, the data suggest that more than one modifier gene may be involved in determining severity of disease in HFE C282Y homozygotes. Our results identify candidate genes for expanded studies that would examine their functional significance for iron absorption and metabolism. Disclosures: No relevant conflicts of interest to declare.

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Discrepancy between Serum Ferritin and Liver Iron Concentration in a Patient with Hereditary Hemochromatosis – The Value of T2* MRI

Case Reports in Oncology ◽

10.1159/000507756 ◽

2020 ◽

Vol 13 (2) ◽

pp. 712-715

Author(s):

Mustafa A. Al-Tikrity ◽

Mohamed A. Yassin

Keyword(s):

Iron Overload ◽

Serum Ferritin ◽

Ferritin Level ◽

Hereditary Hemochromatosis ◽

Iron Concentration ◽

Hfe Gene ◽

Liver Iron Concentration ◽

C282y Mutation ◽

Liver Iron ◽

T2 Mri

Primary hemochromatosis is an inherited disorder, and the homeostatic iron regulator (HFE) gene C282Y mutation is a common cause of hemochromatosis in Europe. We are reporting a case of a 56-year-old female known to have hemochromatosis with the HFE gene C282Y mutation with a serum ferritin level of 482 μg/L who underwent heart and liver T2* MRI which showed no evidence of iron overload – neither in the heart nor in the liver. This indicates that there is a discrepancy between serum ferritin and liver iron concentration by MRI and the superiority of T2* MRI in diagnosis and follow-up of iron overload in patients with hereditary hemochromatosis.

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