Original research paper

Long-term effects of an oral iron chelator, deferasirox, in hemodialysis patients with iron overload Cheng-Hsu Chen1,2,3,4, Kuo-Hsiung Shu1,5, Youngsen Yang4,6 1

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Division of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan, 2Department of Internal Medicine, Chiayi Branch, Taichung Veterans General Hospital, Chiayi, Taiwan, 3 Department of Life Science, Tunghai University, Taichung, Taiwan, 4School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan, 5School of Medicine, Chung Shan Medical University, Taichung, Taiwan, 6Division of Hematology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan

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Background/Purpose: Retention of excess iron from transfused blood in organs in patients with renal anemia may lead to various systemic complications. Iron chelating agents such as deferasirox (DFX) decrease such iron overload. This study assessed the efficacy, safety, and tolerability of DFX in hemodialysis (HD) patients with iron overload. Methods: We retrospectively (February 2008 to June 2012) reviewed data for eight HD patients with endstage renal disease who were prescribed DFX (15 mg/kg/day) for transfusion-induced iron overload. Baseline and post-treatment levels of hematocrit, ferritin, erythropoietin (EPO), transferrin saturation (TSAT), total and unsaturated iron-binding capacity (TIBC and UIBC, respectively), and blood transfusion volumes were measured. Treatment efficacy was evaluated by observing changes in ferritin and TSAT during the study period; monthly EPO doses and blood transfusions were also recorded. Safety was evaluated in the form of adverse events. Results: DFX administration caused statistically significant reductions in TSAT (68.2–49.2%; P = 0.036) and ferritin (3133.1–1215.6 ng/ml; P = 0.017). Significant post-treatment increases in UIBC (63.3–196.6 μg/dl; P = 0.018) and TIBC (210.0–422.4 μg/dl; P = 0.012) were also observed. While there were no significant differences in hematocrit values or EPO requirements after treatment, significant reductions in average monthly transfusion volumes (P = 0.026) were recorded. DFX was generally well tolerated; common adverse effects included nausea, vomiting, diarrhea, and abdominal pain. Conclusion: DFX significantly improved iron metabolism in HD patients with iron overload and had an acceptable frequency of adverse effects.

Introduction

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Keywords: Deferasirox, End-stage renal disease, Iron chelator, Iron overload, Renal anemia

Renal anemia is a common complication in patients with chronic kidney disease (CKD), especially in those receiving dialysis. CKD-related renal anemia is primarily treated with recombinant human erythropoietin (EPO). Despite the availability and extensive use of EPO in uremia therapy since 1989, a significant proportion of patients on hemodialysis (HD) and receiving EPO treatment additionally require blood transfusions for immediate correction of their RBC Correspondence to: Youngsen Yang, Division of Hematology, Department of Internal Medicine, Taichung Veterans General Hospital, Address: 1650 Taiwan Boulevard Sect. 4, Taichung 40705, Taiwan. Email: [email protected]

© W. S. Maney & Son Ltd 2014 DOI 10.1179/1607845414Y.0000000199

mass, which has decreased because of the symptomatic anemia.1,2 Although blood transfusions have become much safer over the last few decades, non-infectious complications of transfusion are still the cause of a majority of morbidity and mortality associated with transfusions worldwide;3–5 transfusion are a major concern in patients on dialysis or progressing to end-stage renal disease (ESRD).6 Acquired iron accumulation might develop in CKD, and in patients on dialysis as exogenous iron received from multiple blood transfusions or iron therapy in different disease entities or states can cause iron overload. In patients undergoing dialysis, massive iron deposits in various organs may lead to architectural and

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(TSAT) >25%. They were not malignancy under treatment with chemotherapy, bone marrow transplantation, and total body irradiation; or active of lupus nephritis, active infections, and inflammation in the observation period.

Treatment and assessments DFX (corresponding to 15 mg/kg/day for weight) was prescribed for patients with a ferritin level >2000 ng/ml according to the regulation for Bureau of National Health Insurance Reimbursement in Taiwan. The dose was reduced to 5–10 mg/kg at onset of adverse events (AEs). At baseline, demographic characteristics were recorded for each patient in addition to the cause of ESRD and blood transfusion. Further, ferritin and TSAT levels were recorded at baseline and assessed monthly after DFX therapy was administered. TSAT is the percentage of ratio of serum iron and total iron-binding capacity (TIBC). Hematocrit (Hct) and EPO levels, TIBC, unsaturated iron-binding capacity (UIBC), and blood transfusion volumes were measured monthly along with parameters to determine liver and renal function.

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functional disturbances and consequent life-threatening conditions such as cardiomyopathy, hepatic cirrhosis, proximal myopathy, diabetes mellitus, arthropathy, or immune dysfunction.7 The various therapeutic approaches to iron overload-related anemia include intravenous ascorbic acid (vitamin C) administration or chelating therapy with deferoxamine (DFO). However, the efficacy and safety of vitamin C treatment have not been well-established,8 and DFO has several side effects such as hypotension during infusion, ophthalmic and auditory toxicity, infections, allergic and skin reactions, and pulmonary, renal, and neurological effects.9,10 Deferasirox (DFX; Exjade,® Novartis Pharmaceuticals), a once-daily oral iron chelator, reduces iron burden under iron-overload conditions and has been found to be safe and efficacious in the treatment of patients with β-thalassemia, sickle cell anemia, and myelodysplastic anemia.11–15 DFX may, however, cause acute renal failure (ARF), and creatinine clearance rate of 2-fold the upper limit of normal are listed as contraindications by Novartis and the Food and Drug Administration.16 It is a tridentate iron chelator with high affinity and selectivity for Fe3+. DFX is primarily metabolized by glucuronidation with subsequent hepatobiliary excretion,17 predominantly via the fecal route.18 Thus, it can be hypothesized that DFX is safe in patients with ESRD on long-term HD without fear of ARF. To the best of our knowledge, no clinical trials have previously evaluated the efficacy and safety of DFX in patients with ESRD. This was the first exploratory study to evaluate the effectiveness and safety of DFX in Taiwanese ESRD patients on HD with iron overload.

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We conducted a retrospective analysis of eight patients with ESRD on long-term HD who had iron overload because of long-term transfusions from February 2008 to June 2012. Clinical and laboratory data were retrieved from the Taiwan Society of Nephrology (TSN) Dialysis Registry and through monthly hematological examination. This study was approved by the Human and Ethic Committee of Taichung Veterans General Hospital (CE 11240) and was carried out according to the principles of the Declaration of Helsinki.

Patients The study patients were aged ≥18 years with ESRD on long-term HD for more than 6 months with iron overload because of long-term transfusions despite EPO treatment for anemia and transferrin saturation

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The efficacy of DFX was analyzed by monitoring the change in ferritin and TSAT levels during the study period. In addition, the baseline and post-treatment hemoglobin (Hb) and Hct levels, monthly doses of EPO, and the amount of blood transfusions were also compared. Further, we also recorded the side effects of DFX (mainly gastrointestinal, hepatic, and dermatological) during the study period.

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Methods Study design

Outcome measures

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Statistical analysis Statistical analysis was performed using SPSS 13.0 for Windows (SPSS Inc., Chicago, IL, USA). Descriptive statistics were obtained for continuous variables, and comparisons were made using corresponding nonparametric approaches (Wilcoxon signed-rank test). The last available observation data of the patients were compared with their baseline values regardless of the duration of chelating therapy. The generalized estimating equation (GEE) method was used to correlate the longitudinal effect of DFX treatment with respect to change in serum ferritin level and Hct, monthly requirement of blood transfusion, and monthly dosage of EPO. A P < 0.05 was considered to show statistical significance.

Results Demographic characteristics The mean age of patients was 52 .8 ± 15.4 years (range: 33.6–74.3 years), and HD duration was 6.8 ± 6.0 years (range: 0.2–15.7 years; Table 1) before use of DFX. The underlying diseases in the eight ESRD patients with iron overload were chronic glomerulonephritis

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Table 1

Deferasirox in hemodialysis patients with iron overload

Clinical characteristics of eight HD patients with transfusional iron overload receiving iron chelation therapy with DFX

Patient Gender

Age (years)

HD duration (years)

DFX Tx duration (months)

HBsAg/ HCV

Cause of ESRD

Female 48.6 Male 37.3

4.2 0.2

22.8 13.2

N/N N/N

ESRD DN

3

Female 67.3

0.4

14.4

N/N

DN

4

Female 69.1

1.6

13.2

N/N

MM

5 6 7

Female 46.8 Female 33.6 Female 74.3

12.9 8.2 15.7

13.2 7.2 6

N/N N/N N/P

ESRD SLE UCC

8

Female 45.0

11.1

7.2

N/N

CGN

Adverse effects

Skin rash1 Diarrhea1, abdominal cramping1 NHL Diarrhea1, abdominal cramping1 MM Chest pain, constipation1 Poor EPO response Nausea1, vomiting1 Autoimmune Nausea1, vomiting1 Poor EPO response Epigastralgia1, constipation1 EPS Epigastralgia1, liver dysfunction1 Aplastic anemia MDS

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Cause of blood transfusion

CGN, chronic glomerulonephropathy; DFX Tx, deferasirox treatment; DN, diabetic nephropathy; EPO, erythropoietin; EPS, encapsulating peritoneal sclerosis; ESRD, end-stage renal disease; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; MDS, myelodysplasia syndrome; MM, multiple myeloma; N, negative; NHL, non-Hodgkin’s lymphoma; P, positive; SLE, systemic lupus erythematosus; UCC, uroepithelial cell carcinoma. The AEs were graded according to ‘Common Terminology Criteria for Adverse Events (CTCAE)’.19 Grade 1, mild; Grade 2, moderate; Grade 3, severe or medically significant but not immediately life-threatening; Grade 4, lifethreatening consequences; Grade 5, death related to AE.

Safety

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There were several AEs associated with the initial chelating therapy; of these, the most common was gastrointestinal tract disturbances (in seven patients), followed by skin lesion, chest tightness, and liver dysfunction (in one patient each) (Table 1). However, all of these were mild and improved with dose adjustment.

Efficacy

0.017), respectively. The individual change in ferritin level as compared to baseline is shown in Fig. 1. The average reduction in ferritin level was −10.05% (range: −4.18 to −15.57%) monthly, except in Patient 1.

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(n = 3), diabetic nephropathy (n = 2), systemic lupus erythematosus (n = 1), urothelial carcinoma with bilateral nephrectomy and cystectomy (n = 1), and multiple myeloma (n = 1).

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In this study that assessed the data of 12.2 ± 5.5 months (range: 6–23 months), there were no significant differences in liver function, blood sugar and electrolyte levels, dialysis adequacy of Kt/V and urea reduction ratio, and nutritional status (albumin and normalized protein catabolic rate).There was no influence of intact parathyroid hormone (i-PTH) or calcium and phosphate level observed in our study (Table 2).

Iron metabolism and hematopoiesis Analysis of the iron status showed that UIBC and TIBC had increased significantly from 63.3 ± 45.7 to 196.6 ± 118.0 μg/dl (P = 0.018) and from 210.0 ± 27.6 to 422.4 ± 255.9 μg/dl (P = 0.012), respectively, after DFX treatment. The free iron level showed no significant difference after treatment (142.1 ± 40.7 vs. 219.1 ± 209.9; P = 0.293; Table 3). Administration of DFX resulted in a statistically significant reduction in TSAT and ferritin levels from 68.2 ± 19.6 to 49.2 ± 21.0% (P = 0.036) and from 3133.1 ± 1313.4 to 1215.6 ± 1292.9 ng/ml (P =

Table 2 Comparison of the effect of DFX in HD patients with iron overload

Variable Glucose (mg/dl) Cholesterol (mg/dl) Triglyceride (mg/dl) Albumin (mg/dl) Total protein (mg/dl) AST (U/l) ALT (U/l) Alkaline phosphatase (U/l) Total bilirubin (mg/dl) Pre-dialysis BUN (mg/ dl) Creatinine (mg/dl) Uric acid (mg/dl) Na (mEq/l) K (mEq/l) Ca (mg/dl) P (mg/dl) Intact PTH (pg/ml) CRP (mg/dl) URR Kt/V (Gotch) nPCR TACurea

Before

P value*

After

99.8 177.4 111.9 4.0 6.9 35.0 39.9 303.6

±22.0 ±75.9 ±58.5 ±0.4 ±0.6 ±23.2 ±40.4 ±460.4

125.5 154.6 103.9 3.9 6.3 32.8 34.3 177.9

±74.8 ±58.6 ±52.9 ±0.5 ±0.6 ±19.6 ±27.4 ±242.1

0.463 0.107 0.674 0.395 0.027 0.440 0.735 0.128

0.6 65.8

±0.1 ±10.3

0.5 58.0

±0.3 ±21.9

0.109 0.917

7.4 7.0 137.9 5.0 9.3 4.5 205.6 4.0 0.8 1.5 1.0 28.6

±3.0 ±1.3 ±3.87 ±0.5 ±1.1 ±1.2 ±98.1 ±2.4 ±0.0 ±0.1 ±0.3 ±9.8

7.7 7.6 138.1 4.9 9.3 4.7 140.8 1.7 0.8 1.6 1.0 31.4

±2.5 ±1.8 ±4.8 ±0.7 ±0.6 ±1.2 ±110.7 ±1.4 ±0.0 ±0.2 ±0.3 ±15.4

0.889 0.612 0.732 0.670 1.000 0.624 0.249 0.027 0.528 0.575 0.892 1.000

*Wilcoxon signed-rank test. ALT, alanine transaminase; AST, aspartate transaminase; Ca, calcium; K, potassium; Kt/V, a number used to quantify HD treatment adequacy; Na, sodium; nPCR, normalized protein catabolic rate; P, phosphorus; PTH, parathyroid hormone; TACurea, time-averaged concentration of blood urea nitrogen; URR, urea reduction ratio.

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Table 3 Metabolic changes of iron regulation and response of hematopoiesis before and after administration of DFX in HD patients with iron overload

Variable

Before

Fe (μg/dl) UIBC (μg/dl) TIBC (μg/dl) Ferritin (ng/ml) TSAT (%) EPO (IU/kg/week) Blood transfusion (ml) WBC (/mm3) Hct (%) Platelet (×1000/ mm3)

After

P value*

142.1 63.3 210.0 3133.1 68.2 340.3 388.2

±40.7 ±45.7 ±27.6 ±1313.4 ±19.6 ±540.2 ±525.9

219.1 196.6 422.4 1215.6 49.2 280.4 197.1

±209.9 ±118.0 ±255.9 ±1292.9 ±21.0 ±44.5 ±353.3

0.293 0.018 0.012 0.017 0.036 0.037 0.005

6.3 28.0 175.3

±3.0 ±4.1 ±49.3

5.9 27.5 181.9

±1.9 ±5.6 ±82.6

0.327 0.674 1.000

*Wilcoxon signed-rank test. EPO, erythropoietin; Fe, iron; Hct, hematocrit; TIBC, total ironbinding capacity; TSAT, transferrin saturation; UIBC, unsaturated iron-binding capacity; WBC, white blood cell. The darbepoetin alfa (Aranesp®) 20 μg/vial is arbitrarily equivalent to EPO-β (Recormon®) 4000 IU.

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All patients had refractory anemia with EPO resistance (340.3 ± 54.2 IU/kg/week) and needed chronic blood transfusion (388.2 ± 525.9 ml/month) to maintain their Hct at 28.0 ± 4.1%. Interestingly, DFX therapy improved iron regulation and maintained the Hct at 27.5 ± 5.6% (P=0.674) with lesser doses of EPO (280.4 ± 44.5 IU/kg/week; P = 0.037) and blood transfusion (197.1 ± 353.3 ml/month; P = 0.005; Table 3). Comparison of the longitudinal effect of DFX treatment showed that there was no correlation between Hct (Fig. 2A; P = 0.577) and monthly dosage of EPO (Fig. 2B; P = 0.190) before and after DFX administration; rather, the treatment had significantly decreased the average monthly transfused blood volume (Fig. 2C; P = 0.026) and serum ferritin level (Fig. 2D; P = 0.014) over time.

iron supplement.20 Though the common practice is giving oral or intravenous iron supplementation along with EPO for erythropoiesis in HD patients, there are still significant iron overload seen in the serum and in major organs.21 Increased deposition of iron in organs leads to iron overload and has been suggested to raise the cardiovascular risk in the general population;22,23 high levels of serum ferritin is a marker of morbidity and mortality in HD patients.24–26 The long-term consequences of iron toxicity, such as cirrhosis, cardiomyopathy, and endocrine disorders,7 are preventable and mostly reversible by effective iron chelation therapy. DFO is the current standard therapy for iron chelation.18 For nearly 50 years, DFO has been used to mobilize and reduce iron overload and is administered intravenously because of its short half-life and very poor oral bioavailability. However, this treatment is ineffective against iron loss or mobilization in HD patients with iron overload.27 Furthermore, deferiprone is less efficient than DFO in binding iron, and its well-recognized and serious AEs such as neutropenia and agranulocytosis further limit its use. Research shows that the oral iron chelator DFX with doses varying from 5 to 30 mg/kg body weight and dose escalations up to 40 mg/kg is generally well tolerated and is effective in the treatment of various transfusion-dependent anemias.14,15,18 In this study, 15 mg/kg dose of DFX was used, which was consistent with that used in other studies in patients with kidney disease.28,29 DFX has been shown to be generally well tolerated in adults and children with different chronic anemias.30 Common AEs reported in this study included gastrointestinal disturbances and rash, which are consistent with those observed in other studies with DFX.15,18 However, these events rarely required drug discontinuation and many resolved spontaneously.30 Interestingly, severe symptomatic hypocalcemia was reported in a patient undergoing peritoneal dialysis and receiving DFX therapy for iron overload,31 but there was no influence of iPTH or calcium and phosphate level in our study. A recent pilot study that evaluated pharmacokinetics and safety of DFX in subjects with CKD undergoing HD reported no attrition in patients due to any AEs from DFX.31 Similar results were observed in this study. The current study demonstrated that DFX was well tolerated in HD patients with ESRD. Although DFX is not recommended for patients with renal impairment in consideration of its nephrotoxicity, we believe that it can be considered safe in patients with ESRD undergoing renal replacement without being concerned about complications such as ARF. The efficacy analysis in our study was based on reduction in ferritin and TSAT levels at the end of

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Discussion

Iron accumulation is a common feature observed in HD patients with CKD-related anemia receiving regular blood transfusions in addition to EPO and

Figure 1 Percentage of the change of serum ferritin level after DFX treatment over time.

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Figure 2 Change in (A) hematocrit (Hct), (B) average EPO dosage, (C) average blood transfusion, and (D) serum ferritin level monthly before and after DFX treatment analyzed with GEE model. Note: The boxes represent the 25th and 75th percentiles, while the whiskers correspond to the 10th and 90th percentiles. The medians are connected.

acting independently from cell iron deprivation by chelation and reactive oxygen species scavenging. This mechanism could explain the Hb improvement after in vivo treatment.34 However, hematologic improvement has also been observed with DFO and deferiprone, which do not alter NF-κB, cannot fully account for this effect.35,36 Several studies35,37,38 and ours demonstrated that DFX could significantly reduce serum ferritin levels, support the role of pharmacological effects of DFX on hematopoiesis, redistribution of iron from storage sites to hematopoietic tissue,37,38 or an effect on the neoplastic clone or bone marrow microenvironment.39 Additional benefits with DFX dosing include that it can be tailored according to individual patient’s needs for transfusion requirements, severity of iron overload, and treatment goal (i.e. maintenance or reduction of body iron levels).30 Furthermore, DFO requires a subcutaneous delivery 5–7 days/week, leading to poor compliance.17 However, DFX is orally bioavailable, with its terminal elimination half-life (t1/2) between 8 and 16 hours, thus allowing for once-daily administration.18 Therefore, superior satisfaction and convenience of DFX therapy vs. DFO may translate into improved patient compliance, thereby increasing the effectiveness of chelation therapy. Since DFX has also been shown to be effective in patients who were previously inadequately chelated with DFO (due to poor tolerance or compliance, or contraindications),

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study period. On an average, the monthly reduction in ferritin level was 10.05%, and the therapeutic target of 2000 ng/ml in our 312 HD patients) is lesser in HD patients in recent years, and lack of well-controlled laboratory conditions and clinical comparison prevent the validation of the therapeutic effects and safety. Fortunately, there were no severe AEs in this observation, and similar to treatment of thalassemia and MDS, most patients experienced only gastrointestinal symptoms, which could be attenuated by dosage adjustment. The second limitation is the lack of quantification of cardiac and hepatic iron, even by non-invasive MRI , to estimate iron overload. Therefore, we could not demonstrate the alteration in tissue iron and functional improvement of organs after DFX therapy. Chelation therapy is mandatory to reduce the toxic effects of iron on the myocardium and liver in thalassemia.14,40 Definitely, the dynamic changes in the iron profile seen in our study can offer part of the evidence of the evanescent tissue iron. Since only eight patients were included in this preliminary study, there is a need for well-designed studies with larger patient population to validate the effects of DFX in reversing the iron overload in the organs of patients undergoing dialysis. Iron overload can lead to serious consequences. In HD patients with iron overload, DFX could significantly improve iron metabolism with an acceptable frequency of AEs. These preliminary data provide the efficacy and tolerability for long-term use of oral DFX iron chelation therapy in Taiwanese ESRD patients undergoing HD with iron overload; the data also show that DFX might improve erythropoiesis through its pleomorphic capability. A longer duration of follow-up to validate its potential benefits of increasing BFU-E proliferation, reticulocyte count, and iron utilization may be justified in such group of patients.

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Acknowledgments

The authors thank Dr Lin-Hwei Chong, Dr MingTien Chen, and Dr Chin-Chun Du for their cooperation in collecting patient data, and Ms YiJyun Ye for her effort in data analysis. Medical writing services were provided by Cactus Communications and funded by Taiwan Society of Bone and Marrow Transplantation. The authors retained full control of manuscript content.

Disclaimer statements Contributors Providing concept and design and data collection and analysis: C.H.C., K.-H.S., Y.Y.;

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31 Yusuf B, McPhedran P, Brewster UC. Hypocalcemia in a dialysis patient treated with deferasirox for iron overload. Am J Kidney Dis. 2008;52:587–90. 32 Breccia M, Finsinger P, Loglisci G, Federico V, Santopietro M, Colafigli G, et al. Deferasirox treatment for myelodysplastic syndromes: ‘real-life’ efficacy and safety in a single-institution patient population. Ann Hematol. 2012;91:1345–9. 33 Aucella F, Vigilante M, Scalzulli P, Musto P, Crisetti A, Modoni S, et al. Desferrioxamine improves burst-forming unit-erythroid (BFU-E) proliferation in haemodialysis patients. Nephrol Dial Transplant. 1998;13:1194–9. 34 Messa E, Carturan S, Maffè C, Pautasso M, Bracco E, Roetto A, et al. Deferasirox is a powerful NF-kappaB inhibitor in myelodysplastic cells and in leukemia cell lines acting independently from cell iron deprivation by chelation and reactive oxygen species scavenging. Haematologica. 2010;95:1308–16. 35 Gattermann N, Finelli C, Della Porta M, Fenaux P, Stadler M, Guerci-Bresler A, et al. Hematologic responses to deferasirox therapy in transfusion-dependent patients with myelodysplastic syndromes. Haematologica. 2012;97(9):1364–71. 36 Jensen PD, Heickendorff L, Pedersen B, Bendix-Hansen K, Jensen FT, Christensen T, et al. The effect of iron chelation on haemopoiesis in MDS patients with transfusional iron overload. Br J Haematol. 1996;94(2):288–99. 37 Vreugdenhil G, Smeets M, Feelders RA, van Eijk HG. Iron chelators may enhance erythropoiesis by increasing iron delivery to haematopoietic tissue and erythropoietin response in ironloading anaemia. Acta Haematol. 1993;89(2):57–60. 38 Nolte F, Höchsmann B, Giagounidis A, Lübbert M, Platzbecker U, Haase D, et al. Results from a 1-year, open-label, single arm, multi-center trial evaluating the efficacy and safety of oral deferasirox in patients diagnosed with low and int-1 risk myelodysplastic syndrome (MDS) and transfusion-dependent iron overload. Ann Hematol. 2013;92(2):191–8. 39 Messa E, Cilloni D, Messa F, Arruga F, Roetto A, Saglio G. Deferasirox treatment improved the hemoglobin level and decreased transfusion requirements in four patients with the myelodysplastic syndrome and primary myelofibrosis. Acta Haematol. 2008;120(2):70–4. 40 Garadah TS, Mahdi N, Kassab S, Abu-Taleb A, Shoroqi I, Alawadi AH. The impact of two different doses of chelating therapy (deferasirox) on echocardiographic tissue Doppler indices in patients with thalassemia major. Eur J Haematol. 2011;87:267–73.

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19 National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services. [Accessed 2013 May 20] Common terminology Criteria for Adverse Events (CTCAE) Version 4.0. Published May 28, 2009; Revised Version 4.03 June 14, 2010 (Vol. Available from: http://evs.nci.nih.gov/ ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5×7.pdf). 20 Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group. KDIGO clinical practice guideline for anemia in chronic kidney disease. Kidney Int. 2012;2(Suppl): 279–335. 21 Ghoti H, Rachmilewitz EA, Simon-Lopez R, et al. Evidence for tissue iron overload in long-term hemodialysis patients and the impact of withdrawing parenteral iron. Eur J Haematol. 2012; 89(1):87–93. 22 Salonen JT, Nyyssönen K, Korpela H, Tuomilehto J, Seppänen R, Salonen R. High stored iron levels are associated with excess risk of myocardial infarction in eastern Finnish men. Circulation 1992;86:803–11. 23 Heath AL, Fairweather-Tait SJ. Health implications of iron overload: the role of diet and genotype. Nutr Rev. 2003;61: 45–62. 24 Sengoelge G, Sunder-Plassmann G, Hörl WH. Potential risk for infection and atherosclerosis due to iron therapy. J Ren Nutr. 2005;15:105–10. 25 Yamamoto H, Tsubakihara Y. Limiting iron supplementation for anemia in dialysis patients – the Basis for Japan’s conservative guidelines. Semin Dial. 2011;24:269–71. 26 Kletzmayr J, Hörl WH. Iron overload and cardiovascular complications in dialysis patients. Nephrol Dial Transplant. 2002; 17(Suppl 2):25–9. 27 Deira J, Diego J, Martínez R, Oyarbide A, González A, Díaz H, et al. Comparative study of intravenous ascorbic acid versus lowdose desferrioxamine in patients on hemodialysis with hyperferritinemia. J Nephrol. 2003;16:703–9. 28 Tsai CW, Yang FJ, Huang CC, Kuo CC, Chen YM. The administration of deferasirox in an iron-overloaded dialysis patient. Hemodial Int. 2012;17:131–3. 29 Maker GL, Siva B, Batty KT, Trengove RD, Ferrari P, Olynyk JK. Pharmacokinetics and safety of deferasirox in subjects with chronic kidney disease undergoing haemodialysis. Nephrology (Carlton). 2013;18:188–93. 30 Cappellini MD. Exjade® (deferasirox, ICL670) in the treatment of chronic iron overload associated with blood transfusion. Ther Clin Risk Manag. 2007;3:291–9.

Deferasirox in hemodialysis patients with iron overload

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Long-term effects of an oral iron chelator, deferasirox, in hemodialysis patients with iron overload.

Background/Purpose Retention of excess iron from transfused blood in organs in patients with renal anemia may lead to various systemic complications. ...
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