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Regular red blood cell (RBC) transfusions are the principal supportive therapy for many rare anaemias. Although transfusion requirements may vary according to diagnosis, chronic transfusion therapy inevitably leads to iron overload that can cause significant damage to the heart, liver and endocrine glands (1, 2). In regularly transfused patients with β-thalassaemia, there are substantial data reporting the efficacy and safety of iron chelation therapy to treat iron overload (3–5). Data supporting the use of iron chelation therapy in other transfusion-dependent anaemias such as myelodysplastic syndromes (MDS), aplastic anaemia (AA) and sickle cell disease (SCD) are also accumulating (4–8) and suggest that response with respect to iron balance is mainly dependent on chelator dose and transfusional iron-loading rate (4, 9). Studies in patients with rare anaemias related to decreased RBC production or ‘production anaemias’ [including Diamond-Blackfan anaemia (DBA) and pure red cell aplasia] as well as those in patients with haemolytic anaemias have been limited (4), and response has not been analysed with respect to the underlying mechanism of anaemia. The 1-yr Evaluation of Patients’ Iron Chelation with Exjade® (EPIC) study enrolled a large number of patients with a variety of transfusion-dependent anaemias (5), thereby allowing the investigation of disease-specific considerations that might affect iron chelation therapy with deferasirox (Exjade®; Novartis Pharma AG, Basel, Switzerland). Data from patients with rare transfusion-dependent anaemias recruited into the EPIC study were included in these analyses. The question as to whether the response to iron chelation therapy differs if the anaemia results primarily from decreased red cell production vs. when there is an underlying haemolytic mechanism remains to be answered. The rationale for the potentially variable response is that iron pools available for chelation may differ in haemolytic anaemias from those of production anaemias as a result of a greater rate of RBC catabolism. One approach to interrogating the access of chelators to iron pools is by the measurement of labile plasma iron (LPI); a directly chelatable redox-active subfraction of plasma non-transferrin bound iron (NTBI) (10). Cellular uptake of NTBI, through mechanisms including calcium channels (11) and zinc transporters (12), contributes to the iron-mediated cell damage (10, 13). NTBI and LPI are known to increase not only as a result of iron overload (14, 15) but also from ineffective erythropoiesis (16, 17) and when erythropoiesis is abrogated such as following myeloablation (18). LPI levels and the response to iron chelation may thus differ, depending on the underlying pathological mechanisms of anaemia. Therefore, in addition to assessing response of serum ferritin levels to deferasirox, LPI levels have been measured before and during iron chelation therapy. LPI levels have been compared between patients with haemolytic and production anaemias and related to the rates of transfusional iron loading and to serum ferritin levels.

WOS: 000275981900009, PubMed ID: 19996412, Cardiac iron overload causes most deaths in beta-thalassemia major. The efficacy of deferasirox in reducing or preventing cardiac iron overload was assessed in 192 patients with beta-thalassemia in a 1-year prospective, multicenter study. The cardiac iron reduction arm (n = 114) included patients with magnetic resonance myocardial T2* from 5 to 20 ms (indicating cardiac siderosis), left ventricular ejection fraction (LVEF) of 56% or more, serum ferritin more than 2500 ng/mL, liver iron concentration more than 10 mg Fe/g dry weight, and more than 50 transfused blood units. The prevention arm (n = 78) included otherwise eligible patients whose myocardial T2* was 20 ms or more. The primary end point was the change in myocardial T2* at 1 year. In the cardiac iron reduction arm, the mean deferasirox dose was 32.6 mg/kg per day. Myocardial T2* (geometric mean +/- coefficient of variation) improved from a baseline of 11.2 ms (+/- 40.5%) to 12.9 ms (+/- 49.5%) (+ 16%; P < .001). LVEF (mean +/- SD) was unchanged: 67.4 (+/- 5.7%) to 67.0 (+/- 6.0%) (-0.3%; P = .53). In the prevention arm, baseline myocardial T2* was unchanged from baseline of 32.0 ms (+/- 25.6%) to 32.5 ms (+/- 25.1%) (+ 2%; P = .57) and LVEF increased from baseline 67.7 (+/- 4.7%) to 69.6 (+/- 4.5%) (+ 1.8%; P < .001). This prospective study shows that deferasirox is effective in removing and preventing myocardial iron accumulation. This study is registered at http://clinicaltrials.gov as NCT00171821. (Blood. 2010; 115: 2364-2371), Novartis Pharma AG; Novartis Pharmaceuticals; British Heart FoundationBritish Heart Foundation [PG/09/074/27961]; National Institute for Health ResearchNational Institute for Health Research (NIHR) [NF-SI-0508-10081], This study was sponsored by Novartis Pharma AG. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals.

Our goal is to provide a well-integrated assessment of critical zone properties and processes that scale from microsites to catenas, watersheds, landscapes, and the region, and from minutes to hours, days, months, and years. These assessments as part of LCZO2 will contribute to our understanding of the controls on weathering, soil development, C and nutrient storage and loss, soil and sediment transport, and ultimately landscape evolution

Our goal is to provide a well-integrated assessment of critical zone properties and processes that scale from microsites to catenas, watersheds, landscapes, and the region, and from minutes to hours, days, months, and years. These assessments as part of LCZO2 will contribute to our understanding of the controls on weathering, soil development, C and nutrient storage and loss, soil and sediment transport, and ultimately landscape evolution

PubMed ID: 22271905, Background Prospective data on cardiac iron removal are limited beyond one year and longer-term studies are, therefore, important. Design and Methods Seventy-one patients in the EPIC cardiac substudy elected to continue into the 3 rd year, allowing cardiac iron removal to be analyzed over three years. Results Mean deferasirox dose during year 3 was 33.6±9.8 mg/kg per day. Myocardial T2*, assessed by cardiovascular magnetic resonance, significantly increased from 12.0 ms ±39.1% at baseline to 17.1 ms ±62.0% at end of study (P5 to

Many patients with chronic anaemia require blood transfusions as part of their treatment regimen. As a result, iron overload will inevitably develop if not adequately managed by iron chelation therapy. There are many guidelines relating to transfusion and chelation practices for patients with transfusion-dependent anaemia; however, there is a lack of information on how treatment practices differ around the world. The objective of this manuscript is to highlight key features of current transfusion and chelation management, including similarities and differences across various anaemias and between geographical regions worldwide.Data collected at study entry to the multicentre Evaluation of Patients' Iron Chelation with Exjade (EPIC) study, which recruited 1,744 patients with a variety of transfusion-dependent anaemias across 23 countries from three geographic regions, were assessed. These analyses compared transfusion and chelation treatment prior to the start of study treatment, together with iron burden assessed at study entry by serum ferritin, liver iron concentration and labile plasma iron levels.Data show that transfusion and iron chelation practices differ between anaemias and between geographical regions; this may be linked to availability and accessibility of transfusion and chelation therapy, patients' compliance, physicians' attitudes, costs and use of treatment guidelines. Approximately 60% of these transfusion-dependent patients were severely iron overloaded with a serum ferritin level over 2,500 ng/mL, indicating that the risks of iron burden may have been underestimated and current iron chelation therapy, if considered, may not have been adequate to control iron burden.

Although thalassaemia is highly prevalent in the Asia-Pacific region, clinical data on efficacy and safety profiles of deferasirox in patients from this region are rather limited. Recently, data from the multicentre Evaluation of Patients’ Iron Chelation with Exjade (EPIC) study in 1744 patients with different anaemias has provided an opportunity to analyse 1115 thalassaemia patients, of whom 444 patients were from five countries in the Asia-Pacific region (AP) for whom thalassaemia management and choice of iron chelators were similar. Compared to the rest of the world (ROW), baseline clinical data showed that the AP group appeared to be more loaded with iron (3745.0 vs. 2822.0 ng/ml) and had a higher proportion on deferoxamine monotherapy prior to the study (82.9 vs. 58.9%). Using a starting deferasirox dose based on transfusional iron intake and tailoring it to individual patient response, clinical efficacy based on serum ferritin reduction in AP and ROW thalassaemia patients was similar. Interestingly, the AP group developed a higher incidence of drug-related skin rash compared to ROW (18.0 vs. 7.2%), which may indicate different pharmacogenetic backgrounds in the two populations. Our analysis confirms that, with appropriate adjustment of dose, deferasirox can be clinically effective across different regions, with manageable side effects.

WOS: 000286902400010, PubMed ID: 21071497, Background The efficacy of cardiac iron chelation in transfusion-dependent patients has been demonstrated in one-year prospective trials. Since normalization of cardiac T2* takes several years, the efficacy and safety of deferasirox was assessed for two years in patients with beta-thalassemia major in the cardiac sub-study of the EPIC trial. Design and Methods Eligible patients with myocardial T2* greater than 5 to less than 20 ms received deferasirox, with the primary endpoint being the change in T2* from baseline to two years. Results Baseline myocardial T2* was severe (>5 to = 5%) increased serum creatinine, rash and increased alanine aminotransferase. Conclusions Continuous treatment with deferasirox for two years with a target dose of 40 mg/kg/d continued to remove iron from the heart in patients with beta-thalassemia major and mild, moderate and severe cardiac siderosis. (Clinicaltrials.gov identifier: NCT 00171821), Novartis Pharma AG; British Heart FoundationBritish Heart Foundation [PG/09/074/27961]; National Institute for Health ResearchNational Institute for Health Research (NIHR) [NF-SI-0508-10081], this study was sponsored by Novartis Pharma AG. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals.

Abstract 4276 Background: To date, the efficacy of various iron chelators in reducing cardiac iron, a leading cause of death in transfused patients with β-thalassemia major (TM), has been demonstrated in prospective controlled studies of up to 1-yr duration. Since removal of iron from the heart takes several years, it is important to assess longer-term effects of iron chelation therapy in terms of cardiac iron removal. We report here end-of-study (EOS) results from the EPIC cardiac substudy in TM patients treated with deferasirox for up to 3 yrs. Methods: Patients aged ≥10 yrs with myocardial T2* >5 to 2500 ng/mL, MR (R2) liver iron concentration (LIC) >10 mg Fe/g dry weight (dw) and ≥50 lifetime transfused blood units were included in the study. Deferasirox was initiated at 30 mg/kg/day and increased to 40 mg/kg/day by the start of yr 2. Dose decreases were allowed for safety reasons. Primary endpoint was change in myocardial T2* from baseline (BL) to 3 yrs. Results: Seventy-one patients completed 2 yrs of treatment and entered the 3rd yr of the study. Mean age was 20.5 ± 7.4 yrs. BL cardiac T2* was >5 to 5 to After 3 yrs, 68.1% of patients with BL T2* 10 to 5 to Of 71 patients, 66 (93.0%) completed the 3rd yr. Reasons for discontinuation were unsatisfactory therapeutic effect (n=3) and consent withdrawal (n=2). There were no deaths during the 3-yr study. Drug-related AEs (≥5%) decreased year by year: increased blood creatinine (n=19 [26.8%] vs n=16 [22.5%] vs n=9 [12.7%]), rash (n=11 [15.5%] vs n=0 vs n=0), increased ALT (n=5 [7.0%] vs n=3 [4.2%] vs n=2 [2.8%]), increased AST (n=4 [5.6%] vs n=3 [4.2%] vs n=1 [1.4%]) and diarrhea (n=4 [5.6%] vs n=1 [1.4%] vs n=0). In yr 3, serious AEs included atrial fibrillation, chronic sinusitis, femur fracture, gastritis, muscle abscess and rheumatic fever (all n=1); none were considered deferasirox-related. Six patients (8.5%) had 2 consecutive increases in serum creatinine >33% above BL and upper limit of normal (ULN); 3 patients in the 1st yr and 3 in the 3rd yr. Two (2.8%) patients had 2 consecutive increases in ALT >10 × ULN; 1 patient in the 2nd yr and 1 patient in both the 2nd and 3rd yr. Conclusion: This is the first prospective study to report 3-yr data on cardiac iron removal for an iron chelator. Once-daily deferasirox monotherapy at doses of 30–40 mg/kg/day effectively removed cardiac iron, allowing 68% of patients with moderate-to-mild cardiac iron loading to normalize and 50% of patients with severe myocardial iron loading at BL to reduce their cardiac iron levels to the moderate-to-mild range, associated with a much lower risk of heart failure. Importantly, there were no reports of death during the study. The long-term improvements in cardiac iron loading with deferasirox at doses of >30 mg/kg/day were associated with a manageable safety profile, maintenance of normal cardiac function and a concomitant significant decrease in hepatic and total body iron burden by nearly 50% over the 3 yrs. Disclosures: Pennell: Siemens: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Apotex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; CVIS: Equity Ownership. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Cappellini:Novartis: Speakers Bureau. Aydinok:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ibrahim:Novartis: Honoraria. Li:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Viprakasit:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kattamis:Novartis: Honoraria, Research Funding, Speakers Bureau. Smith:Novartis: Consultancy, Research Funding. Habr:Novartis: Employment. Domokos:Novartis: Employment. Roubert:Novartis: Employment. Taher:Novartis: Honoraria, Research Funding.

Abstract 4272 Background: Globally, a number of management guidelines provide recommendations for transfusion and iron chelation therapy across various transfusion-dependent anemias. Most treatment guidelines aim to control body iron burden by maintaining serum ferritin Methods: Patients aged ≥2 years with serum ferritin levels ≥1000 ng/mL, or 20 transfusions or 100 mL/kg of red blood cells), and liver iron concentration ≥2 mg Fe/g dry weight were enrolled in the study. Baseline data were reported according to underlying anemias: thalassemia major (TM), thalassemia intermedia (TI), myelodysplastic syndromes (MDS), sickle cell disease (SCD) and aplastic anemia (AA), and by geographical regions: Europe, Middle East/Africa and Asia-Pacific. Results: Of 1744 patients enrolled in the EPIC study, 1558 are included in this analysis (680 from Europe; 275 from Middle East/Africa; 603 from Asia-Pacific; 937 TM, 84 TI, 341 MDS, 116 AA and 80 SCD). Across all regions, patients with TM spent a larger proportion of their lifetime (88–92%) on transfusion therapy compared with other anemias; this was consistent across geographical regions. For patients with TM, mean number of transfusion episodes in the year prior to study entry was lower in the Asia-Pacific region (14.9; n=416; mean patient age 16.2 years) than in Europe (22.7; n=279; mean patient age 24.9 years). In patients with AA, their proportion of lifetime receiving transfusions was also lower in the Asia-Pacific region (20.3%; n=82; mean patient age 33.2 years) than in Europe (42.7%; n=29; mean patient age 36.1 years). The proportion of patients receiving previous iron chelation therapy (deferiprone and/or deferoxamine [DFO]) varied considerably across geographical regions. In all patients, 22% were chelation-naïve; the highest proportion of chelation-naïve patients was in the Asia-Pacific region. In TM patients, the percentage of chelation-naïve patients varied considerably across regions being only 0.4% of patients in Europe compared with 5.4% in the Middle East/Africa and 12.5% in the Asia-Pacific region. For AA patients, 48.3% were chelation-naïve in Europe compared with 76.8% in the Asia-Pacific region. In TM patients, the proportion of their lifetime receiving chelation therapy was lower (48.9%) in the Asia-Pacific region than in Europe (63.6%). In patients with AA, the proportion of lifetime receiving chelation therapy was also lower in the Asia-Pacific region (6.3%; n=19) compared with Europe (26.3%; n=15). Median baseline serum ferritin level was >2500 ng/mL across all anemias. Serum ferritin levels were ≥2500 ng/mL in 61.3% of patients across regions (50.6% [Europe], 59.3% [Middle East/Africa] and 74.3% [Asia-Pacific]). For patients with TM, TI, AA and SCD, serum ferritin levels were substantially higher in the Asia-Pacific region compared with other regions (Figure). In the Asia-Pacific region, the proportion of patients with serum ferritin levels ≥4000 ng/mL varied between 31.1% and 53.6% across anemias, compared with 14.3–37.5% in Europe. Conclusions: There are many differences in transfusion and iron chelation practices across regions, with most prominent differences in the Asia-Pacific region. Factors contributing to these differences might include regional variations in specific disease characteristics (severity, transfusion requirement), treatment practices (eg, hemoglobin level at which transfusion is initiated), the availability and accessibility of transfusion and iron chelation therapy including patients' compliance and physician attitude and adherence to treatment guidelines. The high proportion of patients with baseline serum ferritin >2500 ng/mL suggests that previous iron chelation regimens with DFO and/or deferiprone prior to the EPIC study were suboptimal with limitations for adequate control of iron burden across geographical regions. A greater improvement in iron chelation practices is warranted across the globe with an immediate focus on the Asia-Pacific region. Disclosures: Viprakasit: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gattermann:Novartis: Honoraria, Research Funding. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Taher:Novartis: Honoraria, Research Funding. Habr:Novartis: Employment. Roubert:Novartis: Employment. Domokos:Novartis: Employment. Cappellini:Novartis: Speakers Bureau.

Abstract 3803 Poster Board III-739 Background Transfusional iron overload can cause hepatocellular injury, which manifests as increased liver transaminase levels and, in some cases, may progress to cirrhosis. The once-daily oral iron chelator deferasirox (Exjade®) has been shown to reduce iron overload in patients with various transfusion-dependent anemias, and a previous analysis demonstrated a correlation between decreased iron overload and improved transaminase levels [Brissot P et al. Blood 2006;108(11):abst 3817]. As liver dysfunction is a common complication in patients with myelodysplastic syndromes (MDS), this analysis evaluates the relationship between serum ferritin (as a marker of iron overload) and alanine aminotransferase (ALT; as a marker of liver function) during deferasirox treatment in a large MDS population. Methods This analysis is based on data from iron overloaded MDS patients aged ≥2 years who were enrolled in the 1-year multicenter EPIC study; patients with a life expectancy Results In total, 341 patients with MDS (mean age 67.9 ± 11.4 years) were enrolled in the EPIC study. Mean actual deferasirox dose during treatment was 19.2 ± 5.4 mg/kg/day. Median serum ferritin at baseline, 3, 6, 9 and 12 months was 2730, 2358, 2210, 2076 and 1904 ng/mL, respectively, and the median change from baseline was significant at 12 months (P=0.0019). Mean ALT at the same time points was 59.7, 48.4, 42.0, 40.5 and 36.1 U/L, respectively; mean change from baseline in ALT at 12 months was also significant (P Conclusions In these chronically transfused MDS patients, deferasirox treatment produced a significant decrease in serum ferritin during 1 year of treatment. Improvements in ALT, which is an important indicator of hepatocellular injury, mirrored the reductions in serum ferritin and these changes were significantly correlated. Additional prospective studies are warranted to further investigate this association between iron burden and liver dysfunction in MDS. Disclosures: Gattermann: Novartis: Honoraria, Participation in Advisory Boards on deferasirox clinical trials. Habr:Novartis Pharmaceuticals: Employment. Domokos:Novartis Pharma AG: Employment. Roubert:Novartis Pharma AG: Employment. Fenaux:Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Ortho Biotech: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

Abstract 2486 Poster Board II-463 Introduction: Iron chelation therapy (ICT) is essential in removing excess iron deposited in body organs, ultimately preventing organ failure and extending the lives of patients (pts) with transfusion-dependent hematological disorders such as β-thalassemia. Conventional ICT (deferoxamine, Desferal®, DFO) requires a burdensome regimen (subcutaneous delivery 5–7 times a week) that has been shown to negatively impact pts' health-related quality of life (HRQL) and adherence to therapy. Adherence to ICT affects survival and therefore a well-tolerated and effective ICT regimen is required. The once-daily oral chelator, deferasirox (Exjade®) offers 24-hour ICT, 7 days a week and is potentially less burdensome to pts. Methods: As part of a larger single-arm, multicenter, open-label trial investigating the efficacy and safety of deferasirox (EPIC study), 217 β-thalassemia pts >16 years of age were included in this subanalysis. Findings reported here investigate differences in satisfaction, adherence and HRQoL following treatment with deferasirox, in β-thalassemia patients with prior experience of DFO monotherapy, or DFO in combination with deferiprone (Ferriprox®, L1). All pts were asked at baseline and week 52 (end of study [EOS]) to complete the 19-item Satisfaction with ICT questionnaire (SICT) and the 36-item Short Form health survey (SF-36). Mean change scores between baseline and EOS on the four domains of the SICT (Perceived Effectiveness of ICT, Side Effects of ICT, Acceptance of ICT, and Burden of ICT) and the eight domains (Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health) and two summary scores (Physical and Mental Component Scores) of the SF-36 were calculated for patients who completed the respective instruments at both timepoints. Higher scores on the SICT and SF-36 represent greater HRQL, satisfaction with, and adherence to treatment. Adherence to deferasirox was assessed by two SICT items asking pts how often they thought about stopping their ICT, and how often they took their ICT exactly as directed by their doctor. Results: 217 β-thalassemia pts were recruited (mean age 30.6 ± 7.7); 42.9% (n = 93) male, 57.1% (n = 124) female. Of 216 pts with prior history of ICT, 62.0% (n=134) had prior DFO monotherapy and 37.0% (n=80) had prior DFO in combination with L1 (2 patients had prior LI monotherapy; not included in this analysis due to the small patient number). SICT and SF-36 mean-change domain scores were based on patients who completed questionnaires at baseline and EOS (SICT: 105 DFO and 46 DFO+L1 pts; SF-36: 90 DFO and 42 DFO+L1 pts). Significant improvements (p Conclusions: β-thalassemia pts with prior history of ICT (DFO monotherapy or DFO+L1) demonstrated improved satisfaction and adherence to ICT following treatment with deferasirox. Improvements in HRQL were also observed and were generally greater in pts previously treated with DFO monotherapy compared with pts who previously received DFO+L1 combination therapy. Disclosures: Porter: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Vifor International: Membership on an entity's Board of Directors or advisory committees. Habr:Novartis Pharmaceuticals: Employment. Domokos:Novartis Pharma AG: Employment. Roubert:Novartis Pharma AG: Employment. Rofail:Employed by Mapi Values, a health outcomes research agency that consults to the pharmaceutical industry. We are paid consultants for Novartis Pharmaceutical Corporation for patient-reported outcomes in iron overload: Consultancy. Gater:Employed by Mapi Values, a health outcomes research agency that consults to the pharmaceutical industry. We are paid consultants for Novartis Pharmaceutical Corporation for patient-reported outcomes in iron overload: Consultancy. Baladi:Novartis Pharmaceuticals: Employment. Cappellini:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genzyme: Membership on an entity's Board of Directors or advisory committees.

Abstract 4062 Poster Board III-997 Background Over 70% of deaths in regularly transfused patients with β-thalassemia major (TM) are related to iron-induced cardiomyopathy. Deferasirox (Exjade®), in a sub-study of the 1-year multicenter prospective EPIC trial, demonstrated efficacy in reducing myocardial iron in TM patients with mild, moderate and severe cardiac siderosis, as evidenced by a statistically significant improvement in myocardial T2*. We herein report the extension phase results from the same study in patients who have received up to 2 years of deferasirox therapy. Methods Patients aged ≥10 years with myocardial T2* >5–2500 ng/mL, MR (R2) LIC >10 mg Fe/g dry weight (dw), and a lifetime minimum of 50 transfused blood units were included in the cardiac sub-study. Deferasirox was initiated at 30 mg/kg/day and increased to 40 mg/kg/day by the time patients had entered the 1-year extension. Dose decreases were allowed for safety reasons. The primary endpoint was change in myocardial T2* from baseline to 2 years. Results Out of 100 patients who entered the 1-year extension phase, 85 completed (85%); 24-month CMR data are available for 81 patients. Mean age was 20.6 ±7.3 years. Baseline cardiac T2* was Reasons for discontinuation were: unsatisfactory therapeutic effect (n=8), consent withdrawal (n=3), protocol violation (n=2), lost to follow up (n=1) and abnormal laboratory value (increased urinary protein/creatinine ratio) leading to consent withdrawal (n=1); no deaths were reported. Incidence of investigator-assessed drug-related AEs (≥5%) decreased overall from the core phase to the extension: increased blood creatinine (n=21 [21.0%] vs n=18 [18.0%]), rash (n=15 [15.0%] vs n=0), increased alanine aminotransferase (ALT) (n=6 [6.0%] vs n=4 [4.0%]) and increased aspartate aminotransferase (n=4 [4.0%] vs n=3 [3.0%]). There were no drug-related serious AEs over 2 years. In total, 4 patients (4.0%) had increased serum creatinine >33% above baseline and the upper limit of normal (ULN) on two consecutive visits; 3 patients (3.0%) during the core and 1 (1.0%) during the extension. 4 (4.0%) patients had increased ALT >10xULN on two consecutive visits; 2 patients (2.0%) during the core and 2 (2.0%) during the extension; levels were already >ULN at baseline in these patients. Conclusions This is the first large prospective study to report 2-year data on cardiac iron removal for any iron chelator. Results show that continued therapy with deferasirox for up to 2 years at doses 30–40 mg/kg/day was effective in removing iron from the heart in TM patients with mild, moderate and severe cardiac siderosis. Myocardial T2* continued to improve in year 2 and the statistically significant improvement from baseline was associated with maintenance of normal cardiac function and a concomitant decrease in hepatic and total body iron burden. Overall, deferasirox was well tolerated. Disclosures: Pennell: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Apopharma: Consultancy, Honoraria; Cardiovascular Imaging Solutions: Equity Ownership; Siemens: Research Funding. Off Label Use: THE SPECIFIC USE OF CHELATION FOR CARDIAC SIDEROSIS IS OFF-LABEL. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Vifor International: Membership on an entity's Board of Directors or advisory committees. Cappellini:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genzyme: Membership on an entity's Board of Directors or advisory committees. Chan:Novartis: Honoraria, Research Funding. Aydinok:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ibrahim:Novartis: Research Funding. Li:Novartis: Consultancy, Speakers Bureau. Viprakasit:Thai Government : Employment; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Government Pharmaceutical Organization of Thailand: Honoraria, Research Funding. Kattamis:Novartis: Consultancy, Honoraria, Speakers Bureau. Smith:Novartis Pharma AG: Consultancy, Employment at Royal Brompton Hospital funded by Novartis Pharma AG. Habr:Novartis Pharmaceuticals: Employment. Domokos:Novartis Pharma AG: Employment. Roubert:Novartis Pharma AG: Employment. Taher:Novartis: Honoraria, Research Funding.

Abstract 4058 Poster Board III-993 Background Despite the availability of effective chelators, many patients (pts) with β-thalassemia major (TM) present with high iron burden and serum ferritin (SF) >2500 ng/mL, demonstrated to be associated with significant negative outcomes including cardiac disease and organ failure. In the large, prospective EPIC trial including 854 TM pts who received prior chelation therapy, median baseline SF was 3139 ng/mL despite 10.8 yrs of therapy; hence the therapeutic goal was to reduce iron burden. Previous studies have shown that in TM pts with high transfusional iron, ≥30 mg/kg/day deferasirox (Exjade®) doses significantly reduce SF, while 20 mg/kg/day doses maintained SF levels. The objective of this analysis was to assess whether a mean actual deferasirox dose ≥30 mg/kg/day is effective in reducing SF in iron-overloaded pts with TM irrespective of prior chelation therapies. Methods Pts with TM (≥2 yrs) and transfusional iron overload as defined by SF levels ≥1000 ng/mL or 20 transfusions or 100 mL/kg of blood) and R2 MRI-confirmed liver iron concentration >2 mg Fe/g dry weight were enrolled. Initial deferasirox dosing (10–30 mg/kg/day) was dependent on transfusion requirements and adjusted according to the protocol by 5–10 mg/kg/day (range 0–40 mg/kg/day) every 3 months based on SF trends and safety markers. Pts previously chelated with monotherapy deferoxamine (Desferal®; DFO) or deferiprone (Ferriprox®; DFP) or a combination of both and who received a mean actual deferasirox dose ≥30 mg/kg/day over 1 yr were included. The primary efficacy endpoint was the change in SF at 1 yr from baseline (BL). Results Overall, 129 TM pts (15%) who were previously chelated with DFO and/or DFP were treated with a mean actual deferasirox dose of ≥30 mg/kg/day during the 1 yr EPIC trial; 83 pts received prior DFO or DFP monotherapy and 46 received a combination of both. Mean age was 19.5±8.2 vs 23.0±7.2 yrs in prior monotherapy and prior combination therapy pts, respectively. A mean of 167 mL/kg vs 191 mL/kg was transfused in the yr prior to study entry and the mean duration of prior chelation therapy was 11.7±7.7 yrs vs 14.5±7.9 yrs, respectively. During the study, mean transfusional iron intake was similar in both groups (0.36±0.2 and 0.34±0.1 mg/kg/day, respectively). In prior monotherapy pts (mean dose 33.9±2.2 mg/kg/day), median SF decreased from 4885 ng/mL at BL to 4282 ng/mL after 1 yr (Figure) resulting in a decrease from BL of 1024 ng/mL (P Overall, five pts (3.9%) discontinued therapy. Reasons for withdrawal were adverse events (AEs; cardiac failure), abnormal laboratory values (increased transaminases), consent withdrawal, lost to follow-up and protocol violation (all n=1). The most common investigator-assessed drug-related AEs were rash (n=14, 10.9%) and diarrhea (n=12, 9.3%). One pt (0.8%) had serum creatinine >33% above BL and the upper limit of normal (ULN) on two consecutive visits and one pt (0.8%) had increased alanine aminotransferase >10xULN on two consecutive visits; levels were already elevated. Conclusions This heavily transfused subgroup of TM pts, who had received prior chelation therapy with DFO and/or DFP for an average >10 yrs, continued to have high SF levels >4500 ng/mL. Monotherapy with ≥30 mg/kg/day deferasirox for 1 yr led to significant and clinically relevant reductions in SF in these pts irrespective of previous chelation therapies and was well tolerated. Longer-term studies are required to assess whether continued deferasirox could reduce SF Disclosures: Taher: Novartis: Honoraria, Research Funding. Chan:Novartis: Honoraria, Research Funding. Li:Novartis: Consultancy, Speakers Bureau. Lin:Taiwan Pediatric Onclogy Group (TPOG): Consultancy; Novartis: Honoraria, Speakers Bureau. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Vifor International: Membership on an entity's Board of Directors or advisory committees. Sutcharitcharan:Novartis: Honoraria, Research Funding; Novo Nordisk: Honoraria. Habr:Novartis Pharmaceuticals: Employment. Domokos:Novartis Pharma AG: Employment. Roubert:Novartis Pharma AG: Employment. Cappellini:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genzyme: Membership on an entity's Board of Directors or advisory committees.

Abstract 5107 Background Many thalassemia major (TM) patients have concomitant hepatitis B and/or C infection and data suggest that iron overload in these patients increases the risk of liver fibrosis progression. Deferasirox (Exjade®), which has demonstrated efficacy and safety in reducing iron overload in a variety of transfusion dependent anemias, has been uncommonly associated with elevations of transaminases suggestive of hepatitis (0.3%). However, whether patients' viral hepatitis status affects the overall and liver safety of deferasirox remains unclear. The prospective, multicenter EPIC study of deferasirox enrolled some patients with a history of hepatitis B or C. This sub-analysis of EPIC assesses the overall and liver safety of deferasirox over 1 year of treatment in TM patients with and without a history of hepatitis B or C. Methods Patients aged ≥2 years with transfusion-dependent TM and serum ferritin (SF) levels of ≥1000 ng/mL, or 20 transfusions or >100 mL/kg of red blood cells), or R2 MRI-confirmed liver iron concentration of >2 mg Fe/g dry weight were enrolled. Deferasirox starting dose was 10–30 mg/kg/day depending on the frequency of blood transfusions. Protocol-specified dose adjustments of 5–10 mg/kg/day (range 0–40) were performed every 3 months based on SF trends and safety markers. Safety was evaluated through continuous monitoring and recording of adverse events (AEs), as well as monthly blood chemistry assessments including alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Results Of 937 enrolled patients with TM, 258 (27.5%) had a history of hepatitis B or C and 679 (72.5%) did not. Compared with patients with no viral hepatitis, patients with a history of hepatitis B or C were older (mean age 26.5 ± 9.9 vs 15.3 ± 9.5 years), more commonly splenectomized (50.4 vs 29.9%), received more transfusions (195 vs 188 mL/kg) and were chelated for longer prior to study entry (15.9 ± 10.5 vs 8.7 ± 7.4 years). In total, 212 (82.2%) and 636 (93.7%) of patients with and without viral hepatitis, respectively completed the study. The most common drug-related AEs were gastrointestinal disorders, such as diarrhea (14.7% vs 6.2%, respectively; P33% above baseline and ULN on two consecutive visits Overall median SF decreased from baseline (3157 ng/mL) by 129 ng/mL after 1 year (P=0.0007) at a mean actual dose of 24.2 ± 5.6 mg/kg/day and mean transfusional iron intake of 0.43 ± 0.2 mg/kg/day. Reduction in SF was similar in patients with or without a history of viral hepatitis (–113 and –148 ng/mL, respectively). Conclusions This sub-analysis of EPIC demonstrates that once-daily deferasirox is well tolerated in patients with TM irrespective of viral hepatitis history with no significant difference in the incidence of abdominal pain, nausea and skin rash. Increases in ALT >10 x ULN were very low and occurred at a comparable frequency in patients with and without viral hepatitis. Mean liver transaminases, although higher at baseline in patients with a history of hepatitis B or C compared to those without, decreased in both groups, suggesting an overall improvement in liver function with deferasirox treatment. Reduction in SF was similar in both patient groups. Further confirmatory data are required to evaluate the effect of hepatitis viral load on the response to deferasirox therapy. Disclosures Cappellini: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genzyme: Membership on an entity's Board of Directors or advisory committees. Kattamis:Novartis: Consultancy, Honoraria, Speakers Bureau. Chan:Novartis: Honoraria, Research Funding. Lin:Taiwan Pediatric Onclogy Group (TPOG): Consultancy; Novartis: Honoraria, Speakers Bureau. Sutcharitchan:Novartis: Honoraria, Research Funding; Novo Nordisk: Honoraria. Taher:Novartis: Honoraria, Research Funding. Habr:Novartis Pharmaceuticals: Employment. Domokos:Novartis Pharma AG: Employment. Roubert:Novartis Pharma AG: Employment. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Vifor International: Membership on an entity's Board of Directors or advisory committees.

Abstract 5106 Background Heart failure secondary to myocardial siderosis remains the main cause of death in regularly transfused patients with β-thalassemia. Once-daily oral iron chelation therapy with deferasirox (Exjade®) has been shown to reduce body iron burden in patients with transfusion-dependent anemias, and the removal of myocardial iron has been demonstrated in several clinical studies including the prospective, multicenter EPIC study. Here we report for the first time an evaluation of right ventricular (RV) function assessed using magnetic resonance (MR) techniques in β-thalassemia patients with myocardial siderosis treated with deferasirox in the EPIC study. Methods The cardiac sub-study of EPIC enrolled patients with β-thalassemia aged ≥10 yrs who had MR myocardial T2* >5–2500 ng/mL, MR (R2) liver iron concentration (LIC) of >10 mg Fe/g dry weight (dw), and a lifetime minimum of 50 transfused blood units. Deferasirox was initiated at 30 mg/kg/day and subsequent dose adjustments of 5–10 mg/kg/day were based on changes in SF, month-6 cardiac T2* and safety parameters. The following RV parameters were assessed using MR; ejection fraction (RVEF), volumes (end-systolic [RVESV] and end-diastolic [RVEDV]) and mass (RVM). All parameters were assessed at the CMR core laboratory in London, UK after 6 and 12 months of deferasirox treatment. Results 114 patients were enrolled in the cardiac sub-study (54 male, 60 female; mean age 20.9 ± 7.3 years). Baseline myocardial T2* was Conclusions To our knowledge, this is the first study to show a change in RV volumes and improvement in RV function associated with iron chelation. The RVEF improved with increased RVEDV and decreased RVESV, which is suggestive of improved RV and left ventricular compliance respectively resulting from removal of myocardial iron. However, improvements in pulmonary vascular resistance may also play a role. Disclosures Smith: Novartis Pharma AG: Consultancy, Employment at Royal Brompton Hospital funded by Novartis Pharma AG. Pennell:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Apopharma: Consultancy, Honoraria; Cardiovascular Imaging Solutions: Equity Ownership; Siemens: Research Funding. Off Label Use: THE SPECIFIC USE OF CHELATION FOR CARDIAC SIDEROSIS IS OFF-LABEL. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Vifor International: Membership on an entity's Board of Directors or advisory committees. Cappellini:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genzyme: Membership on an entity's Board of Directors or advisory committees. Chan:Novartis: Honoraria, Research Funding. Aydinok:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ibrahim:Novartis: Research Funding. Lee:Novartis: Consultancy, Speakers Bureau. Viprakasit:Thai Government: Employment; Novartis: Honoraria, Research Funding; GPO-L-ONE clinical study sponsor by Government Pharmaceutical Organization of Thailand: Honoraria, Research Funding. Kattamis:Novartis: Consultancy, Honoraria, Speakers Bureau. Habr:Novartis Pharmaceuticals: Employment. Domokos:Novartis Pharma AG: Employment. Hmissi:Novartis Pharma AG: Employment. Taher:Novartis: Honoraria, Research Funding.

Abstract 3806 Poster Board III-742 Background Although iron overload in patients with myelodysplastic syndromes (MDS) is a negative prognostic factor for survival, many chronically transfused patients are not regularly evaluated for iron overload and remain unchelated. The once-daily oral iron chelator deferasirox (Exjade®) maintains or reduces body iron in patients with MDS, however, it has not previously been assessed based on chelation history. This analysis therefore evaluates the efficacy and safety of deferasirox in a large population of chelation-naïve and previously chelated patients with MDS. Methods This analysis is based on data from iron overloaded MDS patients aged ≥2 years who were enrolled in the 1-year multicenter EPIC study; patients with a life expectancy Results In total, 341 MDS patients were enrolled; 165 (48.4%) were chelation-naïve, 176 (51.6%) previously chelated with deferoxamine and/or deferiprone. Overall, 326 patients (95.6%) were aged ≥50 years. Baseline demographics, including median serum ferritin levels, were comparable between the two cohorts. Median serum ferritin decreased significantly in the overall population from baseline to month 12 (P=0.002; Figure). Serum ferritin levels also decreased in chelation-naïve (P=0.004) and in previously chelated (P=0.19) patients; median change was not significantly different between the two cohorts (P=0.107). Chelation-naïve and previously chelated patients who had a relatively low mean iron intake and baseline iron burden achieved a median reduction in serum ferritin with an average actual dose of 33% above baseline and >ULN; there were no progressive increases. One chelation-naïve patient (0.3%) who had normal baseline alanine aminotransferase levels had an increase >10 × ULN on two consecutive visits. Conclusions Although baseline serum ferritin levels were >2500 ng/mL, almost 50% of patients were chelation-naive, suggesting that the importance to treat iron overload continues to be underestimated in the MDS population. For previously chelated patients these data suggest that iron burden was not adequately managed with previous regimens. Irrespective of chelation history, with appropriate dosing based on transfusion requirements, serum ferritin levels and safety markers, deferasirox effectively decreased serum ferritin to Disclosures: Habr: Novartis Pharmaceuticals: Employment. Domokos:Novartis Pharma AG: Employment. Roubert:Novartis Pharma AG: Employment. Rose:Novartis: Research Funding. Gattermann:Novartis: Honoraria, Participation in Advisory Boards on deferasirox clinical trials.

Background: Labile plasma iron (LPI) is a toxic, directly chelatable form of non-transferrin- bound iron that is produced continually in conditions of iron overload and, due to rapid uptake into hepatocytes, myocardium and endocrine tissues, leads to secondary expansion of the cellular iron pool. The sustained presence of an iron chelator in the plasma may help avoid accumulation of LPI, thereby minimizing iron-related morbidity and mortality. This analysis evaluates the effect of deferasirox on LPI levels in patients (pts) with transfusion-dependent anemias enrolled in the large-scale, prospective, 1-yr multicenter EPIC trial. Methods: Enrolled pts were aged ≥2 yrs, had transfusion-dependent anemia and serum ferritin (SF) levels of ≥1000 ng/mL, or 20 transfusion episodes or >100 mL/kg of RBCs) and an R2 MRI-confirmed LIC >2 mg Fe/g dry weight (dw). Deferasirox starting dose was determined based on blood transfusion frequency. Dose adjustments in steps of 5–10 mg/kg/day (in the range 0–40 mg/kg/day) were based on SF trends and safety markers. Blood samples to measure LPI and assess the deferasirox pharmacokinetic profile were taken pre-administration and 2 hrs post administration at baseline and wks 12, 28 and 52. Results: LPI data are available from 1602 pts (825 M, 777 F; mean 30.4±23.0 yrs). Underlying anemias were: β-thalassemia (n=1029), myelodysplastic syndromes (MDS; n=305), aplastic anemia (AA; n=104), sickle cell disease (SCD; n=79), rare anemias (mostly hemolytic in nature) (n=42), and other conditions associated with anemias requiring transfusion (n=43). Mean LPI, pre and post deferasirox administration, at baseline and wks 12, 28 and 52 are shown in Table 1. Table 1. Mean LPI, pre and post deferasirox administration, at baseline and after repeat doses Baseline Week 12 Week 28 Week 52 Pre Post Pre Post Pre Post Pre Post NOTE: Data are mean LPI±SD (μmol/L); normal levels are 0–0.40 μmol/L All pts 0.89 ±1.84 0.33 ±1.59 0.30 ±0.90 0.11 ±0.56 0.27 ±0.87 0.11 ±0.62 0.47 ±1.35 0.30 ±1.33 β-thalassemia 1.25 ±2.34 0.58 ±2.10 0.40 ±1.07 0.15 ±0.67 0.34 ±0.94 0.13 ±0.72 0.60 ±1.55 0.39 ±1.52 MDS 0.53 ±0.63 0.02 ±0.11 0.08 ±0.28 0.02 ±0.10 0.15 ±0.88 0.03 ±0.18 0.14 ±0.32 0.02 ±0.07 AA 0.23 ±0.34 0.01 ±0.02 0.08 ±0.20 0.01 ±0.04 0.06 ±0.20 0.01 ±0.03 0.04 ±0.10 0.03 ±0.10 SCD 0.11 ±0.54 0.04 ±0.29 0.09 ±0.42 0.06 ±0.31 0.11 ±0.28 0.14 ±0.46 0.10 ±0.21 0.07 ±0.19 Rare anemias 0.50 ±0.55 0.01 ±0.04 0.05 ±0.13 0.01 ±0.03 0.06 ±0.18 0.01 ±0.03 0.29 ±0.52 0.02 ±0.03 Overall mean deferasirox dose during the 1-yr treatment period was 22.4±6.0 mg/kg/day (β-thalassemia, MDS, AA, SCD and rare anemias: 24.3±5.5, 19.3±5.7, 17.8±4.7, 20.2±3.8 and 18.6±5.6 mg/kg/day, respectively). At each time point, peak LPI levels observed just before deferasirox dosing were decreased compared with baseline and were mostly within the normal range from week 12 onwards in each underlying anemia. A small rebound at 52 wks was seen in the thalassemia sub-group: this could be associated with decreased compliance or other reasons, to be investigated further. In all pts, mean steady-state plasma concentration (ie pre-administration value) of deferasirox at wks 12, 28 and 52 was 32.9, 35.9 and 39.4 μmol/L, respectively. At each time point this was approximately half of the concentration value observed at 2 hrs post administration (84.4, 89.3 and 97.0 μmol/L, respectively). Conclusions: The results from this 1-yr study confirm the ability of once-daily deferasirox to provide sustained reduction in toxic LPI levels across various transfusion-dependent anemias, supporting previous data in pts with β-thalassemia. This is likely due to trough levels of deferasirox being within the therapeutic range, thereby preventing LPI levels rebounding between doses. Deferasirox therapy may therefore reduce unregulated tissue iron loading and prevent further end-organ damage in these pts.

Introduction: Iron chelation therapy (ICT) is essential in removing excess iron deposited in body organs, ultimately preventing organ failure and extending the lives of patients (pts) with transfusion-dependent hematological disorders such as β-thalassemia and myelodysplastic syndromes (MDS). As a life-long treatment, traditional ICT (deferoxamine, Desferal®, DFO) is based on a burdensome regimen (subcutaneous delivery 5–7 times a week) that has been shown to negatively impact on pts’ health-related quality of life (HRQoL). The oral chelator deferasirox (Exjade®) is less burdensome to pts offering 24-hour ICT, 7 days a week. Methods: This substudy was part of a single arm, multicenter, 1-year open-label trial (the EPIC study) to investigate the efficacy/safety of deferasirox. The first 558 pts with a variety of hematological disorders were recruited. These pts came from sites in seven countries: Australia, Belgium, France, Germany, UK, Greece, and Italy. Treatment-naïve pts and those having previously received ICT (DFO or deferiprone [Ferriprox®] exclusively, or combined) participated (n=558). Pts were asked at baseline, week 4 and week 52 (end of study [EOS]) to complete the 36-item Short Form health survey (SF-36). The SF-36 is a self-administered questionnaire and measures eight HRQoL domains: physical functioning; role-physical; bodily pain; general health; vitality; social functioning; role-emotional; and mental health. Mean change in SF-36 domain scores were calculated for all pts who had completed data at baseline and week 4, as well all those with completed data at baseline and EOS. All domains are scored so that higher scores indicate a better QoL. Results: Overall, the mean age of the 558 pts (274 β-thalassemia, 168 MDS, 50 sickle cell disease and 66 other anemias) recruited to take part in this substudy was 40.8 years (SD=22.58); 51.5% of patients (n=289) were male and 48.5% (n=272) were female. Within this sample, 337 pts aged ≥16 years completed the SF-36 at baseline, 322 at week 4 and 277 at EOS. Mean domain scores for pts at baseline, week 4 and EOS are presented in Table 1. With the exception of role-emotional (mean=0.78, SD=40.56), mean change in SF-36 domain scores significantly improved (P Table 1. SF-36 domain scores at baseline, week 4 and EOS in pts aged 3 16 years and treated with deferasirox SF-36 domains Baseline mean (SD) Week 4 mean (SD) End of study mean (SD) Physical functioning 66.32 (25.98) n=336 69.70 (25.98) n=317 71.67 (26.95) n=275 Role-physical 54.33 (42.43) n=331 61.03 (42.69) n=315 62.38 (41.71) n=270 Bodily pain 65.80 (26.89) n=336 74.67 (26.16) n=322 73.11 (27.20) n=276 General health 46.62 (21.15) n=330 48.01 (22.32) n=311 48.42 (22.19) n=269 Vitality 51.12 (21.28) n=328 54.57 (22.06) n=316 55.80 (23.06) n=272 Social functioning 71.73 (25.74) n=336 74.77 (23.72) n=321 73.05 (24.71) n=276 Role-emotional 68.05 (40.92) n=326 69.60 (41.60) n=313 69.81 (40.44) n=270 Mental health 67.04 (19.85) n=328 70.40 (19.73) n=316 67.85 (20.19) n=272 Conclusions: Since mean change scores were often of the magnitude of 3 to 5 units for role-physical and bodily pain, these results indicate clinically meaningful improvement for pts with hematological disorders receiving deferasirox.

Introduction: Iron chelation therapy (ICT) is essential for the treatment of iron overload and is routinely used life-long to help extend patients’ (pts) lives. Conventional ICT (deferoxamine, Desferal®, DFO) is burdensome to pts in terms of method (subcutaneous infusions) and duration (typically 8–12 hours, 5–7 days per week). Deferasirox (Exjade®) is an oral chelator that offers 24-hour ICT, 7 days a week and consequently is less burdensome to pts. Pt-reported outcomes can augment what is known about ICT from clinical and physiological assessments, and they are important since they represent how a pt feels. Methods: As part of a large, single arm, multicenter, 1-year open-label trial (the EPIC study) to assess the efficacy and safety of deferasirox in pts with transfusion-dependent iron overload, β-thalassemia (n=270) and MDS pts (n=87), previously receiving ICT (DFO, deferiprone [Ferriprox®] or combined), were recruited from sites in Australia, Belgium, France, Germany, UK, Greece and Italy. All pts aged ≥16 years were asked to complete the 19-item Satisfaction with ICT questionnaire (SICT) at baseline and week 52 (end of study [EOS]). The SICT is a validated questionnaire assessing pt satisfaction over 4 domains of ICT: perceived effectiveness; side effects; acceptance; burden. Higher SICT scores represent greater levels of satisfaction with each domain. Mean change domain scores were calculated for all pts who had completed data at both time points. Adherence to deferasirox was assessed by asking pts how often they thought about stopping their ICT, and how often they took their ICT exactly as directed by their doctor. Pts responded from 1 ‘Never’ to 5 ‘Always’, and the frequency of pts responding ‘Never’ and ‘Always’ for each item at baseline and EOS was calculated. Results: Mean age of β-thalassemia pts was 26.2 years (SD=11.36); 45.6% (n=123) were male and 54.4% (n=147) were female. MDS pts had a mean age of 66.4 years (SD=10.75); 57.5% (n=50) males and 42.5% (n=37) females. There were 181 β-thalassemia and 57 MDS pts aged ≥16 years who completed the SICT at study baseline. Baseline and EOS mean SICT scores are presented in Table 1. Significant improvements in mean change domain scores were reported in β-thalassemia ( P

Background: The 1-year, prospective, multicenter EPIC trial, the largest ever conducted for an iron-chelating agent, evaluated the efficacy and safety of the once-daily, oral chelator deferasirox (Exjade®) in patients (pts) with transfusion-dependent anemias. 54% of 1744 pts had β-thalassemia major, providing one of the largest data sets assessing the use of deferasirox in this group. Data from this subgroup are presented. Methods: Pts (≥2 years old) with transfusional iron overload due to β-thalassemia and serum ferritin (SF) levels of ≥1000 ng/mL or 20 transfusions or 100 mL/kg of blood) and R2 MRI-confirmed liver iron concentration >2 mg Fe/g dry weight, received an initial deferasirox dose of 10–30 mg/kg/day dependent on transfusion requirements. Protocol-specified dose adjustments in steps of 5–10 mg/kg/day (range 0–40 mg/kg/day) were done every 3 months based on SF trends and safety markers. The change at week 52 from baseline (BL) was the primary efficacy endpoint. Results: 937 pts with β-thalassemia major, 450 males and 487 females (mean age 18.4±10.8 years), were enrolled. Median BL SF was 3157 ng/mL (range 462–22320). In the year prior to enrollment, pts received a mean of 189.8 mL/kg of blood (range 0–1768). Most pts (n=625; 66.7%) had received deferoxamine (DFO); 234 (25.0%) DFO/deferiprone combination, 12 (1.3%) deferiprone alone and four (0.4%) other therapy; 66 (7.0%) were chelation naive. 798 pts (85%) started on ≤20 mg/kg/day and 139 (15%) on >20 mg/kg/day. 51% required a dose increase at a median of 24 weeks after treatment initiation (range 2–53). After 1 year, median SF significantly decreased from BL by 129 ng/mL (P=0.0007) at an average actual dose of 24.2±5.6 mg/kg/day. Pts receiving an average actual dose of ≥30 mg/kg/day achieved a significant reduction in SF at 1 year. Pts receiving an average actual dose of Table 1. Median change from BL in SF (ng/mL) by average actual dose received BL End of study Average actual dose categories Mean iron intake, mg/kg/day n Median SF n Median change from BL in SF P -value versus BL Only 9.5% of pts (n=89) discontinued therapy. Reasons for withdrawal were AEs (n=31, 3.3%), consent withdrawal (n=24, 2.6%), unsatisfactory therapeutic effect (n=12, 1.3%), lost to follow-up (n=5, 0.5%), death (n=4, 0.4%, three due to cardiac failure and one to septicemia following surgery, none treatment related by investigators’ assessment) and other (n=13, 1.4%). The most common investigator-assessed drug-related AEs were rash (n=115, 12.3%), diarrhea (n=76, 8.1%) and abdominal pain (n=50, 5.3%). The majority of AEs were mild-to-moderate (>95%). Thirty-seven pts (3.9%) had serum creatinine >33% above BL and the upper limit of normal (ULN) on two consecutive visits; there were no progressive increases. Five (0.5%) pts had an increase in alanine aminotransferase >10×ULN on two consecutive visits; levels were already elevated in four pts. Conclusions: These data confirm that in heavily iron-loaded pts with β-thalassemia major, higher deferasirox doses are needed to achieve significant reductions in SF, while lower doses are able to maintain iron balance. The starting dose guided by the rate of iron intake from blood transfusions and current iron burden should be titrated individually and promptly (at 3 months) according to SF trends and safety markers. Deferasirox treatment in this subgroup was generally well tolerated (including doses ≥30 mg/kg/day) with a low discontinuation rate.

Background: Deferasirox is a once-daily oral iron chelator with established dose-dependent efficacy for treating transfusional iron overload. In registration trials, the starting dose was based on baseline liver iron concentration (LIC). The prospective multicenter EPIC trial, the largest ever conducted for an iron chelator, included patients (pts) with a variety of transfusion-dependent anemias and was designed to evaluate the efficacy and safety of fixed starting doses of deferasirox based on transfusion history, with subsequent dose titration based on serum ferritin (SF) trends. One-year results are presented. Methods: Pts (aged ≥2 yrs) had transfusion-dependent anemia and SF levels ≥1000 ng/mL, or 20 transfusions or >100 mL/kg of RBCs) and R2 MRI-confirmed LIC of >2 mg Fe/g dry weight (dw). Deferasirox starting dose was 20 mg/kg/d for pts receiving 2–4 blood units/mth. An initial dose of 10 or 30mg/kg/d was considered for pts receiving less or more frequent blood transfusions, respectively. Protocol-specified dose adjustments of 5–10 mg/kg/d (range 0–40 mg/kg/d) were done every 3 months based on SF trends and safety markers. Primary efficacy endpoint was SF change from baseline (BL) at 1 year. Results: 1744 pts (901 M, 843 F; mean age 30.6±23.3 yrs) were enrolled; 33.1% (n=577) aged 20 mg/kg/d. 39% of pts had dose increases at a median of 24 weeks after treatment initiation (range 2–53). Overall, median SF was significantly decreased from BL by 264 ng/mL after 1 year (P Table 1. Median change from BL in SF (ng/mL) and mean iron intake (mg/kg/day) by average actual dose BL End of study Over the study Average actual dose categories N Median SF (ng/mL) N Median change from BL in SF (ng/mL) P -value vs BL N Mean iron intake (mg/kg/day) 1389 pts (79.6%) completed 1 year; reasons for discontinuation were adverse events (AEs; n=153; 8.8%), consent withdrawal (n=77; 4.4%), unsatisfactory therapeutic effect (n=20; 1.1%) and various other reasons (n=62; 3.6%); there were 31 (1.8%) drug related SAEs and 42 deaths, none assessed by investigators as treatment related. The most common drug-related (investigator-assessed) AEs were diarrhea (n=251; 14.4%), rash (n=174; 10.0%), nausea (n=135; 7.7%) and abdominal pain (n=97; 5.6%). 175 pts (10.0%) had serum creatinine value >33% above BL and the upper limit of normal (ULN) on two consecutive visits; there were no progressive increases. 13 (0.7%) had an increase in alanine aminotransferase >10×ULN on two consecutive visits; levels were already elevated in 11 pts. Conclusions: This large study confirms deferasirox efficacy in achieving a reduction of iron load across a wide range of pts with transfusion-related iron overload. It also supports the clinical approach to fixed starting dose of deferasirox based on iron intake from ongoing blood transfusions and current iron burden with subsequent individual dose titration every 3 months according to SF trends and safety markers. Deferasirox was generally well tolerated with a safety profile consistent with data from previous clinical trials.

Background: The prospective, 1-yr multicenter EPIC trial evaluated the efficacy and safety of once-daily oral deferasirox (Exjade®) in more than 1700 patients (pts) with transfusion-dependent anemias. Data were collected from each patient at enrollment, providing an insight into transfusion history, body iron burden, and the nature and success of previous chelation therapy in a large group of pts with iron overload previously treated with chelation therapy. Methods: Enrolled pts were aged ≥2 yrs, had transfusion-dependent anemia and serum ferritin (SF) levels of ≥1000 ng/mL, or 20 transfusions or >100 mL/kg of RBCs) and MRI-assessed liver iron concentration (LIC) >2 mg Fe/g dry weight (dw). Baseline assessments included transfusion history, previous chelation therapy, SF levels and LIC (if carried out) in the previous yr. Results: 1744 pts (901 M, 843 F) were enrolled. Underlying anemias were: thalassemia major (TM; n=937), thalassemia intermedia (TI; n=84), myelodysplastic syndromes (MDS; n=341), aplastic anemia (AA; n=116), sickle cell disease (SCD; n=80), rare anemias (red cell aplasia and anemias mostly hemolytic in nature; n=43), Diamond-Blackfan anemia (DBA; n=14), and various other conditions associated with anemias requiring transfusion (n=129). Baseline characteristics for key underlying anemias are presented in Table 1. Median SF levels were >2500 ng/mL and mean LIC in the previous yr was >7 mg Fe/g dw in all groups (except DBA for SF levels). MDS pts had received the most transfusions in the previous yr, although they had also spent a smaller proportion of their lifetime, and less total time, receiving transfusions than any other cohort. Together with AA pts, the MDS cohort also contained the highest proportion of pts who were chelation-naive (68% and 48%). SCD pts were the least-transfused group in terms of amount of blood given, but had been receiving transfusions for more than 13 yrs. As expected, TM pts had spent the greatest proportion of their lifetime on transfusions and received the greatest volume of blood per kg in the previous yr. The group labeled by investigators as TI were relatively heavily transfused for this patient population. Table 1. Baseline characteristics for key underlying anemias | | All (n=1744) | TM (n=937) | TI (n=84) | MDS (n=341) | AA (n=116) | SCD (n=80) | Rare (n=43) | DBA (n=14) | |:-----------------------------------:| ------------ | ---------- | --------- | ----------- | ---------- | ---------- | ----------- | ---------- | | *Mean ± SD; **Median | | Age, yrs* | 30.6±23.3 | 18.4±10.8 | 19.2±14.4 | 67.9±11.4 | 33.3±17.1 | 23.9±13.2 | 39.5±22.7 | 17.3±13.2 | | Transfusions in last yr* | 17.8±12.5 | 17.5±8.8 | 13.5±7.1 | 24.3±17.7 | 12.5±13.0 | 10.7±8.2 | 21.0±18.7 | 19.0±18.7 | | Total transfused in last yr, mL/kg* | 159±136 | 190±139 | 155±87 | 116±123 | 116±179 | 84±57 | 153±142 | 185±148 | | Total yrs on transfusions* | 12.3±10.4 | 16.8±10.4 | 10.2±7.8 | 3.6±4.6 | 6.1±5.7 | 13.0±9.6 | 10.9±11.8 | 13.3±10.0 | | % of lifetime on transfusions* | 62.9±39.4 | 89.8±15.2 | 61.2±28.8 | 5.7±8.4 | 27.1±29.3 | 59.5±30.1 | 44.3±41.5 | 87.5±23.2 | | LIC in last yr, mg Fe/g dw* | 10.7±9.0 | 9.5±7.8 | 9.7±5.5 | 14.4±8.5 | 12.0±4.3 | 11.8±8.4 | – | 8.8±4.2 | | SF, ng/mL** | 3135 | 3157 | 3493 | 2730 | 3254 | 3163 | 3161 | 2289 | | Prior chelation, % | | | | | | | | | | DFO | 58.6 | 66.7 | 78.6 | 40.2 | 26.7 | 62.5 | 55.8 | 71.4 | | Deferiprone | 1.6 | 1.3 | – | 4.1 | – | 1.3 | 2.3 | – | | DFO/deferiprone | 16.7 | 25.0 | 4.8 | 7.0 | 5.2 | 12.5 | 11.6 | 14.3 | | Other | 0.3 | 0.4 | – | 0.3 | – | – | – | – | | None | 23.0 | 7.0 | 16.7 | 48.4 | 68.1 | 23.8 | 30.2 | 14.3 | Conclusions: Data from this study population show that, although most pts with thalassemia, SCD, DBA and rare anemias had received previous chelation therapy, LIC and SF levels were above levels associated with significant negative outcomes (>7 mg Fe/g dw and >2500 ng/mL, respectively), which suggests that previous chelation practices were sub-optimal. Many pts with MDS and AA were chelation-naive despite being heavily iron overloaded, highlighting that the risks of iron overload are still underestimated. These data highlight the need to carefully monitor iron levels in pts at risk of iron overload and initiate chelation therapy to avoid serious clinical sequelae.

Background: Heart failure secondary to myocardial siderosis remains the main cause of death in regularly transfused patients (pts) with β-thalassemia, hence the importance of using a chelator that can reduce cardiac iron. Deferasirox (Exjade®), a once-daily, oral iron chelator, has demonstrated removal of cardiac iron in preclinical and small clinical studies. The EPIC trial is a 1-yr, multicenter prospective longitudinal study, and is the largest of its kind for any chelation therapy. Here we report the EPIC cardiac sub-study, which evaluates the cardiac efficacy of deferasirox in β-thalassemia pts with myocardial siderosis. Methods: The sub-study of EPIC included pts with β-thalassemia aged ≥10 yrs who were eligible for enrollment in the core trial and who had magnetic resonance (MR) myocardial T2* >5–2500 ng/mL, MR (R2) liver iron concentration (LIC) >10 mg Fe/g dw, and a lifetime minimum of 50 transfused blood units. Deferasirox was initiated at 30 mg/kg/d and subsequent dose adjustments of 5–10 mg/kg/d were based on changes in SF, month-6 cardiac T2* and safety parameters. The primary endpoint was the change in myocardial T2* from baseline to 1 yr. Secondary endpoints included change in LVEF, SF and LIC at 1 yr. Results: Enrolled into this sub-study were 114 pts (54 M, 60 F; mean 20.9±7.3 yrs), of whom the baseline myocardial T2* was 4% increase) was seen in 69.5%; no change in 14.3%; and worsening (>4% decrease) in 16.2%. LVEF remained stable throughout the study: 67.4±5.7% to 67.1±6.0% (P=ns). Overall both mean LIC and median SF were reduced significantly from baseline by −6.6±9.9 mg Fe/g dw and −1257 ng/mL (P33% above baseline and the upper limit of normal (ULN) on two consecutive visits; there were no progressive increases. Two (1.8%) pts had an increase in alanine aminotransferase >10×ULN on two consecutive visits; levels were already elevated in these pts. Conclusions: In β-thalassemia pts with myocardial siderosis, deferasirox at a mean dose of 32.6 mg/kg/d over 1 yr removes iron from the heart. The statistically significant improvement in myocardial T2* was associated with maintained ejection fraction. Concomitantly, a significant decrease in hepatic and total body iron burden was also seen. Deferasirox treatment was generally well tolerated. Ongoing one-yr extension of this sub-study will elucidate further the cardiac efficacy of deferasirox.

Background: Many patients (pts) with myelodysplastic syndromes (MDS) [particularly those with Low- or Int-1-risk] are susceptible to iron overload from ongoing blood transfusions and increased dietary iron absorption. Deferasirox (Exjade®) has shown efficacy in maintaining or reducing body iron (assessed by liver iron concentration [LIC] and serum ferritin [SF]) in MDS pts. More recently, the efficacy and safety of deferasirox in pts with various underlying anemias, including MDS, was evaluated in the large EPIC study. Data for MDS pts are presented here. Methods: The EPIC study was a 1-yr, openlabel, single-arm, multicenter trial. Pts with transfusion-dependent MDS and SF ≥1000 ng/ mL, or SF 20 transfusions or 100 mL/kg of blood and an R2 MRI-confirmed LIC >2 mg Fe/g dry weight (dw), received an initial deferasirox dose of 10–30 mg/kg/day. SF was assessed monthly and protocol-specified dose adjustments in steps of 5–10 mg/kg/day (range 0–40 mg/kg/day) were done every 3 mths based on SF trends and safety markers. Primary efficacy endpoint was the change in SF from baseline at 12 mths. Safety assessments included monitoring of adverse event (AE) and laboratory parameters. Results: 341 MDS pts (204 M, 137 F; mean age 67.9 yrs, range 11–89 yrs) with median baseline SF of 2730 (range 951–9465) ng/mL were enrolled. Mean transfusion duration was 3.6 yrs, and pts received a mean of 116.4 mL/kg of blood in the previous yr. Almost half (48.4%) of all pts had not received any prior chelation therapy; 40.0% had previously received deferoxamine (DFO), 4.1% deferiprone, 7.0% combination DFO/ deferiprone, and 0.3% other therapy. Overall, mean actual dose of deferasirox over 1 yr of treatment was 19.2±5.4 mg/kg/day. At 12 mths, there was a significant reduction in median SF from baseline (by LOCF: –253.0 ng/mL; P=0.0019). Median SF (range) ng/mL values at baseline, 3, 6, 9 and 12 mths were 2729.5 (951–9465; n=336), 2358.0 (534–46569; n=263), 2209.5 (357–10066; n=230), 2076.0 (358–25839; n=197) and 1903.5 (141–10155; n=174), respectively. Overall, 48.7% of pts (n=166) discontinued therapy. Reasons for withdrawal included AEs [n=78, 23% (n=44, 13% for drug-related AEs)], consent withdrawal (n=33, 10%), unsatisfactory therapeutic effect (n=6, 2%), lost to follow-up (n=2, 33% above baseline (in normal range), 10.6% had two values above ULN, and 24.9% had both two consecutive values >33% and >ULN; 19 pts had dose decreases and 10 dose interruptions due to abnormal creatinine; there were no progressive increases. One patient (10xULN on two consecutive visits. Conclusions: In this large cohort of MDS pts with iron overload, deferasirox provided significant reduction in SF levels over 1-yr treatment with appropriate dose adjustments every 3 mths based on SF trends and safety markers. The AE profile in this study is consistent with previously reported deferasirox data in MDS pts. The discontinuation rate was higher in this subgroup. Investigations are ongoing to assess possible contributing factors including associated comorbidities, age of pts, and others.

Background: Steroid-resistant patients with Diamond-Blackfan anemia (DBA) require life-long transfusion therapy, which ultimately results in toxic iron overload. Efficacy and safety of a once-daily, oral iron chelator, deferasirox (Exjade®), in patients with DBA have been demonstrated in one trial in which patients were dosed based on liver iron concentration (LIC) at enrollment. More recently, patients with various transfusion dependant anemias have been enrolled as part of a large, prospective, multicenter trial, the EPIC study, to evaluate whether fixed starting doses of deferasirox, based on transfusion history and subsequent dose titration, can provide clinically acceptable chelation, as measured by serum ferritin (SF). Data for the DBA sub-group are presented. Methods: Fourteen patients with transfusion-dependent DBA and SF levels of ≥1000 ng/mL, or 20 transfusions or 100 mL/kg of blood) and a R2 MRI confirmed LIC >2 mg Fe/g dry weight, were enrolled. Deferasirox was administered at an initial dose of 10–30 mg/kg/day depending on transfusion requirements, with dose adjustments in steps of 5–10 mg/kg/day (in the range 0–40 mg/kg/day) based on assessment of 3-month SF trends and safety markers. SF was assessed every 4 weeks; the primary efficacy endpoint was change in SF from baseline at 52 weeks. Safety assessments included adverse event (AE) monitoring and assessment of laboratory parameters. Results: Male (n=7) and female (n=7) patients with DBA (mean age 17.3 years), had a median baseline SF of 2288.8 ng/mL, and received a mean of 185.0 mL/kg of blood in the year prior to enrollment. Most patients had received previous chelation therapy with deferoxamine (DFO; 71.4%); two patients (14.3%) had received combination DFO/deferiprone and two (14.3%) had received no prior chelation therapy. All patients completed 12 months of treatment with no discontinuation. At 12 months, a significant reduction in SF from baseline was observed in the total population at an average actual dose of 21.0±4.8 mg/kg/day (−789.5 ng/mL; 2288.8 ng/mL [baseline]; P=0.0121). A similar reduction was seen in patients receiving an average actual dose of deferasirox ≥20–80%). There were no clinically relevant changes in markers of renal function. Two (14.3%) patients had an increase in alanine aminotransferase (ALT) that exceeded >10xULN (upper limit of normal) on two consecutive visits; all had elevated ALT levels at baseline. Conclusions: Over a 1-year treatment period, deferasirox significantly reduced iron burden in transfusion-dependent DBA patients with iron overload. Efficacy was demonstrated in patients receiving doses above and below 20 mg/kg/day, suggesting the need to individually titrate the dose according to the rate of iron intake from ongoing blood transfusions, as well as current iron burden and target SF levels. Deferasirox was well tolerated, with an AE profile similar to that observed in other patient groups.

We prove the following theorem: if a subalgebraB of an algebraG is spanned by root vectors, then ifX is a regular element ofG, the limit {ie160-1} Ad exptX(B) exists and is isomorphic toB, i.e.B “survives” contraction withX. The algebraSL(2C) is considered as an example. In particular it is shown thatSL(2C) itself survives and applications to relativistic scattering theory are indicated.