Cardiac Iron Removal Research Articles

Moxibustion with deferasirox results in safe, accelerated, and sustained cardiac iron chelation for a young Diamond Blackfan Anemia patient: An integrative case report

Diamond Blackfan Anemia (DBA) is a rare blood disorder of bone marrow failure typically identified in the first year of life. Due to treatment limitations, nearly all DBA patients are reliant upon chronic red cell infusion for some period of their lives. Repeat blood transfusion invariably leads to iron overload, which creates significant and life-threatening side effects. In this case report, a female child of 2 years and 8 months with DBA was diagnosed via T2* MRI imaging with potentially emergent levels of cardiac iron overload as a result of chronic red cell infusion. According to Chinese, Japanese, and integrative medicine principles, moxibustion was applied externally in conjunction with the prescribed oral chelation agent, deferasirox (DFX), over a period of six months. Analysis of repeat imaging at six months showed complete removal of cardiac iron and a one-third decrease in hepatic iron. In addition, there was no evidence of known risks to high-dose chelation, including renal, aural, or ocular damage. Follow-up examination two years after initial imaging showed no evidence of cardiac iron deposition with hepatic iron levels below minimum levels recommended for chelation despite the medical necessity of continued red cell infusion. This case study suggests that an integrative medical approach combining DFX with moxibustion may safely accelerate and sustain iron chelation for transfusion-dependent DBA patients. Recommendations for a successful approach to integrative iron chelation are provided in the case discussion.

Deferiprone exerts a dose-dependent reduction of liver iron in adults with iron overload.

While doses of deferiprone up to 75mg/kg/d have been demonstrated to be effective in cardiac iron removal, their efficacy in the reduction of liver iron has been equivocal. The aim of this study was to evaluate the effect of deferiprone dose on liver iron concentrations in adult iron overload patients. A single-centered, retrospective, cohort observational study was conducted involving 71 patients exposed to deferiprone doses up to 113mg/kg/d between January 2009 and June 2015 for a median of 33months. At the end of the study period, liver iron measured by R2 MRI was reduced by a mean 1.7mg/g dw. A dose effect was observed, with incremental reductions of 2.8mg/g dw in end of study LIC for every 10mg/kg/d higher dose of deferiprone (P<0.001). A dose effect was also observed in end of study ferritin and cardiac iron concentration measured by T2* MRI (P<0.0001 and P=0.048, respectively). No associations between adverse effects and deferiprone dose were observed, but there was a trend toward higher rates of agranulocytosis at higher doses and two of three hereditary hemochromatosis patients developed this complication. The present study failed to demonstrate that the use of deferiprone at >90mg/kg/d was associated with increased risk of agranulocytosis or neutropenia, but did demonstrate more effective liver iron control in iron overload patients.

Deferiprone for the treatment of transfusional iron overload in thalassemia

ABSTRACTIntroduction: Transfusional iron overload can lead to hepatic fibrosis, arrhythmias and congestive heart failure and a number of endocrinopathies. Deferiprone is an oral iron chelator approved for use in the United States as a second line agent for the treatment of transfusional iron overload in patients with thalassemia.Areas covered: This article will review the data regarding the efficacy of deferiprone for iron chelation and prevention and reversal of iron related complications, the drug’s adverse effect profile, and the use of this drug in combination regimens.Expert commentary: Extensive data support that deferiprone is particularly efficacious at cardiac iron removal and therefore, a chelator regimen that contains deferiprone is generally recommended when there is significant cardiac iron loading and/or in the setting of iron-related cardiac disease. The most concerning side effects of deferiprone are agranulocytosis and milder forms of neutropenia, which require appropriate monitoring and patient/provider education.

Association of Liver Iron Concentration Levels with Myocardial T2* Responses in Transfusion-Dependent Thalassemia Major Patients Treated with Deferasirox and Deferoxamine- Extension of Cordelia Study

Background: Beta thalassemia major patients (pts) are at an increased risk of heart failure, due to the deposition of iron in the heart causing myocardial siderosis. Intensive long-term iron chelation therapy (ICT) is required to obtain a normal myocardial T2* (mT2* >20 ms). Previously published studies suggested that cardiac iron removal lags changes in liver iron, and liver iron concentration (LIC) may affect the rate of removal of cardiac iron (Porter et al, ASH 2013). The objective of these analyses was to evaluate the association of the severity of LIC levels with the change in mT2* responses in pts with myocardial siderosis when treated with deferasirox (DFX) and deferoxamine (DFO) for up to 24 months (mo) in the CORDELIA study. Due to the very low pt numbers in the DFO arm, the results for these pts are not presented here. Methods: The study design, inclusion, and exclusion criteria have been reported previously (Pennell et al, Am J Hematol. 2015). Pts were categorized into LIC Results: Of 197 pts, 160 (81.2%) completed 12 mo of treatment and 146 (74.1%) entered into the extension study whereas 103 pts continued on initially assigned treatment. Pts completing 24 mo of treatment included 65 (87.8%) of 74 pts (mean age 20.1±6.9 years, 59.5% male) on DFX and the results for these pts are presented as follows. Average actual doses (mg/kg/d) were 26.7±8.9, 31.5±7.4, 38.0±2.9 for LIC The LIC levels for pts categorized by LIC For pts with BL LIC The mT2* responses for pts categorized according to visit specific LIC levels (LIC Discussion: Overall, DFX treatment resulted in a substantial decrease in LIC and improved mT2*. These results suggest a greater difference in mT2* improvement and CIC reduction in pts who achieved lower LIC during treatment with DFX. This divergence was progressive with time, being maximal at Mo 24. Thus, a therapeutic response in LIC with DFX may be associated with a greater likelihood of improving mT2*. Pts with high LIC ≥15 may require an effective long-term treatment with higher doses of ICT to have an improvement in mT2*, suggesting that cardiac iron removal is likely to be slow in heavily iron overloaded pts. These results are consistent with the previous report which showed a significant decrease in LIC and increased mT2* responses at Mo 36 in pts who attained lower end-of-year LIC levels when treated with DFX (Porter et al, ASH 2013) and highlight the potential value of monitoring the liver and cardiac responses during ICT. To further understand the kinetics between liver and cardiac iron removal, prospective investigation is warranted. Disclosures Pennell:Novartis: Consultancy, Research Funding; Apotex: Consultancy, Research Funding. Porter:Celgene: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria. Piga:Acceleron: Research Funding; Cerus: Research Funding; Apopharma: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding; Celgene Corporation: Honoraria. Han:Novartis: Employment. Vorog:Novartis: Employment. Aydinok:Cerus: Research Funding; Sideris: Research Funding; Novartis: Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Relative Trends in Myocardial T2* Versus Myocardial Iron Concentration As Representations of Myocardial Iron Chelation Efficacy in Patients with β Thalassemia Major Treated with Deferasirox for up to 3 Years

▪Background: Heart failure due to iron-induced cardiomyopathy is rare yet remains one of the leading causes of death in patients with β thalassemia. Using myocardial T2* (mT2*) cardiovascular magnetic resonance (CMR) to estimate myocardial iron burden has improved the management of cardiac siderosis. Myocardial T2* >20 ms is considered normal and as iron accumulates, mT2* reduces, with values <10 ms associated with an increased risk of heart failure. As reported by Carpenter et al (2011), a calibration for CMR R2* against atomic emission spectroscopy-measured myocardial iron concentration (MIC), showing a curvilinear relationship between R2* and MIC, actual MIC can now also be assessed and affords an additional efficacy measure for patients undergoing iron chelation therapy. In a previous post-hoc analysis of the 3-year EPIC (Evaluation of Patients’ Iron Chelation with Exjade®) cardiac substudy, the long-term effects of deferasirox on mT2* and MIC were reported. Here, we report relative trends between mT2* and MIC as a representation of myocardial chelation efficacy by determining how far the patient has progressed from baseline toward reaching normal levels, in order to further understand the interpretation of these two parameters.Methods: Patients aged ≥10 years with mT2* >5 to <20 ms by CMR, left ventricular ejection fraction ≥56%, serum ferritin >2500 ng/mL, MR (R2) liver iron concentration >10 mg Fe/g dry weight (dw) and ≥50 lifetime transfused blood units were included in the study. Cardiac iron removal was analyzed over 3 years in patients with mT2* at baseline and each considered time point. Post-hoc calculation of MIC from mT2* values was conducted using the formula described by Carpenter et al as follows: [Fe] = 45.0 x (mT2*)−1.22 where [Fe] is measured in milligrams per gram dw and mT2* is measured in milliseconds. Data are presented descriptively as the percentage of the progression of the patients toward achieving normalization of mT2* (>20 ms) or MIC (>1.16 mg Fe/g dw as derived from the formula based on normal mT2*) by mT2* at baseline: >5 to <10 ms, 10 to <15 ms and 15 to <20 ms.Results: Data were analyzed at Month 12 (n=67: baseline mT2* >5 to <10 ms, n=24; 10 to <15 ms, n=19; 15 to <20 ms, n=24), Month 24 (n=66: baseline mT2* >5 to <10 ms, n=24; 10 to <15 ms, n=18; 15 to <20 ms, n=24) and Month 36 (n=63: baseline mT2* >5 to <10 ms, n=22; 10 to <15 ms, n=18; 15 to <20 ms, n=23). As previously reported (Pennell et al. 2012), geometric mean mT2* in the overall population significantly increased from 12.0 ms at baseline to 13.9 ms at Month 12, 15.6 ms at Month 24 and 17.1 ms at Month 36. In parallel, mean MIC significantly decreased from 2.43 mg Fe/g dw at baseline to 2.10 mg Fe/g dw at Month 12, 1.94 mg Fe/g dw at Month 24 and 1.80 mg Fe/g dw at Month 36. The median percentage progression of patients towards normalizing mT2* and MIC by baseline mT2* category are presented in the Figure. In patients with severe myocardial iron overload at baseline, the percentage toward normalization in mT2* in the first, second and third year was less than the percentage towards normalization in MIC. This difference was less pronounced, but still evident, in patients with mild-to-moderate myocardial iron overload. [Display omitted] Discussion: The calibration of the relationship between CMR measurements and MIC by Carpenter et al allows an additional assessment to mT2* to determine chelator efficacy in terms of the actual concentration of iron in the myocardium. Here we show that, particularly in patients with severe myocardial iron overload, when analyzing the progression towards normalization, improvement in MIC is proportionally greater than that seen with mT2*. It could be interpreted that a small improvement (ie 1 ms) in mT2* when baseline values are >5 to <10 ms is not equivalent in terms of myocardial iron removal to a small improvement in patients with less severe myocardial iron overload at baseline; a consequence of the reciprocal relationship between mT2* and MIC. Therefore, analysis of mT2* only may underestimate the efficacy of iron chelation with respect to the myocardium in patients with severe myocardial iron loading (mT2* <10 ms) and thus MIC may better reflect response to chelation therapy. It would therefore be valuable if MIC were calculated and reported in parallel with mT2* when assessing and monitoring patients on iron chelation therapy across a range of baseline mT2* values. DisclosuresPorter:Novartis: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Celgene: Consultancy; Cerus: Membership on an entity’s Board of Directors or advisory committees; Alnylam: Membership on an entity’s Board of Directors or advisory committees. Taher:Novartis: Honoraria, Research Funding. Aydinok:Novartis: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. El-Ali:Novartis: Employment. Barbier:Novartis: Employment. Cappellini:Novartis: Honoraria, Speakers Bureau; Genzyme: Honoraria.

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

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

Impact Of Liver Iron Overload On Myocardial T2* Response In Transfusion-Dependent Thalassemia Major Patients Treated With Deferasirox For Up To 3 Years

Background Patients with myocardial iron overload require effective cardiac iron removal to minimize the risk of cardiac complications. The 3 year EPIC cardiac sub-study showed that the oral iron chelator, deferasirox (DFX), effectively reduced cardiac iron overload. Previous reports demonstrate that cardiac iron removal is slow and suggest that liver iron concentration (LIC) may affect cardiac iron removal rate by chelators (Pennell et al., 2012; Blood). The objective of these analyses was to evaluate the impact of the severity of the liver iron overload on the change in myocardial T2* (mT2*) for patients receiving up to 3 years of DFX treatment in the EPIC sub-study. Methods Inclusion and exclusion criteria have been described previously (Pennell et al. , 2012; Haematologica). Patients were categorized into LIC ≤15 and >15 mg Fe/g dry weight (hereafter mg/g) at baseline (BL) and by LIC 15 mg/g at 12, 24, and 36 months to assess the impact of BL LIC and changes in LIC overtime on mT2*, respectively. During study, LIC and mT2* were measured every 6 months. Efficacy was assessed in per-protocol population that entered third year extension. Here, mT2* is presented as the geometric mean (Gmean) ± coefficient of variation (CV) unless otherwise specified. Statistical significance was established at α-level of 0.05 using a 2-sided paired t-test for within group comparisons and ANOVA for multiple group comparisons. All p -values were of exploratory nature for this post-hoc analysis. Results Of the 71 patients, who continued into study year 3, 68 patients considered evaluable were included in this analysis (per protocol population); 59 patients had LIC values available at end of study (EOS). Mean age was 20.5 ±7.35 years and 61.8 % of patients were female. Mean actual dose of DFX (mg/kg/day) was 32.1 ±5.5 and 35.1 ±4.9 in patients with BL LIC ≤15 and >15 mg/g, respectively. At EOS, mean actual doses were 32.9 ±5.4 (LIC 15 mg/g). Overall, patients had high BL LIC (Mean, 29.0 ±10.0 mg/g); 61 patients had LIC >15 (30.8 ±8.8) mg/g, only 7 patients had LIC ≤15 (12.7 ±1.1) mg/g, and no patients had LIC 15 mg/g, respectively. Notably, 51.9% of patients with BL LIC >15 mg/g achieved EOS LIC <7 mg/g. Overall, mean mT2* was 12.8 ±4.6 ms. The impact of BL LIC on mT2* and LIC response was as follows: in patients with LIC ≤15 mg/g (Mean BL mT2*, 14.2 ±3.6 ms) and >15 mg/g (BL mT2*, 12.7 ±4.7 ms), mT2* increased by 52% (Mean abs. change, 7.5 ±4.1 ms, p =0.0016) and 46% (7.3 ±7.3 ms, p 15 mg/g, (20.1 ±10.6 ms) displaying a lag of nearly 12 months. The relation between post-BL LIC on mT2* response at 12, 24 and 36 months is shown in the figure. At 12 months, there was no significant difference in mT2* that had occurred in patients with LIC 15 mg/g (13% increase; 1.9 ±3.2 ms). However, at 24 months, there was a statistically significant difference amongst the 3 subgroups in percent increase in the mT2* that had occurred; patients with LIC 15 mg/g had 54% (Mean abs. change, 8.3 ±7.3 ms), 33% (5.2 ±5.2 ms) and 10% (2.1 ±4.3 ms) increase ( p 15mg/g group. At all-time points, in patients who achieved an LIC <7 mg/g, a statistically significant increase in T2* from BL had occurred. Discussion Overall, DFX treatment resulted in a significant decrease in LIC and improved mT2*. A greater difference in mT2* improvement was shown to have occurred in patients who achieved lower end-of-year LIC after treated with DFX. This divergence was progressive with time, being maximal at 36 months. Thus, a therapeutic response in LIC with DFX is associated with a greater likelihood of improving mT2*. This may assist in monitoring liver and cardiac response to DFX. Prospective evaluation of this relationship is indicated. ![Graphic][1] Disclosures: Porter: Novartis Pharma: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Celgene: Consultancy. Taher: Novartis Pharma: Honoraria, Research Funding. Aydinok: Novartis Oncology: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Cappellini: Novartis Pharma: Honoraria, Speakers Bureau; Genzyme: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Kattamis: Novartis: Research Funding, Speakers Bureau; ApoPharma: Speakers Bureau. El-Ali: Novartis Pharma: Employment. Martin: Novartis Pharma: Employment. Pennell: Novartis: Consultancy, Honoraria, Research Funding; ApoPharma: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria. [1]: /embed/inline-graphic-1.gif

Deferasirox Compared With Deferoxamine For The Removal Of Cardiac Iron In Patients With β-Thalassemia Major: 2-Year Data From The Cordelia Extension

Deferasirox Compared With Deferoxamine For The Removal Of Cardiac Iron In Patients With β-Thalassemia Major: 2-Year Data From The Cordelia Extension

Cardiovascular Function and Treatment in β-Thalassemia Major

This aim of this statement is to report an expert consensus on the diagnosis and treatment of cardiac dysfunction in β-thalassemia major (TM). This consensus statement does not cover other hemoglobinopathies, including thalassemia intermedia and sickle cell anemia, in which a different spectrum of cardiovascular complications is typical. There are considerable uncertainties in this field, with a few randomized controlled trials relating to treatment of chronic myocardial siderosis but none relating to treatment of acute heart failure. The principles of diagnosis and treatment of cardiac iron loading in TM are directly relevant to other iron-overload conditions, including in particular Diamond-Blackfan anemia, sideroblastic anemia, and hereditary hemochromatosis. Heart failure is the most common cause of death in TM and primarily results from cardiac iron accumulation. The diagnosis of ventricular dysfunction in TM patients differs from that in nonanemic patients because of the cardiovascular adaptation to chronic anemia in non-cardiac-loaded TM patients, which includes resting tachycardia, low blood pressure, enlarged end-diastolic volume, high ejection fraction, and high cardiac output. Chronic anemia also leads to background symptomatology such as dyspnea, which can mask the clinical diagnosis of cardiac dysfunction. Central to early identification of cardiac iron overload in TM is the estimation of cardiac iron by cardiac T2* magnetic resonance. Cardiac T2* <10 ms is the most important predictor of development of heart failure. Serum ferritin and liver iron concentration are not adequate surrogates for cardiac iron measurement. Assessment of cardiac function by noninvasive techniques can also be valuable clinically, but serial measurements to establish trends are usually required because interpretation of single absolute values is complicated by the abnormal cardiovascular hemodynamics in TM and measurement imprecision. Acute decompensated heart failure is a medical emergency and requires urgent consultation with a center with expertise in its management. The first principle of management of acute heart failure is control of cardiac toxicity related to free iron by urgent commencement of a continuous, uninterrupted infusion of high-dose intravenous deferoxamine, augmented by oral deferiprone. Considerable care is required to not exacerbate cardiovascular problems from overuse of diuretics or inotropes because of the unusual loading conditions in TM. The current knowledge on the efficacy of removal of cardiac iron by the 3 commercially available iron chelators is summarized for cardiac iron overload without overt cardiac dysfunction. Evidence from well-conducted randomized controlled trials shows superior efficacy of deferiprone versus deferoxamine, the superiority of combined deferiprone with deferoxamine versus deferoxamine alone, and the equivalence of deferasirox versus deferoxamine.

A Multicenter, Randomized, Open-Label Trial Evaluating Deferasirox Compared with Deferoxamine for the Removal of Cardiac Iron in Patients with β-Thalassemia Major and Iron Overload (CORDELIA).

Abstract 2124 Background: Without effective iron chelation therapy (ICT), patients with transfusional iron overload are at risk of excess iron-related cardiac complications. Cardiac iron accumulation can be measured using T2* magnetic resonance (normal >20 ms, high risk Methods: Patients with β-thalassemia major, cardiac T2* 6–20 ms, no clinical symptoms of cardiac dysfunction, aged ≥10 yrs, history of ≥50 transfusions, left ventricular ejection fraction (LVEF) ≥56% and liver iron concentration (LIC) ≥3 mg Fe/g dry weight (dw) were recruited. Patients were randomized to an intensified DFO regimen with a target dose of 50–60 mg/kg/d sc for 8–12 hrs, 5–7 d/wk, or deferasirox with a target daily oral dose of 40 mg/kg/d. Dose adjustment recommendations were based on continuous assessment of efficacy and safety markers. Efficacy was assessed in the per-protocol analysis population. Primary efficacy endpoint was change after 1-yr treatment (using last available value ≥150 d after randomization) in cardiac T2* expressed as the ratio of geometric means (Gmean) at end of study (EOS) over baseline (BL) for deferasirox divided by the ratio of Gmeans for DFO. Non-inferiority was pre-defined if the lower limit of the 2-sided repeated 95% confidence interval (CI) for ratio of Gmeans was >0.9. Results: From 925 screened patients, 197 patients (mean age 19.8 ± 6.4 yrs) were randomized. Mean time since start of transfusions was 19.3 and 18.4 yrs in deferasirox and DFO patients, respectively. All patients had received previous ICT. At BL, Gmean cardiac T2* was 11.4 ms; mean ± SD LIC was 29.8 ± 17.5 mg Fe/g dw in deferasirox patients and 30.3 ± 17.9 mg Fe/g dw in DFO patients; median (range) serum ferritin level was 5062 (613–15331) and 4684 (677–13342) ng/mL, respectively. 160 (81.2%) patients completed 1 yr. Mean actual dose of deferasirox was 36.7 ± 4.2 mg/kg/d and DFO was 41.5 ± 8.7 mg/kg/d for 7 d/wk. Overall, Gmean cardiac T2* increased by 12% with deferasirox and 7% with DFO after 1 yr (Fig A). The Gmean ratio between the two arms was 1.0557 (95% CI 0.9981, 1.1331). Lower limit of the 95% CI was >0.9, demonstrating non-inferiority of deferasirox vs DFO, with a trend towards superiority ( P =0.0567). Trends toward increases were observed in patients with severe or mild/moderate cardiac iron (Fig B, C). In patients with BL LIC LVEF was stable with deferasirox (BL 66.9 ± 5.61%; EOS 66.3 ± 5.8%) and DFO (BL 66.4 ± 5.2%; EOS 66.4 ± 5.8%). LIC absolute change from BL was –8.9 ± 11.4 (95% CI –11.5, –6.4) mg Fe/g dw for deferasirox and –12.7 ± 11.4 (–15.3, –10.1) mg Fe/g dw for DFO. Overall adverse event (AE) rates were 67.7% in deferasirox patients and 75.8% in DFO patients. In deferasirox patients, most common AEs were diarrhea (12.5%), proteinuria (11.5%) and influenza (10.4%). Most common AEs in DFO patients were proteinuria (8.8%), upper respiratory tract infection (8.8%) and influenza (6.6%). Serious AEs occurred in 10.7% patients overall (10.4% deferasirox; 11.0% DFO), with many related to the underlying disease. 3 deferasirox patients and 1 DFO patient had 2 consecutive serum creatinine increases >33% above BL and >upper limit of normal (ULN). Overall, 14.6% of deferasirox patients and 3.3% of DFO patients had ALT levels >5xULN and >2xBL. One death (arrhythmia) in the deferasirox arm was considered unrelated to study drug. One death (meningitis) in a DFO patient was suspected to be related to DFO. Discussion: CORDELIA, the first randomized controlled trial comparing deferasirox with DFO for cardiac iron removal, met its primary endpoint in demonstrating non-inferiority of deferasirox vs DFO, with a trend for superiority. There was a trend toward more pronounced improvements in cardiac T2* with deferasirox vs DFO in patients with BL LIC Disclosures: Pennell: Novartis: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Siemens: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Apotex: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; CVIS: Equity Ownership. Porter: Novartis: Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Piga: Novartis: Membership on an entity9s Board of Directors or advisory committees, Research Funding. Lawniczek: Novartis: Employment. Habr: Novartis: Employment. Weisskopf: Novartis: Employment. Zhang: Novartis: Employment. Aydinok: Ferrokin: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau.

Cardiac iron removal and functional cardiac improvement by different iron chelation regimens in thalassemia major patients

Heart failure due to myocardial iron overload remains the leading cause of morbidity and mortality in adult thalassemia major (TM) patients. We evaluated the removal of cardiac iron and the changes of cardiac function by different iron chelation in TM patients by T2* cardiac magnetic resonance (CMR). Sixty-seven TM patients (27 males/40 females; mean age, 35 ± 6 years) on different chelation regimens underwent T2* CMR at baseline (t (0)), after 6-14 months (t (1)) and after 32 ± 7 months (t (2)). Patients were divided in four groups according to chelation treatment: group A (deferasirox), group B (deferoxamine), group C (combined treatment, deferoxamine plus deferiprone) and group D (deferiprone alone). Myocardial T2* at t (0) was <10 ms in 8 patients, between 10 and 20 ms in 22 patients and ≥ 20 ms in 37 patients. Progressive changes in T2* were observed at t (1) and t (2). Ten patients (10/36, 27.8 %) in group A, three patients (3/15, 20 %) in group B and three patients (3/12, 25 %) in group C moved from an abnormal T2* to normal values. We observed an improvement of left ventricular ejection fraction and a reduction of end-systolic and end-diastolic left ventricular volumes only in patients in group A with baseline cardiac T2* between 10 and 20 ms. Rigorous compliance to any chelation therapy at proper doses significantly improve myocardial T2*. Treatment with deferasirox significantly improves left ventricular function. Combination therapy seems to ameliorate cardiac T2* in a shorter period of time in severe siderosis.

Deferasirox for up to 3 years leads to continued improvement of myocardial T2* in patients with -thalassemia major

Prospective data on cardiac iron removal are limited beyond one year and longer-term studies are, therefore, important. 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. 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 (P<0.001), corresponding to a decrease in cardiac iron concentration (based on ad hoc analysis of T2*) from 2.43 ± 1.2 mg Fe/g dry weight (dw) at baseline to 1.80 ± 1.4 mg Fe/g dw at end of study (P<0.001). After three years, 68.1% of patients with baseline T2* 10 to <20 ms normalized (≥ 20 ms) and 50.0% of patients with baseline T2* >5 to <10 ms improved to 10 to <20 ms. There was no significant variation in left ventricular ejection fraction over the three years. No deaths occurred and the most common investigator-assessed drug-related adverse event in year 3 was increased serum creatinine (n = 9, 12.7%). Three years of deferasirox treatment along with a clinically manageable safety profile significantly reduced cardiac iron overload versus baseline and normalized T2* in 68.1% (32 of 47) of patients with T2* 10 to <20 ms.

Improvement of Cardiac Function and Cardiac Volumes in Patients Treated with Deferasirox

Abstract 2159 INTRODUCTION.The iron chelation therapy in thalassemia major (TM) patients has been demonstrated to reduce cardiac morbidity and mortality. Deferoxamine (DFO) significantly improved survival but its use has several limitations due to reduced compliance. The once-daily oral chelator deferasirox (DFX) has been shown to remove iron from the liver and from the heart, with improved compliance. The efficacy of DFX in removing cardiac iron has been shown and significant improvements in myocardial T2* in patients with b-thalassemia with T2* levels < 20 ms have been demonstrated. The introduction in the clinical practice of the T2* Cardiac Magnetic Resonance (CMR) evaluation permitted a rapid, direct and highly reproducible method to assess myocardial and hepatic iron overload; moreover this technique allows to evaluate cardiac morphology and function. We evaluated the removal of cardiac iron and the cardiac function parameters in TM patients treated with DFX, undergoing CMR,followed at Hereditary Anemia Centre, Department of Internal Medicine in Milan. METHODS.Forthy-one TM patients (22 females, 19 males, mean age 32 ± 6 yrs), treated with DFX, followed in a single centre, underwent a CMR, performed at baseline (T0), after a variable period of exposure to DFX (median: 12 months, range 4–48 months) and then after at least 6 months of treatment (T1) (median 12 months, range 6–19 months). CMR was performed at Cardiology and CMR Department “A. De Gasperis” at Niguarda Ca’ Granda Hospital in Milan, using a 1.5 Tesla MR scanner (Avanto Siemens, Erlangen). The signal intensity of this region was measured for each image with the use of commercial software (CMRtools, Cardiovascular Imaging Solutions, London, UK). All T2* analyses were performed blinded to patient details. Ventricular volumes were analyzed with the same software and stroke volume and ejection fraction calculated from end diastolic and end systolic ventricular volumes. Patients were divided in two groups: group A (28 patients) with baseline T2* values > 20 ms and group B (12 patients) with baseline T2* between 10 and 20 ms. RESULTS.In the overall population, the mean deferasirox dose was 26±7 mg/kg/day; dose adjustment was based on iron intake and on liver and cardiac iron overload at CMR. Despite different durations of deferasirox exposure and different levels of myocardial iron overload, an average improvement of myocardial T2* from 27.4 ms to 29.8 ms was observed at T1 (P=0.004). A significant improvement in LVEF from 63.6 % to 66.5 % (P=0.013), indicative of improved cardiac function, was also observed. Similarly, both end-systolic and end-diastolic ventricular volume assessments (EDV, EDVI, ESV, ESVI) showed significant improvement at T1. No difference in median serum ferritin levels were found between group A and B. Myocardial T2* increased in both groups with DFX treatment, with a significant improvement observed in Group B patients (T2* at T0 was 15.7 ± 2.7 ms and at T1 19.6 ± 3.8 ms, P=0.003) (Table 1). LVEF significantly increased in both groups, from 65.7% to 68.0 % in Group A (P=0.01) and from 59.7% to 64.3% in Group B (P=0.04) (Table 1). In Group A, improvements in EDV, ESV and ESVI were also significant with deferasirox treatment; in Group B significant improvements were observed in ESV and ESVI (Table 1). CONCLUSION.These data confirm the effects of iron chelation with deferasirox in removing cardiac iron in beta TM patients with mild-to-moderate myocardial iron overload and preventing accumulation of myocardial iron in patients with normal baseline cardiac iron levels. Interestingly, improvements in cardiac function were observed both in patients with and without myocardial iron overload at baseline, however it was more significant in patients with normal T2* at baseline.Table 1Group A and B: left ventricular parameters and heart T2* at T0 and T1.Group A, baseline T2* >20 msGroup B, baseline T2* 10–20 msT0T1P-valueT0T1P-valueSerum ferritin (ng/mL)1003804ns7861118nsT2* heart (ms)33.1 ± 7.234.7 ± 9.30.415.7 ± 2.719.6 ± 3.80.003LVEF (%)65.7 ± 5.268.0 ± 5.20.0159.7 ± 6.464.3 ± 5.70.04EDV (mL)142.7 ± 35.6134.8 ± 30.90.01139.8 ± 28.5130.4 ± 25.80.11EDVI (mL/m2)87.6 ± 21.283.6 ± 15.10.0685.3 ± 14.077.7 ± 10.90.06ESV (mL)48.9 ± 16.143.4 ± 13.40.00156.0 ± 14.848.3 ± 15.10.03ESVI (mL/m2)30.2 ± 9.328.0 ± 5.20.0133.9 ± 6.928.3 ± 7.30.01 Disclosures:No relevant conflicts of interest to declare.

Long-Term Use of Deferiprone Enhances Significantly the Left Ventricular Ejection Function in Thalassemia Major

Abstract 5302 Background:A multicentre randomized controlled trial (RCT) was designed to assess the effectiveness of long-term sequential deferiprone-deferoxamine (DFO-DFP) versus DFP alone to treat thalassaemia major (TM) (Maggio et al.,2009). Effectviness, survival, adverse events and costs were comparable between the groups. These findings were confirmed in a further 21-month follow-up (Pantalone et al., 2011). Moreover, deferiprone-alone has been reported to be superior to deferoxamine for the removal of cardiac iron and improvement in left ventricular ejection function (LVEF). However, little is known of its relative effect on LVEF after long-term treatment. Therefore, data from this prospective RCT were retrospectively analyzed to assess the LVEF responses to these treatments. Methods:In this retrospective survey of RCT, 99 patients with TM received, from September 30, 2000 to December 31, 2007, LVEF study consecutively (Table I). Generalized Estimating Equations (GEE) model was used to show the possible change of the mean of LVEF over the time between the Sequential DFP-DFO versus the DFP (Hedeker & Gibbons, 2006). This approach was implemented in the ’xtgee’ procedure of Stata 11 software (StataCorp, College Station, TX, USA). All of the statistical analyses were performed under code at the Department for Mathematical and Statistical Sciences ’S. Vianelli’, University of Palermo (Italy) by A.V. Results:Baseline findings are shown on Table I. Figure 1 shows the proÞles of the GEE model for the change in the mean LVEF between the two groups. The regression coefficient of treatment suggests as, the DFP-group shows statistically significant increase of mean ejection fraction over time (Coeff. 0,97, 95% CI (0,51; 1,44), p-value<0,0001, Fig. I). Actually, while the Sequential DFP-DFO treatment shows a slight advantage in terms of difference in the mean of LVEF (Coeff. 2,36, 95% CI (0,02; 4,71), p-value=0,047,Fig. I), it does not increase significantly LVEF over the time (Coeff. −0,34, 95% CI (−1,09; 0,39), p-value=0,359).Table IBaseline findings in the 99 patients included in the retrospective cohort studyFindingsDFP-groupSequential-groupp-valueN° pts (99)6039Females (%)22 (36,66)21 (53,84)Age in years31±7,5231±8,660,96Hgb, g/l*9,24±0,879,32±0,680,78ALT, IU/L*49,73±37,8838,27±45,970,43LIC, mg/g/dw2946,03±2026,562351,08±2234,030,38Total blood transfusion, ml/kg/year8716,172±2111,048268,02±2561,870,34Mean ferritin, mg/l1664,21±846,621717,54±497,790,84Mean basal EF < 55% (n°)52±2,19 (6)50,66±3,05 (3)0,47Basal mean ejection fraction59,25±4,2560,89±5,780,10Mean age at DFO starting, years5,75±4,345,03±4,610,46Splenectomy (%)33(55)27 (69,23)0,26Cirrhosis (%)54 (90,00)38 (97,43)0,16Arrhythmia (%)49 (81,66)35 (89,74)0,31HCV-RNA positive (%)42 (70,00)30 (76,92)0,51 [Display omitted] Discussion:Previous retrospective studies suggested as deferiprone –treated patients had higher LVEF in comparison with Deferoxamine (DFO) or Deferasirox (DFX) treated groups (Anderson et al., 2002; Pepe et al., 2011). Moreover, survival analysis suggested a substantial decline in cardiac deaths in recent years, related to switching high-risk patients from subcutaneous desferrioxamine to chelation regimes which include the oral chelator deferiprone (Borgna-Pignatti et al., 2006; Telfer et al., 2009). Finally, Pennell et al. 2006 suggested, during a RCT over 1 year comparing DFO versus DFP, as LVEF increased significantly more in the deferiprone-treated group (3.1% vs 0.3% absolute units; P =.003). This retrospective survey of long-term prospective RCT, shows as the effect of deferiprone-alone treatment increases significantly during the years (Coeff. 0,97, 95% CI (0,51; 1,44), p-value<0,0001, Fig. 1). Cardioprotective effect of deferiprone on mitochondrial function in cultured, iron-loaded heart cells has been suggested (Link et al., 1999;Glickstein et al., 2006;Xu et al.,2006), even at concentrations below the iron-mobilizing effect (Link et al.,1999). These findings clincally support as long-term treatment with DFP-alone enhances LVEF over the years and may prevent death due to heart failure in patients with thalassemia major. Disclosures:Off Label Use: Deferiprone on sequencial way with Deferoxamine.

Heterogeneity In Regional Myocardial T2* Improvement After Deferiprone Therapy,

Abstract 3176Myocardial siderosis is a major cause of death in Thalassemia Major (TM). Intensification of iron chelation therapy (ICT) can reverse cardiac toxicity and improve survival. Cardiac magnetic resonance (CMR) imaging with T2* analysis of a single region of interest (ROI) within the mid septum has been shown to be representative of overall myocardial iron concentration. Histological studies, however, demonstrate heterogeneity in myocardial iron. To date, dynamics of cardiac iron removal by ICT has not been well studied. Deferiprone (DFP) is an effective oral myocardial iron chelator. This study aims to examine patterns of myocardial iron removal by DFP using a 4 segmental CMR T2* approach. All patients receiving DFP for myocardial iron overload at Toronto General Hospital, up until March 2011 were evaluated retrospectively. CMR was performed on a 1.5 Tesla scanner (Siemans, Germany) before and after DFP treatment using a gradient-multi-echo sequence and cardiac gating. 4 to 5 short-axis slices were acquired at 8 echo times (TE) in a single end-expiratory breath hold. T2* analysis was performed using CMR 42 software (Circle software, Calgary, Canada). A basal- and mid-ventricular short axis slice was chosen for analysis. CMR were analyzed by a single observer who remained blinded to the timing of the scans in relation to therapy. CMR were performed on 19 TM patients (37% (n=7) males, mean age 31 years) at an average of 83 days before and 205 days after the commencement of DFP. The average daily dose of DFP was 87mg/kg. 42% (n=8) of patients were on DFP alone and 58% (n=11) were on combination therapy with Deferoxamine (n=10) or Deferasirox (n=1). There was significant variation in myocardial T2* across the 4 regions assessed both before (P<0.001) and after (P=0.001) treatment. Prior to treatment, T2* values were lowest in the mid anteroseptum and highest in the basal inferoseptum (P<0.050) (Figure 1). Following treatment with DFP, T2* values improved significantly across all myocardial regions (P<0.030 for all). The overall median increase in T2* value was 1.6 ms (IQR: −0.2 to 4.5 ms). In the patient subgroup with severe iron overload (baseline T2* ≤10ms; n=11), the improvement in T2* varied across all 4 myocardial regions and showed a trend towards statistical significance (P=0.091). The greatest improvement was observed in the basal inferoseptum (median T2* change 4.8 ms; IQR: 0.0 to 7.2 ms) and the least improvement in the mid anteroseptum (median T2* change 1.1 ms; IQR 0.3 to 4.3 ms) (Figure 2). In this patient subgroup, trends towards significance were also demonstrated for greater improvement in median T2* in the basal (4.5 ms; IQR: 0.6 to 5.9 ms) versus mid septum (2.0 ms; IQR: −0.1 to 5.4 ms, P=0.075) and in the inferoseptum (3.9 ms; IQR: 0.0 to 6.3 ms) versus the anteroseptum (3.1 ms; IQR: 0.4 to 4.4 ms, P=0.084). The data indicate variable regional response to DFP chelation therapy that trended towards statistical significance in patients with severe myocardial iron overload (T2* ≤10 ms). The greatest increase in T2* values was observed in the myocardial region with the highest baseline T2* (basal inferoseptum) while the smallest improvement was seen in the region with the lowest baseline T2* (mid anteroseptum). This suggests that effective chelation may be more challenging in areas with more severe iron deposition. However, there was a non-significant trend to greater increase in T2* across all myocardial regions after treatment in patients with an overall baseline T2* ≤10 ms, versus T2* >10ms. Regional variability in T2* change following DFP therapy has not been previously investigated. Further studies using a multi-segmental T2* analysis approach may improve understanding of the dynamics of iron removal and provide new avenues for optimizing iron chelating regimens to maximize iron removal and improve patient-outcomes. [Display omitted] [Display omitted] Disclosures:Off Label Use: Deferiprone is an unlicensed drug in Canada and USA. It is an oral iron chelator.

Continued Improvement and Normalization of Myocardial T2* In Patients with β-thalassemia Major Treated with Deferasirox (Exjade®) for up to 3 Years

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 3 rd yr of the study. Mean age was 20.5 ± 7.4 yrs. BL cardiac T2* was >5 to st , 2 nd and 3 rd yr, respectively. Geometric mean T2* significantly increased from 11.9 ms ± 39.0% at BL to 13.9 ms ± 46.9% after 1 yr, 15.6 ms ± 57.7% after 2 yrs, and continued to increase to 17.1 ms ± 62.0% after 3 yrs, (increase from BL of 17% at 1 yr, 31% at 2 yrs and 44% at 3 yrs; P 5 to After 3 yrs, 68.1% of patients with BL T2* 10 to 5 to P P Of 71 patients, 66 (93.0%) completed the 3 rd 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 1 st yr and 3 in the 3 rd yr. Two (2.8%) patients had 2 consecutive increases in ALT >10 × ULN; 1 patient in the 2 nd yr and 1 patient in both the 2 nd and 3 rd 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 entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Apotex: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; CVIS: Equity Ownership. Porter: Novartis: Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Cappellini: Novartis: Speakers Bureau. Aydinok: Novartis: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ibrahim: Novartis: Honoraria. Li: Novartis: Honoraria, Membership on an entity9s Board of Directors or advisory committees. Viprakasit: Novartis: Honoraria, Membership on an entity9s 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.

Deferasirox—current knowledge and future challenges

Since the last Cooley's symposium in 2005, our knowledge and clinical experience with deferasirox had advanced considerably. This has been based on prospective multicenter clinical trials, on a scale hitherto unprecedented for chelation therapy, now totalling over 7,400 patients. Here, current knowledge about the clinical effects of deferasirox is described in key areas, namely, the pharmacokinetics and its relevance to mechanisms of action; effects on iron balance; effects on serum ferritin; long-term tolerability; and effects on cardiac iron removal. Challenges for future research include a better understanding of the relationship of serum ferritin to iron balance; the optimal target level and rate of decrease in serum ferritin to achieve a "soft landing," as ferritin values fall below 500-1,000 microg/L; the use of surrogate markers, such as mT2*, to infer the likely effects on long-term survival; and the safety and efficacy of deferasirox when combined with other chelators.

Introduction of higher doses of deferasirox: better efficacy but not effective iron removal from the heart and increased risks of serious toxicities

Importance of the field: Thousands of iron loaded patients are using deferasirox, who are not aware of the new, fatal and irreversible serious toxic side effects, the need for prophylaxis and the availability of more effective and less toxic chelation therapies.Areas covered in this review: Updating on efficacy issues in relation to the introduction of higher deferasirox doses and comparison to existing chelation therapies. A new maximum dose of 40 mg/kg/day has been introduced for deferasirox in an attempt to achieve negative iron balance in thalassemia and other transfused iron loaded patients. A marginal increase in cardiac iron removal using doses of 30 – 40 mg/kg/day suggests that the rate of iron removal by deferasirox is insufficient by comparison to the deferiprone/deferoxamine combination, where total and rapid clearance of excess cardiac iron and normalization of the body iron stores could be achieved.What the reader will gain: Identification of drug interactions and new fatal and permanent toxic side effects of deferasirox and implications on efficacy, toxicity and cost of using higher doses. Deferasirox has been identified to cause fatal gastrointestinal hemorrhages, renal tubulopathy, hepatic and renal failure, alopecia and anaphylactic reactions in addition to previously reported fatal or serious toxic side effects such as agranulocytosis, renal and hepatic toxicity, skin rash and gastric intolerance. Interactions with UDP-glucuronosyl transferase inducers, CYP2C8 and CYP3A4 substrates and drugs affecting enterohepatic recycling are likely to affect deferasirox's efficacy and toxicity. Increased toxicity is expected from the use of higher doses of deferasirox and regular prophylactic monitoring is required to avoid fatal and permanent toxicity incidences. The increased costs from higher doses of deferasirox will mostly affect patients living in the developing countries.Take home message: Only few patients may benefit from the introduction of higher doses of deferasirox. There is a need for introducing more effective prophylactic measures. Safer, more effective and less costly chelation treatments are available using deferiprone, deferoxamine and their combination.

Efficacy and Safety of Deferasirox (Exjade®) in β-Thalassemia Patients with Myocardial Siderosis: 2-Year Results From the EPIC Cardiac Sub-Study.

Abstract 4062Poster Board III-997 BackgroundOver 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. MethodsPatients aged ≥10 years with myocardial T2* >5–<20 ms (indicating cardiac siderosis) by cardiovascular magnetic resonance (CMR), left ventricular ejection fraction (LVEF) ≥56%, serum ferritin >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. ResultsOut 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 <10 ms (severe cardiac siderosis) in 39 patients (39%) and 10–20 ms (mild-to-moderate cardiac siderosis) in 61 (61%). 67.0% had received prior deferoxamine (DFO) and 33.0% prior DFO/deferiprone combination therapy. Mean actual deferasirox dose increased from 33.1 ±3.7 mg/kg/day in the core 1-year phase to 36.1 ±7.4 mg/kg/day during the extension. Continued improvement in myocardial T2* was observed in the extension phase so that after 2 years of deferasirox treatment, T2* had significantly increased from a baseline geometric mean of 11.2 to 15.3 ms (P<0.001). Significant increases from 7.3 to 9.3 ms (P<0.001) and from 14.6 to 19.9 ms (P<0.001) were respectively noted in patients with baseline T2* <10 and 10–20 ms (Figure). LVEF remained stable in both subgroups throughout the 2-year follow up period. Both mean LIC and median serum ferritin were significantly reduced from baseline by 10.7 ± 12.8 mg Fe/g dw and 2343 ng/mL (range –12795 to 25127), respectively (P<0.001; based on last-observation-carried-forward analysis). [Display omitted] 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. ConclusionsThis 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.

Iron chelation therapy in the management of thalassemia: the Asian perspectives

Worldwide, thalassemia is the most commonly inherited hemolytic anemia, and it is most prevalent in Asia and the Middle East. Iron overload represents a significant problem in patients with transfusion-dependent beta-thalassemia. Chelation therapy with deferoxamine has traditionally been the standard therapeutic option but its usage is tempered by suboptimal patient compliance due to the discomfort and demands associated with the administration regimen. Therefore, a great deal of attention has been focused on the development of oral chelating agents. Deferiprone, even though available for nearly two decades in Asia with recent encouraging data on cardiac iron removal and long-term efficacy, has serious adverse effects including agranulocytosis and neutropenia which has impeded it from routine clinical practice. A novel oral chelator; deferasirox is effective throughout a 24 h dosing period and both preclinical and clinical data indicate that it successfully removes both hepatic and cardiac iron. In Asia, optimal management of severe thalassemia patients and the availability and access to oral iron chelators still presents a major challenge in many countries. In this regard, the development and implementation of consensus guidelines for management of Asian patients with transfusion-dependent thalassemia will be a major step towards improving and maintaining the continuity of patient care.