Frequency, Pattern, and Associations of Renal Iron Accumulation in Sickle Beta-Thalassemia

Abstract Background: Chronically transfused homozygous sickle cell disease (HbSS) patients were shown to have higher kidney iron deposition than thalassemia major patients, not associated to total body iron and mainly caused by chronic hemolysis. Kidney iron deposition has not been explored in sickle beta-thalassemia (Sβ-thal), resulting from the inheritance of both sickle cell and beta-thalssemia genes. Aim: This multi center study aimed to study frequency, pattern, and associations of renal iron accumulation in sickle beta-thalassemia. Methods: Thirty-three Sβ-thal patients (36.49±14.72 years; 13 females) consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia (E-MIOT) network were considered. Moreover, 20 healthy subjects, 14 HbSS patients and 71 thalassemia major (TM) patients were included as comparison groups. Hepatic, cardiac, pancreatic, and renal iron overload was quantified by the gradient-echo T2* technique. In each kidney T2* was measured in anterior, posterolateral, and posteromedial parenchymal regions and the global T2* value was calculated as the average of the two kidneys T2* values. Results. Global renal T2* were significantly higher in healthy subjects versus both Sβ-thal patients (49.68±10.09 ms vs 43.19±8.07 ms; P=0.013) and HbSS patients (49.68±10.09 ms vs 26.21±17.07 ms; P<0.0001). Sβ-thal patients showed comparable age, sex, frequency of regular transfusion, hematochemical parameters, and hepatic, cardiac and pancreatic iron load than HbSS patients, but they had a significant lower frequency of renal iron overload (global renal T2*<31 ms) (9.1% vs 57.1%; P=0.001). Regularly transfused patients (16 Sβ-thal and 10 HbSS) were compared with TM patients, homogeneous for age and sex, but TM started regular transfusions significantly earlier and they were more frequently chelated. No significant difference was detected in terms of hepatic and cardiac iron levels, but TM patients had significantly lower pancreas T2* values than both the other two groups and significantly higher global renal T2* values than HbSS patients (42.87±9.43 ms vs 24.39±15.74 ms; P=0.001). In Sβ-thal patients no significant difference was detected between T2* values in left and right kidneys, and global renal T2* values were not associated to age, gender, splenectomy, and they were comparable between regularly transfused and non transfused patients. No correlation was detected between renal T2* values and serum ferritin levels or iron load in the other organs. Global renal T2* values were not associated with serum creatinine levels but showed a significant inverse correlation with serum lactate dehydrogenase (Figure 1). Conclusion. Renal iron deposition is not common in Sβ-thal patients, with a prevalence significantly lower compared to that of HbSS patients, but with a similar underlying mechanism due to the chronic hemolysis. Figure 1 Figure 1. Disclosures Pepe: Bayer S.p.A.: Other: no profit support; Chiesi Farmaceutici S.p.A: Other: no profit support. Maggio: Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corp: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees.

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Study of Renal Iron Overload by T2* MRI in a Large Cohort of Thalassemia Major Patients

Blood ◽

10.1182/blood.v120.21.5177.5177 ◽

2012 ◽

Vol 120 (21) ◽

pp. 5177-5177

Author(s):

Antonella Meloni ◽

Daniele De Marchi ◽

Vincenzo Positano ◽

Gaetano Giuffrida ◽

Sabrina Armari ◽

...

Keyword(s):

Iron Overload ◽

Conflicts Of Interest ◽

Left Kidney ◽

Significant Negative Correlation ◽

Thalassemia Major ◽

Iron Deposition ◽

Significant Difference ◽

The Mean ◽

The Right ◽

T2 Mri

Abstract Abstract 5177 Background. Renal dysfunction has been reported in adult subjects with thalassemia major (TM) since 1975. One of the main cause is the iron overload consequent to regular transfusions. Multiecho T2* MRI is a well-established technique for cardiac and hepatic iron overload assessment, but there very few report concerning the kidneys. The aims of this study were to describe the T2* values of the kidneys in patients with TM, to investigate the correlation between renal and myocardial or hepatic siderosis and biventricular cardiac function. Methods. 119 TM patients (58 men, 30. 7 ± 8. 2 years) enrolled in the Myocardial Iron Overload (MIOT) networks underwent MRI. For the measurement of iron overload, multiecho T2* sequences were used. The left ventricle was segmented into a 16-segments standardized model and the T2* value on each segment was calculated as well as the global value. In the liver, the T2* value was assessed in a single region of interest (ROI) in a homogeneous area of the parenchyma. For each kidney, T2* values were calculated in three different ROIs and were averaged to obtain a representative value for the kidney. The mean T2* value over the kidneys was also calculated. Cine images were obtained to quantify biventricular morphological and functional parameters in a standard way. Results. T2* values in the right kidney were significant lower than in the left kidney (40. 3±11. 9 ms vs 44. 1±12. 7 ms, P<0. 0001). The mean T2* value over the kidneys was 42. 2±11. 9 ms and 40 patients (33. 6%) had a pathological value (T2*<36 ms, lower limit of normal evaluated on 20 healthy subjects). The mean T2* value did not show a significant difference amongst men ad women (43. 2±11. 7 ms versus 41. 3±12. 1 ms, P=0. 378). The mean T2* values increased with age in a significant manner (r=0. 321, P<0. 0001). There was a significant negative correlation between serum ferritin levels and mean renal T2* values (r=-0. 446, P<0. 0001). Significant positive correlations of the mean T2* values were demonstrated for liver (r=0. 511, P<0. 0001) and global heart (r=0. 262, P=0. 004) T2* values (Figure 1). No correlation was found between renal iron overload and bi-ventricular function parameters. Conclusions. Systemic T2* differences between left and right kidneys were found, with significant lower values in the right one. Mean T2* value increased with age. We confirmed that kidney iron deposition was not very common in TM, but it was correlated with iron deposition in liver and heart. Disclosures: No relevant conflicts of interest to declare.

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

Blood ◽

10.1182/blood.v122.21.1016.1016 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1016-1016 ◽

Cited By ~ 2

Author(s):

John Porter ◽

Ali T Taher ◽

Yesim Aydinok ◽

Maria D Cappellini ◽

Antonis Kattamis ◽

...

Keyword(s):

Iron Overload ◽

Board Of Directors ◽

Research Funding ◽

Iron Removal ◽

Advisory Committees ◽

Liver Iron ◽

Cardiac Iron ◽

Significant Difference ◽

Liver Iron Overload ◽

The Impact

Abstract 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 <7, 7–≤15 and >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 <7 mg/g), 38.0 ±3.4 (LIC 7–≤15 mg/g), and 37.6 ±3.1 (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 <7 mg/g. After 36 months, a significant mean decrease from BL in LIC of -7.6 ±4.6 mg/g (p = 0.0049) and -16.8 ±14.0 mg/g (p <0.001) was observed in patients with LIC ≤15 and >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<0.001), respectively. Patients with BL LIC ≤15 normalized mT2* in 24 months (Mean, 20.0 ±6.0 ms) versus 36 months for patients with BL LIC >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 <7 mg/g (24% increase; mean abs. change, 3.5 ±2.3 ms), LIC 7–≤15 mg/g (19% increase; 3.4 ±5.2 ms) and those 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 <7, LIC 7-≤15 and 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 <0.001), respectively. Similarly, at 36 months, the mT2* had increased by 71% (Mean abs. change, 10.3 ±6.6 ms) in the LIC <7 mg/g group; a 31% increase (5.3 ±5.0 ms) had occurred in the LIC 7– ≤15 mg/g group; and an 18% (3.3 ±6.0 ms) increase (p <0.001) had occurred in the LIC >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. 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.

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A Randomised 1 Year Study Evaluating the Impact of Vitamin C Supplementation on Systemic Iron Parameters of Iron Overload in Thalassemia Major Patients on Long-Term Treatment with Deferasirox

Blood ◽

10.1182/blood.v128.22.1288.1288 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1288-1288

Author(s):

Yesim Aydinok ◽

Metin Delebe ◽

Gunes Basol ◽

Selen Bayraktaroglu ◽

Nihal Karadas ◽

...

Keyword(s):

Iron Overload ◽

Board Of Directors ◽

Research Funding ◽

Thalassemia Major ◽

Average Dose ◽

Advisory Committees ◽

Baseline Characteristics ◽

Labile Iron ◽

The Impact

Abstract Background Ascorbic acid (AA) supplementation has traditionally been used in iron overloaded patients as means to increase iron chelation efficacy and replenish AA oxidized by labile iron found in those patients. The rationale leaned on AA's ability to render stored iron accessible to chelation, as found in urinary iron excretion following deferoxamine infusion. However, as AA increases labile iron redox-cycling and ensuing toxicity, we set to assess the long term benefits versus toxicity risks of the combined chelator-AA treatment. Objectives Perform a prospective, open-label, randomized and controlled 1 year study on thalassemia patients treated with deferasirox (DFX) in order to assess the effects of AA supplementation on: a. markers of systemic iron overload in selected organs and in plasma and b. markers of plasma labile iron (LPI) as potential contributors to oxidative stress toxicity. Patients and Methods Enrolment: 22 beta thalassemia major (TM) patients ≥10 years treated >2 years with DFX. Exclusion: cardiac dysfunction/arrhythmia or mT2* MRI <6 ms. Study: patients previously unexposed to AA received once-daily DFX (up to 40 mg/kg/d) with or without 125 mg AA for 1 year. All parameters were measured at baseline (BL); serum ferritin (SF) monthly, liver iron (LIC by MRI) and cardiac iron (mT2*MRI) after 1y. e-LPI (surrogate NTBI marker) and LPI (plasma redox-active labile iron marker) were assessed at BL, mo 1 & 6 by FeROS™ (Aferrix, Ltd) and fasting plasma AA at BL and EOS (fluorimetrically). Blood samples were withdrawn on the morning of transfusion day, 24 hours after last DFX (+/- AA) administration. Safety was followed using laboratory and clinical tests. AA levels were also determined in 23 healthy individuals (age and gender matched). Results 22 TM patients were enrolled (mean age 23.5, range 10-34 y). The average dose ± SD of DFX given to all 22 patients was 38±4.5 mg/kg/d. 11 patients were randomised to receive DFX and the others with DFX supplemented with 125 mg AA (mean 2.4±0.5, range 1.9-4.2 mg/kg) for 1 year. At BL, the AA levels were significantly lower in the TM group compared to controls (2.44 ± 3.38 vs 9.60± 4.36 mg/dl respectively, p<0.000001). 11 of 22 patients had AA levels >-2SD of control group whereas the other 11 patients showed normal ranges of AA. The AA deficient patients were those that showed significantly higher SF, LIC and lower mT2* at BL (Table 1). In the DFX+AA arm, 5/11 (45%) patients had subnormal AA levels at BL but attained normal status after 1 year, as did all others on AA. Of the 5/11 (45%) DFX-treated patients that did not receive AA had normal BL AA and only 2/11 maintained normal AA status at EOS. A significant correlation was obtained between BL SF, LIC and mT2* and e-LPI (r 0.49, p 0.025; r 0.57, p 0.01; r -0.43, p 0.057 respectively) but not with LPI. The changes associated with DFX alone or with AA from BL to EOS were subtle for all parameters measured (Table 2). Importantly, eLPI and LPI remained at basal levels throughout 6 months treatment in both arms. With DFX alone, LPI were 0.34±0.30 units (mM iron) (BL) & 0.63±0.58 (6 mo); eLPI: 1.71±1.93 at BL & 2.48±3.11 (6 mo). DFX+AA: LPI were 0.33±0.46 (BL) & 0.35±0.44 (6 mo); eLPI: 2.13±1.71 (BL) & 1.78±1.51 (6 mo). Conclusions TM patients on long term DFX without AA supplementation showed subnormal, AA levels. This was most pronounced in TM patients with higher liver and heart iron. The addition of AA to DFX normalized the AA levels but did not increase the e-LPI and LPI during 6 mo, indicating no apparent risk of iatrogenic toxicity by AA to DFX. Moreover, AA may enhance the efficacy of DFX in cardiac and hepatic iron. The small rise in SF versus fall in LIC in the DFX+AA arm might need further exploration. Table 1 Baseline characteristics of patients based on AA status Table 1. Baseline characteristics of patients based on AA status Table 2 Changes in iron overload markers in patients treated with DFX or DFX+AA over 1 year Table 2. Changes in iron overload markers in patients treated with DFX or DFX+AA over 1 year Disclosures Aydinok: Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Cerus: Research Funding; Shire: Research Funding. Cabantchik:Aferrix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Hinoman: Consultancy; Novartis Pharmeceuticals: Honoraria, Speakers Bureau; Apopharma: Honoraria, Speakers Bureau.

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Role of T1 Mapping As a Complementary Tool to T2* for Cardiac Iron Overload Assessment

Blood ◽

10.1182/blood.v128.22.3624.3624 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3624-3624

Author(s):

Camilla Torlasco ◽

Elena Cassinerio ◽

Patrizia Pedrotti ◽

Andrea Faini ◽

Marco Capecchi ◽

...

Keyword(s):

Iron Overload ◽

Board Of Directors ◽

T1 Mapping ◽

Short Axis Slice ◽

Strong Relationship ◽

Thalassemia Major ◽

Advisory Committees ◽

Mean Values ◽

End Diastolic Volume ◽

Log Linear

Abstract Introduction. Iron overload-related heart failure is the principal cause of death in transfused Thalassemia Major (TM) (Modell B, Cardiovasc Magn Reson 2008;10:42-48). Iron toxicity is dose dependent so a strategy of chelation therapy titration (Kirk P, Circ 2009;120:1961-1968) before the onset of left ventricle (LV) impairment changes outcomes (AlpenduradaF, Eur Heart J. 2010; 31:1648-54). The presence of iron in tissue detectably changes the magnetic properties of water, T1, T2 and T2*, as validated against tissue in animal and human models (Carpenter JP, Circ 2011;14:1519-28). T2*, the most used technique, is susceptible to non-iron influence (susceptibility artefact) and has low accuracy for high and low iron levels (Carpenter JP, J Cardiovasc Magn Reson. 2014;12:16-62). T1 mapping could complement T2* as it appears to have superior reproducibility and to detect mild iron missed by T2* (Abdel-Gadir A. J Cardiovasc Magn Reson. 2015;17(Suppl1):P312. Sado DM, J Magn Reson Imaging. 2015;41:1505-11), but studies to date have been small and not using state-of-the-art sequences. Methods. In a prospectively single centre study of 138 TM patients and 32 healthy volunteers (HV) (no known medical conditions, normal CMR scan), we compared T1 mapping (Modifier Lock Locker Inversion sequence - MOLLI - Siemens Works in progress 448B) to the gold-standard dark (DB) and bright (BB) blood T2*, acquired on an Avanto 1.5T (Siemens Healthcare, Erlangen, Germany). For both T2* sequences, a single 10mm mid-ventricular short axis slice was imaged at 8 echo-times (2.58ms to 18.19ms, increment 2.23ms), flip angle=20¡, FOV read/phase=400mm/56,3%. The same slice was used for T1 images (thickness 6mm, distance factor=67%, FOV read/phase=360/75%, TR=740, TE=1.13, with motion correction for the in-line map generation). Results and discussion.All participants provided informed consent. Table1 illustrates patients' and HV's details. T2* was defined normal under the cutpoint value of 20ms. T1 normal range, defined by the HV cohort was 918-1015ms (the 2.5-97.5 quantiles with CI 95%). For DBT2*<20ms, both BBT2* and T1 mapping were broadly indistinguishable from DBT2* (DBT2* vs BBT2* R2=0.95; DBT2* vs T1 R2=0.92; all p<0.001). All subjects with low DBT2* (n=24, 17.4%) had low T1; 52 patients had normal DBT2* but low T1 mapping, i.e. 38% patients were reclassified from normal to iron loaded by T1. The relationship between DBT2* and MOLLI was described by a log-log linear regression (R2=0.80, p<0.001). Upper panel of Fig1 shows T1 vs DBT2* correlation over a 20ms window as the window moves by 1ms at a time on X-axis (so at X-axis point 'n', the Y-value is the R2 of the correlation of DBT2* vs T1 over the range n-to-n+20ms). As shown by lower panel of Fig1, three domains can be observed: strong relationship in the T2*=0-20ms range (R2=0.92, p<0.001); good relationship in the 21-28ms range, where the curve depicts a plateau (R2=0.80-0.77, p<0.001) and no relationship above 28ms. Given the conservative approach used to set T2* normality as above 20ms (Carpenter JP, Circ 2011;14:1519-28), the evidence that T2* SD values increase even for borderline T2* mean values (~20ms) (Anderson LJ, Eur Heart J. 2001;22:2171-9), and that 39% of normal T2* subjects have a low T1, we support prior suggestions that T1 is detecting mild iron in most of the subjects with DBT2*=20-28ms, missed by T2* as the threshold has had to be set too low for sensitivity reasons (Sado DM, J Magn Reson Imaging. 2015;41:1505-11). T1 mapping is thus a useful complementary tool to T2* both for clinical and research purposes. The reported reproducibilities of T1 square for power calculations and would translate into 6.25 to 49 times more power in studies to detect iron change (Alam MH, J Cardiovasc Magn Reson. 2015;24:17-102). Colour maps make iron instantly visible and add a confirmation step. Whether mild iron missed by T2* is important is unclear. In our cohort, 24-months follow-up was available for 9 patients with normal DBT2* and low T1. Although no statistical consideration is possible due to the small number, in those patients an increase in LV end diastolic volume was observed (from 78±18ml to 84±15ml), suggesting possible cardiotoxicity of even mild amount of iron. Further work is needed, especially in frail cohorts like children starting chelation and around pregnancy. Table 1 Table 1. Figure 1 Figure 1. Disclosures Moon: gsk: Consultancy; Genzyme: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees. Cappellini:Novartis: Membership on an entity's Board of Directors or advisory committees; Genzyme-Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

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Investigating Zeta Globin Gene Expression to Develop a Potential Therapy for Alpha Thalassemia Major

Blood ◽

10.1182/blood-2020-142922 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 3-4

Author(s):

Georgia L. Gregory ◽

Beeke Wienert ◽

Marisa Schwab ◽

Billie Rachael Lianoglou ◽

Roger P. Hollis ◽

...

Keyword(s):

Board Of Directors ◽

Globin Gene ◽

Thalassemia Major ◽

Beta Thalassemia ◽

Beta Globin ◽

Wild Type ◽

Advisory Committees ◽

Alpha Thalassemia ◽

Alpha Globin ◽

Zeta Globin Gene

Introduction: Alpha globin mutations are very common worldwide, and the severity of resulting anemia depends on the number and type of mutated alleles. While the 4 gene mutation (alpha thalassemia major, ATM) was previously deemed fatal except in rare cases, emerging evidence indicates that survival to birth and good postnatal outcomes are possible with in utero transfusions. We hypothesized that the embryonic zeta globin gene, which is expressed early in gestation prior to alpha globin, may compensate for the lack of alpha globin and that induction of zeta globin after it has naturally been silenced may become a new therapy for patients with ATM. Methods: We evaluated mutations in the UCSF international registry of patients with ATM to understand factors related to patient survival with and without in utero transfusions. We then engineered Human Umbilical Cord Derived Erythroid Progenitor Cells (HUDEP-2 cells) carrying the common SEA alpha globin deletion, in which zeta globin expression is preserved (H-SEA), as well as those on which the zeta globin genes were deleted (HBZ-/-) using CRISPR-Cas9. We evaluated the expression of alpha and zeta globins using qPCR, Western blot, and flow cytometry. We generated lentiviral vectors expressing zeta globin under the control of beta-globin promoters to examine changes in both zeta and alpha globin in a dynamic way. Results: None of the registry patients who survived to birth spontaneously (n=11) had a mutation that involves a concomitant deletion in zeta globin (such as the -FIL, -THAI, or -MEDII mutation), while alpha globin mutations extending into the zeta globin gene were found in 14 of 37 (38%) patients who were diagnosed prenatally, suggesting that the presence of zeta globin may play a role in the ability to survive to birth without fetal therapy. Interestingly, we found that H-SEA clones express higher levels of zeta globin than WT cells, as illustrated by quantitative real-time PCR (Fig 1A), Western blot (Fig 1B) and flow cytometry (Fig 1C). These cells also developed beta globin dimers due to excess unpaired beta-globin chains, as demonstrated by Western blotting with and without reducing agents, indicating that they are an appropriate cell model for ATM. We next generated HUDEP-2 clones lacking zeta globin (HBZ KO) and transduced these clones with lentiviral vectors expressing high levels of zeta globin (lenti-zeta) (Fig 1D). Western blotting revealed that increasing the levels of zeta globin in these cells resulted in decreased expression of alpha globin, suggesting reciprocal control between these genes (Fig 1E). Most importantly, we saw a reduction in toxic beta-globin dimers in H-SEA cells expressing high levels of zeta-globin after transduction with lenti-zeta, suggesting that zeta globin could functionally replace the missing alpha-globin (Fig 1 F,G). To understand transcriptomic differences in H-SEA cells that may result in increased zeta globin expression, we performed bulk RNA sequencing of wild type and H-SEA clones. We confirmed that zeta expression is significantly upregulated in H-SEA compared to wild type (log2 fold change of 4.25, p=2.24E-38). Pathway analysis of differentially expressed genes is ongoing. Conclusions: Our international patient registry suggests that expression of zeta globin may play a role in the spontaneous survival to birth in a subset of patients. Zeta globin expression is increased in the setting of H-SEA cells in vitro, and restoration of zeta expression by lentivirus results in a reduction of toxic beta globin dimers in these ATM cells. Furthermore, expressing zeta globin at high levels in H-WT cells decreased alpha globin expression, suggesting a reciprocal regulation of these two genes. This concept is similar to the relationship between fetal gamma and adult beta globins which has been exploited for therapeutic editing approaches in patients with beta-thalassemia. At this point, the natural repressor of zeta globin is not yet known, but our data suggests that a strategy of upregulating zeta globin could potentially be developed to mimic the ongoing trials of using the BCL11A repressor to induce gamma globin in patients with beta thalassemia and sickle cell disease. Disclosures Wienert: Integral Medicines: Current Employment. Kohn:Allogene Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orchard Therapeutics: Consultancy, Patents & Royalties, Research Funding. MacKenzie:Acrigen: Membership on an entity's Board of Directors or advisory committees; Ultragenyx: Research Funding.

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What Predicts Adrenal Insufficiency in Patients with Thalassemia Major?

Blood ◽

10.1182/blood.v118.21.5299.5299 ◽

2011 ◽

Vol 118 (21) ◽

pp. 5299-5299

Author(s):

Karen E Huang ◽

Steven D Mittelman ◽

Thomas D. Coates ◽

Mitchell Geffner ◽

John C Wood

Keyword(s):

Iron Overload ◽

Adrenal Insufficiency ◽

Board Of Directors ◽

Cortisol Level ◽

Research Funding ◽

Thalassemia Major ◽

Stimulation Test ◽

Glucagon Stimulation Test ◽

Advisory Committees ◽

Research Contract

Abstract Abstract 5299 Background: Thalassemia is one of the most common genetic blood disorders worldwide. With recent improvements in medical therapy, patients with transfusion-dependent thalassemia, i.e., thalassemia major, are living longer. As a result, there is a greater need to address endocrine complications related to chronic iron overload. Adrenal insufficiency (AI), in particular, is important to identify because therapies are available and can be life-saving. Objectives: The objectives of this study are to determine the prevalence of AI in our population of subjects with thalassemia major; to identify risk factors that predict AI in these individuals; and to localize the origin of the AI within the hypothalamic-pituitary-adrenal (HPA) axis. Methods: This is a prospective study of individuals with thalassemia major with an enrollment goal of 30 subjects. All subjects enrolled were initially tested for AI using a glucagon stimulation test. Those found to have AI (stimulated cortisol <18 mcg/dL) subsequently underwent an ovine corticotrophin-releasing hormone (oCRH) stimulation test for confirmatory purposes and to define the physiological basis for the AI. Results: Eleven subjects (8 - 29 years old, 6 female) have been enrolled to date. In our population of patients with TM, the prevalence of AI was 55%. There was no correlation between age, number of years transfused, or ferritin levels and AI. All male patients failed the glucagon stimulation test, whereas 5 of 6 females passed the glucagon stimulation test, p = 0.0024. There was no correlation between 8 AM ACTH levels and 8 AM cortisol levels. There was a significant correlation (p = 0.025) between 8 AM cortisol level and peak cortisol level following glucagon stimulation testing. Of the six subjects with AI, two subjects subsequently failed the oCRH stimulation test (peak cortisol < 21.9 mcg/dL). In these two subjects, peak oCRH ACTH levels were elevated, 144 and 164 pg/mL, respectively, suggesting primary adrenal insufficiency. Conclusions: We conclude that 8 AM cortisol level is a good predictor of adrenal insufficiency in our population, and can potentially be used as a simple screening test for AI with a strong negative predictive value. There appears to be a male predominance of AI in our population. This may indicate a protective role of female sex in this population. Two subjects had classic primary AI with robust ACTH levels in the face of inadequate cortisol production following oCRH testing. Four subjects (all males) who failed the glucagon stimulation test subsequently demonstrated normal ACTH and cortisol response to oCRH, indicating a possible hypothalamic origin to their AI. This dysfunction is likely independent of iron overload and warrants further investigation. Alternatively, these subjects may have impaired sympathetic nervous system function leading to hypoglycemic unawareness. Both outcomes are novel to the field and of medical significance. Disclosures: Geffner: Daiichi- Sankyo: Steering Committee for Clinical Trial; Eli Lilly, Inc.: Research Contract; Endo Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Genentech, Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ipsen: Data Safety Monitoring Board and Research Contract; Novo Nordisk: Research Funding; Pfizer, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Iron Overload Is Highly Prevalent in All Disease Severity States in Pyruvate Kinase Deficiency (PKD)

Blood ◽

10.1182/blood.v128.22.2430.2430 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2430-2430

Author(s):

Eduard J van Beers ◽

Wilma Barcellini ◽

Stefan W. Eber ◽

Janet L Kwiatkowski ◽

Jennifer A Rothman ◽

...

Keyword(s):

Iron Overload ◽

Board Of Directors ◽

Disease Severity ◽

Research Funding ◽

Chelation Therapy ◽

Iron Status ◽

Compound Heterozygous ◽

Advisory Committees ◽

Cardiac Iron ◽

Significant Difference

Abstract Background: PKD causes a defect in glycolysis resulting in a hereditary non-spherocytic hemolytic anemia. The prevalence of iron overload is not well described for PKD. Aim: We aim to describe the demographic features and prevalence of iron overload in transfusion dependent and transfusion independent patients with PKD. Methods: Between March 2014 and April 2016, 203 patients enrolled on the PKD Natural History Study at 29 IRB approved sites. All patients were confirmed to have two compound heterozygous or homozygous mutations in the PKLR gene. Children < 1 year of age (n=9) were excluded from this analysis, because elevated ferritin levels are less reliably related to iron overload. Patients were designated with iron overload at the time of enrollment if the plasma ferritin was >1000 ng/mL or the patient was on chelation therapy at any time during the prior 12 months. Patients were designated with having had iron overload if a MRI ever showed liver iron content (LIC) >3 mg/g dry weight or if they had ever received chelation therapy. Tests of association were performed using Fisher's exact test (categorical) and Wilcoxon rank sum test (continuous). Linear associations between variables were measured by Pearson correlation coefficient. P-values <0.05 were considered statistically significant. Results: Of the 194 patients, 111 (57%) were adults ≥18 years and 83 (43%) were children. The median age of enrollment was 20.6 y (range: 1.3-69.9). Splenectomy had been performed in 65% (126/194). Screening ferritin levels were available for 72% (140/194) and LIC for 32% (62/194). At enrollment, 48% (70/147) had iron overload as defined by ferritin and/or current chelation. Using the LIC criterion, iron overload had been present at some point in 86% (95/110) of patients. Ferritin positively correlated with LIC (n=45); r=0.62, p<0.0001. However, of 29 patients with an LIC measurement and a mean ferritin <1000 ng/mL, 15 (52%) had a LIC >3 mg/g DW. Baseline characteristics in patients with and without iron overload are shown in the Table. Notably, even in patients that were never regularly transfused and had a hemoglobin (Hb) >8.7 g/dl, the prevalence of iron overload was 26% (8/31). The frequency of iron overload was significantly higher in patients who had a prior splenectomy (p<0.0001), even after controlling for transfusion history (p<0.0001). Age was associated with iron overload (p=0.046); although, the age range of patients with iron overload was broad (1.3-69.9 years). The frequency of iron overload was significantly higher in those with a lower baselineHb(p=0.004) and higher bilirubin (p=0.03). Data on cardiac iron status was available for 66 patients.Only 2 had cardiac iron overload (defined as T2*<20ms); they were age 5 (T2* 17.8ms, LIC 5 mg/g) and 22 years (T2* 19.7ms, LIC 14 mg/g) at the time of the MRI. Of the 194 patients, 52 (27%) were from the Pennsylvania Amish community. These patients were managed differently than the non-Amish, in that only 2% of the Amish patients were on iron chelation therapy in the 12 months prior to enrollment compared with 43% among the non-Amish cohort. In addition, the Amish had a significant higher prevalence of splenectomy (96% vs 52%, p<0.0001) and proportion who had been historically transfused (79% vs 32%, p<0.0001). Despite these differences, the Amish patients had a lower prevalence of iron overload (34% vs. 51%). There was no significant difference inHbor enrollment age between the Amish and non-Amish cohorts. Conclusion: Iron overload is a common, serious complication in PKD, regardless of age, disease severity, or transfusion status. Although ferritin correlates with LIC for the PKD population overall, at the individual patient level, ferritin is not a good predictor of LIC and a ferritin <1000 ng/ml does not exclude hepatic iron overload. Therefore, we recommend that all patients with PKD starting at age 1 year should be screened annually for iron overload using ferritin and, at least once, using MRI. Disclosures Barcellini: Agios: Consultancy. Neufeld:Novartis: Consultancy. Morton:Agios Pharmaceuticals: Research Funding. Yaish:Octapharma: Other: Study investigator. Kuo:Agios Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Apotex: Other: unrestricted educational grant; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Thompson:bluebird bio: Consultancy, Research Funding; Eli Lily: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mast: Research Funding; Baxalta (now part of Shire): Research Funding; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Amgen: Research Funding. Grace:Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Prospective Changes of Pancreatic Iron in Thalassemia Major

Blood ◽

10.1182/blood-2021-144590 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3084-3084

Author(s):

Alessia Pepe ◽

Laura Pistoia ◽

Crocetta Argento ◽

Luciana Rigoli ◽

Monica Benni ◽

...

Keyword(s):

Iron Overload ◽

Board Of Directors ◽

Serum Ferritin ◽

Iron Concentration ◽

Pancreatic Head ◽

Thalassemia Major ◽

Common Finding ◽

Inverse Association ◽

Advisory Committees ◽

Baseline Serum

Abstract Introduction. Pancreatic iron deposition is a common finding in thalassemia major, being detected in more than one third of patients undergoing their first T2* Magnetic Resonance Imaging scan (MRI) for this purpose. However, no longitudinal studies on pancreatic iron are available in literature. Aim: The aim of this multicenter study was to evaluate the changes in pancreatic iron overload in TM patients enrolled in the Extension-Myocardial Iron Overload in Thalassemia (E-MIOT) Network who performed a baseline and a follow-up (FU) MRI scan at 18 months. Methods. We considered 416 TM patients (37.77±10.46 years; 220 females) consecutively enrolled. Iron overload was quantified by the T2* technique. T2* measurements were performed over pancreatic head, body and tail and global value was the mean. Results. Pancreatic iron overload (global pancreas T2*<26 ms) was detected in 367 (88.2%) patients. Of them, only 14 (3.8%) improved at the FU. Out of the 49 (11.8%) patients without baseline pancreatic iron overload, 15 (30.6%) showed pancreatic iron overload at the FU MRI. A significant inverse association was detected between % change in global pancreas T2*and baseline global pancreas T2* values (R=-0.369; P<0.0001). Patients with baseline pancreatic iron overload showed significantly higher % changes in global pancreas T2* values (see Figure). Changes (%) in global pancreas T2* were not associated with baseline serum ferritin levels or MRI liver iron concentration (LIC) values but were inversely correlated with % changes in serum ferritin levels (R=-0.199; P<0.0001) and % changes in MRI LIC values (R=-0.255; P<0.0001). A significant positive association was found between % changes in global pancreas and global heart T2* values (R=0.133; P=0.007). At baseline MRI, 169 patients showed an alteration of glucidic metabolism: 32 had impaired fasting glucose, 65 impaired glucose tolerance, and 72 diabetes mellitus. These patients showed significantly higher % changes in global pancreas T2* than patients with a normal glucidic metabolism (33.06±79.48% vs 11.93±59.47%; P=0.003). Conclusions. Our data showed that it is difficult to remove the iron from the pancreas and higher improvements were detected in more heavily loaded patients, with alterations of glucidic metabolism. The reduction in pancreatic iron was paralleled by a decrease in hepatic and cardiac iron. Figure 1 Figure 1. Disclosures Pepe: Bayer S.p.A.: Other: no profit support; Chiesi Farmaceutici S.p.A: Other: no profit support. Maggio: Bluebird Bio: Membership on an entity's Board of Directors or advisory committees; Celgene Corp: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

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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).

Blood ◽

10.1182/blood.v120.21.2124.2124 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2124-2124 ◽

Cited By ~ 2

Author(s):

Dudley J Pennell ◽

John B Porter ◽

Antonio Piga ◽

Yongrong Lai ◽

Amal El-Beshlawy ◽

...

Keyword(s):

Iron Overload ◽

Board Of Directors ◽

Lower Limit ◽

Research Funding ◽

Thalassemia Major ◽

Iron Removal ◽

Efficacy And Safety ◽

Advisory Committees ◽

Cardiac Iron ◽

Randomized Controlled

Abstract 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 <10 ms). There are few randomized controlled trials assessing ICT for cardiac iron removal. CORDELIA is a Phase II, multinational, randomized comparison of efficacy and safety of 1-yr treatment with deferasirox or deferoxamine (DFO). Primary objective was non-inferiority of deferasirox vs DFO for cardiac iron removal after 1 yr. 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 <7 mg Fe/g dw, increase in cardiac T2* was 30% for deferasirox (n=11) and 10% for DFO (n=8), for BL LIC 7–<15 mg Fe/g dw increase was 19% (n=14) for deferasirox and 13% (n=14) for DFO, and in patients with BL LIC ≥15 mg Fe/g dw increase was 9% (n=66) and 5% (n=59), respectively. 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 <15 mg Fe/g dw. The frequency of AEs was similar between treatment groups and the deferasirox safety profile was comparable to previous reports. Disclosures: Pennell: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; 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; CVIS: Equity Ownership. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Piga:Novartis: Membership on an entity's 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.

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Changes in CMR Parameters and Prediction of Cardiac Complications in Thalassemia Major: Fibrosis Tells Us More Than Iron

Blood ◽

10.1182/blood-2021-144584 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2014-2014

Author(s):

Alessia Pepe ◽

Laura Pistoia ◽

Pietro Giuliano ◽

Nicola Giunta ◽

Rosamaria Rosso ◽

...

Keyword(s):

Iron Overload ◽

Board Of Directors ◽

Myocardial Fibrosis ◽

Thalassemia Major ◽

Cardiac Complications ◽

Myocardial Iron ◽

Advisory Committees ◽

Risk Class ◽

Cox Regression Analysis

Abstract Introduction. Cardiovascular magnetic Resonance (CMR) has dramatically changed the clinical practice and improved the prognosis in thalassemia major (TM). This is the first study evaluating the predictive value of changes in CMR parameters (myocardial iron, function, and fibrosis) for cardiac complications in TM. Methods. We followed prospectively 709 TM patients (374 females; 29.77±8.53 years) consecutively enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) Network who performed a baseline and a 1 st follow up CMR scan after 18 months. Myocardial iron overload (MIO) was measured by multislice multiecho T2* technique and atrial dimensions and biventricular function by cine images. Macroscopic myocardial fibrosis was detected by late gadolinium enhancement technique. Risk classes were defined based on the 4 patterns of MIO from worst to normal. For patients with baseline MIO (at least one segmental T2*<20 ms), improvement was defined as a transition to a better risk class, stabilization as no change in risk class, and worsening as a transition to a worse risk class. For patients without baseline MIO, the worsening was the transition to a worse risk class. The percentage change was used for continuous variables. For biventricular ejection fractions, improvement was a %change>10%, stabilization a %change between -10% and 10%, and worsening a %change<-10%. For biventricular volumes, LV mass index, and atrial areas, improvement was a % change<-10%, stabilization a % change between -10% and 10%, and worsening a % change>10%. Myocardial fibrosis was considered absent if not detected in any of the two CMRs and present if detected in at least one examination . Results. During a mean follow-up of 89.4±33.3 months, cardiac events were recorded in 50 (7.1%) patients: 24 (48%) episodes of heart failure, 24 (48%) arrhythmias (23 supraventricular and 1 hypokinetic), and 2 (4.0%) pulmonary hypertension. Mean time from the 1 st follow up CMR to the development of a cardiac complication was 75.31±35.35 months. In the univariate Cox regression analysis, cardiac iron cleareance and myocardial fibrosis were identified as univariate prognosticators (Table 1). In the multivariate analysis only myocardial fibrosis remained an independent predictor factor. Conclusion. The presence of myocardial fibrosis at the baseline CMR or developed within 18 months emerges as the strongest long-term predictor for cardiac complications in TM. Our data demonstrate the importance in using the contrast medium for CMR scans in thalassemia patients. Figure 1 Figure 1. Disclosures Pepe: Bayer S.p.A.: Other: no profit support; Chiesi Farmaceutici S.p.A: Other: no profit support. Maggio: Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corp: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees.

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