A MRI Prospective Survey on Heart and Liver Iron and Cardiac Function in Thalassemia Major Patients Treated with Deferasirox Versus Deferiprone and Desferrioxamine in Monotherapy

Abstract Background: No prospective data are available about the efficacy of deferasirox versus deferiprone and desferrioxamine in monotherapy. Our study aimed to prospectively assess the efficacy of deferasirox versus deferiprone and desferrioxamine in monotherapy in a large cohort of thalassemia major (TM) patients by quantitative Magnetic Resonance (MR). Methods: Among the 2551 TM patients enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) network we selected those with an MR follow up study at 18±3 months who had been received one chelator alone between the 2 MR scans. We identified three groups of patients: 235 treated with DFX, 142 with DFP and 162 with DFO. Iron overload was measured by T2* multiecho technique. Liver T2* values were converted into liver iron concentration (LIC) values. Biventricular function parameters were quantitatively evaluated by cine images. Results: Excellent/good levels of compliance were similar in the DFX (98.7%) vs DFP (96.3%) and DFO (97.5%) groups. Among the patients with myocardial iron overload at baseline, in all three groups there was a significant improvement in the global heart T2* value (DFX: +4.58±5.91ms P<0.0001, DFP: 8.53±6.97ms P<0.0001 and DFO: +3.93±5.21 ms P<0.0001) and a reduction in the number of pathological segments (DFX: -4.49±4.55 P<0.0001, DFP: -8.08±5.5.84 ms P=0.001 and DFO: -3.65±3.81 ms P<0.0001). In DFP and in DFO groups there was a significant improvement in left ventricular ejection function (LVEF) (+4.86±6.99% P=0.044 and +3.87±7.48% P=0.004, respectively). Only in the DFP group there was a significant improvement in right ventricular ejection function (RVEF) (6.69±4.61% P=0.001). The improvement in the global heart T2* was significantly lower in the DFX versus the DFP group , but it was not significantly different in the DFX versus the DFO group (Figure 1). The improvement in the LVEF was significantly higher in both DFP and DFO groups than in the DFX group while the improvement in the RVEF was significantly higher in the DFP than in DFX group (Figure 2). Among the patients with hepatic iron at baseline (LIC≥3mg/g dw) the changes were not significantly different in DFX versus the other groups. Conclusions: Prospectively in a large clinical setting of TM patients, DFX monotherapy was significantly less effective than DFP in improving myocardial siderosis and biventricular function and it was significantly less effective than DFO in improving the LVEF. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Pepe: Chiesi Farmaceutici and ApoPharma Inc.: Other: Alessia Pepe is the PI of the MIOT project, that receives no profit support from Chiesi Farmaceutici S.p.A. and ApoPharma Inc..

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Prospective Survey on Heart and Liver Iron and Heart Function in Thalassemia Major Patients Treated with Sequential deferiprone–desferrioxamine Versus Deferiprone and Desferrioxamine in Monotherapy

Blood ◽

10.1182/blood.v118.21.5298.5298 ◽

2011 ◽

Vol 118 (21) ◽

pp. 5298-5298

Author(s):

Alessia Pepe ◽

Antonella Meloni ◽

Giuseppe Rossi ◽

Anna Spasiano ◽

Domenico Giuseppe D'Ascola ◽

...

Keyword(s):

Cardiac Function ◽

Iron Overload ◽

Heart Function ◽

Thalassemia Major ◽

Left Ventricular ◽

The Other ◽

Hepatic Iron ◽

Myocardial Iron ◽

Liver Iron ◽

Biventricular Function

Abstract Abstract 5298 Introduction: Magnetic Resonance (MR) is the unique non invasive suitable technique to evaluate quantitatively the changes in cardiac and hepatic iron and in cardiac function in thalassemia major (TM) patients under different chelation regimens. This study aimed to prospectively assess the efficacy of the sequential deferiprone–deferrioxamine (DFP-DFO) versus deferiprone (DFP) and deferrioxamine (DFO) in monotherapy in a large cohort of TM patients by quantitative MR. Methods: Among the first 1135 TM patients enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) network, 392 patients performed a MR follow up study at 18±3 months. We evaluated prospectively the 35 patients treated with DFP-DFO versus the 39 patients treated with DFP and the 74 patients treated with DFO between the 2 MR scans. Iron concentrations were measured by T2* multiecho technique. Biventricular function parameters were quantitatively evaluated by cine images. Results: Excellent/good levels of compliance were similar in the DFP-DFO (97.1%) versus DFP (94.9%) and DFO (95.9%) groups. No significant differences were found in the frequency of side effects in DFP-DFO (15.6%) versus DFP group (9.4%). The percentage of patients who maintained a normal global heart T2* value (≥20 ms) was comparable between DFP-DFO (96%) versus DFP (100%) and DFO (98.1%) groups. Among the patients with myocardial iron overload (MIO) at baseline (global heart T2*<20 ms), in all three groups there was a significant improvement in the global heart T2* value (DFO-DFP: P=0.004, DFP: P=0.015 and DFO: ms P=0.007) and a significant reduction in the number of pathological segments (DFO-DFP: P=0.026, DFP: P=0.012 and DFO: P=0.002). In DFO-DFP and DFP groups there was a significant increment in the left ventricular (LV) ejection fraction (EF) (P=0.035 and P=0.045, respectively) as well as in the right ventricular (RV) EF (P=0.017 and P=0.001, respectively). The improvement in the global heart T2* and in biventricular function were not significantly different in DFO-DFP compared to the other groups (Table 1). Among the patients with hepatic iron at baseline (T2*<9.2 ms), only in DFO group there was a significant improvement in the liver T2* value (2.0±3.5 ms P=0.010). Liver T2*changes were not significantly different in DFO-DFP versus the other groups. Conclusions: Prospectively we did not find significant differences on cardiac and hepatic iron or in cardiac function in TM patients treated with sequential DFP–DFO therapy versus the TM patients treated with DFO or DFP in monotherapy. Disclosures: Pepe: Novartis: Speakers Bureau; Apotex: Speakers Bureau; Chiesi: Speakers Bureau. Off Label Use: Association of two chelators commercially available in order to obtain a higher efficacy. Lai:Novartis: Honoraria, Research Funding.

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Comparison of Deferasirox, Deferiprone, and Desferrioxamine Effectiveness on Myocardial Iron Concentrations and Biventricular Function by Quantitative MR in Beta-Thalassemia Major

Blood ◽

10.1182/blood.v112.11.3872.3872 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3872-3872

Author(s):

Alessia Pepe ◽

Brunella Favilli ◽

Vincenzo Positano ◽

Paolo Cianciulli ◽

Anna Spasiano ◽

...

Keyword(s):

Iron Status ◽

Group Versus ◽

Thalassemia Major ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Beta Thalassemia ◽

Myocardial Iron ◽

Liver Iron ◽

Biventricular Function ◽

Iron Concentrations

Abstract Despite dramatic gains in life expectancy in the desferrioxamine era for thalassemia major patients, the leading cause of death for this young adult’s population remains iron-induced heart failure. For this reason, strategies to reduce heart disease by improving chelation regimens have the highest priority in this phase. These strategies include development of novel oral iron chelators to improve compliance. Oral deferipron was proved more effective than subcutaneous desferrioxamine in removing cardiac iron. The novel oral one-daily chelator deferasirox has been recently commercially available but its long-term efficacy on myocardial iron concentrations and cardiac function is unknown. Aim of this study was to compare in thalassemia major patients the effectiveness of deferasirox, deferipron, and desferrioxamine on myocardial and liver iron concentrations and bi-ventricular function by quantitative magnetic-resonance imaging (MRI). Among the 550 thalassemic subjects enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) network between September 2006 and September 2007, we selected patients receiving one chelator alone for longer than one year. MIOT is an Italian network of six MR sites where the cardiac and liver iron status is assessed by validated and homogeneous standard procedures. We identified three groups of patients: 24 treated with deferasirox, 42 treated with deferipron and 89 treated with desferrioxamine. The three groups were matched for gender, Hb pre-transfusion levels, age of starting chelation, and good compliance to the treatment. The deferasirox group was significantly younger (26±7 years) than the deferipron (32±9 years) and desferioxamine group (33±8 years) (P=0.0001) and showed significantly higher mean serum ferritin levels (2516±2106 ng/ml) than the deferipron (1493±1651 ng/ml) and the desferrioxamine group (987±915 ng/ml) (P=0.0001). Myocardial iron concentrations and distribution were measured by MRI T2* multislice multiecho technique. Biventricular function parameters were quantitatively evaluated by cine-dynamic MRI images. Liver iron concentrations were measured by MR T2* multiecho technique. Written informed consent was obtained from all subjects. The global heart T2* value was significantly higher in the deferipron group (34±11 ms) versus the deferasirox (21±12 ms) and the desferrioxamine group (27±11 ms) (P=0.0001), as showed in Figure A. The T2* in the mid ventricular septum was significantly higher in the deferipron (36 ± 12 ms) versus the deferasirox (20 ± 12 ms) and the desferrioxamine group (28 ± 13 ms) (P = 0.0001). The number of segments with normal T2* value was significantly higher in the deferipron and the desferrioxamine group versus the deferasirox group (14 ± 2 versus 11 ± 6 versus 7 ± 7 segments; P = 0.0001). Among the biventricular function parameters, we found higher left ventricular ejection fractions in the deferipron and the desferrioxamine group versus the deferasirox group (64 ± 7 versus 62 ± 6 versus 58 ± 7 %; P = 0.005), as showed in Figure B. Liver T2* values were significantly higher in the desferrioxamine group versus the deferipron and the deferasirox group (10 ± 9 versus 6 ± 6 versus 5 ± 5 segments; P = 0.002). In conclusion, Oral deferipron seems to be more effective than oral deferasirox and subcutaneous desferrioxamine in removal of myocardial iron with concordant positive effect on left global systolic function. Figure Figure

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The effect of deferasirox on cardiac iron in thalassemia major: impact of total body iron stores

Blood ◽

10.1182/blood-2009-11-250308 ◽

2010 ◽

Vol 116 (4) ◽

pp. 537-543 ◽

Cited By ~ 84

Author(s):

John C. Wood ◽

Barinder P. Kang ◽

Alexis Thompson ◽

Patricia Giardina ◽

Paul Harmatz ◽

...

Keyword(s):

Left Ventricular Ejection Fraction ◽

Ejection Fraction ◽

Iron Concentration ◽

Left Ventricular ◽

Ventricular Ejection ◽

Left Ventricular Ejection ◽

Liver Iron ◽

Ventricular Ejection Fraction ◽

Iron Stores ◽

Cardiac Iron

AbstractWe present results from a prospective, multicenter, open-label, single-arm study evaluating response of cardiac and liver iron to deferasirox therapy for 18 months. Twenty-eight patients with abnormal T2* and normal left ventricular ejection fraction were enrolled from 4 US centers. All patients initially received deferasirox doses of 30 to 40 mg/kg per day. Patients were severely iron overloaded: mean liver iron concentration (LIC) 20.3 mg Fe/g dry weight, serum ferritin 4417 ng/mL, and cardiac T2* 8.6 ms. In the intent-to-treat population, 48% reached the primary endpoint (cardiac T2* improvement at 18 months, P = not significant). There were 2 deaths: 1 from congestive heart failure and 1 from sepsis. In the 22 patients completing the trial, LIC and cardiac T2* improvements were 16% (P = .06) and 14% (P = .07), respectively. Cardiac T2* improvement (13 patients) was predicted by initial LIC, final LIC, and percentage LIC change, but not initial cardiac T2*. Cardiac iron improved 24% in patients having LIC in the lower 2 quartiles and worsened 8.7% in patients having LIC in the upper 2 quartiles. Left ventricular ejection fraction was unchanged at all time points. Monotherapy with deferasirox was effective in patients with mild to moderate iron stores but failed to remove cardiac iron in patients with severe hepatic iron burdens. This study was registered at www.clinicaltrials.gov as #NCT00447694.

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Efficacy of deferasirox in reducing and preventing cardiac iron overload in β-thalassemia

Blood ◽

10.1182/blood-2009-04-217455 ◽

2010 ◽

Vol 115 (12) ◽

pp. 2364-2371 ◽

Cited By ~ 119

Author(s):

Dudley J. Pennell ◽

John B. Porter ◽

Maria Domenica Cappellini ◽

Amal El-Beshlawy ◽

Lee Lee Chan ◽

...

Keyword(s):

Iron Overload ◽

Iron Reduction ◽

Geometric Mean ◽

Iron Concentration ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Liver Iron ◽

Ventricular Ejection Fraction ◽

Cardiac Iron ◽

Cardiac Iron Overload

Cardiac iron overload causes most deaths in β-thalassemia major. The efficacy of deferasirox in reducing or preventing cardiac iron overload was assessed in 192 patients with β-thalassemia in a 1-year prospective, multicenter study. The cardiac iron reduction arm (n = 114) included patients with magnetic resonance myocardial T2* from 5 to 20 ms (indicating cardiac siderosis), left ventricular ejection fraction (LVEF) of 56% or more, serum ferritin more than 2500 ng/mL, liver iron concentration more than 10 mg Fe/g dry weight, and more than 50 transfused blood units. The prevention arm (n = 78) included otherwise eligible patients whose myocardial T2* was 20 ms or more. The primary end point was the change in myocardial T2* at 1 year. In the cardiac iron reduction arm, the mean deferasirox dose was 32.6 mg/kg per day. Myocardial T2* (geometric mean ± coefficient of variation) improved from a baseline of 11.2 ms (± 40.5%) to 12.9 ms (± 49.5%) (+16%; P < .001). LVEF (mean ± SD) was unchanged: 67.4 (± 5.7%) to 67.0 (± 6.0%) (−0.3%; P = .53). In the prevention arm, baseline myocardial T2* was unchanged from baseline of 32.0 ms (± 25.6%) to 32.5 ms (± 25.1%) (+2%; P = .57) and LVEF increased from baseline 67.7 (± 4.7%) to 69.6 (± 4.5%) (+1.8%; P < .001). This prospective study shows that deferasirox is effective in removing and preventing myocardial iron accumulation. This study is registered at http://clinicaltrials.gov as NCT00171821.

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Onset of Cardiac Iron Loading in a Large and Homogeneous Cohort of Thalassemia Major Paediatric Patients

Blood ◽

10.1182/blood.v118.21.2157.2157 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2157-2157

Author(s):

Alessia Pepe ◽

Antonella Meloni ◽

Brunella Favilli ◽

Marcello Capra ◽

Domenico Giuseppe D'Ascola ◽

...

Keyword(s):

Iron Overload ◽

Serum Ferritin ◽

Conflicts Of Interest ◽

Thalassemia Major ◽

Left Ventricular ◽

Myocardial Iron ◽

Cardiac Iron ◽

Paediatric Patients ◽

Biventricular Function ◽

Significant Difference

Abstract Abstract 2157 Introduction: Magnetic Resonance Imaging (MRI) by the T2* technique allows highly reproducible and non invasive quantifications of myocardial iron burden and it is the gold standard for quantifying biventricular function parameters. It is important to determine the appropriate age to start MRI screening, because its high cost. Few data are available in the literature and they are contrasting. So the aim of this study was to address this issue in our paediatric patients with thalassemia major (TM). Methods: We studied retrospectively 72 patients (47 males, 4.2–17.9 years old, mean age 13.03 ± 3.70 years), enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) network. Myocardial iron overload was measured by T2* multislice multiecho technique. Biventricular function parameters were quantitatively evaluated by cine images. Results: The global heart T2* value was 29.7 ± 11.2 ms (range 6.2 – 48.0 ms). No significant correlation was found between global heart T2* value and age (see figure). The global heart T2* value did not show significant differences according to the sex (male 30.2 ± 11.0 ms versus female 28.7 ± 11.8 ms, P=0.568). Sixteen patients (22%) showed an abnormal global heart T2* value (<20 ms) and none of them was under 8 years of age. Global heart T2* value was negatively correlated with mean serum ferritin levels. Odds Ratio for high serum ferritin levels (≥ 1500 ng/ml) was 8.4 (1.01–69.37, OR 95%CI) for abnormal global heart T2* values (< 20 ms). The global heart T2* value did not show a significant difference with respect to the chelation therapy (P=0.322). No significant correlations were found between the global heart T2* values and the bi-atrial areas or the LV and RV morphological and functional parameters. Eight patients showed a left ventricular (LV) ejection fraction (EF) < 57% and none of them was under 7 years of age. Two patients showed a right ventricular (RV) EF < 52% and none of them was under 14 years of age. Conclusion: The MRI screening for both cardiac iron overload and function assessment can be started for TM patients at the age of 7 years. At this age not sedation is generally needed. If the availability of cardiac MRI is low, the serum ferritin levels could be used as a discriminating factor. Disclosures: No relevant conflicts of interest to declare.

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A MRI Prospective Survey on Cardiac and Hepatic Iron and Cardiac Function in Thalassemia Major Patients Treated with Sequential deferiprone–desferrioxamine versus Deferasirox

Blood ◽

10.1182/blood.v118.21.1087.1087 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1087-1087

Author(s):

Alessia Pepe ◽

Antonella Meloni ◽

Giuseppe Rossi ◽

Domenico Giuseppe D'Ascola ◽

Marcello Capra ◽

...

Keyword(s):

Cardiac Function ◽

Iron Overload ◽

Right Ventricular ◽

Systolic Function ◽

Thalassemia Major ◽

Ventricular Ejection ◽

Hepatic Iron ◽

Myocardial Iron ◽

Liver Iron ◽

Cardiac Iron

Abstract Abstract 1087 Introduction: No data are available in literature about possible different changes in cardiac and hepatic iron and in cardiac function in thalassemia major (TM) patients treated with sequential deferipron–desferrioxamine (DFP-DFO) versus deferasirox (DFX). Magnetic Resonance (MR) is the unique non invasive suitable technique to evaluated quantitatively this issue.Our aim was to prospectively assess the efficacy of the DFP-DFO vs DFX in a large cohort of TM patients by quantitative MR. Methods: Among the first 1135 TM patients enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) network, 392 patients performed a MR follow up study at 18 ± 3 months according to the protocol. We evaluated prospectively 35 patients treated with DFP-DFO versus 80 patients treated with DFX between the 2 MR scans. Cardiac iron was evaluated by T2* multiecho multislice technique. Biventricular function parameters were quantitatively evaluated by cine images. Liver iron was measured by T2* multiecho technique. Results: Excellent/good levels of compliance were similar in the two groups (DFP-DFO 97.1% vs DFX 98.8%; P=0.544). Among the patients with no significant myocardial iron overload (MIO) at baseline (global heart T2*≥20 ms), there were no significant differences between groups to maintain the patients without myocardial iron overload (DFP-DFO 96% vs DFX 98%; P=0.536). Among the patients with MIO at baseline, in both groups there was a significant improvement in the global heart T2* value (DFP-DFO: 4.8±3.9 ms P=0.004 and DFX: 3.5±4.7 P=0.001) and a significant reduction in the number of pathological segments (DFP-DFO: −3.2±3.8 P=0.026 and DFX: −2.4±3.8 P=0.003). Only in sequential group there was a significant increment in the left and right ventricular ejection fractions (4.3±5.1% P=0.035 and 6.7±6.6% P=0.017, respectively). The improvement in the global heart T2* was not significantly different between groups. The improvement in the left as well in the right ventricular ejection fractions was significantly different between groups (P=0.009 and P=0.015, respectively) (Figure 1). Among the patients with hepatic iron at baseline (T2*<9.2 ms), only in the DFX group there was a significant improvement in the liver T2* value (2.6±5.3 ms P=0.001). The changes in liver T2* were significantly higher in DFX group than in DFP-DFO (0.5±2.0 ms) group (P=0.030) (Figure 2). Conclusions: In TM patients prospectively no significant differences on cardiac iron were found between sequential DFP–DFO treatment versus DFX in monoterapy, although the DFP-DFO treatment was significantly more effective in improving biventricular global systolic function. Conversely, DFX was significantly more effective in reducing hepatic siderosis. Disclosures: Pepe: Novartis: Speakers Bureau; Apotex: Speakers Bureau; Chiesi: Speakers Bureau. Off Label Use: Association of two chelators commercially available in order to obtain a higher efficacy. Borgna-Pignatti:Apotex: Honoraria; Novartis: Honoraria, Research Funding.

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Regional Myocardial Contractility In Thalassemia Major By Magnetic Resonance Tagging

Blood ◽

10.1182/blood.v122.21.4708.4708 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4708-4708

Author(s):

Antonella Meloni ◽

Chiara Tudisca ◽

Emanuele Grassedonio ◽

Giancarlo Izzi ◽

Maddalena Lendini ◽

...

Keyword(s):

Magnetic Resonance ◽

Iron Overload ◽

Myocardial Contractility ◽

Healthy Subjects ◽

Conflicts Of Interest ◽

Thalassemia Major ◽

Left Ventricular ◽

Myocardial Iron ◽

Cardiac Iron ◽

Biventricular Function

Introduction Magnetic resonance (MR) tagging analyzed by dedicated tracking algorithms allows very precise measurements of myocardial motion and characterization of regional myocardial function. No extensive data are available in literature. Our aim was to quantitatively assess for the regional myocardial contractility in thalassemia major (TM) patients and to correlate it with heart iron overload and global biventricular function. Methods Seventy-four TM patients (46 F; 31.8 ± 8.5 yrs) enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) network underwent MR (1.5T). Three short-axis (basal, medial and apical) tagged MR images were analyzed off-line using harmonic phase (HARP) methods (Diagnosoft software) and the circumferential shortening (Ecc) was evaluated for all the 16 myocardial segments. Four main circumferential regions (anterior, septal, inferior, and lateral) were defined. The same axes were acquired by a T2* GRE multiecho technique to assess myocardial iron overload (MIO). Biventricular function parameters were quantitatively evaluated by cine images. Results Segmental ECC values ranged from -9.66 ± 4.17 % (basal anteroseptal segment) to 13.36 ± 4.57 % (mid-anterior segment). No significant circumferential variability was detected. Compared with previous studied healthy subjects, TM patients showed strain values significantly lower in all the circumferential regions at each level (mean difference from 4 % to 13 %; P<0.001 for all the comparisons). Segmental Ecc values were not significantly correlated with the correspondent T2* values and no correlation was detected considering the global values, averaged over all segmental values. Three groups identified on the basis of cardiac iron distribution: no MIO, heterogenous MIO and homogeneous MIO. The global ECC was comparable among the three groups (-11.56 ± 1.60 % vs -11.70 ± 2.43 % vs -11.14 ± 1.95 %; P=0.602). Global ECC values were not significantly correlated with age and were comparable between the sexes. Circumferential shortening was not associated to left ventricular (LV) volumes and ejection fraction (with a P>0.5 in all the comparisons). Conclusions TM patients showed a significantly lower cardiac contractility compared with healthy subjects, but this altered contractility was not related to cardiac iron, volumes and function. Disclosures: No relevant conflicts of interest to declare.

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Prospective Comparison on Cardiac and Hepatic Iron and Cardiac Function by MR in Thalassemia Major Patients Treated with Combination Deferiprone–Desferrioxamine Versus Deferiprone and Desferrioxamine in Monoterapy,

Blood ◽

10.1182/blood.v118.21.3194.3194 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3194-3194

Author(s):

Alessia Pepe ◽

Antonella Meloni ◽

Pasquale Pepe ◽

Marcello Capra ◽

Domenico Giuseppe D'Ascola ◽

...

Keyword(s):

Iron Overload ◽

Left Ventricular ◽

Controlled Study ◽

Hepatic Iron ◽

Myocardial Iron ◽

Liver Iron ◽

Multi Centre Study ◽

Baseline Serum ◽

Cardiac Iron ◽

Biventricular Function

Abstract Abstract 3194 Introduction: Using T2* Magnetic Resonance (MR) a randomized placebo controlled study from Sardinia demonstrated combination therapy with deferiprone and desferrioxamine (DFP+DFO) significantly more effective than DFO in improving myocardial iron. One non-randomized study from Sardinia and one observational study from Greece seem to confirm for DFP+DFO therapy the most rapid clearance of cardiac iron. No data are available in literature about prospective comparisons on cardiac iron and function and liver iron in TM patients treated with DFP+DFO versus DFP and DFO in monotherapy. The aim of our multi-centre study was to assess prospectively in a large clinical setting the efficacy of the DFP+DFO versus DFP and DFO in TM patients by quantitative MR. Methods: Among the 1135 TM patients enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) network we selected those with an MR follow up study at 18±3 months who had been received one chelator alone between the 2 MR scans We evaluated prospectively the 51 patients treated with DFP+DFO versus the 39 patients treated with DFP and the 74 patients treated. Iron overload was measured by T2* multiecho technique. Biventricular function parameters were quantitatively evaluated by cine images. Results: The dosages were: combined therapy DFP 61.9±24.3 mg/kg per 6.1±1.4 days/week and DFO 40.7±6.0 per 3.5±1.1 days/week; DFP 73±13 mg/kg per 6.1±1.4 days/week; DFO 40.7±6.5 per 5.4±0.93 days/week. Excellent/good levels of compliance were comparable in the DFP+DFO (90.2%) versus DFP (94.9%) and DFO (95.9%) groups. The percentage of patients who maintained a normal global heart T2* value (≥20 ms) was comparable between DFP+DFO (96%) versus (100%) and DFO (98.1%) groups. Among the patients with myocardial iron overload at baseline (global heart T2*<20 ms), in all three groups there was a significant improvement in the global heart T2* values (combination: P=0.001; deferiprone: P=0.015 and desferrioxamine: P=0.007) and a significant reduction in the number of segments with an abnormal T2* value (combination: P=0.004; deferiprone: P=0.012 and desferrioxamine: P=0.002). Only in the deferiprone group there was a significant improvement in the left ventricular (LV) ejection fraction (EF) (P=0.045) while improvement in the right ventricular (RV) EF was significant in both combination (P=0.024) and deferiprone (P=0.001) groups. The changes in the global heart T2* as well as in biventricular function were not significantly different in DFO+DFP versus DFO or DFP groups (Table 1). After correction for influential covariates statistically different at baseline (global heart, age and HIC), the changes in global heart T2* values between the combination and the desferrioxamine groups became statistically different (P=0.014). Among the patients with hepatic iron at baseline (T2*<9.2 ms), the improvement in the liver T2* values was significant in the combination and in the desferrioxamine groups (combination: 4.9±6.0 ms P<0.0001; deferiprone: 2.1±4.8 ms P=0.070 and desferrioxamine: 2.0±3.5 ms P=0.010). The increase in liver T2* values was higher in combination versus deferiprone group, with a P-value near to the statistically significance (P=0.062); after covariates adjustment for the variable statistically different at baseline (serum ferritin) the significance was reached (P=0.043). The increase in liver T2* values was significant higher in combination than in desferrioxamine group (P=0.008), even after covariates adjustment. Conclusions: Prospectively in TM patients at the dosages used in the clinical practice combined DFP+DFO showed superior reduction in myocardial iron only versus the DFO in monotherapy and it did not show better improvement in biventricular function in comparison to DFO and DFP monotherapy. On the other hand, combined DFP+DFO was significantly more effective in the reduction of the liver iron versus DFO and DFP in monotherapy. Disclosures: Pepe: Novartis: Speakers Bureau; Apotex: Speakers Bureau; Chiesi: Speakers Bureau. Off Label Use: Association of two chelators commercially available in order to obtain a higher efficacy.

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Association Between Cardiac Iron Clereance and Hepatic Siderosis

Blood ◽

10.1182/blood.v128.22.4833.4833 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4833-4833

Author(s):

Alessia Pepe ◽

Laura Pistoia ◽

Domenico D'Ascola ◽

Maria Rita Gamberini ◽

Francesco Gagliardotto ◽

...

Keyword(s):

Iron Overload ◽

Iron Concentration ◽

Thalassemia Major ◽

Hepatic Iron ◽

Liver Iron Concentration ◽

Liver Iron ◽

Cardiac Iron ◽

Follow Up Study ◽

Hepatic Iron Overload

Abstract Introduction. The aim of this multicenter study was to evaluate in thalassemia major (TM) if the cardiac efficacy of the three iron chelators in monotherapy was influenced by hepatic iron levels over a follow up of 18 months. Methods. Among the 2551 TM patients enrolled in the MIOT (Myocardial Iron Overload in Thalassemia) network we evaluated prospectively the 98 patients those with an MR follow up study at 18±3 months who had been received one chelator alone between the 2 MR scans and who showed evidence of significant cardiac iron (global heart T2*<20 ms) at the basal MRI. Iron overload (IO) was measured by T2* multiecho technique. We used cardiac R2* (equal to 1000/T2*) because cardiac R2* is linearly proportional to cardiac iron and hepatic T2* values were converted into liver iron concentration (LIC) values. Results. We identified 3 groups of patients: 47 treated with deferasirox (DFX), 11 treated with deferiprone (DFP) and 40 treated with desferrioxamine (DFO). Percentage changes in cardiac R2* values correlated with changes in LIC in both DFX (R=0.469; P=0.001) and DFP (R=0.775; P=0.007) groups. All patients in these 2 groups who lowered their LIC by more than 50% improved their cardiac iron (see Figure 1). Percentage changes in cardiac R2* were linearly associated to the log of final LIC values in both DFX (R=0.437; P=0.002) and DFP groups (R=0.909; P<0.0001). Percentage changes in cardiac R2* were not predicted by initial cardiac R2* and LIC values. In each chelation group patients were divided in subgroups according to the severity of baseline hepatic iron overload (no, mild, moderate, and severe IO). The changes in cardiac R2* were comparable among subgroups (P=NS) (Figure 2). Conclusion. In patients treated with DFX and DFP percentage changes in cardiac R2* over 18 months were associated with final LIC and percentage LIC changes. In each chelation group percentage changes in cardiac R2* were no influenced by initial LIC or initial cardiac R2*. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Pepe: Chiesi Farmaceutici and ApoPharma Inc.: Other: Alessia Pepe is the PI of the MIOT project, that receives no profit support from Chiesi Farmaceutici S.p.A. and ApoPharma Inc..

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The Importance of Cardiac T2* Magnetic Resonance Imaging for Monitoring Cardiac Siderosis in Thalassemia Major Patients

Tomography ◽

10.3390/tomography7020012 ◽

2021 ◽

Vol 7 (2) ◽

pp. 130-138

Author(s):

Narumol Chaosuwannakit ◽

Pattarapong Makarawate ◽

Chinnadol Wanitpongpun

Keyword(s):

Left Ventricular Ejection Fraction ◽

Serum Ferritin ◽

Iron Concentration ◽

Thalassemia Major ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Liver Iron ◽

Ventricular Ejection Fraction ◽

Cardiac Siderosis ◽

T2 Mri

Objective: Cardiac T2* magnetic resonance imaging (MRI) has recently attracted considerable attention as a non-invasive method for detecting iron overload in various organs in thalassemia major patients. This study aimed to identify the prevalence of cardiac siderosis in thalassemia major patients and evaluate cardiac T2* MRI for monitoring cardiac siderosis before and after patients receive iron chelation therapy and its relation to serum ferritin, left ventricular ejection fraction, and liver iron concentration. The information gathered would be used for the direct monitoring, detection, and treatment of complications early on. Methods: A total of 119 thalassemia major patients were recruited in the present study. The cardiac T2* MRI was compared to serum ferritin levels, liver iron concentration (LIC), and left ventricular ejection fraction. All patients were classified into four groups based on their cardiac siderosis as having normal, marginal, mild to moderate, or severe cardiac iron overload. At the follow-up at years one, three, and five, the cardiac T2* MRI, LIC, serum ferritin, and left ventricular ejection fraction (LVEF) were determined. Results: The prevalence of cardiac siderosis with cardiac T2* MRI ≤ 25 ms was 17.6% (n = 21). There was no correlation between cardiac T2* MRI and serum ferritin, liver iron concentration, and LVEF (p = 0.39, 0.54, and 0.09, respectively). During one year to five years’ follow-up periods, cardiac T2* MRI (ms) in patients with severe cardiac siderosis had significantly improved from 8.5 ± 1.49 at baseline to 33.9 ± 1.9 at five years (p < 0.0001). Patients with severe, mild-moderate, marginal, and no cardiac siderosis had median LIC (mg/g dw) of 23.9 ± 6.5, 21.6 ± 13.3, 25.3 ± 7.7, and 19.9 ± 5.5 at baseline, respectively. Conclusions: This study supports the use of cardiac T2* MRI to monitor cardiac iron overload in patients who have had multiple blood transfusions. Early diagnosis and treatment of patients at risk of cardiac siderosis is a reasonable method of reducing the substantial cardiac mortality burden associated with myocardial siderosis. Cardiac T2* MRI is the best test that can identify at-risk patients who can be managed with optimization of their chelation therapy.

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