Myocardial iron overload

2018 ◽  
pp. 364-374
Author(s):  
John P Carpenter ◽  
John C Wood ◽  
Dudley J Pennell
Keyword(s):  
Heart Failure ◽  
Iron Overload ◽  
Iron Concentration ◽  
Left Ventricular ◽  
Breath Hold ◽  
Liver Iron ◽  
Cardiac Iron ◽  
Single Breath ◽  
Developing Heart ◽  
Cost Efficient

The heart is the target lethal organ in thalassaemia major. Cardiovascular magnetic resonance (CMR) measures iron using the magnetic relaxation time T2*. This allows comparison with the left ventricular function and conventional iron measurements such as liver iron and serum ferritin. The single breath-hold cardiac-gated CMR acquisition takes only 15 seconds, making it cost-efficient and relevant to developing countries. Myocardial T2* of <20 ms (increased iron) correlates with reduced left ventricular ejection fraction, but poor correlation exists with ferritin and liver iron, indicating poor capability to assess future risk. Myocardial T2* of <10 ms is present in >90% of thalassaemia patients developing heart failure, and approximately 50% of patients with T2* of <6 ms will develop heart failure within 1 year without intensified treatment. The technique is validated and calibrated against human heart iron concentration. The treatment for iron overload is iron chelation, and three major trials have been performed for the heart. The first trial showed deferiprone was superior to deferoxamine in removing cardiac iron. The second trial showed a combination therapy of deferiprone with deferoxamine was more effective than deferoxamine monotherapy. The third trial showed that deferasirox was non-inferior to deferoxamine in removing cardiac iron. Each drug in suitable doses can be used to remove cardiac iron, but their use depends on clinical circumstances. Other combination regimes are also being evaluated. Use of T2*, intensification of chelation treatment, and use of deferiprone are associated with reduced mortality (a reduction in deaths by 71% has been shown in the United Kingdom). The use of T2* and iron chelators in the heart has been summarized in recent American Heart Association guidelines.

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

Blood ◽  
2010 ◽  
Vol 115 (12) ◽  
pp. 2364-2371 ◽  
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.

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

Blood ◽  
2010 ◽  
Vol 116 (4) ◽  
pp. 537-543 ◽  
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.

Randomized Controlled Trial of the Efficacy and Safety of Deferiprone in Iron-Overloaded Patients with Sickle Cell Disease or Other Anemias

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 618-618
Author(s):  
Janet L. Kwiatkowski ◽  
Mohsen Saleh Elalfy ◽  
Caroline Fradette ◽  
Mona Hamdy ◽  
Amal El-Beshlawy ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Iron Overload ◽  
Research Funding ◽  
Iron Concentration ◽  
Advisory Committees ◽  
Liver Iron ◽  
Cardiac Iron ◽  
Upper Limit ◽  
Iron Load ◽  
The Difference

Background: Patients with sickle cell disease (SCD) or other rare anemias whose care includes chronic blood transfusions must receive iron chelation to prevent the morbidity of iron overload. Currently, only deferoxamine (DFO) and deferasirox (DFX) are approved chelators in these patient populations. This randomized open-label trial evaluated if the efficacy of deferiprone (DFP) was non-inferior to DFO. DFO was used as the comparator product since DFX was not approved as first-line treatment for SCD at trial initiation. Methods: Participants at 27 sites in 8 countries were randomized in a 2:1 ratio to receive either DFP or DFO for up to 12 months. Those with lower transfusional iron input and/or less severe iron load were prescribed either DFP 25 mg/kg of body weight t.i.d. or DFO 20 mg/kg (children) or 40 mg/kg (adults); those with higher iron input and/or more severe iron load received either DFP 33 mg/kg t.i.d. or DFO up to 40 mg/kg (children) or 50 mg/kg (adults). Dosages could be adjusted over the course of the trial if necessary. Efficacy endpoints were the changes from baseline in liver iron concentration (LIC), cardiac iron, and serum ferritin (SF) at Month 12. The primary endpoint was based on LIC, and for the demonstration of non-inferiority of DFP to DFO, the upper limit of the 95% confidence interval for the difference between treatments had to be no more than 2 mg/g dry weight (dw). All patients had their neutrophil count monitored weekly, whereas other safety assessments and compliance with study therapy were evaluated monthly. Acceptable compliance was defined as taking 80% to 120% of the prescribed dosage. Results: A total of 228 of the targeted 300 patients were dosed with 152 receiving DFP and 76 receiving DFO, to assess non-inferiority. There were no significant differences between the groups in any demographic measures: in each treatment group, 84% of patients had SCD and the remainder had other, rarer forms of transfusion-dependent anemia. Mean age at enrollment was 16.9 years (± 9.6); 53.1% of patients were male; and 77.2% were white, 16.2% black, and 6.6% multi-racial. Over the course of the study, 69% of patients in the DFP group and 79% in the DFO group had acceptable compliance with treatment. Based on the Pocock's α spending function, a more stringent confidence level of 96.01% was applied to the calculation of confidence interval for the evaluation of non-inferiority. For the primary efficacy endpoint, the least squares (LS) mean change in LIC (measured as mg/g dw) was -4.04 for DFP, -4.45 for DFO; the upper limit of the 96.01% confidence interval for the difference was 1.57, thereby demonstrating non-inferiority of DFP to DFO. The upper limit for the subpopulation of patients with SCD also met the non-inferiority criterion. For the secondary endpoints, the change in cardiac iron (measured as ms on MRI T2*, log-transformed) was approximately -0.02 for both; and for SF (measured as μg/L), it was -415 vs. -750 for DFP vs. DFO, respectively. The difference between the groups was not statistically significant for both endpoints. With respect to safety, there was no statistically significant difference between the groups in the overall rate of adverse events (AEs), treatment-related AEs, serious AEs, or withdrawals from the study due to AEs. Agranulocytosis was seen in 1 DFP patient vs. no DFO patients, while events of less severe episodes of neutropenia occurred in 4 vs. 1, respectively. All episodes of agranulocytosis and neutropenia resolved. There was no significant treatment group difference in the rates of any of the serious AEs. Conclusion: The efficacy of DFP for the treatment of iron overload in patients with SCD or other rare anemias is not inferior to that of DFO, as assessed by changes in liver iron concentration. non-inferiority was supported by the endpoints on cardiac iron load and SF. The safety profile of DFP was acceptable and was similar to that previously seen in thalassemia patients, and its use was not associated with unexpected serious adverse events. The results of this study support the use of DFP for the treatment of iron overload in patients with SCD or other rare transfusion-dependent anemias. Note: The authors listed here are presenting these findings on behalf of all investigators who participated in the study. Disclosures Kwiatkowski: Terumo: Research Funding; Imara: Consultancy; bluebird bio, Inc.: Consultancy, Research Funding; Agios: Consultancy; Novartis: Research Funding; Celgene: Consultancy; Apopharma: Research Funding. Fradette:ApoPharma: Employment. Kanter:Sangamo: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Imara: Consultancy; Guidepoint Global: Consultancy; GLG: Consultancy; Cowen: Consultancy; Jeffries: Consultancy; Medscape: Honoraria; Rockpointe: Honoraria; Peerview: Honoraria; SCDAA: Membership on an entity's Board of Directors or advisory committees; NHLBI: Membership on an entity's Board of Directors or advisory committees; bluebird bio, Inc.: Consultancy; Modus: Consultancy, Honoraria. Tsang:Apotex Inc.: Employment. Stilman:ApoPharma: Employment. Rozova:ApoPharma: Employment. Sinclair:ApoPharma: Employment. Shaw:ApoPharma: Employment. Chan:ApoPharma: Employment. Toiber Temin:ApoPharma: Employment. Lee:ApoPharma: Employment. Spino:ApoPharma: Employment. Tricta:ApoPharma: Employment. OffLabel Disclosure: Deferiprone is an oral iron chelator.

Multi-echo Dixon and breath-hold T2-corrected multi-echo single-voxel MRS for quantifying hepatic iron overload in rabbits

2021 ◽  
pp. 028418512110630
Author(s):  
Fanyu Zhao ◽  
Yidi Chen ◽  
Huiting Zhang ◽  
Chenhui Li ◽  
Liling Long
Keyword(s):  
Iron Overload ◽  
Fatty Liver ◽  
Iron Concentration ◽  
Liver Fat ◽  
Breath Hold ◽  
Proton Density ◽  
Hepatic Iron ◽  
Diagnostic Efficiency ◽  
Liver Iron ◽  
Single Voxel

Background Three-dimensional (3D) multi-echo-Dixon (ME-Dixon) and breath-hold T2-corrected multi-echo single-voxel MR spectroscopy (HISTO) can simultaneously quantify liver fat and liver iron. However, their diagnostic efficacy and application scope for quantitative iron in co-existing fatty liver have not been adequately evaluated. Purpose To evaluate the accuracy of ME-Dixon and HISTO for quantitative analysis of hepatic iron in rabbits with iron deposition and fatty liver using liver–iron concentration (LIC) as a reference standard. Material and Methods ME-Dixon, HISTO, and conventional two-dimensional multi-echo gradient echo (GRE) sequences were performed on 42 rabbits. The following parameters were calculated: R2* from ME-Dixon and GRE; proton density fat fraction (PDFF) from the ME-Dixon, HISTO (normal TE range), and HISTO-H (extended TE range); and R2_water from HISTO and HISTO-H. The LIC and liver–fat concentration (LFC) were measured through chemical analysis, and their relationship with the MRI parameters were assessed. Receiver operating characteristic (ROC) curves and the area under the curve (AUC) were used to evaluate the diagnostic efficiency. Results LIC was significantly correlated with R2_HISTO-H, R2*_Dixon, and R2*_GRE ( r = 0.858, 0.910, 0.931, respectively; P < 0.001) and weakly with R2_HISTO ( r = 0.424; P = 0.008). A strong correlation was also observed between the LFC and PDFF obtained from HISTO, HISTO-H, and ME-Dixon ( r = 0.776, 0.811, 0.888, respectively; P < 0.001). ME-Dixon showed the best performance with moderate iron overload (AUC = 0.983). Conclusion 3D ME-Dixon is useful for quantifying the LIC, especially with co-existing fatty liver. Its diagnostic performance is also superior to that of the HISTO sequence.

Clinical Relevance of Cardiac Iron Overload Estimated by MRI T2* in Regularly Transfused Low Risk MDS.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2666-2666 ◽  
Author(s):  
C. Ferte ◽  
O. Ernst ◽  
O. Beyne-Rauzy ◽  
M.P. Chaury ◽  
S. Brechignac ◽  
...  
Keyword(s):  
Iron Overload ◽  
Cardiac Mri ◽  
Iron Content ◽  
Clinical Signs ◽  
Left Ventricular ◽  
Low Risk ◽  
Liver Iron ◽  
Cardiac Iron ◽  
Cardiac Symptoms ◽  
Cardiac Iron Overload

Abstract Background: Cardiac iron overload is the first cause of mortality in thalassemia. In MDS, a causal relationship between cardiac iron overload and death is not as well established and heart complication may be of intricate origins in these elderly pts. Cardiac MRI T2* allows accurate measurement of heart iron and is influenced by iron content only (and not by other cardiac diseases). T2* value < 20ms is clearly associated with cardiac iron overload. A few reports (Winder et al ASH 2005, Chacko J BJH2006;133: supp1) showed no cardiac iron overload by T2* in small numbers of multitransfused MDS. We performed a similar analysis in our transfused low risk MDS pts. Methods: We prospectively evaluated by MRI both cardiac T2* according to Anderson (Eur Heart J 2001) and liver iron content (LIC ) according to Gandon (Lancet 2004) and cardiac function by echocardiography in multitransfused low risk MDS pts. Cardiac MRI T2* was also assessed in 33 controls. Results: 21 MDS were analyzed, 9M/12F. Median age: 75 years ( 50–83); FAB : RA= 3, RAS=13, RAEB = 3, CMML n=1, unclassified n=1. Karyotype: fav n= 1, Int n= 18, failure n=1. IPSS: low n= 10, Int I n= 10, unavailable n=1. Median interval from MDS diagnosis and first transfusion was 40 and 24 months respectively. At inclusion, median number of RBC units transfused was 81 (range 6–282, and greater than 100 in 8 pts). Median serum ferritin level was 2152 ng/ml and 11 patients were on chelation therapy (CT). 9/21 pts had cardiac symptoms and were on cardiac therapy. LVEF was below normal (55%) in 3/21 cases. Left ventricular telediastolic diameter LVTD was above normal (normal 53 mm) in 6/14 pts evaluated. Median LIC was 350 micromoles/g/dw (95–898 ). Median Cardiac T2* was 27 ms (8–74) and did not differ significantly from controls (T2*=27ms+/−6.4). No correlation was found between cardiac T2* and ferritin, LIC, LVEF, time from MDS diagnosis. However 3/21 pts had cardiac iron overload with T2* < 20 (18ms,15ms,8ms respectively). LVEF and number of RBC units transfused of these pts was respectively 69%,51%,33% and 119,150,282 RBC units. Two of them were on iron CT, one of them since 8 years. The last 2 pts had clinical signs of cardiac failure unexplained by other causes and both had increased LVTD. Conclusions: Although cardiac T2* did not differ significantly in transfused MDS and in controls, 3 heavily transfused (all in the 8 patients who had received >100 RBC units) had clear cardiac iron overload, clinically relevant in 2 of them and not correlated with higher liver iron overload. Differences between our study and previous studies could be due to the higher number of transfused RBC units in our pts with abnormal T2*, as compared to a median of 50 in the study of Winder, but further studies are required to confirm this finding.

Exjade® Reduces Cardiac Iron Burden in Chronically Transfused β-Thalassemia Patients: An MRI T2* Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2781-2781 ◽  
Author(s):  
J. Wood ◽  
A.A. Thompson ◽  
C. Paley ◽  
B. Kang ◽  
P. Giardina ◽  
...  
Keyword(s):  
Ejection Fraction ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Left Ventricular ◽  
Iron Removal ◽  
Left Ventricular Ejection ◽  
Liver Iron ◽  
Ventricular Ejection Fraction ◽  
Cardiac Iron ◽  
The Mean

Abstract Introduction: Despite the routine use of iron chelation therapy, cardiac iron overload results in cardiomyopathy, congestive heart failure and death in approximately 71% of pts with β-thalassemia. Recent MRI studies suggest that the kinetics of cardiac iron uptake and elimination differ from that of liver. Furthermore, different chelators appear to exhibit unique profiles of relative heart and liver iron removal. Deferasirox (DFX; Exjade®) is a once-daily oral iron chelator with demonstrated efficacy in reducing liver iron. In addition, preclinical and single-institution clinical studies have demonstrated cardiac iron removal. This study is a prospective, single-arm multi-institutional trial designed to evaluate the effect of DFX on cardiac iron in pts with β-thalassemia major. Here, we report preliminary results from the first 15 pts who completed 6 months of treatment. Methods: This ongoing study will enroll 30 pts at 4 US centers. DFX is administered at 30–40 mg/kg/day for 18 months. Entry criteria include MRI evidence of cardiac iron (T2* <20 ms) and normal left ventricular ejection fraction (LVEF ≥56%). Serum ferritin is assessed monthly and MRI assessments for liver iron concentration (LIC), cardiac T2* and LVEF are assessed every 6 months. Labile plasma iron (LPI), serum creatinine, biochemical and hematological status are being monitored. Results: At the time of this analysis, 15 of 17 pts had 6 months of evaluation; all were dosed at 30 mg/kg/day. One of the excluded pts was found ineligible (LVEF <56% at baseline) and the other developed cardiac failure prior to 6 months and was switched to continuous DFO (deferoxamine). This pt had markedly elevated cardiac iron (T2*=1.8 ms) at enrollment. All results are reported as mean±SEM (range) unless otherwise stated. Baseline: All 15 evaluable pts (3 male, 12 female; aged 10–43 years) received ≥150 lifetime transfusions. Ferritin was 4927±987 ng/mL (395–10751; n=12). Cardiac T2* was 9.8±1.13 ms (5.0–16.1), LIC was 16.6±4.27 mg/g dw (3.6–62.3) and ejection fraction was 61.2±1.83%. LPI was 0.72±0.28 μmol/L (n=11) and 33% of pts started with abnormal LPI (≥0.5 μmol/L). 6 Month results: At 6 months, the mean decrease in ferritin was 516 ng/mL; 14 of 15 (93%) pts had decreases in hepatic and cardiac iron. The mean reductions in cardiac and hepatic iron were 17.8% (P=0.0136) and 27.0% (P=0.0027), respectively (Figure). There was no change in LVEF by MRI. All patients had normal LPI at 6 months; for pts with abnormal LPI at baseline, the mean LPI dropped from 1.6±0.3 to 0.26±0.1 μmol/L (P=0.003). No pts developed creatinine >upper limit of normal. Four pts had abnormal transaminases on ≥2 occasions but all 4 were abnormal at baseline. Conclusions: The 30 mg/kg/day dose was well tolerated and led to negative cardiac and liver iron balance in 93% of pts. These results are encouraging given this heavily iron-overloaded and heavily transfused population of β-thalassemia pts. Ongoing assessments over 12 and 18 months will elucidate if DFX continues to improve cardiac iron burden and maintain/improve cardiac function in severely iron-overloaded pts. Figure Figure

Deferasirox (Exjade®) Monotherapy Significantly Reduces Cardiac Iron Burden in Chronically Transfused β-Thalassemia Patients: An MRI T2* Study

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3882-3882 ◽  
Author(s):  
John C Wood ◽  
Alexis A. Thompson ◽  
Carole Paley ◽  
Barinder Kang ◽  
Patricia Giardina ◽  
...  
Keyword(s):  
Iron Concentration ◽  
Safety Data ◽  
Left Ventricular ◽  
Mean Difference ◽  
Left Ventricular Ejection ◽  
Patient Death ◽  
Liver Iron ◽  
Ventricular Ejection Fraction ◽  
Cardiac Iron ◽  
Long Term Study

Abstract Introduction: Despite the availability of iron chelation therapy, accumulation of excess iron in the heart results in cardiomyopathy, congestive heart failure (CHF) and death in approximately 71% of transfused patients with β-thalassemia (β-thal) major. In preclinical and single-institution clinical studies, Exjade®(deferasirox, DFX) has demonstrated efficacy in decreasing cardiac iron. This ongoing study evaluates the effects of DFX on cardiac iron and left ventricular ejection fraction (LVEF) in patients (pts) with β-thal major in a prospective, single-arm, multi-center trial using cardiac MRI T2*. Here, we report preliminary results from patients who have completed 12 or 18 months of treatment. Methods: Twenty-eight pts were enrolled at four US centers. DFX was administered at 30–40 mg/kg/day for 18 months. Entry criteria included MRI evidence of cardiac iron (T2* <20 ms) and normal LVEF (≥56%). Serum ferritin (SF) was assessed monthly and MRI assessments for liver iron concentration (LIC), cardiac T2* and LVEF were done every 6 months. Serum creatinine (SCr), biochemical and hematological status were also monitored. All results are reported as mean±SE (range) unless otherwise stated. Results: At the time of analysis, 18 pts had 12-month evaluations and 12 pts had 18-month evaluations. Five pts discontinued (one non-compliance, two patient decisions, and two deaths). Both deaths were considered unrelated to DFX treatment; the first patient enrolled with markedly elevated baseline cardiac iron (T2*=1.8 ms) and died secondary to CHF. The second patient death was due to sepsis and multi-organ failure. Baseline: All 18 evaluable pts (three male, 15 female; aged 10–44 years) received ≥150 lifetime transfusions. SF was 4324±912 ng/mL (395–16,249). Cardiac T2* was 9.6±0.97 ms (4.6–16.1), LIC was 18.7±3.8 mg Fe/g dry weight (dw; 3.6–62.3) and LVEF was 61.7±1.0%. 12-Month results: At 12 months, 7/18 pts were on 40 mg/kg/day. 12/18 pts (67%) had an increase in cardiac T2* with a mean difference of 2.2 ms (18%; P=0.025). 13/18 pts (72%) had a decrease in LIC with a mean difference of 2.4 mg Fe/g dw (25%; P=0.032). LVEF remained stable. SF fell by 583 ng/mL (n=18; 22%; P=0.147). 18-Month results: At 18 months, 3/12 pts were on 40 mg/kg/day. 10/12 pts (83%) had an increase in cardiac T2* with a mean difference of 4.1 ms (35%; P=0.001). 11/12 pts (92%) had a decrease in LIC with a mean reduction of 4.7 mg Fe/g dw (50%; P=0.003). Mean LVEF trended upward from 61.5 to 63.3% (n=13; P=0.2). SF fell by 1373 ng/mL (n=11; 46%, P=0.006). Safety data from pts (n=25) treated with 30–40 mg DFX were in line with previous studies. The most common drug-related adverse events (AEs; eight pts; 32%) were gastrointestinal in nature. 1/25 patients experienced a suspected SAE (hospitalization due to abdominal pain and vomiting) but completed the study. One patient developed SCr >upper limit of normal (ULN). Two pts (8%) had abnormal transaminases (≥5×ULN) on ≥2 occasions but both had abnormal values at baseline. Conclusions: DFX monotherapy significantly improved cardiac and liver iron after 12 and 18 months. Overall, doses from 30–40 mg/kg/day were well tolerated. Cardiac T2* improvement rates were 1.5–1.9% per month, which is comparable to other monotherapy trials. A trend towards improved LVEF was seen in patients completing 18 months of therapy; however, a larger, long-term study will be required to confirm whether DFX can significantly improve cardiac function in this population. Figure Figure

Calibration of Improved T2* Method for the Estimation of Liver Iron Concentration in Transfusional Iron Overload.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2004-2004 ◽  
Author(s):  
Maciej W Garbowski ◽  
John-Paul Carpenter ◽  
Gillian Smith ◽  
Dudley J Pennell ◽  
John B Porter
Keyword(s):  
Liver Biopsy ◽  
Iron Concentration ◽  
Cardiovascular Imaging ◽  
Breath Hold ◽  
Liver Iron Concentration ◽  
Liver Iron ◽  
Single Breath ◽  
Single Breath Hold ◽  
Tissue Iron ◽  
The Relationship

Abstract Abstract 2004 Poster Board I-1026 Background and rationale Non-invasive estimation of tissue iron concentration is being used increasingly to follow responses to chelation therapy. Magnetic resonance (MR) T2* was originally developed to estimate myocardial iron but the first description of the myocardial T2* method also demonstrated a clear relationship between liver T2* and liver iron concentration (LIC) measured by biopsy (Anderson, Eur Heart J 2001). The inclusion of liver analysis at this time was intended mainly to show the relationship of T2* to tissue iron rather than as a standard method for LIC measurement, particularly as the echo times used were too long to measure the high iron levels commonly found in the liver. Since this work, other MR methods such as the R2 technique (St. Pierre, Blood 2004) have been specifically validated to measure LIC. However, if T2* could be validated and calibrated appropriately for LIC, it may be convenient to measure liver and heart iron at the same time using this rapid technique. Since the initial calibration of the T2* method, there have been major improvements in scanner technology and hardware. In the original paper, eight different echo times were acquired (TE 2.2- 20.1ms), each of which required a separate breath-hold with important implications for image registration regarding the measurement of T2*. Much shorter, more closely spaced echo times are now possible in a single breath-hold which makes the calculation of T2* more accurate, especially at higher liver iron concentrations where T2* is short. Methods: A large cohort of patients at UCLH have had liver biopsies as part of iron chelation studies on Deferasirox, while continuing to be monitored by T2* of both heart and liver. Data pairs for LIC calibration curve plots were chosen as nested values by shortest biopsy-to-MR time lapse criterion (±75 days) from all biopsy and hepatic T2* results. Liver biopsy iron was measured in a single central laboratory in Rennes, France (Clinique des Maladies du Foie [Clinic for Hepatic Illnesses], Center Hospitalier Universitaire) on paraffin embedded sections as previously described (Soriano-Cubells MJ, Atomic Spectrosc. 1984). All MR scans were performed on a 1.5T Sonata MR scanner (Siemens, Germany) using a 4-channel anterior phased array coil at Royal Brompton Hospital, London. A transverse slice through the centre of the liver was imaged using a multi-echo single breath-hold gradient echo T2* sequence with a range of echo times (TE 0.93-16.0ms). T2* decay was measured using Thalassaemia tools (Cardiovascular Imaging Solutions, London, UK) from a region of interest (ROI) in an area of homogeneous liver tissue, avoiding blood vessels and other sources of artefact. To account for background noise, a truncation method was used for curve-fitting (He, Magn Reson Med 2008). All T2* measurements were performed in triplicate by 2 independent observers choosing three separate ROIs to analyse. The ROIs were chosen to be as large as possible in three separate areas of the liver (anterior, mid/lateral and posterior). Spearman correlation method was used to estimate the degree of relationship between biopsy LIC and hepatic R2* (1/T2*) values, both of which showed positive skew. Results and conclusions: 61 patients had both liver biopsy and liver MR measurements undertaken. However, only 18 had biopsies within 75 days of MR T2* measurement and these are the patients included in the following analysis. There is a linear relationship between biopsy LIC and the reciprocal of T2* (R2*), given by: LIC = 0.03 x R2* + 0.74 (R2=0.96 p<0.0001, slope 95% CI 0.027-0.033, with y intercept CI -0.73 to 2.2). The 95% confidence intervals for the linear regression line were calculated from the SEM and are shown as the broken lines (Figure 1). Staging of fibrosis/cirrhosis provided in biopsy reports was not found to significantly affect regression analysis contrary to previous studies. The inset shows the relationship between T2* and biopsy LIC. The new calibration shows acceptable linearity and reproducibility over an LIC range up to 30mg/g dry weight and gives LIC values approximately 1.94 times higher than the original method reported by Anderson. Comparison of these values with those obtained by SQUID and Ferriscan would also be of interest. Disclosures: Pennell: Cardiovascular Imaging SOlutions, London, UK: Director.

Initial Liver Iron Predicts Cardiac Chelation Efficacy of Deferasirox (Exjade®) Monotherapy in Chronically Transfused β-Thalassemia (β-Thal) Patients: 18- and 24-Month Data.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4069-4069
Author(s):  
John C. Wood ◽  
Alexis A. Thompson ◽  
Carole Paley ◽  
Tara Glynos ◽  
Barinder Kang ◽  
...  
Keyword(s):  
Iron Overload ◽  
Board Of Directors ◽  
Research Funding ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Employment Equity ◽  
Advisory Committees ◽  
Liver Iron ◽  
Cardiac Iron ◽  
Equity Ownership

Abstract Abstract 4069 Poster Board III-1004 Introduction Transfused patients with β-thal major are known to experience clinical consequences of cardiac iron overload despite the widespread use of iron chelation therapy. Approximately 71% of patients will suffer cardiomyopathy, congestive heart failure (CHF) and death. Previous trials have confirmed the efficacy of deferasirox (Exjade®) in removing cardiac iron in patients with β-thal major. This ongoing study evaluates the effects of deferasirox on cardiac iron and left ventricular ejection fraction (LVEF) in patients with β-thal major in a prospective, single-arm, multi-center trial using cardiac MRI T2*. All patients have completed 18 months of therapy and we also report preliminary results from 24 months. Methods 28 patients were enrolled at four US centers. Entry criteria included MRI evidence of cardiac iron (T2* <20 ms) and normal LVEF (≥56%). Deferasirox was administered at 30–40 mg/kg/day for 18 months. Following core study completion (18 months), patients could continue treatment for an additional 6 months if their 18-month cardiac T2* was <20 ms and they demonstrated ≥25% improvement in cardiac T2* or LIC from baseline. Serum ferritin (SF) was assessed monthly. Liver iron concentration (LIC), cardiac T2* and LVEF were assessed by MRI every 6 months. Serum creatinine (SCr), biochemical and hematological status were also monitored. All results are reported as mean ± SE (range) unless otherwise stated. Baseline: All 26 evaluable patients (7 M/19 F; aged 10–44 years) received ≥150 lifetime transfusions. SF was 4307 ± 613 ng/mL (312–12,655), cardiac T2* was 9.5 ± 0.8 ms (1.8–16.1), LIC was 20.6 ± 3.15 mg Fe/g dry weight (dw; 3.6–62.3) and LVEF was 61.8 ± 0.8%. Results At the time of analysis, 22 and 9 patients had 18- and 24-month evaluations, respectively. Six patients discontinued the core trial due to patient decision (n=2), adverse events (AEs; n=2) or abnormal lab tests (n=2). Two of these patients died after discontinuing; the first enrolled with markedly elevated baseline cardiac iron (T2* = 1.8 ms) and died secondary to CHF. The second patient withdrew due to an AE and died 2 months later due to sepsis and multi-organ failure. 18-month results: At 18 months, 10/22 patients were on 40 mg/kg/day. The mean improvement in cardiac T2* from baseline in all patients was 2.2 ms (22%; P=0.016), with 13 patients improving, four remaining stable (T2* change <10%) and five worsening. Baseline LIC was a powerful predictor of response (Figure); cardiac T2* in 14 patients with LIC <18.5 mg Fe/g dw improved 2.2% per month, with 13/14 patients showing large improvements and one patient remaining stable. In contrast, in eight patients with LIC >18.5 mg Fe/g dw, mean T2* worsened 1.4% per month (P<0.0001); three patients remained stable and five worsened significantly. Improvements in cardiac iron were correlated with changes in LIC (r2 = 0.27, P=0.013). In general, initial T2* did not predict therapeutic response, although all three patients with T2* <6 ms increased their cardiac iron. LIC decreased 4.1 mg Fe/g dw over the study interval (P=0.003). LVEF remained stable. 24-month results: At 24 months, 7/9 patients were on 40 mg/kg/day. Relative to the 18-month time-point, 8/9 patients (89%) increased their cardiac T2*, with a mean improvement of 2.7% per month. Mean LIC, SF and LVEF were unchanged over the extension. Safety parameters from patients treated with 30–40 mg/kg/day deferasirox (n=25) were in line with previous studies at 20–30 mg/kg/day. Conclusions Deferasirox monotherapy resulted in statistically significant improvements in cardiac and hepatic iron after 18 months. Baseline LIC <18.5 mg Fe/g dw was a strong predictor of favorable response. LVEF remained stable during the study. Patients in the extension (18–24 months) improved their cardiac T2* without further improvements in LIC or SF. Deferasirox monotherapy at 30–40 mg/kg/day provides good cardiac chelation in patients with moderate cardiac and liver iron burdens. More aggressive therapy is warranted for more severe iron overload. Disclosures: Wood: Novartis: Research Funding. Thompson:Novartis: Research Funding. Paley:Novartis Pharmaceuticals: Employment, Equity Ownership. Glynos:Novartis Pharmaceuticals: Employment. Kang:Novartis Pharmaceuticals: Employment, Equity Ownership. Giardina:Novartis: Research Funding, Speakers Bureau. Harmatz:Ferrokin: Membership on an entity's Board of Directors or advisory committees; Apotex: Membership on an entity's Board of Directors or advisory committees. Coates:Hope Pharma: Consultancy, Research Funding; Sangart Pharma: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau.

The Effect of Supplemental Ascorbate on Defersirox Iron Chelation In the Iron-Loaded Gerbil

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2059-2059
Author(s):  
Maya Otto-Duessel ◽  
Casey Brewer ◽  
Aleya Hyderi ◽  
Jens Lykkesfeldt ◽  
Ignacio Gonzalez-Gomez ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Content ◽  
Iron Concentration ◽  
Iron Chelation ◽  
Iron Dextran ◽  
Iron Loading ◽  
Liver Iron ◽  
Cardiac Iron ◽  
Liver Iron Content ◽  
Wet Weight

Abstract Abstract 2059 Introduction: Iron dextran injections are often used to induce iron overload in rodents, for the purposes of assessing iron chelation therapy. In gerbils, we have previously described that deferasirox therapy preferentially clears hepatocellular iron when compared with reticuloendothelial stores. Ascorbate deficiency, which is common in humans with iron overload, produces similar profound disparities between reticuloendothelial and parenchymal iron stores. We postulated that iron-induced ascorbate deficiency might be exaggerating reticuloendothelial iron retention in gerbils receiving deferasirox therapy. This study examined the effect of supplemental ascorbate on spontaneous iron loss and deferasirox chelation efficiency in the iron-dextran loaded gerbil. Methods: 48 female gerbils underwent iron dextran loading at 200 mg/kg/week for 10 weeks. Sixteen animals were sacrificed at 11 weeks to characterize iron loading; eight were on standard rodent chow and eight had chow supplemented with 2250 ppm of ascorbate. 32 additional animals that were not ascorbate supplemented during iron loading transitioned into the chelation phase. Half were subsequently placed on ascorbate supplemented chow and both groups were assigned to receive either deferasirox 100 mg/kg/day five days per week or sham chelation. Animals received iron chelation for twelve weeks. Liver histology was assessed using H & E and Prussian blue stains. Iron loading was ranked and graded on a five-point scale by an experienced pathologist screened to the treatment arm. Iron quantitation in liver and heart was performed by atomic absorption. Results: Table 1 one summarizes the findings. During iron dextran loading, ascorbate supplementation lowered wet weight liver iron concentration but not liver iron content suggesting primarily changes in tissue water content. Spontaneous iron losses were insignificant, regardless of ascorbate therapy. Deferasirox lowered liver iron content 56% (4.7% per week) in animals without ascorbate supplementation and 48.3% (4.0% per week) with ascorbate supplementation (p=NS). Cardiac iron loading, unloading and redistribution were completely unaffected by ascorbate supplementation. Spontaneous iron redistribution was large (1.9% – 2.3% per week). Deferasirox chelation did not lower cardiac iron to a greater degree than spontaneous cardiac iron redistribution. Histologic grading paralleled tissue wet weight iron concentrations. Ascorbate treatment lowered the rank and absolute iron score in liver during iron loading (p=0.003) and there was a trend toward lower iron scoring in sham treated animals (p=0.13). Ascorbate had no effect on histological score or relative compartment distributions of iron in deferasirox chelated animals (p=0.5). Ascorbate supplementation was sufficient to increase total plasma ascorbate levels from 25 ± 12.2 uM to 38.4 ± 11 uM at 10 weeks (p=0.03). In the liver, ascorbate increased from 1203 ± 212 nmol/g of tissue to 1515 ± 194 nmol/g of tissue (p=0.01) with supplementation. No significant change in total ascorbate was observed in the heart. Discussion: We hypothesized that ascorbate supplementation might improve reticuloendothelial iron accessibility to deferasirox by facilitating redox cycling. Although gerbils synthesize their own ascorbate, supplementation was able to raise both serum and hepatic total ascorbate levels. However, increasing ascorbate did not change either the amount or distribution of tissue iron in deferasirox-treated animals. Disclosures: Nick: Novartis: Employment. Wood:Novartis: Research Funding; Ferrokin Biosciences: Consultancy.

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