Vitamin D Deficiency Is Associated with Cardiac Iron Loading in Thalassemia Major.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 574-574
Author(s):  
John C. Wood ◽  
Susan Claster ◽  
Susan Carson ◽  
Khanna Rachna ◽  
Thomas Hofstra ◽  
...  
Keyword(s):  
Vitamin D ◽  
Multivariate Analysis ◽  
Vitamin D Deficiency ◽  
Transferrin Saturation ◽  
Thalassemia Major ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Iron Loading ◽  
Liver Iron ◽  
Cardiac Iron

Abstract Vitamin D deficiency is epidemic in the United States and is associated with decreased calcium absorption and metabolism, leading to bone loss, muscle weakness, and impaired pancreatic function. Many thalassemia major patients, as a result of decreases sunlight exposure and increased metabolic demand, are vitamin D deficient. We hypothesized that vitamin D deficiency might be associated with cardiac siderosis and impaired cardiac function through its modulation of calcium signaling in these patients. Methods: Permission for review of medical records was obtained from the Committee on Clinical Investigation at Children’s Hospital Los Angeles. We compared vitamin D25-0H and D1-25 levels in our thalassemia major patients with cardiac R2* (1/T2*) and left ventricular ejection fraction (LVEF) from the patient’s most recent cardiac MRI. Time difference between the exams was 2.8 ± 3.3 months with a range of 0.2 to 9.4 months. Other parameters recorded included age, gender, ferritin, liver iron (by MRI) and transferrin saturation. Univariate and multivariate regression was performed using JMP 5.1 (SAS, Cary, NC). Results: Twenty four patients had records suitable for review. There were 11 women and 13 men with a mean age of 14.7 ± 7.6 years [1.4 – 25.8]. Population was moderately iron overloaded with ferritin values of 2089 ± 1920 ng/ml [246 – 8230], liver iron 13.7 ± 11.4 mg/g dry wt [2–39.5], cardiac R2* 65 ± 61 Hz [19.8 – 229], and transferrin saturation 84 ± 18% [36%–106%]. Vitamin D25-OH levels were markedly depressed, 17.1 ± 8.5 pg/ml [1–33], with 13/24 values below the lower limit of 20 ng/ml. Surprisingly, vitamin D1-25OH levels were normal or elevated in all patients, 59.9 ± 19.5 pg/ml [32–103] with four patients exceeding the upper limit of normal of 71 pg/ml. There was no correlation between D25-0H and D1-25OH levels. D25-OH levels (but not D1-25OH levels) fell sharply with age (r2 = 0.48) and were negatively associated with liver iron (r2 = 0.20). Figures 1 and 2 demonstrated cardiac R2* and LVEF as functions of D25-OH levels. Cardiac R2* was log-linearly correlated with D25-OH level (r2 = 0.44, p=0.0001; levels below 13 ng/ml were associated with severe cardiac iron loading. Multivariate analysis of D25-OH, D1-25, HIC, ferritin, age, and transferrin saturation demonstrated that D25-0H and ferritin are the sole predictors of abnormal cardiac R2*, accounting for 38% and 5% of the variability respectively. LVEF was also negatively related to D25-OH levels (r2 = 0.35, p = 0.002). In multivariate analysis, vitamin D250H and vitamin D1-25OH levels accounted for 50% of the LVEF variability, independent of cardiac R2*. Conclusion Vitamin D deficiency is common in thalassemia major patients and strongly associated with cardiac iron uptake and ventricular dysfunction. Figure Figure Figure Figure

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.

scholarly journals Pancreatic iron loading predicts cardiac iron loading in thalassemia major

Blood ◽  
2009 ◽  
Vol 114 (19) ◽  
pp. 4021-4026 ◽  
Author(s):  
Leila J. Noetzli ◽  
Jhansi Papudesi ◽  
Thomas D. Coates ◽  
John C. Wood
Keyword(s):  
Chelation Therapy ◽  
Early Recognition ◽  
Young Patients ◽  
Thalassemia Major ◽  
Iron Deposition ◽  
Iron Loading ◽  
Resonance Imaging ◽  
Liver Iron ◽  
Cardiac Iron ◽  
Negative Predictor

Abstract Diabetes mellitus and cardiomyopathy are common in chronically transfused thalassemia major patients, occurring in the second and third decades of life. We postulated that pancreatic iron deposition would precede cardiac iron loading, representing an environment favorable for extrahepatic iron deposition. To test this hypothesis, we examined pancreatic and cardiac iron in 131 thalassemia major patients over a 4-year period. Cardiac iron (R2* > 50 Hz) was detected in 37.7% of patients and pancreatic iron (R2* > 28 Hz) in 80.4% of patients. Pancreatic and cardiac R2* were correlated (r2 = 0.52), with significant pancreatic iron occurring nearly a decade earlier than cardiac iron. A pancreatic R2* less than 100 Hz was a powerful negative predictor of cardiac iron, and pancreatic R2* more than 100 Hz had a positive predictive value of more than 60%. In serial analysis, changes in cardiac iron were correlated with changes in pancreatic iron (r2 = 0.33, P < .001), but not liver iron (r2 = 0.025, P = .25). As a result, pancreatic R2* measurements offer important early recognition of physiologic conditions suitable for future cardiac iron deposition and complementary information to liver and cardiac iron during chelation therapy. Staging abdominal and cardiac magnetic resonance imaging examinations could significantly reduce costs, magnet time, and need for sedation in young patients.

Reduction of Hepatic Iron in Patients with Thalassemia Major According to Iron Chelation Regime Assessed by MRI T2*

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5410-5410
Author(s):  
Vassilios Ladis ◽  
Giorgos Chouliaras ◽  
Kirikos Zannikos ◽  
Panagiotis Moraitis ◽  
Eleni Berdoussi ◽  
...  
Keyword(s):  
Statistical Significance ◽  
Linear Regression Analysis ◽  
Thalassemia Major ◽  
Rate Of Change ◽  
Hepatic Iron ◽  
Iron Loading ◽  
Liver Iron ◽  
Cardiac Iron ◽  
Iron Load ◽  
Number Of Patients

Abstract In 212 thalassemia major patients, repeated assessments for cardiac and hepatic iron (LIC) assessed by Magnetic Resonance Imaging (MRI – T2*) have been performed. The chelation regimes were either desferrioxamine (DFO), deferiprone (DFP), combination of DFO and DFP (Comb) or deferasirox (DFX). In general over the last few years, tailoring of chelation therapy has been principally guided by the cardiac iron loading. As many patients had been found to have excess cardiac iron, the majority (48%) had been placed on Comb. Patients were grouped according to the degree of siderosis. A T2* of &lt;1.6ms was regarded as heavy LIC, between 1.6–4.0 moderate, 4.1–9.0 mild and &gt; 9.1 acceptable. Taking into account that the change in T2* is not necessarily linear with respect to time and as the overall time of exposure to DFO, DFP and Comb regimes was significantly greater than that with DFX it was unjustified to perform comparative analysis using the total time period of the patients who were on any of the non DFX regimes. Therefore, to compare the efficacy of the four regimes on LIC, we performed an analysis using student T test to assess the rate of change only between the first and second MRI in patients with comparable LIC according to each chelation regime with adjustment for overall time of exposure (Table 1). Using the same data and applying linear regression analysis (Table 2) we compared the effect of DFO to the other three regimes in the annual rate of increasing hepatic T2*. Only Comb is effective at all levels of hepatic iron loading in reducing the iron content. DFX is effective in the mildly iron loaded patients and for the moderately iron loaded patients, its efficacy approaches statistical significance. DFP does not seem to significantly decrease LIC at any level of hepatic iron load however the numbers of patients in that group are very small. Interestingly DFO seems the least effective at all levels of hepatic iron loading and particularly in the heavy loaded patients. This factor may be related to poor compliance to its use as the patients who have reached such levels of iron load are more often those who are not compliant. In the comparison analysis to DFO, only Comb is significantly better and DFP and DFX are equivalent to it. In addition Comb is more effective than DFX and DFP in that over 12 months it would increase the T2* by 3.8ms (p &lt;0.001) and 3.9ms (p 0.012) respectively. DFX and DFP are similar in efficacy in that they maintain the liver iron at the same levels (DFP vDFX 0.009ms p=0.95). In patients with hepatic T2* &gt;9ms, 4 of 11 on DFO, 5 of 6 on DFX, 7 of 11 on DFP and 3 of 22 on Comb fell below 9. It is of note that DFO only maintains LIC and that a number of patients in the normal range increased LIC. Taking this data into account the DFX and DFP results are compatible with those seen both in the clinic and in trials. It is apparent however that combination therapy is the most effective regime for reducing hepatic iron significantly. As with cardiac iron loading, by knowing the degree of hepatic iron loading by the non-invasive T2* measurement and being able to manipulate patients chelation regimes, it seems possible to be able to have patients free of excess hepatic iron and potentially reduce other iron related morbidities as well. Table 1 Annual estimated mean change in T2* according to severity of hepatic siderosis Regime Heavy Moderate Mild ΔT2* p ΔT2** p ΔT2* p *tm= mean time (in months) between MRI studies DFO n= 42 tm*= 24.6 0.05 0.5 0.57 0.37 0.1 0.7 DFP n= 11 tm= 23.8 0.56 0.25 0.88 0.31 3.5 0.19 Comb n= 101 tm=21.7 1.17 0.0064 3.6 &lt;0.001 5.9 &lt;0.001 DFX n=58 tm=15.2 3.1 0.11 1.25 0.06 3.8 0.014 Table 3 Mean estimated difference in T2* Standard Error p DFP v. DFO −0.7 1.6 0.7 Comb v DFO 3.1 1.05 0.03 DFX v DFO −0.7 1.2 0.5

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.

scholarly journals A Randomized, Placebo-Controlled, Double-Blind Trial of the Effect of Combined Therapy With Deferoxamine and Deferiprone on Myocardial Iron in Thalassemia Major Using Cardiovascular Magnetic Resonance

Circulation ◽  
2007 ◽  
Vol 115 (14) ◽  
pp. 1876-1884 ◽  
Author(s):  
M.A. Tanner ◽  
R. Galanello ◽  
C. Dessi ◽  
G.C. Smith ◽  
M.A. Westwood ◽  
...  
Keyword(s):  
Cardiovascular Magnetic Resonance ◽  
Magnetic Resonance ◽  
Ejection Fraction ◽  
Endothelial Function ◽  
Thalassemia Major ◽  
Iron Chelator ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Iron Loading ◽  
Myocardial Iron

Background— Cardiac complications secondary to iron overload are the leading cause of death in β-thalassemia major. Approximately two thirds of patients maintained on the parenteral iron chelator deferoxamine have myocardial iron loading. The oral iron chelator deferiprone has been demonstrated to remove myocardial iron, and it has been proposed that in combination with deferoxamine it may have additional effect. Methods and Results— Myocardial iron loading was assessed with the use of myocardial T2* cardiovascular magnetic resonance in 167 patients with thalassemia major receiving standard maintenance chelation monotherapy with subcutaneous deferoxamine. Of these patients, 65 with mild to moderate myocardial iron loading (T2* 8 to 20 ms) entered the trial with continuation of subcutaneous deferoxamine and were randomized to receive additional oral placebo (deferoxamine group) or oral deferiprone 75 mg/kg per day (combined group). The primary end point was the change in myocardial T2* over 12 months. Secondary end points of endothelial function (flow-mediated dilatation of the brachial artery) and cardiac function were also measured with cardiovascular magnetic resonance. There were significant improvements in the combined treatment group compared with the deferoxamine group in myocardial T2* (ratio of change in geometric means 1.50 versus 1.24; P =0.02), absolute left ventricular ejection fraction (2.6% versus 0.6%; P =0.05), and absolute endothelial function (8.8% versus 3.3%; P =0.02). There was also a significantly greater improvement in serum ferritin in the combined group (−976 versus −233 μg/L; P <0.001). Conclusions— In comparison to the standard chelation monotherapy of deferoxamine, combination treatment with additional deferiprone reduced myocardial iron and improved the ejection fraction and endothelial function in thalassemia major patients with mild to moderate cardiac iron loading.

scholarly journals Effects of Vitamin D on Left Ventricular Ejection Fraction in Patients with Systolic Heart Failure: A Double-Blind Randomized Clinical Trial

2020 ◽  
Vol 18 (3) ◽  
Author(s):  
Reza Hassanzadeh-Makoui ◽  
Maziar Jamei ◽  
Masoud Hassanzadeh-Makoui ◽  
Hamid Khederlou
Keyword(s):  
Heart Failure ◽  
Vitamin D ◽  
Placebo Group ◽  
Ejection Fraction ◽  
Vitamin D Deficiency ◽  
Intervention Group ◽  
Systolic Heart Failure ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction

Background: Heart failure is a pathophysiologic state in which the cardiac output is not able to supply the body with enough oxygen and nutrients. The prevalence of heart failure has increased dramatically over the last decades. Vitamin D levels in patients with chronic heart failure are lower than healthy controls, and vitamin D deficiency has a direct relationship with mortality. Objectives: This study aimed to evaluate the effect of vitamin D on the improvement of left ventricular ejection fraction in patients with systolic heart failure. Methods: In this case-control clinical trial, 142 patients with chronic systolic heart failure were identified. Based on the inclusion and exclusion criteria, 114 patients were enrolled in the study and randomly divided into two groups. One group (n = 58) received 50,000 units of vitamin D capsules weekly for eight weeks, and the patients in the other group (n = 56) received a placebo. After excluding 15 patients from the placebo group and 17 patients from the intervention group during the study, according to the exclusion criteria, 41 patients were evaluated in both groups for ejection fraction changes after two months. Results: According to the results of this research, there were no statistically significant differences in the baseline parameters between the two studied groups. The intervention group consisted of 18 female and 23 male patients with a mean age of 61.68 ± 19.8 years. Moreover, the placebo group included 21 female and 20 male patients with a mean age of 62.12 ± 18.2 years. After a 2-month follow-up, the intervention group showed statistically significant changes in ejection fraction, end-diastolic volume, and heart failure class compared to the placebo group. Also, the serum level of albumin and vitamin D in the intervention group was significantly higher than the placebo group. Conclusions: The results of this study show that vitamin D treatment can improve the ejection fraction and functional ability of patients with vitamin D deficiency. If more comprehensive studies support this hypothesis, vitamin D deficiency assessment and correction in patients with chronic heart failure may be recommended.

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

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

Blood ◽  
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

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.

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