Hepatic and Cardiac Iron-load in Children on Long-term Chelation with Deferiprone for Thalassemia Major

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 <1.6ms was regarded as heavy LIC, between 1.6–4.0 moderate, 4.1–9.0 mild and > 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 <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* >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 <0.001 5.9 <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

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Glutathione S-Transferase Gene Polymorphism and Heart Iron Overload in Thalassemia Major.

Blood ◽

10.1182/blood.v110.11.2767.2767 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2767-2767

Author(s):

Raffaella Origa ◽

Stefania Satta ◽

M. Dolores Cipollina ◽

Lucia Perseu ◽

Annalisa Agus ◽

...

Keyword(s):

Iron Overload ◽

Serum Ferritin ◽

Thalassemia Major ◽

Myocardial Iron ◽

Gstm1 Null Genotype ◽

Glutathione S Transferase ◽

Body Iron ◽

Cardiac Iron ◽

Iron Load ◽

Allelic Distribution

Abstract Heart is the target lethal organ for iron accumulation in thalassemia major. Currently, magnetic resonance imaging (MRI) is the only non-invasive method with the potential to assess myocardial iron. MRI T2* has proven to be a fast, simple, robust and clinically useful tool for the assessment of cardiac iron load. In chelated patients, myocardial iron is usually inversely related to compliance with chelation while there is no meaningful correlation with liver iron and serum ferritin concentration measured at the time of T2* assessment. However, in a subset of patients, myocardial iron overload occurs despite an history of good compliance with chelation therapy, suggesting the possible role of genetic factors. Several gene polymorhisms including apolipoprotein epsylon and HLA haplotypes have been described as protective or predisposing factors for cardiac iron dysfunction. Wu et al. (2006) analyzed polymorphisms of two endogenous antioxidant enzymes, glutathione S-transferase M1 (GSTM1) and glutathione S-transferase T1 (GSTT1). They found that the GSTM1 null (deleted) genotype was associated with a decreased signal intensity ratio on MRI, suggesting that genetic variations of the GSTM1 enzyme are associated with cardiac iron deposition. The aim of the current study was to evaluate if the GSTM1 null genotype is a predisposing factor for myocardial iron overload in thalassemia major patients on chelation treatment with desferrioxamine with low body iron load as assessed by serum ferritin levels. Allelic distribution of wild and null GSTM1 genotype was assessed in 24 patients with thalassemia major in whom the severe myocardial iron overload (T2* <10 msec) was unexpected based on low body iron load (mean of lifelong serum ferritin determinations 1360 ± 268 ng/ml), and in 26 thalassemia patients in whom the myocardial iron overload was expected based on high body iron load (mean of lifelong serum ferritin determinations 4724 ± 1530 ng/ml). Twenty-six healthy subjects were analyzed as controls. We found that the GSTM1 null genotype was more frequent in thalassemia patients with unexpected myocardial iron load (p=0.02) than in patients with expected myocardial iron load (Table 1). The presence of the GSTM1 null genotype can therefore explain in part the development of severe myocardial iron overload in thalassemia major patients who have been adequately chelated since their first years of life. Based on the inhibition of the cardiac ryanodine receptor calcium channels by members of the glutathione transferase structural family, and given the little difference in permeability among divalent cations in those channels, we hypothesized that the deletion of GSTM1 is associated with increased entry of iron into the myocites, in patients with thalassemia major. Further studies are needed to understand the mechanisms that underlie the association between GSTM1 gene polymorphisms and predisposition to myocardial iron overload. Table 1. Allelic distribution of wild and null GSTM1 genotype in beta thalassemia patients with expected and unexpected heart iron overload, and in 26 healthy controls GSTM1 wild GSTM1 wild GSTM1 null GSTM1 null n % n % χ2 test : A vs C p>0.05; A vs B p=0.02; B vs C p=0.04 A. Thalassemic patients with expected heart iron overload 17 65.4 9 34.6 B. Thalassemic patients with unexpected heart iron overload 8 33.3 16 61.5 C. Healthy controls 16 61.5 10 38.4

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A Decade Follow-up of a Thalassemia Major (TM) Cohort Monitored by Cardiac Magnetic Resonance Imaging (CMR): Significant Reduction In Patients with Cardiac Iron and In Total Mortality

Blood ◽

10.1182/blood.v116.21.1011.1011 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1011-1011 ◽

Cited By ~ 7

Author(s):

Alison S Thomas ◽

Maciej Garbowski ◽

Ai Leen Ang ◽

Farrukh T Shah ◽

J. Malcolm Walker ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Chelation Therapy ◽

Thalassemia Major ◽

Iron Loading ◽

Myocardial Iron ◽

Advisory Committees ◽

Cardiac Iron

Abstract Abstract 1011 Background. CMR was introduced in London to assess myocardial iron loading in 1999 and some of these patients now have 10 years of follow-up, most with contemporary CMR determinations. The impact of long-term monitoring of myocardial iron loading in thalassemia major (TM) on the proportion of patients with increased myocardial iron (cT2* <20ms) and on patterns of mortality has not been previously described in a longitudinal cohort over this duration. Patients and Methods. All patients regularly attending two London thalassemia centres, who received their first CMR Jan 1999 - Dec 2000 were analyzed as a cohort. Patients underwent initial CMR at the Royal Brompton Hospital and received CMR follow up (FU) either there or at the Heart Hospital (UCLH). 132 patients were identified as having received a CMR in 1999–2000. A minimum 7 years CMR FU was required for inclusion in the long-term CMR analysis. 109 patients had at least 7 years of CMR follow up (range 7.0–10.6 years, median 9.2). The median age at 1st CMR was 27.9 years (range 7.7 – 49.5 years). At baseline, patients were receiving chelation with deferoxamine (DFO) monotherapy (70%), deferiprone (DFP) monotherapy (21%), or a combination of these agents (9%). At latest FU, patients were receiving DFO (32%), deferasirox (DFX) (28%), DFP (22%), or combined DFP and DFO therapy (18%). Results: Improvement in cardiac iron: In 1999–2000, 60% of TM patients had cT2* values ≤20ms and 17% had cT2* values <10ms. By contrast, at long term FU, only 23% now have cT2* ≤20ms, 7% have cT2* values <10ms (p<0.001). Changes to chelation therapy: 31% of patients stayed on the same chelator; 33% had 1 chelator switch, 26% 2 switches and 11% 3 or more switches. 18 switches in chelation therapy were due to side-effects (12 DFP, 5 DFX, 1 DFO). There were 9 breaks in chelation therapy during pregnancy in 8 different women. The proportions of patients with T2* < 20ms fell significantly for those who remained on DFO or DFP monotherapies throughout, or who changed chelation modalities on only one (p=0.002) or two (p=0.02) occasions. Patients who received had 3 or more switches did not show a improvement in this respect. The latter group was also the only subset that showed significant deterioration in myocardial iron (p<0.001). Mortality rates: the overall mortality rate for the initial cohort was 1.65 per 1000 patient years (95% CI 0.71 – 3.24); median age at death 35.6 years (range 27.3–48.4). This is a substantial improvement in the mortality index compared with the UK thalassemia registry data, of 4.3 per 1000 patient years during the period 2000–2003 (Modell et al, JCMR, 2008). The incidence rate ratio is 0.387 (95% CI 0.11–0.961), p<0.05, with patients in our cohort 61% less likely to die than those in the 2000–2003 cohort. Causes of death: there were 8 deaths during the FU period: 3 with complications of hepatitis C (all with cT2* > 20ms), 3 with sepsis (2 with cT2* <10ms and impaired ejection fraction, 1 with cT2* of 18ms), 1 with breast cancer, 1 with sudden unexplained death (cT2* > 20ms). Thus in only 2 patients could excessive cardiac iron loading be considered a causal/contributory factor. There was no significant difference in the baseline cT2* between those who died and those currently still alive (p= 0.2), meaning that death as a drop-out cause does not explain iron loading trends over FU. Chelators at death: DFO (4), DFP (2), DFX (1), combination (1). Conclusions: Over a decade we have seen an almost 3 fold fall in the proportion of patients with myocardial iron overload. Mortality has become substantially lower and cardiac iron overload is no longer the leading cause of mortality. In addition to CMR, this decade has seen the advent of two new oral iron chelators and many patients switched chelation regimen, sometimes several times, during the follow up period. Whilst the contribution of the individual components of this practice to the improved outcome cannot be concluded without randomized studies, it is clear that this modern management of TM is associated with reduced TM mortality. Disclosures: Off Label Use: Deferiprone is off label in the USA but licensed in Europe. Shah:Novartis: Honoraria, Speakers Bureau; Apotex/ Swedish Orphan: Honoraria. Pennell:Siemens: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Apotex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Cardiovascular Imaging Solutions: Director of CVIS, Equity Ownership. Porter:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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

Blood ◽

10.1182/blood.v126.23.2155.2155 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2155-2155 ◽

Cited By ~ 1

Author(s):

Dudley J Pennell ◽

John B Porter ◽

Antonio Piga ◽

Jackie Han ◽

Alexander Vorog ◽

...

Keyword(s):

Research Funding ◽

Iron Concentration ◽

Thalassemia Major ◽

Iron Removal ◽

Liver Iron Concentration ◽

Liver Iron ◽

Time Points ◽

Cardiac Iron ◽

Time Point

Abstract Background: Beta thalassemia major patients (pts) are at an increased risk of heart failure, due to the deposition of iron in the heart causing myocardial siderosis. Intensive long-term iron chelation therapy (ICT) is required to obtain a normal myocardial T2* (mT2* >20 ms). Previously published studies suggested that cardiac iron removal lags changes in liver iron, and liver iron concentration (LIC) may affect the rate of removal of cardiac iron (Porter et al, ASH 2013). The objective of these analyses was to evaluate the association of the severity of LIC levels with the change in mT2* responses in pts with myocardial siderosis when treated with deferasirox (DFX) and deferoxamine (DFO) for up to 24 months (mo) in the CORDELIA study. Due to the very low pt numbers in the DFO arm, the results for these pts are not presented here. Methods: The study design, inclusion, and exclusion criteria have been reported previously (Pennell et al, Am J Hematol. 2015). Pts were categorized into LIC <7, 7 to <15 and ≥15 mg Fe/g dry weight (here after mg/g) both at baseline (BL) and specific visits, to assess the relation of absolute LIC and changes in LIC overtime, with mT2* and cardiac iron concentration (CIC), respectively. During the study, mT2* (ms), and LIC (mg/g) were measured every 6 mo at the same time point. CIC (mg/g) was analyzed as a post hoc parameter derived from mT2*. The change in mT2* was assessed as geometric mean (Gmean)±coefficient of variation (CV), ratio of the Gmean at specific time points divided by that at BL (Gmean at specific time point/Gmean BL) and both CIC and LIC as mean±SD, unless otherwise specified. Results: Of 197 pts, 160 (81.2%) completed 12 mo of treatment and 146 (74.1%) entered into the extension study whereas 103 pts continued on initially assigned treatment. Pts completing 24 mo of treatment included 65 (87.8%) of 74 pts (mean age 20.1±6.9 years, 59.5% male) on DFX and the results for these pts are presented as follows. Average actual doses (mg/kg/d) were 26.7±8.9, 31.5±7.4, 38.0±2.9 for LIC <7, 7 to <15, ≥15, respectively, during the extension study. The LIC levels for pts categorized by LIC <7, 7 to <15 and ≥15 improved from BL to Mo 24 as follows: 72% decrease (mean absolute change, -15.1±14.1), 66% decrease (-26.6±13.0), and 19% decrease (-10.2±15.7), respectively. For pts with BL LIC <7, 7 to <15, ≥15, mT2* improved from BL to Mo 24 as follows: 43% increase (14.0±18.1 to 21.6±31.1; mean abs change, 7.8±4.0), 50% increase (12.3±34.4 to 19.1±46.4; 8.0±6.0), and 30% increase (11.1±30.8 to 14.5±40.8; 4.1±5.0). The CIC values improved from BL to Mo 24 by 38% (1.8±0.4 to 1.1±0.5), 40% (2.3±0.9 to 1.4±0.7), and 23% (2.6±1.0 to 1.9±1.0), respectively. The mT2* responses for pts categorized according to visit specific LIC levels (LIC <7, 7 to <15, ≥15) from BL to Mo 12 were 22% increase (mean abs change, 3.7±4.3) in LIC <7, 21% increase (2.7±2.0) in LIC 7 to <15, and 7% increase (1.5±3.2) in LIC ≥15. From BL to Mo 24, mT2* increased by 51% (mean abs change, 7.8±5.3), 35% (4.1±2.5), and 11% (2.0±4.4), respectively. The CIC levels improved from BL to Mo 24 by 40% (mean abs change, -1.0±0.8) in LIC <7, 31% (-1.0±0.6) in LIC 7 to <15, and 6% (-0.1±0.8) in LIC ≥15. The change in mT2* (Gmean ratio) at Mo 6, 12, 18 and 24 are shown in the Figure A. The mT2* response was higher in pts who achieved a lower LIC category (LIC <7) at respective time points and this change in mT2* was more apparent at 18 and 24 mo of treatment with DFX. Discussion: Overall, DFX treatment resulted in a substantial decrease in LIC and improved mT2*. These results suggest a greater difference in mT2* improvement and CIC reduction in pts who achieved lower LIC during treatment with DFX. This divergence was progressive with time, being maximal at Mo 24. Thus, a therapeutic response in LIC with DFX may be associated with a greater likelihood of improving mT2*. Pts with high LIC ≥15 may require an effective long-term treatment with higher doses of ICT to have an improvement in mT2*, suggesting that cardiac iron removal is likely to be slow in heavily iron overloaded pts. These results are consistent with the previous report which showed a significant decrease in LIC and increased mT2* responses at Mo 36 in pts who attained lower end-of-year LIC levels when treated with DFX (Porter et al, ASH 2013) and highlight the potential value of monitoring the liver and cardiac responses during ICT. To further understand the kinetics between liver and cardiac iron removal, prospective investigation is warranted. Disclosures Pennell: Novartis: Consultancy, Research Funding; Apotex: Consultancy, Research Funding. Porter:Celgene: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria. Piga:Acceleron: Research Funding; Cerus: Research Funding; Apopharma: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding; Celgene Corporation: Honoraria. Han:Novartis: Employment. Vorog:Novartis: Employment. Aydinok:Cerus: Research Funding; Sideris: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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