Thalassaemia International Federation | A non-profit, non-governmental patient-driven organization, founded in 1986

Summarized by Dr. Michael Angastiniotis – TIF Medical Advisor

Introduction

It has been known for a long time that the most frequent cause of death in transfusion-dependent Thalassaemia Major is heart disease, representing more than 50% of deaths. These have been reported in several survival studies (1, 2, 3 & 4). Methods to improve the outcome of cardiac complications have been a major concern for both treating physicians and patients for many years. Methods must include early prevention, detection, assessment of severity, monitoring progress and therapeutic interventions which must include control of the iron toxicity to the heart, as well as improved cardiological management.

To control iron toxicity to the heart both the total body overload needs to be kept in check, with adequate chelation treatment, but also iron should be removed specifically from heart muscle cells (cardiomyocytes). With the newer magnetic resonance methods, which can assess both myocardial and liver iron levels as well as cardiac function, it is becoming apparent that progressive myocardial iron deposition can occur, despite good compliance to Desferrioxamine, low Ferritin and minimal liver iron (5 & 6).

Studies at the cellular level

The mechanisms of damage to heart muscle fibres are well known. In conditions of iron overload, proteins which bind iron are overwhelmed and free labile iron, unbound to proteins (NTBI), through reactions like the Fenton reaction, produce reactive-oxidant species (ROS) These will cause oxidative damage to lipids in cell membranes and organelles.

Iron chelating agents should target the free, labile, iron pool in the plasma, but also the iron within the cells (Labile Cell Iron or LCI). There have been several in vitro studies which investigate the intracellular action of chelating agents. They usually use myocardial cells or animal models. In one recent study (7), rat heart cells were used to study the extraction of labile cell iron by the currently used chelating agents Desferrioxamine, Deferiprone and Deferasirox. Not surprisingly the smaller molecules of the orally active chelators gained access to the LCI pools of the heart muscle cells more rapidly than Desferrioxamine, binding the intracellular iron and attenuating ROS formation.

Deferiprone

The ability to remove intracellular cardiac iron has been demonstrated for Deferiprone both by in vitro and in clinical studies (8). Clinical evidence is accumulating that Deferiprone actually has the same properties in vivo as well as in vitro experiments, and therefore is effective in removing iron from the heart.

The question is whether these properties will make a long-term difference to morbidity and survival. The evidence that is accumulating comes from three kinds of study: a) epidemiological studies, which refer to the changes in cardiac morbidity and mortality related to Deferiprone treatment; b) changes in cardiac iron deposition related to Deferiprone treatment; and c) changes in the cardiac function before and after introducing Deferiprone.

Epidemiological Studies of cardiac morbidity and mortality

The first study was from the Turin Thalassaemia Clinic (9) and like most studies of this group, it is a retrospective analysis. Of 129 patients treated regularly with Desferrioxamine, 54 were switched to Deferiprone (not because of heart problems) for 4-5 years. Worsening pre-existing cardiac abnormalities or the development of new heart complications occurred in 2 patients on Deferiprone (4%), while in 15 (20%) of those on Desferrioxamine. Also no patients died of the group on deferiprone, while three died of the Desferrioxamine group. At the start of the study period there was no significant difference in the prevalence of heart disease between the two groups. The probability of worsening cardiac status was about 5-fold higher in the Desferrioxamine treated group. The difference remained significant even after correction for the younger age of the Deferiprone group. The authors were also careful to monitor compliance, so that the difference between the two groups was minimal. The conclusion is that compared to standard therapy, Deferiprone results in greater cardio-protection.

In a second Italian study (10) the authors compared 359 patients (3,610 patient years) treated with Desferrioxamine alone to 157 (750 patient years) treated with Deferiprone. The patients were comparable for age and sex, but those put on Deferiprone had significantly higher serum ferritin levels. Their findings were that the patients who switched to Deferiprone had a lower prevalence of cardiac events, whereas the Desferrioxamine group experienced 52 cardiac events (defined as cardiac failure or arrhythmia) including 15 cardiac related deaths. In this study, there is a possibility of bias in favour of Deferiprone, since patients were on this treatment for a shorter period of time – perhaps not long enough for cardiac events to occur. There may also, however, be a bias against Deferiprone, since patients were initially put on this medication as part of a compassionate use –programme, with defined criteria (serum ferritin greater than 2,000µg/L, LIC greater than 4mg/g liver dry weight and non-compliance or intolerance to desferrioxamine). The baseline iron overload was therefore greater in the deferiprone group. The fact that there were no cardiac events with Deferiprone in 150 patients over 750 patient-years of exposure is highly significant.

In an analysis of the risk factors for death in patients with Β-thalassaemia (11), the authors concluded that ‘inclusion of Deferiprone in the therapeutic plan resulted in a 3-fold reduction in the risk of death’. They collected data from 31 Italian Thalassaemia centres, in a retrospective one-to-one matched case-control study in which the 42 deaths from 1997-2001 were matched with age and sex controls and the risk factors for death were identified. The most frequent cause of death was cardiopathy (69% of deaths). In comparing the compliance in those that died with the controls, it was found that compliance to iron chelation was judged to be good in 21% of those that died, and good in 67% of the controls. 38% of the controls were taking Deferiprone for 1 to 9 years, while of those that died only 17% were on Deferiprone and were taking the drug for 0.4 to 4 years. Deferiprone thus emerges as a protector “against mortality”. Taking this evidence in conjunction with other studies, the probable explanation is that this is due to its cardioprotective properties.

In a study of survival of the thalassaemia patients from Cyprus (4), it was noted that there was an increase in cardiac deaths from 1980 – 2000, but after that, there was a steady decline. This decline coincided with the introduction of Deferiprone (in most cases in combination with Desferrioxamine). Prior to 2000 only 18 patients were on this treatment, whereas by the end of 2004, there were 125 patients (23% of the total). This study does not prove the cardioprotective properties of Deferiprone, alone or in combination, but lends support to the body of evidence which is accumulating in other studies.

Studies assessing heart iron and heart function

In two large multi-centre randomised clinical trials (12 & 13), conducted in Italy, heart iron content was estimated using magnetic resonance imaging (MRI), heart to muscle signal intensity ratios, comparing patients taking either Desferrioxamine (59mg/kg/day) or Deferiprone (75mg/kg/day) for 1 year. After 1 year the authors of these studies noted no difference in the reduction of heart iron contents between the two groups of patients.

The findings of these trials were contradicted when the new magnetic resonance T2* was introduced to assess myocardial iron concentration and ventricular function (14). The first retrospective study (15), using the T2* technique to compare a group of patients (15 patients) on long-term Deferiprone treatment, with a matched group (30 patients) on long-term Desferrioxamine demonstrated that the Deferiprone group had significantly less myocardial iron and higher ejections fractions.

T2* was also the instrument used in a randomised controlled trial, again comparing Deferiprone with Desferrioxamine and the effect on the heart (16). In this study, 61 patients, all previously on Desferrioxamine were randomised to receive Deferiprone (29 patients) at a dose of 92mg/kg/day (greater than the standard dose of 75mg/kg/ day) or to receive Desferrioxamine (32 patients) at a dose of 43mg/kg/day for 5 days per week. Treatment was given for 1 year and measurements were repeated. Improved myocardial T2* was significantly greater for Deferiprone (27% compared to 13% seen in the Desferrioxamine group). Also the left ventricular ejection fraction increased significantly more in the Deferiprone group (3.1% vs 0.3%). Another important observation in this study was that there was no increase in adverse events in the Deferiprone group, despite the increased dose.

An Italian group used a new approach to compare Deferiprone vs Desferrioxamine effect on the heart. Instead of using the already standardised T2* single measurement in the mid-ventricular septum, they sought to also investigate the marked heterogeneity of iron distribution in heart muscle, using multislice, multiecho T2* sequences. They compared 18 patients receiving long-term Deferiprone with 18 matched (age and sex) on desferrioxamine, With this approach again, it was confirmed that the T2* value was significantly higher in the Deferiprone group and the number of segments with normal iron content were more in this group. The biventricular function parameters were similar in both groups.

Cardiac function using echocardiography to measure LV systolic, diastolic and global functions were also used by a group in Taiwan (18) to see if 9 patients with myocardial dysfunction could improve if their chelation was switched from desferrioxamine to Deferiprone. They were assessed every 6 months and reversal of the myocardial dysfunction was observed, again indicating a greater beneficial effect on the heart by Deferiprone compared to Desferrioxamine.

These studies have mostly compared Deferiprone with Desferrioxamine. They are a strong indication of the usefulness of Deferiprone in both protecting the heart muscle and also possibly reversing iron induced myocardial dysfunction. This last point, however, seems to be better achieved by combining the two chelators, especially in patients who have either been found to have iron accumulation in the heart by MRI T2* screening, or have already manifested clinical cardiac complications. Evidence for the effectiveness of combination therapy is also accumulating. This has been increasingly adopted since Grady et al (19) first suggested the possibility of a “shuttle” effect between the two chelators. The method has been increasingly adopted by clinicians and clinical trials are confirming their judgement. The latest (20) is a randomised, placebo-controlled, double blind trial comparing combination therapy with desferrioxamine monotherapy. T2* was used to assess iron overload and heart function in patients with mild to moderate iron loading after 12 months’ treatment. There was a significant improvement noted in the group given the combination therapy.

In another recent review (21), it is concluded that in the case of heart failure, that is more advanced heart disease, continuous desferrioxamine treatment is better supported than combination treatment. However, combination treatment can be given practically at early stages of cardiac overload and for longer periods than continuous desferrioxamine.

As the role of Deferiprone in heart iron overload becomes established, the role of Deferasirox in the same clinical situations should also be assessed and compared.

References:

1) Modell, B., Khan, M. and Darlison, M. Survival in beta-thalassaemia major in the UK: data from the UK Thalassaemia register. Lancet (2000), 355:2051-2.
2) Borgna-Pignatti, C., Rugolotto, S., De Stefano, P., Piga, A. et al. Survival and disease complications in Thalasaemia major. Ann, NY Acad, Sci, (1998), 850: 227-31.
3) Borgna-Pignatti, C., Rugolotto. S., De Stefano, P., Zhao, H et al. Survival and complications in patients with thalassaemia major treated with transfusion and desferrioxamine. Haematologica (2004), 89: 1187-93.
4) Telfer, P., Coen, P.G., Christou, S., Hadjigavriel, M., Kolnakou, A. et al. Survival of medically treated thalassaemia patients in Cyprus. Trends and risk factors over the period 1980-2004. Haematologica, (2006), 91(9): 1187-92.
5) Anderson, L.J., Westwood, M.A., Prescott, F., Walker, J.M., Pennell, D.J., Wonke, B. Development of thalassaemic iron overload cardiomyopathy despite low liver iron levels and meticulous compliance to Desferrioxamine. Acta Haematol. (2006), 115(1-2): 100-8.
6) Tanner, M.A., Galanello, R.,Dessi, C., Westwood, M.A. et al. Myocardial iron loading in patients with thalassaemia major on Desferrioxamine chelation. J. Cardiovasc Magn,Reson. (2006), 8(3): 543-7.
7) Glickstein, H., El, B.B., Link, G., Brener, W. Et al. Action of chelators in iron-loaded cardiac cells: Accessibility to intracellular labile iron and functional consequences. Blood, (2006), 108(9): 3195-203.
8) Neufeld, E.J., Oral chelators deferasirox and Deferiprone for transfusional iron overload in thalassaemia major: new data, new questions. Blood (2006), 107(9): 3436-3441.
9) Piga, A., Galggioti, C., Rogliacco, E., Tricta, F. Comparative effects of Deferiprone and Desferrioxamine on survival and cardiac disease in patients with thalassaemia major: a retrospective analysis. Haemtologica (2003), 88(5): 489-496.
10) Borgna-Pignatti, C., Cappellini, M.D., De Stefano, P. et al. Cardiac morbidity and mortality in Desferrioxamine or Deferiprone-treated patients with thalassaemia major. Blood (2006), 107(9): 3733-3737.
11) Ceci, A., Baiardi, P., Catapano, M., Felisi, M., Cianciulli, P. et al. Risk factors for death in patients with b-thalassaemia major: results of a case-control study. Haematologica (2006), 91(10): 1420-1.
12) Maggio, A., D’Amico, G., Morabito, A., Capra, M., Ciaccio, C. et al. Deferiprone versus Desferrioxamine in patients with thalassaemia major: a randomised clinical trial. Blood cell. Mol. Dis. (2002), 28(2): 196-208.
13) Galia, M., Midiri, M., Bartolotta, A., Rizzo, M., Mangiali, A., et al. Potential myocardial iron content evaluation by magnetic resonance imaging in thalassaemia major patients treated with Desferrioxamine or Deferiprone during a randomised multi-centre prospective clinical study. Haemoglobin (2003), 27(2): 63-76.
14) Anderson, L.J., Holden, S., Davis, B., Prescott, E., Charrier, G. et al. Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload. Eur. Heart J. (2001), 22: 2171:2179.
15) Anderson, L.J., Wonke, B., Prescott, E., Holden, S., Walker, J.M., Pennell, D.J. Comparison of effects of oral Deferiprone and subcutaneous Desferrioxamine on myocardial iron concentrations and ventricular function in beta0thalassaemia. Lancet (2002), 360(9332) : 516-20.
16) Pennell, D.J., Berdoukas, V., Karagiorga, M., Ladis, V., Piga, A. et al. Randomised controlled trial of deferiprone or desferrioxamine in beta-thalassaemia major patients with asymptomatic myocardial siderosis. Blood (2006), 107: 3730-3744.
17) Pepe, A., Lombardi, M., Positano, V., Cracolici, E., Capra, M., et al. Evaluation of the efficacy of oral Deferiprone in beta-thalassaemia major by multislice multiecho T2*. Eur. J. Haematol. (2006), 76(3): 183-92.
18) Huang, Y.C., Chang, J.S., Win, K.H., Peng, C.T. Regression of myocardial dysfunction after switching from Desferrioxamine to Deferiprone therapy in beta-thalassaemia major patients. Haempglobin (2006), 30(2): 1229-38.
19) Grady, R.W., Berdoukas, V., Rachmilewitz, E.A., et al. Iron chelation therapy: a better approach. 7TH International Conference on Thalassaemia and the Haemoglobinopathies, Bangkok 1999, (Abstract 0018).
20) Tanner, M.A., Galanello, R., Dessi, M.D., Smith, G.C., et al. A randomised, placebo-controlled, double-blind trial of the effect of combined therapy with Desferrioxamine and Deferiprone on myocardial iron in thalassaemia major using cardiovascular magnetic resonance. Circulation (2007), 115(14): 1876-84.
21) Maggio, A. Light and shadows in the iron chelation treatment of haematological disease. Br. J. Haematol (2007), 138(4): 407-421.