Dr. Chi Kong Li Consultant Paediatrician, Chief, Division of Haematology/Oncology/BMT, Prince of Wales Hospital.

There are now 3 iron chelators available in many countries, namely deferrioxamine, deferiprone and deferasirox. Deferrioxamine has the longest history of clinical use, and its efficacy and side effects are well known to clinicians. Deferiprone has gained popularity among most countries outside North America over the past 10 years, after obtaining its registration in EMA. The oral administration of deferiprone is most welcome by patients who have tolerated the painful injection of deferrioxamine for decades. But even more important is deferiprone’s superior ability to protect the heart, which has been shown to improve survival in many studies. The combined use of deferrioxamine and deferiprone is now recommended by many clinicians for patients who have severe iron overload, especially with cardiac overload as demonstrated by MRI. The new oral chelator, deferasirox, has given the patients and doctors another alternative to remove excessive body iron. Recent studies have provided doctors and patients with the necessary information to help them select among these 3 iron chelators. Doing away with the injectable medicine is the goal for all thalassaemia patients, and also the target of all doctors and researchers. Age of patient, severity of iron overload and organs affected, and the socio-economic situation are all factors which influence the choice of chelator and also the decision about choosing a combination treatment or not.

In most western countries, the number of new cases of thalassaemia major is decreasing or maintained at very low incidence. However, in developing countries or places where prenatal screening is not effectively performed, the number of new cases born every year is still significant. When these transfusion dependent children start to have excessive body iron, chelation therapy usually starts at 2-3 years of age.

The standard treatment is subcutaneous administration of deferrioxamine. The families have to go through the most difficult part of the treatment, learning to insert needles into the abdomen of the young kids.

With the introduction of deferasirox recently, the oral medicine can now be given to children as young as 2 years. The drug can prevent the accumulation of excessive body iron. Unfortunately the high cost of deferasirox is inhibitory to most families who reside in the developing countries. Though the company has provided special packages in some countries to bring down the cost, the cost is still not affordable to many families.

The other oral chelator, deferiprone, previously only in tablet form, is not suitable for young children under the age of 5 years. There was also no clinical data on the safety of deferiprone on very young age. Recently the solution form of deferiprone has been introduced to the market.

A clinical study of deferiprone on children less than 10 years was conducted in Egypt, Malaysia and Indonesia. Fifty-nine children, all of them less than 6 years old, were tested with this medicine in a 6 month study, which showed the short-term efficacy of reducing serum ferritin. Assuming the same biological efficacy as the tablet form, deferiprone solution certainly benefits the young children most, and they may not require injectable iron chelation in the future. However, the study only covers a 6 month period. The long term effect, and, more importantly, the side effects of deferiprone in young children are still unknown. Two of the 59 children receiving deferiprone solution developed agranulocytosis in 6 months. 6% of young children developed mild neutropenia during the study period. It is not known whether the incidence of agranulocytosis will increase with longer duration of deferiprone treatment.1 Joint pain or arthralgia occurred in 4% of patients and one had severe joint pain that required discontinuation of deferiprone treatment. Whether young children with growing skeletal system will be more prone to joint toxicity is a question that still requires more study. More clinical data and longer follow up are required to make recommendation of deferiprone as first line treatment in young children.

In older patients, many studies in the past 10 years concentrated on prevention of cardiac toxicity and thus improvement of survival. Deferiprone or combination of deferirpone with deferrioxamine has been shown to have superior effect in removing excessive iron from the heart. Deferasirox has also been carefully studied regarding the cardiac protective effect. The one year study showed that mild to moderate cardiac iron overload patients benefit more from deferasirox as the T2* measured on cardiac magnetic resonance with better improvement of T2*. With the continuous follow up, further improvement in cardiac iron status was observed at second year and third year of the study.2,3 The process of removing iron from heart cells is slow and it may take several years to achieve very good clearance of heart iron. In patients who have severe iron overload in the heart as demonstrated by T2* < 6ms, the chance of developing heart failure is 47% in one year.4 These patients should receive intensive iron chelation to prevent the heart failure. Combination of deferiprone and deferrioxamine is recommended by most centers. However, studies have shown that about 25% of patients on combination treatment have to stop the combined treatment, and that agranulocytosis is one of the main reasons. The combined use of deferrioxamine and deferasirox, or combined deferasirox and deferiprone is not well studied except for cases reported on a few patients. The combined oral iron chelators option is most attractive as it improves the compliance and may thus improve survival. Deferirpone has better cardiac protective effect, deferasirox appears to have good clearance of liver iron; combined use of both agents may achieve better global body iron control. The optimal dosage of each chelator in combination form is another area of research, lower dose of either agent in combined approach may be possible. Of course the toxicity profile of combined chelators must be carefully studied.

New oral iron chelators are also under study. It is anticipated and hoped that oral chelation therapy will become reality for all thalassaemia major patients, from the very young ones to the elderly.

References:

  1. El Alfy M, Sari TT, Chan LL; Tricta F, El-Beshlawy A. The Safety, Tolerability, and Efficacy of a Liquid Formulation of Deferiprone in Young Children With Transfusional Iron Overload. Journal of Pediatric Hematology/Oncology. 32(8):601-605, November 2010.
  2. Pennell DJ, Porter JB, Cappellini MD, et al. Continued improvement in myocardial T2* over two years of deferasirox therapy in β-thalassemia major patients with cardiac iron overload. Haematologica 2011; 96: 48-54.
  3. Continued Improvement and Normalization of Myocardial T2* in Patients with β-thalassemia Major Treated with Deferasirox (Exjade®) for up to 3 Years. 2010 Annual Meeting of American Society of Hematology, Poster #: III-1055.
  4. Kirk P, Roughton M, Porter JB, et al. Cardiac T2* Magnetic Resonance for Prediction of Cardiac Complications in Thalassemia Major. Circulation 2009;120;1961-1968.

This page was last updated February 2011 by Dr Michael Angastiniotis, MD, DCH (Paediatrician)

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