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

By Dr Michael Angastiniotis, TIF Medical Advisor
May 2008

1. Iron Overload

Since this is the basis of all major complications in transfusion dependent Thalassaemia it is the subject that attracts most attention in clinical research.

An important point to note is made by Wood JC, Origa R et al in Haematologica in April 2008 when they found early onset, in paeadiatric patients, of cardiac iron loading. Should MRI monitoring and appropriate chelation start earlier?
A question that has not been answered is whether measuring free iron (NTBI) will be clinically useful and feasible for routine laboratories. Prof E. Fibach of Israel has described a method of measuring LIP using flow cytometry which is available to most haematology labs. Published in the Br. J Haematol. (Prus E, Fibach E).
Essential reading is R, Galanello’s review on Deferiprone which is a very useful update on the results of this chelator. The report is in a journal called Ther Clin Risk Manag., 2007, 3(5) 795-805.
Prof Amal El- Beshlawy and her colleagues have reported their experience with combination therapy in Ann Hematol, to add to a series of favourable reports of this approach to chelation, which include Tanner MA et al in the Journal of Cardiovascular Magnetic Resonance, in February 2008. In many adult populations of patients in whom cardiac overload is detected with T2* this method is now routine and favoured by patients and physicians over continuous DFO infusions. Experience in Cyprus is similar and a large series is soon to be published.
Concerning Deferasirox: Cheung YF et al in the Br J Haematol in March have looked at arterial and LV function and noted improvement suggesting that this chelator may also enter heart cells to remove iron.
Important reading is also Angelucci E et al published in Haematologica in May. These are the Italian guidelines on iron chelation which represent the evidence based consensus of the experienced Italian group of clinicians.

2. New Iron Chelators

The search for new substances continues quietly at the animal level without any human trials on the horizon. Santos MA and colleagues from Portugal have conducted animal studies using new members of the hydroxypyridone (L1) family- two in combination and found that this speeds up iron excretion. Reported in Hemoglobin this year.

Another team that TIF is watching carefully and hopefully is that of Richardson in Sidney. Please note their study: Lim CK, Kalinowski DS, Richardson DR, on the PCIH class of iron chelators, Mol Pharmacol, April 2008 . They demonstrated chelation from mitochondria in Friedriech’s Ataxia. This means that these substances definitely enter cells and should be cardio-protective in Thalassaemia also.

How can these and other researchers be encouraged to progress to all the necessary steps in drug development. They need pharmaceutical company support but companies already in the field favour their own research. Thalassaemia needs new weapons!

3. Cardiac Complications

The management of heart complications has been revolusionised by early recognition through MRI T2* and mortality is coming down. However Magri D et al from Rome have confirmed that many young asymptomatic patients have impaired myocardial function and so alertness through early monitoring may save even more lives. They also showed that those taking Deferiprone had better heart function indices than those taking DFO.

He T et al published a report on ‘Breath –hold T2 MRI’ in J Cardiov Magnetic Resonance, in February. This may be another MR method available to more locations around the world.

For the management of heart complications the following recent guidelines are essential updates for clinicians:

Cogliandro T, Derci G et al Guideline recommendations for heart complications in Thalassemia major. J Cardiovasc Med, 2008, 9(5): 515-25. These are from the SoSTE group for the study of thalassaema.
Aesopos A, Kati M, Tsironi M. Review of congestive hearty failure in thalassaemia. Hemoglobin, 2008, 32(1-2): 63-73

4. Thrombotic Risk

This is an increasingly recognised complication mainly affecting Thalassaemia intermedia, but may occur in major cases especially in splenectomised patients. Scientists are concerned with elucidating the mechanisms of this potentially dangerous complication and of course management issues. A recent review of the subject:

Taher A, Otrock ZK, Uthman I, Cappellini MD. Thalassaemia and hypercoagulability. Blood Rev, May 2008.

5. Stem Cell Transplantation

The problem with this cure of thalassaemia is that is not available but to a minority of patients who have an HLA compatible donor in the family and who are in good clinical condition especially chelation-wise. Matched but unrelated donors were a taboo until recently but now: Rocha V and Locatelli F ‘ Searching for alternative stem cell donors for pediatric patients” in Bone Marrow Transplant, 2008, 41(2): 207- 214 suggest otherwise. In a lecture to the Ithanet group in November in Cyprus Prof Locatelli showed results suggesting that with a perfect unrelated match and using a new conditioning regimen (replacing Busulphan with a new variant) the results of MUD transplants are as good as those using related donors. This alone will increase the number of eligible children significantly.

Using stem cells from umbilical cord blood showed that GVHD can be reduced. So alternative sources of stem cells are being sought if possible pluri-potential stem cells such as embryonic stem cells. The latter cause ethical groups to jitter but they may potentially allow transplant from non-related donors. Ideas on how to use embryonic cells are now being exchanged between experts in the field. Their use is important for gene therapy also. One important advance in this respect is the finding that adult fibroblasts can be reprogrammed to become pluripotential stem cells. This is another source of stem cells which has uses in gene therapy. See:

Takahashi K, Yamanaka S, Induction of pluripotent stem cells from mouce embryonic and adult fibroblast cultures by defined factors. Cell, 2006, 126: 663-76.

This reverse differentiation of cells has been used to treat thalassaemia by a group in Pakistan by presumably making use of the fact these cells are rich in HbF.

6. Gene Therapy

Human trials have at last arrived in this long awaited cure. Results from the first cases are not yet known but problems have arisen which are being looked at. A second team has now ethical approval to proceed with human trials in the USA but it is not known if any have been attempted. The literature in this field is highly specialised but if anyone wants recent reviews the following are recommended:

Moi P, Sadelain M Towards the genetic treatment of β-thalassemia: new disease models, new vectors, new cells. Haematologica, 2008, 93(3): 325
Lisowski C, Sadelain M Br J Haematol, May 2008.
El-Beshlawy A et al Correction of pre-aberrant m RNA splicing by anti-sense oligonucleotides in beta – thalassaemia Egyptian patients with IVSI-110 mutation. J Paed Hematol Oncol, 2008, 30(4):281-4 (this was a favoured approach of the late Panos Ioannou)

7. HbF Induction

Several teams are working to find substances which will effectively and safely increase foetal haemoglobin. Recently there has been a revival of interest in the use Hydroxyurea (HU) in thalassaemia major since the use in intermedia is already recognised. Following a report from Algeria according to which major patients have become transfusion- free using HU, a new report has come from Georgia (a country with almost 4% carriers which no one has yet visited to see how they manage):

Mtvarelidze Z et al in Georgian Medical News (this little known journal is posted on pubmed).
Koren A et al from Israel, in the Am J Hematol, May 2008, are looking into the genetic factors which favour a good response to this drug.

Other HbF inducers are still being sought. Apart from the well known work of Dr Susan Perrine on short chain fatty acids, now in clinical trials, several other groups are still searching. These include Dr R. Gambari and his team in Italy, Dr Marina Kleanthous and her team in Cyprus and Prof Fibach in Israel. All of these are now in collaboration through the Ithanet project. In his latest paper Dr Gambari (Viola G, Vedaldi D et al) has described substances, called furocoumarines, which induce both HbF and HbA – this should do thalassaemia major a world of good once they leave the laboratory bench.

8. Renal Complications

Kidneys have not been an obvious problem in thalassaemia so far. However kidney stones are beginning to appear and the Ithanet group is looking into the problem in a collaborative study.

Renal function may be affected in thalassaemia both by iron overload and by increased uric acid (hyperuricaemia) due to increased breakdown of red cell especially in low transfusion situations such as thal intermedia:

Ali D and colleagues in an article entitled ‘Comparative evaluation of renal findings in beta thalassaemia major and intermedia’ Saudi J Kidney Dis Transpl, 2008 19(2):206, have shown that hyperuricaemia and microscopic haematuria are indeed more common in thalassaemia intermedia.

Mohkam M et al from Iran have described the “early markers of renal dysfunction in patients with thalassaemia major” in Paediatr Nephrology, February 2008. It may become necessary to use markers such as these in routine monitoring. Sadeghi – Bojd S and colleagues also from Iran, in the Singapore Med J, 2008, 49(5):410-2, described renal tubular function un thalassaemia.

In view of the possibility of drug induced renal damage, these tests should not be ignored. Alertness is indicated.

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

Medical focus

By Dr Michael Angastiniotis, TIF Medical Advisor May 2008