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

By Dr Michael Angastiniotis, TIF Medical Advisor
September 2008

1. Iron Overload and Chelation

Recent articles confirm what we already know: Iron chelation can be improved.

Payne KA et.al in Adv Ther, 2008, 25(8):72-5-42 studied the clinical, quality of life and economic outcomes associated with iron chelation using Desferal and/or Deferiprone in UK patients. They concluded that, in the real world setting, chelation is suboptimal with respect to these outcomes. The same group have developed a new “patient instrument” (questionnaire) which they labeled SICT or Satisfaction with Iron Chelation Therapy, and have supplied it to patients both in the UK and USA and suggest its use in new clinical trials on drugs that will avoid the traditional SC infusion. See further (Rofall D et al, Value Health, 2008, July 11).

The same conclusion, that chelation therapy overall benefits are not always perceived as optimal by patients, is the end result of an Italian study (Scalone L et.al in Curr Med. Res Opih, 2008, 24(7):1905-17).

They conclude that efforts must be focused to improve patients’ acceptance and satisfaction with their therapy. But how? Psychosocial support which is effective in some hands but ignored by most? Perhaps more convenient drugs for the patient is the answer.

Deferasirox, for example, was recently reviewed by Galanello R and Origa R (Expert Rev of Clin Pharm, 2008) and found it “convenient, effective and tolerable”. However new drugs are needed and at least basic research is being conducted (example: Nsimba RY et.al in J. Biochem Mol Toxicol, 2008, 22(4):240-50 who have found three new phytoecdysteroids which can chelate iron). Keeping an eye on these independent groups doing basic research on substances which chelate iron is important, and hopefully the future will bring new choices.

2. Cardiac Iron Load

Accumulation of iron in the heart remains the most important issue in relation to patient safety. One important issue is the question of when does this start, at what age should monitoring begin and when should treatment be intensified to target the heart. One important study to resolve these questions was recently published in Haematologica (2008, 93(6):917-30) by Wood JC et al. The group used CMR (T2*) in paediatric patients. They found that no patient under the age of 9.5 years showed detectable myocardial iron. It was present, however, in 36% of patients 15-18 years. All patients with cardiac iron load had received at least 35g of transfused iron. They suggest that monitoring should start at 8 years or even younger if chelation had been suboptimal.

In the same study the authors point out that LIC and S. Ferritin does not predict cardiac iron accumulation. This is confirmed by Chirnomas SD et.al in the Am. J. Hematol, 2008 in May, who examined both hepatic and cardiac T2* on a wide age range of patients (3-82 years). They recommend monitoring of both liver and myocardial iron with T2* MRI.

The heart iron in Thalassaemia intermedia has not been extensively studied. Origa R et.al in Haematologica, 2008, 93(7):1095-6 sought to provide data, by examining 20 adult intermedia patients with T2* MRI, who were not being chelated regularly. Heart T2* was normal in all of them (i.e. no cardiac iron overload) although in the past other authors found cardiac accumulation in subgroups of intermedia patients. Liver iron concentration was found elevated in 7 out of 11 patients, assessed by the Ferriscan methodology. The general conclusion is that adult intermedia patients should be regularly monitored by both cardiac and LIC MRI.

One question which arises is how patients should be monitored if T2* MRI is not available. If technology and funds are available then one answer seems to be Dual Energy Computed Tomography. (=cDect) Hazirolan T et.al. in the Eur J Radiol, Sept 2008 have found that myocardial iron deposition measured by this method correlates strongly with T2*. However for those less privileged, the value of more readily available techniques needs to be more carefully assessed and a protocol for cardiac investigations constructed. Examples of such possibly useful investigations for thalassaemia patients include:

ECG: to assess QT dispersion, QT- QTc intervals, QT variance, VIS and V5R amplitudes, based on: Ulger Z et.al Am J. Hematol, 2006, 81(12): 901-6 and Magri D et. al Eur J. Haematol, 2007, 79(4): 322-9.
Echocardiography: using Tissue Doppler and Strain imaging, to assess septal systolic myocardial velocity, mean ejection fraction etc. (References: Westwood MA et al, J Magn Res Imaging 2007, 25(6): 1147-51, Hamdy AM, Eur J Echocardiography, 2007, 8:102-9, Magri D et al Eur J Haematol, 2008, 80(6):515-522 and Giakoumis A et.al Cardior Ultrasound, 2007, 5:24.

3. Stem Cell Transplantation

Iron accululation adversely affects haemopoietic stem cell transplants. Pullarkat V et.al in B.M. Transpl. 2008. Sept.1 showed that patients undergoing transplant, for various haematological disorders who had a serum ferritin over 1000ng/ml had a 20% motrality compared to 9% in those with ferritin levels below 1000 ng/ml (P=0.004) at 100 days post transplant. Also the incidence of acute GVHD was 63% and 43% respectively (P=0.009) and there were more blood stream infections – 60% vs 44% (P=0.042). Also iron overload increases the risk of fungal infections after stem cell transplants (Garcia-Vidal C et.al, Clin Inf. Dis, 2008, Sept. 9).

In addition, Iron overload, seems to adversely affect outcomes in liver transplants, leading to disseminated infections (Singh N, Sun HY, Liver Transpl. 2008, 14(9): 1249-55 .

These finding strengthen what is already known, which is that transplants give better results in patients with little iron overload which usually means very young patients (children).

On the subject of stem cell transplantation Andreani M et.al (Blood Transf, 2008, 6(3):143-9) point out that complete replacement of red cell production by donor stem cells in not essential for engraftment and that in 10% of transplanted thalassaemia patients some of their own stem cells remain active in producing red cells (chimerism). However if large numbers of residual host cells are still present in the first 2 months following the transplant, there is a high risk of graft rejection.

4. Gene Therapy

The new factor that seems to have excited researchers in the field is the so called somatic cell reprogramming by which pluripotential stem cells can be produced from the patients own mature somatic cells.

Such a process will provide adequate numbers of stem cells from the patients own tissue, virtually eliminating the rejection issue, which can be used for treatment especially gene therapy.

The technique for the reprogramming was described by Takahashi K and Yamanaka S in Cell, 2006, 126(4): 663-676, although an older version, not believed by scientists, was published by Abuljadyel IS in Curr Med Res Opin, 2003, 19(5):355-75. She (Ilham S Abuljadyel) has been treating thalassaemia patients with their own stem cells and has claimed increase in HbF (which primitive cells should be producing over HbA), and claimed reduction in mean transfusion requirement and lowering of mean S. Ferritin (Abuljadayel IS et. al in Scient World J, 2006, 6:1278-97). Perhaps her process should be looked at again in view of the new respectability of ‘’retroprogrammed’’ mature adult cells.

The new interest in this reprogramming process, as mentioned above, is not for the direct infusion of stem cells into patients but to provide sufficient cells for genetic therapies. This was pointed out by Moi P and Sadelain M in a recent review (Haematologica, 2008, 93(3);325-330). Dr. Sadelain and his group working through a company called Errant Gene Therepeutics have a programme called Thalagen which has gained approval for gene therapy trials involving 10 patients expected to start in Sept. – Oct. 2008, (See www.MySpace.com/patgirondi).

An excellent recent review for those wishing to understand more about the difficulties faced towards safe and effective gene therapy for beta-thalassaemia is presented by Lebensburger J and Persons DA in Curr Opin Drug Discov Devel, 2008. 11(2):225-32.

Egypt has entered the field of genetic therapies by further developing the area of antisense oligonucleotides for b-thalassaemia. (El-Beshlawi A et al J Pedriatic Hematol Oncol, 2008, 30(4):281-4).

Another approach to genetic manipulation is to find a way to reduce a-globin gene expression thus reducing globin chain imbalance and so ineffective erythropoiesis and its consequences. This depends on understanding the process of a-globin gene expression a field being researched by a few groups. An update on current research in this hopeful area is provided by Voon HP and Vadolas J in Haematologica, 2008, Sept. 2 and in the same journal in August (93(8):1238-42 where they showed that short-interfering RNA (siRNA) can be used to mediate reductions in a-globin expression with a potential therapeutic effect in β-thalassaemia.

5. Cerebral Infarcts in Thalassaemia

One worrying report comes from Thailand Metarugcheep P et.al in J Med Assoc Thai, 2008, 1(6):889-94. They report silent cerebral infarcts (detected by MRI) in 24% of patients with beta thal/HbE and only in 11% of Sickle cell patients. This is the opposite of current knowledge and belief, which is that cerebral infarction, silent or not, is a feature of SCD and not thalassaemia. More brain MRI studies are needed in thalassaemia, especially intermedia, to confirm this finding. It may be related to the coagulopathy known to be a complication of thal intermedia.