Special Article

Advances in Management of Thalassemia

M.B. Agarwal
Department of Hematology, Bombay Hospital Institute of Medical Sciences, Mumbai, India

ABSTRACT
Thalassemias represent the most common single-gene disorder causing a major public health problem in India.
Thalassemia and hemoglobinopathies probably developed over 7000 years ago as a defense against malaria. In simple
terms, thalassemia is caused by a mutation in either the -globin chain or the -globin chain which combine equally in red
cells to form hemoglobin. These mutations lead to varying degree of anemia resulting into thalassemia minor, intermedia
or major. Present write up relates to advances in the management of -thalassemia major. [Indian J Pediatr 2009; 76(2):
177-184] E-mail: mbagarwal@hotmail.com
Key words : Thalassemias; Hemoglobinopathies; Anemia; Single-gene disorder; Management

Conventional therapy
Over the last 3 decades, profound improvements in the
management have been observed. The development of
regular transfusion therapy and iron chelation has
dramatically improved the quality of life. It has
transformed thalassemia from a rapidly fatal disease to
a chronic disease compatible with prolonged survival.
Regular and adequate red cell transfusions in adequate
amount every 3 week to maintain pre-transfusion
hemoglobin around 9-10 g/dl has eliminated the
complications of anemia and compensatory bone
marrow expansion (Fig. 1a, 1b & 2). However, because
there is 200 mg of iron in each unit of packed cells, the
repetitive transfusions lead to iron overload. The
accumulation of iron leads to significant morbidity and

Fig. 2. Severe osteopenia affecting vertebral bones (age : 24 years)

Fig 1A & B. Hair-on-end appearance in inadequately transfused

thalassaemia major (age : 18 years).
Correspondence and Reprint requests : Prof. M.B. Agarwal,
MD, MNAMS, Haematology centre, Ghamat Lodge, 2nd Floor
804/-A, Dr B. Ambedkar Road, Above ING Vyasya Bank Dadar
TT, Mumbai-400 014, India.
[Received: December 14, 2008; Accepted December 14,
2008]

Indian Journal of Pediatrics, Volume 76February, 2009

Fig. 3. Morbidities related to iron overload in relation to age.

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M.B. Agarwal
mortality by damaging heart, liver and endocrine
organs ( Fig. 9 ). Fig. 3 shows morbidities related to iron
overload and their time sequence. Regular iron
chelation with desferrioxamine (DFO, desferal),
deferiprone (DFP, L1, kelfer, ferriprox) or deferasirox
(ICL 670, Exjade, Asunra, Desirox) has extended
survival free of iron-induced complications. Today, the
life expectancy of patients with thalassemia major has
increased from 25 years to over 55 years, mainly due to
aggressive transfusion support and chelation coupled
with patients compliance with medical treatment.1
Situation in India
However, these conventional modalities are expensive,
time consuming and inconvenient. In developing
world, especially India, poor availability of proper
medical care, safe and adequate red blood cell
transfusions together with high cost and poor
compliance with chelation therapy remain major
obstacles. Despite the increased life expectancy of
thalassemia, complications keep arising. These relate to
inadequate transfusions, transfusion transmitted viral
diseases, allo-sensitization, iron overload related
endocrine, liver and cardiac disturbances as well as
toxicities of iron chelators. These make conventional
treatment of thalassemia difficult and often fatal. 1
Splenectomy, which has become rarity in western
world, is needed in many patients in India, essentially
due to inadequate transfusions leading to
hypersplenism. Today, the same is performed
laparoscopically with lesser morbidity (Fig. 4).

hep-B) and ribavarin (for hep-C) are important

advances. Cost, however, remains prohibitive.1
Iron overload (fig 5,6,7,8,9)
Complications secondary to iron overload should be
essentially prevented. Their treatment is difficult and
often lifelong. Endocrinopathies secondary to iron
overload include hypogonadism, hypothyroidism,
diabetes mellitus (Fig. 9) and hypoparathyroidism. Most
of these occur towards the end of second decade of life.
These often require lifelong replacement therapy.2 Iron
related cardiac disorders include rhythm disturbances
and cardiac failure (Fig. 7). These form the chief
modality of death in young adults with thalassemia
major. They need inotropic and anti-arrhythmic
medications.3-4 Hepatic iron concentration (HIC) greater
than 15 mg/g dry weight is a risk factor for cardiac
disease. However, the exact relationship between HIC
and heart disease is ill-understood (Fig. 8). Iron related
hepatic cirrhosis and fibrosis are also important
issues(Fig. 5,6).1

Fig. 5 Hepatic iron overload.

Fig. 4 Laparoscopic splenectomy.

Prevention of transfusion transmitted diseases (TTD)

Vaccination is an effective tool to prevent hepatitis-B.
Effective screening has reduced HIV and HCV
infections. However, all of these still remain significant
problems in Indian subcontinent. Treatment of HIV
infection with Highly Active Anti-Retroviral Therapy
(HAART) as well as hepatitis-B and hepatitis-C
infection with pegylated interferon, lamivudine (for
178

Fig 6a & 6b. CT Scan showing tissue iron overload :

Normal volunteer (A) vs Severe iron overload (B).

Indian Journal of Pediatrics, Volume 76February, 2009

Advances in Management of Thalassemia

Fig. 7 Cardiac iron overload.

Fig. 10. SQUID for iron estimation in liver (SQUID : Superconductive Quantum Interference Device).

Fig. 8. Lack of concordance between hepatic & cardiac iron

overload (MRI Scan).

Fig. 9. Pancreatic iron overload (above) vs normal pancreas

(below): Autopsy specimen.

Assessment of overload
Effective management of iron overload requires frequent
evaluation of the body iron stores.5 There is, therefore, a
need for quantitative, non-invasive methods for
measuring body iron that are safe, accurate and readily
available. Serum ferritin measurement, although easy to
perform frequently, has too great a variability. Still ,at
Indian Journal of Pediatrics, Volume 76February, 2009

present, no other simple test is a better predictor. Direct

assessment of hepatic iron content (HIC) by liver biopsy
is the best predictor of the total body iron, but the
procedure is invasive, risky and difficult to perform
repeatedly. At present, Super-conducting Quantum
Interference Device Biomagnetic Liver Susceptometry
(SQUID-BLS) provides the most accurate and bestvalidated non-invasive method for measuring liver
iron (Fig. 10), however, its clinical availability is
restricted, and its use is limited to the liver. 6 The
development of high-transition temperature
ferritometers may improve clinical access in the future.
Recently, magnetic resonance imaging (MRI) has
become a widely available test, and in principle allows
the evaluation of iron overload in all organs that may be
affected by iron overload specially heart, liver and
probably even pancreas (Fig. 8).
Cardiac iron overload cannot be accurately and
easily assessed by repeated endomyocardial biopsies
owing to the heterogeneity of iron distribution and the
risk of complications. One can utilize the non-invasive
method of MRI based relaxation parameters T2 and
T2*(Fig. 8). Low T2* suggests high myocardial iron
content and it is associated with poor ventricular
function, myocardial arrhythmias and need for cardiac
medication. These can be used for repeated estimations.
These results have now been validated.7,8
Studies have also been published comparing
precision and repeatability of the MRI-derived HIC
estimates, obtained by measuring T2*, R2 or the liver-toreference SIR.7,8
Iron chelation (Fig. 11-23)
Desferrioxamine (DFO) and orally effective deferiprone
(DFP), either alone or together, are effective tools for iron
chelation. DFO-related problems include poor
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M.B. Agarwal

Fig. 11. Chelation therapy.

Fig. 14. Deferasirox is specific for iron.

Fig. 12. Chemical structure of iron chelators.

Fig. 13. Deferasirox : Two molecules required to bind one iron

item.

compliance and local reactions at the site of injection.

On the other side, DFP remains a less effective chelator
and it has the problems of marrow toxicity, arthritis, GI
intolerance, zinc deficiency and the controversial
hepatic fibrosis.9 Recent data has favoured DFP as a
more powerful iron chelator for the cardiac iron
overload. The two together probably form the best
modality of iron chelation. The combination fulfils the
shuttle hypothesis, according to which, DFP mobilizes
iron from the stores while DFO puts it out of the body.
Deferasirox (Exjade, Asunra, Desirox) is the new USFDA approved once a day, oral whole body iron
chelator with better efficacy and lack of side-effects. The
dose is around 20 mg/k/d (up to 30 mg/k/d). This has
made the conventional therapy of thalassemia,
relatively more comfortable.10
Implantable central vascular access devices (CVAD)
(Fig. 24) are useful. They are useful both for red blood
cell transfusions as well as intravenous DFO infusion.
These, however, can lead to infections including
staphylococcal bacteremia which can be fatal.1
Deferasirox is a tridentate iron chelator i.e., two
molecules of deferasirox are required to bind one iron
item. Deferasirox is specific for iron (Fig. 14). It is
effective in removing iron from all parts of the body. Fig.
180

Fig. 15. Hepatic iron staining after 1 year of Deferasirox vs DFO

(Desferal.

Fig. 16. Deferasirox restores contractile properties of cardiac cells.

15 shows the efficacy of deferasirox 30 mg/k/d in

removing iron from liver and its comparison with DFO
in the dose of 56 mg/k/d, 5 days/wk. LIC i.e., liver iron
concentration dropped from the baseline of 16.2 mg of
iron/gm of dry weight of liver to 3.3 mg of iron/gm of
dry weight of liver in one year. These results were
similar to those obtained with DFO.
Deferasirox restores contractile properties of cardiac
cells (Fig. 16). This effect is superior to that achievable
by DFO (Fig. 16). Deferasirox is effective in removing
cardiac iron from cultured cardiac cells (Fig. 17). It
causes significant improvement in cardiac T2* as
assessed by MRI (Fig. 18). It also reduces labile pool of
iron (LPI) as shown in Fig. 19.
Indian Journal of Pediatrics, Volume 76February, 2009

Advances in Management of Thalassemia

Fig. 17. Deferasirox is effective in removing cardiac iron from

cultured cells.
Fig. 20. Deferasirox is effective for 24 hours.

Fig. 18. Significant improvement in cardiac T2*.

Fig. 21. Exjade (Deferasirox) removes iron in stool (As against
Deferoxamine which removes iron both in stool and
urine).

Fig. 19. Deferasirox reduces LPI (Labile pool of iron).

Over oral bioavailability of deferasirox is 70%. The

peek plasma level occurs in 1.5 - 4.0 hours. It is almost
100% protein bound. 84% of dose is excreted in faeces.
Area under the curve (AUC) is 50% lower in children
under the age of 6 years. Fig 20 shows that deferasirox
can be given once a day as its efficacy lasts for full 24
hours. Fig 21 compares the modality of iron excretion by
the use of DFO (Deferoxamine) and deferasirox
(Exjade). As shown in the figure, DFO causes excretion
of iron in both urine and faeces while deferasirox does
so almost exclusively through faeces.
Deferasirox is best taken 30 minutes before breakfast
and preferably at the same time everyday. It is available
as dispersible tablets. The vehicle could be water,
orange juice or apple juice (Fig. 22). It should not be
swallowed or chewed. Deferasirox is available as tablet
strength of 400 mg and 100 mg through Novartis. It is
Indian Journal of Pediatrics, Volume 76February, 2009

Fig. 22. Deferasirox tablets to be dissolved in water.

also available in the tablet strength of 250 mg and 500

mg through Cipla. The starting dose is 20 mg/k/d but
based on iron overload, it can vary from 10 to 30 mg/k/
d. Dose increment is exercised at intervals of 3 months
and should not exceed by more than 5 mg/k/d. The
sealing dose is 30 mg/k/d. Higher doses are under
study. There is no data available on combining
deferasirox with either DFO or deferiprone.
The reported adverse effects include non-progressive
increase in S. creatinine (34%), minor GI tract
disturbances (26%), skin rashes not amounting to
discontinuation of the drug (7%) and rise in hepatic
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M.B. Agarwal
recommended for patients who cannot take DFO due to
one or the other reason.
Newer complications
Newer and previously less often described
complications have now been well-recognised. These
include :

Fig. 23. Median change in S. ferritin on Deferasirox therapy.

Hypercoagulable state
Osteoporosis
Hepatocellular carcinoma
Psychosocial problems

Hypercoagulable state
Prothrombotic hemostatic abnormalities leading to a
chronic hypercoagulable state have been noted. These
lead to frequent occurrence of thromboembolic
complications. Increased arterial stiffness secondary to
iron induced lipid peroxidation and development of
atherogenesis-related pathologies have been noted.11
Osteoporosis
Osteopenia and osteoporosis have been noted in aging
population of thalassaemia major. There is serious loss
of bone mineral density (BMD). This loss of BMD is of
multi-factorial origin, however, increased osteoclast
activity plays the most important role. Osteoprotegrin
(OPG) levels are low while the levels of soluble receptor
activator of nuclear factor-kappa B legend (sRANKL)
have varied. Disturbed bone remodeling results from
concerted hormonal changes such as growth hormone,
insulin-like growth factor I and sex hormones.
Administration of pamidronate has shown a
significant increase in BMD of the lumber spine and it
is now recommended that pamidronate at a monthly
dose of 30 mg is an effective treatment for thalassaemic
osteoporosis. 12 Alternative treatment includes
zolendronic acid in the dose of 1 mg as short I.V.
infusion once every 3 months.
Hepatocellular carcinoma

Fig. 24a & 24b. Continuous Desferal therapy using port.

enzymes (2%). The manufacturer also recommends

yearly examination for hearing loss and lenticular
opacities, monthly blood counts and monitoring
physical growth. So far, however, there is nothing to
suggest ill effect of deferasirox on hearing, lens, blood
counts or physical growth except for anecdotal cases.
Overall, deferasirox is a new, potent, safe, once daily,
oral, whole body iron chelator which has a flexible
dose schedule varying from 10 to 30 mg/k/d and it
appears to be a strong contender to replace the older
iron chelators. However, that is not the
recommendation at the moment as the clinical data on
deferasirox is only 3 years old. At the moment, it is
182

Hepatocellular carcinoma (HCC) can complicate liver

cirrhosis secondary both to iron overload and viral
infections. Italians have published 22 cases of HCC in
thalassemia major, 15 of them were males and the mean
age of diagnosis was 45 11 years.13 Eighty-six percent
were infected by hepatitis-C virus and majority were
diagnosed after 1993, suggesting that the problem is
becoming more frequent with the aging population of
thalassemia patients.13
Psychosocial problems
With most of thalassemia major patients achieving
adolescence, psycho-social support has become an
extremely important part of patient and family
management. There is a great need of meeting a genetic
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Advances in Management of Thalassemia

counselor at regular intervals. Unfortunately, there is no
formal programme on this front in India.
Transplantation
Since 1982, hematopoietic stem cell transplantation
(HSCT) has become an alternative modality of
treatment.14 It is the only available procedure that may
lead to cure. HSCT programme for beta thalassemia
major is now well established in India chiefly because
of efforts taken by CMC, Vellore. The advantages of a
life, free from disease and free from daily, tedious and
uncomfortable therapy, are far too many. However,
there is a real risk of dying from HSCT which is related
to patients age, iron overload and liver viral infections.
Adults have worse outcome . Among children, three
classes of risk have been identified on the basis of
regularity of previous iron chelation, liver enlargement
and presence of portal fibrosis. The results of HSCT
from HLA identical related donor are clear. Class 1
patients have a high probability of cure with very low,
early or late morbidity and mortality. The delay in
transplantation allows patients to move to a risk
category beyond class 1 and this substantially reduces
the probability of success. If a donor is available, there is
no reason for denying these patients the chance of
cure.14
Although, majority of HSCT have been from HLAidentical related donor, the same from an unrelated
volunteer, carefully selected by high-resolution HLAtyping, is an alternative for those lacking a compatible
family donor. The results obtained using such donors
are comparable with those obtained employing an
HLA-identical sibling.14
Recently, it has also been demonstrated that cordblood is as effective as, and possibly safer than, bone
marrow for transplantation for paediatric patients. It is
also possible that, in near future, thalassaemic adults
with poor organ function may tolerate and benefit from
transplantation employing non-myeloablative, less
toxic, conditioning regimens which induce mixed
chimerism. This may make an allogeneic HSCT safer for
adults as well as heavily iron-overloaded subjects.14
After successful HSCT, iron overload still remains an
important cause of morbidity. Regular two weekly
phlebotomy programme is safe, efficient and easily
applicable to the ex-thalassemics.14
In past, HSCT for thalassemia was a subject of
vigorous debate. It is not a life-saving procedure. It is an
elective option and has morbidity and mortality. The
ethical aspects for long, remained debatable, especially
as the conventional management of thalassemia kept
improving. Also, there were hopes for the corrective
gene therapy.14 With the passage of time, morbidity and
mortality of HSCT have significantly reduced. This is
Indian Journal of Pediatrics, Volume 76February, 2009

due to molecular tissue typing, better conditioning

regimens and wonderful developments in support
therapy including newer antifungal agents. All these
have made, HSCT more acceptable even for a benign
disease like thalassemia. For a country like India, it is
cost-effective as very few families can afford lifelong
transfusion and chelation.
Gene therapy
Gene therapy is an exciting prospect, although, there are
still formidable obstacles to be overcome before it is
likely to become feasible for the thalassemics. The
efficient gene transfer, especially of a large gene segment
like the globin gene and its regulators, into
haematopoietic stem cells, and sustained gene
expression, have not yet been achieved. Therefore, gene
therapy must await further research.14
Prevention
Although, it is not a part of this write up, it is important
to stress that the most important advance in the field of
thalassemia is its prevention. This has been very
successfully achieved in Mediterranean countries i.e.,
Italy, Greece, Cyprus and Sardinia. There are four
important aspects of prevention :

Awareness
Detection of carrier
Effective counseling
Prenatal diagnosis

Over last two decades, the programme has been

successfully implicated in major cities of India.
However, the desired goal of zero birth rate of
thalassaemia has remained a distant goal. In the
absence of a national thalassemia prevention
programme, this still remains a difficult but extremely
desirable goal.
REFERENCES
1 Cunningham MJ, Macklin EA, Newfeld EJ, Cohen AR.
Complications of -thalassaemia major in North America.
Blood 2004; 104:34-39.
2 De SV. Growth and puberty and its management in
thalassaemia. Horm Res 2002;58 Suppl 1:72-79.
3 Hui L, Leung MP, Ha SY, Chau AKT, Cheung YF. Early
detection of left ventricular dysfunction in patients with
beta thal major by dobutamine stress echocardiography.
Heart 2003; 89:669-670.
4 Westwood M, Anderson LJ, Pennell DJ. Treatment of
cardiac iron overload in thalassaemia major (Ed).
Haematologica 2003;88:481-482.
5 Jensen PD. Evaluation of iron overload. Br J Haematol
2004;124:697-711.
6 Fischer R, Longo F, Nielsen P, Engelhardt R, Hider RC, Piga
A. Monitoring long-term efficacy of iron chelation therapy
by deferiprone and desferrioxamine in patients with beta

183

M.B. Agarwal
thalassaemia major : Application of SQUID biomagnetic
liver susceptometry. Br J Haematol 2003;121:938-948.
7 Anderson LJ, Davis HB, Prescott E, Charrier CC, Bunce
NH, Firmin DN et al. Cardiovascular T2-star (T2*) magnetic
resonance for the early diagnosis of myocardial iron
overload. Eur Heart J 2001;22:2171-2179.
8 Jensen PD, Jansen FT, Christensen T, Eiskjaer H, Baandrup
U, Nielsen JL. Evaluation of myocardial iron by magnetic
resonance imaging during iron chelation therapy with
desferrioxamine indication of close relation between
myocardial iron content and chelation iron pool. Blood 2003;
101:4632-4639.
9 Wanless IR, Sweeney G, Dhillon AP, Guido M, Piga A,
Galanello R et al. Lack of progressive hepatic fibrosis during
long-term therapy with deferiprone in subjects with
transfusion-dependent beta-thalassaemia. Blood 2002;

184

100:1566-1569.
1 0 Agarwal MB. ICL 670 : A new oral chelator : A major
breakthrough in treatment of thalassaemia. Ind J Hematol &
Bl Trans 2003; 31 : 26-28.
1 1 Cheung YF, Chan GCF, Ha SY. Arterial stiffness and
endothelial function in patients with beta-thalassaemia
major. Circulation 2002;106:2561-2566.
1 2 Voskardou E, Terpos E, Spina G, Palermos J, Rahemtulla
A, Loutradi A et al. Pamidronate is an effective treatment
for osteoporosis in patients with beta thalassaemia. Br J
Haematol 2003; 123: 730-737.
1 3 Borgna-Pignatti C, Vergine G, Lombardo T et al.
Hepatocellular carcinoma in the thal syndromes. Br J
Haematol 2004;124:114-117.
1 4 Erer B, Lucarelli G. Bone marrow transplantation in
thalassaemia. Turk J Hematol 1999;16:147-159.

Indian Journal of Pediatrics, Volume 76February, 2009