Management of β-thalassaemia
Without treatment, β-thalassaemia
major is lethal within the first decade of life due to the complex
pathophysiology which leads to wide clinical manifestations. Current
management strategies for these patients comprise blood transfusion,
iron chelation therapy and, for a subset of patients; allogenic bone
marrow transplantation also known as haemopoietic stem cell
transplantation (HSCT). In recent years, a better understanding of the
pathogenesis and clinical effects of the disease has enthused research
into a number of promising novel therapies such as therapies that
modulate foetal haemoglobin (HbF) induction, gene therapy and gene
editing [5], [7], [8]. For this review we will talk about
the current management strategies and focus on novel therapies.
Blood Transfusions
Patients with β-thalassaemia major require lifelong, regular blood
transfusions administered every 2-5 weeks to maintain haemoglobin levels
of at least 9 – 10.5 g/dL. Transfusion is usually started before the
age of 2 years and it provides normal red blood cells and suppresses
ineffective erythropoiesis, also it enables normal growth and physical
activities and helps to reduce hepatosplenomegaly and bone deformities
[9]. It is estimated that approximately 100,000 patients currently
receive regular transfusions for beta-thalassemia worldwide and in some
countries transfusion therapies can be a huge burden. Although processes
for screening, preparation and administration of blood have improved,
blood transfusions expose patients to a number of risks such as
blood-borne infection, alloimmunization and iron overload [7],
[9].
Iron Chelation
In β-thalassaemia patients, iron stores are increased far beyond normal
physiological levels primarily due to increased iron absorptions and
secondary due to transfusions. Unless effective iron chelation therapy
is provided, these patients can suffer from iron overload that affects
the heart, liver and endocrine tissues. Three iron chelators are
currently approved by the regulatory authorities for the treatment of
iron overload in beta-thalassemia [7]. Deferoxamine (DFO), the first
commercially iron chelator is a hexadentate iron chelator that binds
iron in 1:1 complex. It is administered subcutaneously or intravenously
at a dose of 20-50 mg/kg/day. It has a short plasma half-life of 20-30
minutes and therefore it should be administered over a span of 8-10
hours a day on 5-7 days a week [10]. Although the benefits of
deferoxamine are well documented, the demanding regime leads to poor
compliance.
The introduction of two orally active iron chelators; Deferiprone and
Deferasirox were of a great advance in the management of patients with
beta thalassaemia. Deferiprone (DFP), the first oral iron chelator was
approved in 2011, it is a bidentate iron chelator that forms 3:1
complex. It is usually given at a dose of 75-100mg/kg/day three times
daily. DFP may cause gastrointestinal disturbances, increased
liver-enzymes, agranulocytosis and neutropenia and therefore patients on
DFP should be closely monitored Deferasirox (DFX), the other oral iron
chelator is a tridentate that forms 2:1complex. It is given at a dose of
20-40 mg/kg once daily and the most common side effects are
gastrointestinal disturbances, rash and mild increases in serum
creatinine. Sometimes a combination of both iron chelators is used
[7],[11]. Although iron-chelation therapy is available in most
countries, death due to iron overload remains an issue in
beta-thalassaemia patients.
Haemopoietic Stem Cell Transplantation (HSCT)
Until now the only available curative therapeutic approach for patients
with beta-thalassaemia is HSCT. The first HSCT in patients with beta
thalassaemia major took place in the 1980s and early 1990s at the
transplant centre in Pesaro, Italy. Initially, transplant experiences
were limited to good risk young thalassaemia patients with limited
morbidities and from matched sibling donors (MSD)
[12],[13],[14]. With today advances in medicine, HSCT is not
only limited to patients with matched sibling donors but also from
unrelated donors and cord blood transplantation [15]. Instead of
bone marrow, it was proposed to use peripheral blood stem cell
transplantation from HLA-matched siblings but studies showed that this
increased risk of cGVHD [16], [17]. In 2003, the possibility of
using HLA-identical sibling cord blood for HSCT in thalassaemia major
was reported that this type of allograft was associated with decreased
risk of both acute GvHD and chronic GvHD [18].
The best clinical outcomes of HSCT among patients with beta thalassaemia
are reported in those aged under 14 years at transplantation, in fact in
the last decade, almost all transplant centres try to perform HSCT in
the first years of life before iron-related complications develop.
Experience of HSCT in adult patients is still very limited and only few
centres perform HSCT in patients over the age of 18 years. In-fact it is
recommended that HSCT in adults is done only in patients who have been
well-chelated since infancy. About 25-30% of patients with thalassaemia
major have an available MSD but this is not always the case. The
experience of HSCT from HLA-disparate relatives is still very limited
and the results obtained are inferior than those obtained with
HLA-identical siblings as donors. A small study from related donors that
were not MSD had a thalassemia major free survival of 94%. This was
obtained by using a pre-conditioning phase with hydroxyurea, azathiprone
and fludarabine while the conditioning regime included busulfan,
thiotepa, cyclophosphamide and rabbit ATG [19], [20]. In case
that unrelated donors are used for HSCT, the donor must be selected
using high-resolution molecular typing for both HLA class I and II
molecules and a stringent criterion of compatibility with the recipient
[20].
Although HSCT is the only available curative approach for thalassemia,
nevertheless it has been limited by the high cost and significant
drawbacks associated with its implementation which include limited
availability of MHC-matched donors, the need for long-term
immunosuppression and increased risk of immunological complications.
Understanding the pathophysiology and clinical effects of
beta-thalassaemia has stimulated research into a number of promising
therapeutic approaches to tackle this disease.