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.