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Haemoglobin disorders are the most common inherited condition worldwide with at least 5.2% of the world population carrying one or more of the alleles for β-thalassemia, αo-thalassemia or clinically significant haemoglobin variants (HbS, HbC, HbE, HbD). In addition, at least 20% of the world population carries α+-thalassemia [1]. Although initially confined to regions of South-East Asia, Southern China, India, Middle East, Central Asia and the Mediterranean, thalassemia is currently ubiquitous worldwide due to population migrations and intermarriages [2]. Most individuals who harbour the defective thalassemia gene together with a normal globin allele remain asymptomatic as the normal globin allele is able to compensate for haemoglobin production despite the presence of α/β-globin imbalance. In α-thalassemia, defects in any one or two of the four α-globin alleles may result in asymptomatic carriers while in β-thalassemia, heterozygous individuals carrying a single copy of the defective β-globin gene remain asymptomatic.

However, when both genes are defective, either as homozygous or genetic heterozygous compound β-thalassemia, the clinical manifestations are usually severe, presenting within the first 2 years of life, denoted as thalassemia major. Some individuals, who may have mild β-thalassemia mutations (βo+, β++) or co-harbour a β-globin variant e.g. HbE, may have milder clinical progression and present later in life with these individuals denoted as thalassemia intermedia. It is to be noted, however, that the clinical phenotype of HbE/β-thalassemia which is highly prevalent in Southeast Asia, is highly variable and may vary from a condition indistinguishable from thalassemia major to a condition that requires minimal treatment [2]. In the same vein individuals who have only a single normal α-globin allele, may present with thalassemia intermedia clinical phenotype due to the marked α/β-globin imbalance, the severity of which may be further modulated by the type of thalassemia mutation [3]. Loss of all four α-globin alleles is incompatible with life.

The management of thalassemia therefore needs to be double pronged. The first is the screening and identification of asymptomatic carriers, so that appropriate genetic counselling and preventive measures can be undertaken, while the second is directed to afflicted symptomatic individuals who require medical attention to prevent complications associated with both the condition and its treatment.

Screening and thalassemia carrier identification

  1. Top of page
  2. Screening and thalassemia carrier identification
  3. Transfusion therapy
  4. Iron overload and chelation
  5. Haematopoietic stem cell transplantation
  6. Supportive therapy
  7. Conclusion
  8. Disclosures
  9. References

The initial screening for thalassemia usually involves performing a full blood count and analysis of the red cell indices. Most national programs direct such screening to adolescence or mothers attending the antenatal clinic [4–6]. In general, MCH<27 pg, warrants further investigations for confirmation or exclusion of thalassemia. Unfortunately, populations with high prevalence of thalassemia may also have high prevalence of iron deficiency anaemia (IDA), which results in low positive predictive value for discrimination of thalassemia from IDA using red cell indices alone. Various formulae have been developed as well as the use of novel red cell indices to improve the diagnostic efficiency of red cell analysis but none have consistently demonstrated desirable standards of high sensitivity and specificity [7–9].

The identification of α-thalassemia carriers, traditionally is made after exclusion of IDA in a subject with normal electrophoreses and HbA2 levels. This is, however, unreliable especially when the individual carries both α- and β-thalassemia and the elevated HbA2 masks the α-thalassemia [3]. Meanwhile, β-thalassemia heterozygotes are oftentimes identified by raised HbA2, usually by high performance liquid chromatography. Some carriers, however, may be missed by this method if they happen to have a δβ-thalassemia mutation or have silent β-thalassemia mutations. In view of the problems associated with traditional screening, mutation screening and analysis using PCR methods has been proposed as feasible efficient alternatives. Novel approaches such as high-resolution-melt (HRM), multiplex ligation probe amplification (MLPA) analysis and high throughput direct nucleotide sequencing is likely to further improve the screening, identification and confirmation of thalassemia carriers [10,11].

Couples at risk who are identified as thalassemia carriers may be offered the options for pre-gestational (PGD) or prenatal diagnosis (PND) if the woman conceives. The ethical, legal and social implications of such a decision are myriad, especially within the diverse Asian setting and may vary widely from community to community [12]. The provision of appropriate genetic counselling by trained medical personnel is therefore essential.

Transfusion therapy

  1. Top of page
  2. Screening and thalassemia carrier identification
  3. Transfusion therapy
  4. Iron overload and chelation
  5. Haematopoietic stem cell transplantation
  6. Supportive therapy
  7. Conclusion
  8. Disclosures
  9. References

Regular red cell transfusions remain the mainstay of treatment in patients with β-thalassemia major unless the patient undergoes haematopoietic stem cell transplantation (HSCT) successfully. The goal of transfusion therapy is to correct anaemia adequate to maintain quality of life and normal development, suppress erythropoiesis and inhibit gastrointestinal iron absorption. Transfusion therapy is usually aimed at maintaining a pre-transfusion haemoglobin level of 90–100 g/l and a post-transfusion level of 130–140 g/l. Most regular transfusions are commenced by the age of 1 year, although occasionally the decision to start transfusion may be delayed if there is no significant compromise noted with growth, skeletal and cognitive development. It may be advisable though that transfusion not be delayed beyond 2–3 years of age, due to the higher risk of red cell alloimmunization in older children as compared to young infants [13,14]. Transfusion therapy, although life-saving, comes with its own list of inconveniences and hazards. The quality of life and cognition of children with thalassemia is poorer as compared to their unaffected counterparts and can be attributed to the frequent need for them to miss classes to attend the transfusion clinic [15]. Efforts, therefore, need to be made for appropriate scheduling of transfusions, minimize non-availability of blood and eliminate disruption of transfusions due to transfusion reactions such as febrile non-haemolytic transfusion reactions (FNHTR) and urticurial reactions. Red cell units prepared for transfusion should preferably be as fresh as possible (usually <5 days old) and pre-storage leuco-filtered. These steps are likely to contribute to longer intervals in between transfusions and reduced disruptions to transfusions from FNHTR. Complete phenotyping of significant red cell antigens (Rh, Kell, Kidd, Duffy, MNS) should be performed prior to commencing transfusion therapy [14,16]. Full antigen-matched red cells have been advocated for transfusion to prevent alloimmunization, but it is often logistically difficult especially with limited availability of antigen-typed blood off-the shelf. Developments in information technology, high-throughput molecular typing and automated typing systems available at low cost may make this feasible in future. Knowing the red cell antigen profile of the patient is very useful when antibody screens are positive and multiple auto- or alloantibodies are identified. Where multiple alloantibodies are found and the chances of finding a compatible unit from routine blood stocks are low, a panel of regular blood donors, negative for the antigens is instead identified for continued transfusion support of the patient. The effectiveness of transfusion therapy should be monitored by recording the patient’s body weight, pre- and post-transfusion Hb, haematocrit and volume of blood units transfused and the transfusion interval. Increasing transfusion volumes and frequencies signal poor red cell recovery and survival which may be due to hypersplenism, red cell antibodies or poor red cell quality and appropriate interventions need to be taken.

Iron overload and chelation

  1. Top of page
  2. Screening and thalassemia carrier identification
  3. Transfusion therapy
  4. Iron overload and chelation
  5. Haematopoietic stem cell transplantation
  6. Supportive therapy
  7. Conclusion
  8. Disclosures
  9. References

The most profound adverse effect of regular blood transfusion is iron overload as the human body has no effective means of increasing iron excretion to compensate for abnormal iron accumulation, leading to tissue iron deposition and serious consequences on the heart, liver, pituitary, thyroid, parathyroid and pancreas [17]. Limiting red cell transfusions without adversely effecting growth and development is therefore of utmost importance. Nevertheless, iron deposition with increasing serum ferritin level consistently occurs when the patient has received more than 10 red cell transfusions. Serum ferritin is generally a reliable indicator of total body iron stores, provided that iron burdens are low as in early transfused, non-chelated patients [18]. It can be falsely elevated with concomitant inflammatory conditions and liver disease [19]. Another measure for evaluating iron overload, albeit invasive, is determining liver iron concentration (LIC). Both measures may, however, be poorly predictive of cardiac iron overload, which contributes to most deaths in transfusion dependant thalassemia [20]. Cardiac T2*, measured by magnetic resonance imaging (MRI) is superior as a monitoring tool in this respect with patients demonstrating low cardiac T2* having a significant risk of developing overt heart failure over a 12-month period unless appropriate adjustments are made to chelation therapy [21].

To prevent continued accumulation of iron in tissues, iron chelators need to be administered to facilitate removal of iron through faecal and urinary routes [17]. The timing, choice of single or combination, and optimal dosing regimen for iron chelation is still debatable. Three chelating agents, parenterally administered deferoxamine (DFO), and orally administered deferiprone (DFP) and deferasirox (DFS), each with different properties are currently approved for clinical use. The limited accessibility to the drugs due to cost constraints in resource limited countries and poor compliance of patients to chelation regimes further aggravate iron chelation management. Nevertheless, the general recommendation is that iron chelation should be initiated once the patient has received 10–20 units of blood, or with serum ferritin levels above 1000 μg/l [18].

DFO, the first of the iron chelators has been in clinical use for more than 3 decades and is still recommended as the first line chelator where the body iron burden is relatively low and the primary goal of chelation therapy is prophylactic maintenance of iron balance [18]. DFO is, however, a large hexadentate chelator and cannot be orally absorbed and is usually administered as a continuous subcutaneous infusion delivered by a portable pump over 8–12 h, 5–7 times a week [17]. The need for regular continuous subcutaneous infusions thus makes DFO an unattractive treatment choice to many patients, often leading to poor compliance and ultimately contributing to early mortality in some groups of patients [22,23].

DFP meanwhile is a small molecule, bidentate chelator which is efficiently absorbed from the gastrointestinal tract [24]. Although the chelation efficiency of DFP is somewhat similar to DFO, DFP has the added advantage of being small, neutrally charged and with high lipophilicity, giving it superior access to intracellular chelatable iron pools. This contributes to the excellent cardioprotective effect of DFP demonstrated in several clinical studies [25–31]. The cardiac improvements have been even noted to occur before a significant reduction in total body iron. DFP use may, however, be complicated by athropathy, liver enzyme derangements, neutropenia and agranulocytsis, which precludes its use in some patient.

DFS, like DFP is orally administered but has the advantage of a long half-life allowing for once daily dosing as compared to thrice daily for DFP [17,32]. In patients non-compliant with DFO, DFS is an attractive alternative especially in consideration of its better safety profile as compared to DFP [33–35]. Studies suggest that DFS should also be effective in accessing and reducing cardiac iron stores as well as improving left ventricular ejection fraction (LVEF), particularly in patients with mild to moderate hepatic cardiac loading [31,36]. Preliminary results indicate that DFS may contribute to good survival outcomes and improved cardiac morbidity [36–38]. DFP, however, remains superior with regards to cardio-protection as compared to DFS [29,30]. Tailored dosing of DFS based on transfusional iron intake and individual response has been shown to be effective in reducing serum ferritin [33,37]. Interestingly, in a sub-analysis of the EPIC study, it was noted that subjects from the Asia Pacific had higher incidence of drug-related skin rash, implying a potential population driven pharmacogenomic effect [39]. In general though, side-effects with DFS are mild, contributed mainly by gastrointestinal upset, skin rash, ocular and auditory toxicity and mild reversible increase in creatinine [32].

Failure of monotherapy, intolerance and non-compliance coupled with the potential benefit of increased chelation efficacy has led to the advocating for combination iron chelation therapy in some patients [40]. Several drug combinations have been proposed either to be administered simultaneously, sequentially or on alternate periods. Combined DFO and DFP therapy has been found effective in patients with severe iron overload or overt iron related cardiomyopathy [22,28,38,41–44]. DFP and DFO have different tissue distribution and access to iron pools and iron balance studies have indicated that their concurrent use results in an additive or synergistic effect on total daily iron excretion, likely due to a ‘shuttle and sink’ effect. Patients receiving DFP in combination with DFO also show greater reduction in serum ferritin and improvements in LVEF or myocardial T2* over time as compared to those receiving DFO alone. A few reports indicate that combination of DFS with either DFP or DFO is safe and effective although these are either retrospective or limited in subjects [45,46].

Haematopoietic stem cell transplantation

  1. Top of page
  2. Screening and thalassemia carrier identification
  3. Transfusion therapy
  4. Iron overload and chelation
  5. Haematopoietic stem cell transplantation
  6. Supportive therapy
  7. Conclusion
  8. Disclosures
  9. References

Despite the spectacular success in thalassemia management seen in recent times, particularly in the area of transfusion and iron chelation therapy, access to this form of treatment is often curtailed in many parts of the world due to resource and financial limitations. Safe blood and effective chelation therapy are both expensive especially when considering that the treatment is life-long [47,48]. A curative option is thus desirable and may be cost-effective in certain patient populations [49]. However, the only curative option currently available is HSCT, which entails its own set of problems and non-negligible mortality and morbidity.

The major source of haematopoietic stem cells (HSC) for transplant is still derived from HLA-identical sibling bone marrow. The risk classification developed to predict HSCT outcome as outlined by Lucarelli et al. [50] for patients aged less than 17 years is still widely applicable, although it may not be applicable to adult patients. Three pre-transplant risk variables are included in this classification: hepatomegaly, portal fibrosis and irregular chelation history. Patients can thus be stratified into three groups based on them having none (class 1), one or two (class 2), or all three of the risk factors (class 3). With appropriate modifications to conditioning regime and graft-versus-host disease (GVHD) prophylaxis, overall survival and thalassemia-free survival of over 90% and 80%, respectively, is achievable in class 1 and 2 patients [50] while in class 3 patients, thalassemia-free survival may be inferior, ranging from 66% to 80% [51,52]. Adults in general though fare poorly, achieving overall and thalassemia-free survival of only about 65%. HLA-identical sibling, cord blood transplants, when available has shown encouraging results comparable to bone marrow-derived HSCT with less GVHD occurrence [53]. The availability of pre-implantation diagnosis with concurrent HLA typing has made it possible for embryo selection of an HLA-identical non-thalassemic infant donor [54]. This procedure, however, raises very important ethical, legal and social implications and merits serious bioethical debates.

Families, who do not have HLA-identical siblings available for HSCT, may be able to resort to unrelated cord blood transplantation although studies are still limited. In a single centre study from Taiwan involving 35 patients, 30 were alive and transfusion independent after a median follow-up of 36 months [55]. Analysis based on retrospective data obtained from three registries (Eurocord, NCBP, CIBMTR) showed a 2-year overall survival using unrelated cord blood of 62% [56]. Alternatively, HSC obtained from adult matched unrelated donors may be option and has shown considerable success especially with improvements in high resolution molecular HLA typing and stringent selection of best-matched donors. Overall survival and thalassemia-free survival of 79% and 66%, respectively, have been reported among a group of group of paediatric and adult patients transplanted with a matched unrelated donor [57]. Access to unrelated HSC, either in the form of cord blood, peripheral stem cell or bone marrow is, however, costly and limited especially since the same ethnic groups that tend to have high prevalence of thalassemia are the ones poorly represented within cord blood and marrow registries [58].

Haploidentical HSC from a mismatched family member has been explored as a source for HSCT to cater for patients where no HLA-matched donors are to be found. Results of this intervention is, however, limited and is complicated by relatively high rates of graft rejection, delayed immune reconstitution, GVHD and frequency of opportunistic infections [59]. Gene therapy using viral vectors and induced pluripotent stem (iPS) cells are still very early in their development but nevertheless appear as exciting future therapies.

Supportive therapy

  1. Top of page
  2. Screening and thalassemia carrier identification
  3. Transfusion therapy
  4. Iron overload and chelation
  5. Haematopoietic stem cell transplantation
  6. Supportive therapy
  7. Conclusion
  8. Disclosures
  9. References

Effective management of transfusion and iron chelation in highly industrialized countries has ameliorated much of the complications associated with thalassemia and its treatment, and has successfully transformed thalassemia from an invariably fatal disease to a sustainable chronic condition with prolonged survival and a good quality of life. Nevertheless, in resource-limited countries, adverse complications associated with blood transfusion and iron overload continues to occur. A multi-disciplinary team is required to address the various clinical problems that present in the thalassemic individual. Hormonal replacement and supportive medical and psychological therapy is necessary for endocrine complications such as growth delays, hypogonadism, hypothyroidism, hypoparathyroidism and diabetes mellitus. Osteopenia and osteoporosis is observed in a high proportion of well-treated patients which require early dietary interventions, correction of endocrinopathies and bisphosphonate therapy in some individuals. Transfusion transmitted hepatitis C virus (HCV) infection may occur especially where less stringent blood screening methods are practiced. HCV infection and iron overload are mutually reinforcing factors for progression of hepatic fibrosis and negatively impacts on survival and HSCT outcome. Use of anti-virals and interferon can arrest the progression of hepatic fibrosis.

Conclusion

  1. Top of page
  2. Screening and thalassemia carrier identification
  3. Transfusion therapy
  4. Iron overload and chelation
  5. Haematopoietic stem cell transplantation
  6. Supportive therapy
  7. Conclusion
  8. Disclosures
  9. References

The management of thalassemia has shown great strides over the past decades with enhanced understanding and knowledge of the genetic basis of the condition, its pathophysiology and the central role of iron overload in mediating tissue damage. We now have safe and effective red cell transfusions, three iron chelating drugs which are capable of acting additively and synergistically, and improved HSCT transplant regimes using various HSC sources, all of which have been key in improving survival and quality of life of patients with thalassemia. The next hurdle in improving thalassemia management globally is to make such treatment modalities universally available and at an affordable cost, directed to the communities that need them most, which unfortunately have the least access to. Effective screening and prevention programs need to be instituted in tandem to further limit the economic and clinical consequences associated with thalassemia management.

References

  1. Top of page
  2. Screening and thalassemia carrier identification
  3. Transfusion therapy
  4. Iron overload and chelation
  5. Haematopoietic stem cell transplantation
  6. Supportive therapy
  7. Conclusion
  8. Disclosures
  9. References