Abstract
Beta thalassemia (β-thalassemia) is part of a group of inherited hemoglobinopathies caused by a mutation in the beta globin gene, leading to minimal functional hemoglobin and resulting in damaged red blood cells and anemia. β-Thalassemia is most common in the Mediterranean region, South-East Asia, the Indian subcontinent, and the Middle East. Many of these regions include low- and middle-income countries where there are significant unmet needs in the adequate care and management of thalassemia. Patients with transfusion-dependent β-thalassemia, the most severe form of the disease, require regular blood transfusions. Chronic transfusions are often accompanied by iron chelation therapy to manage ferritin levels. Complications caused by transfusions and iron overload are only partially addressed by current treatment strategies, which negatively affect the quality of life of patients with transfusion-dependent β-thalassemia. Until curative modalities become available for all patients worldwide, methods of optimizing supportive treatments are needed to reduce the symptoms of ineffective erythropoiesis; minimize transfusion-related reactions and side effects; reduce rates of alloimmunization and transfusion-transmitted infections; and to reduce the psychosocial burden on both patients and their caregivers. This review aims to provide an overview and comparison of the ways transfusion-dependent β-thalassemia is identified and treated in different geographic regions, to assess unmet needs specific to these regions, and to discuss how therapies currently in development may improve care.
1 Introduction
Thalassemia is a group of inherited hemoglobinopathies in which an autosomal recessive mutation in a globin gene produces too little functional hemoglobin (Hb), resulting in anemia. The most common types are α-thalassemia and β-thalassemia (Mediterranean/Cooley’s anemia) (). Prevalence is highest in people of Mediterranean, Middle Eastern, Indian, South-East Asian, and African origin (tropical and subtropical areas) (Figure 1) (, ).
Figure 1
The deficit in one type of globin (α- or β-subunit) is generally accompanied by normal levels of the other, resulting in an imbalance of globin chain types, with a relative excess of the non-affected globin (). Therefore, in β-thalassemia, the deficiency in the β-globin subunit leads to an excess of α-globin. The α-globin aggregates to form inclusions that damage red blood cells (RBCs), causing hemolysis in the bone marrow and/or spleen. As a consequence, patients with β-thalassemia experience anemia and resulting weakness, fatigue, shortness of breath, headaches or dizziness, hepatosplenomegaly as a result of ineffective erythropoiesis, growth retardation, and heart problems (). The severity of the condition is related to the extent of the imbalance in α-globin and non-α-globin synthesis (, ).
Diagnosis of thalassemia is made based on clinical presentation and on hematologic and molecular/genetic analyses (). Many countries have preconception screening and prevention programs in place to identify carriers of thalassemia (). The most severe types of thalassemia are transfusion-dependent thalassemia (TDT), in which patients have a low level of functional Hb and require regular RBC transfusions. Transfusion-dependent β-thalassemia (TDβT) is the most common form of TDT; previous studies have shown that, worldwide, over 25,500 infants born annually have β-thalassemia that will become transfusion dependent (, ). TDβT is a multifaceted disorder associated with a wide variety of disease manifestations and management strategies. The aim of the present review is to provide an overview and comparison of treatment strategies for TDβT in different geographic regions, to identify unmet needs specific to these regions, and to discuss how therapies currently in development may improve care.
2 β-Thalassemia epidemiology and screening programs
The World Health Organization (WHO) reports that, globally, 40,000 infants annually are born with thalassemia, and the majority of these have β-thalassemia (). Most children with thalassemia are born in low- and middle-income countries (LMICs), predominantly in South-East Asia (Figure 1) (). Migration from regions where β-thalassemia is endemic has resulted in approximately 1.5% of the global population becoming carriers of β-thalassemia genes (), and countries where β-thalassemia is less common, such as the United States, have seen an increase in prevalence. In the last 50 years, prevalence of β-thalassemia in the United States has risen by 7.5% (), partly due to the movement of peoples from Asian and Middle Eastern countries by immigration and adoption (). Furthermore, according to the Cooley’s Anemia Foundation, approximately 12% of US patients with β-thalassemia were adopted from other countries ().
National programs to prevent β-thalassemia via carrier screening, counseling, and prenatal diagnosis in at-risk populations in endemic countries have existed since the 1970s (, ). Since then, several high-income countries (e.g., Italy) have initiated prevention programs that not only include population screening and prenatal diagnosis for thalassemia, but also include public education to remove any stigma associated with the detection of thalassemia genes (). This has resulted in a reduction in the number of children born with thalassemia (). In countries where thalassemia is prevalent, premarital or antenatal screening programs are largely voluntary initiatives offering information to at-risk populations. Therefore, to ensure widespread acceptance and to have maximum impact, they must take into account local needs and customs ().
β-Thalassemia is considered endemic in Italy; the country has had policies in place to reduce the incidence of hemoglobinopathies, including thalassemia, since the 1970s, with free carrier screening and genetic diagnostics widely available (, ). These preventative measures have led to a reduction in the number of children born with thalassemia (), particularly in Sicily, which has seen an 85% decrease in the incidence of β-thalassemia over the last 30 years (). In addition to reducing incidence, research into improving the overall standard of care in Italy has allowed patients with thalassemia to live long into adulthood (Figure 2). An Italian study followed patients with β-thalassemia over 50 years and found that those in younger birth cohorts demonstrated a better rate of survival, owing to an improvement in the standard of care over the years; however, despite these advances, the median age of death in patients with β-thalassemia was still 23.2 years ().
Figure 2
In the United States, although the prevalence of β-thalassemia has increased in recent years, it is not a core condition listed in the United States Recommended Uniform Screening Panel (RUSP) (). Despite this, methodologies used to screen for sickle cell disease (a RUSP core condition) detect a diminished ratio of Hb A to fetal Hb, which is suggestive of β-thalassemia. As such, appropriate care can be received if abnormal Hb levels are detected, to help minimize the impact of the disease (). In countries where β-thalassemia is prevalent, national thalassemia prevention and control programs have also been successfully implemented (Table 1). In Thailand, an upper middle-income country, widespread public education, genetic counseling, and preconception and prenatal screening and diagnosis have been effective in reducing the incidence of thalassemia (). Evidence suggests that despite no change in the prevalence of thalassemia genes among the population, new cases of the disease have been prevented by screening programs (). In Turkey, the Haemoglobinopathy Prevention Program has led to the creation of diagnostic centers for public education on β-thalassemia. Premarital screening tests were performed in 30% of all couples in the first year of the program, increasing to 81% in 2008, resulting in a 90% reduction in new thalassemia births in Turkey (). In Brazil, the β-thalassemia trait is present in around 1.5% of the Caucasian population, with suspected thalassemia major in 0.8% of the total population (); although the prevalence is lower than in Mediterranean or South-East Asian countries, this is still of concern in a country with over 214 million people (). The Brazilian National Neonatal Screening Program provides access to the majority of the country through separate State Neonatal Screening Programs (). The availability of screening for thalassemia and other hemoglobinopathies is important in a country with a diverse genetic background related to previous colonization and migration from the Mediterranean region and Africa ().
Table 1
| Country | High income | Upper-middle income | Lower-middle income | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Italy | USA | Cyprus | Turkey | Thailand | Brazil | Morocco | Pakistan | Egypt | |
| Screening programs () | Yes | Yes | Yes | Yes | Yes | Yes | No | Yes | Yes |
| Specific legislation on safety and quality of blood for transfusion () | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes |
| National guidelines on the clinical use of blood () | Yes | Yes | No | Yes | Yes | Yes | Yes | Yes | Yes |
| Specialized thalassemia centers | Yes | Yes | Yes | Yes | No | No | Yes | Yes | Yes |
| Whole-blood donations per 1,000 of the population (, ) | 42.5 | 35.3 | 53.0 | 29.1 | 16.0 | 18.6 | 8.9 | 10.9 | 4.3 |
| RBC transfusions per 1,000 of the population (–) | 40.6 | 33.1 | 51.8 | 27.9 | 15.1 | 6.4 | 8.2 | 3.5 | 4.2 |
| Chelation availability (–) | DFO, DFP, and DFX available via the national health service | DFO, DFP, and DFX available to those who are insured | DFO, DFP, and DFX available via the national health system | DFO, DFP, and DFX available via universal health insurance | DFO, DFP, and DFX available via universal health coverage | DFO, DFP, and DFX available via universal health coverage | DFO, DFP, and DFX available to those who are voluntarily insured | DFO, DFP, and DFX available to those who are voluntarily insured | DFO, DFP and DFX available to those who are voluntarily insured |
| MRI units per 1 million of the population (–) | 30.22 | 38.96 | 21.00 | 10.92 | 27.87 | 6.79 | 0.36 | 0.13 | 2.00 |
Availability of management strategies for transfusion-dependent β-thalassemia in countries where thalassemia is prevalent.
DFO, deferoxamine/desferrioxamine; DFP, deferiprone; DFX, deferasirox; MRI, magnetic resonance imaging; RBC, red blood cell.
In lower-income countries, awareness of β-thalassemia plays a role in the epidemiology of the disease. In Pakistan, the burden of β-thalassemia is high and life expectancy of patients with thalassemia is around 10–12 years owing to a lack of healthcare resources and the limited availability of safe donor RBCs (). The Punjab Thalassemia Prevention Project offers cascade screening for relatives of children with β-thalassemia (). A study of northern Moroccans with hemoglobinopathies found that 50% of couples were consanguineous compared with 30% in the general population. In the hemoglobinopathy population studied, a significant decrease of 14% was found in the prevalence of consanguineous marriages compared with the previous generation. This may be attributed to awareness campaigns informing the population of the risks of consanguineous marriage ().
The migration of people from regions where β-thalassemia is prevalent has an impact on the healthcare systems of the host country. Overlooking new residents will likely change the epidemiology of β-thalassemia and it is important that these people are included in relevant screening programs (, ). Despite the relative success of screening programs worldwide, not offering the services to migrants negatively affects the epidemiology of the disease. Following an influx of refugees at the beginning of the Syrian civil war, over one-quarter of a million babies were born to Syrian couples living in Turkey between 2011 and 2017 (). Difficulties in communication and understanding of medical terminology led to these refugees being overlooked by screening programs (). Owing to the large volume of migrant workers coming to Thailand, it has been recommended that the Thai government extend prevention and control programs to include migrant workers living in the country, many of whom come from other countries where β-thalassemia is endemic ().
3 Management of transfusion-dependent β-thalassemia
3.1 Treatment guidelines
The aim of β-thalassemia treatments is primarily to suppress the ineffective erythropoiesis that causes symptoms of anemia, with conventional treatments focused on RBC transfusion and iron chelation (). In Europe, few countries provide dedicated thalassemia services, and details of measures for patient monitoring and treatment are, overall, very scarce (). Italy has, arguably, one of the best standards of care for thalassemia as a result of the high prevalence and availability of resources. A survey of 114 Italian treatment centers reported that complete blood count, ferritin level, echocardiography, and T2*-weighted magnetic resonance imaging (MRI) were commonly performed in the preceding 12 months. Approximately half of patients reviewed were reported to have received ≥ 3 units of RBCs per month, with deferasirox chelation therapy (Table 2) administered in two-thirds of patients ().
Table 2
| Treatment | Action | Administration |
|---|---|---|
| Blood transfusion () | Provide healthy RBCs | Every 2–5 weeks to maintain a pretransfusion Hb level of 95–105 g/L |
| Bone marrow transplantation () | Provide healthy hematopoietic stem cells | N/A—surgical treatment |
| Desferrioxamine () | Iron-chelating agent | Transdermal infusion over 8–12 hours, five or six times per week; IV, continuous infusion in heart failure |
| Deferiprone () | Iron-chelating agent | Tablet or liquid taken three times per day |
| Deferasirox () | Iron-chelating agent | Tablet taken once per day |
| Luspatercept () | Erythroid-maturation agent to reduce anemia | Subcutaneous injection every 3 weeks |
Key available treatments for transfusion-dependent β-thalassemia.
Hb, hemoglobin; IV, intravenous; N/A, not applicable; RBC, red blood cell.
Many countries have their own national guidelines with recommendations for the care of patients with thalassemia (Table 1). For example, in South America, Brazil has comprehensive guidelines for the management of TDβT (), and in South-East Asia, Thailand has recommendations for RBC transfusions in patients with TDT (). In recent years, six major TDT management guidelines have been published (the Thalassemia International Federation, and national guidelines for Australia, Canada, Italy, the United Kingdom, and the United States of America). These guidelines are aligned on most aspects of management, although there are some differences in iron overload monitoring and when to administer chelation therapy (). Iron loading can be monitored with MRI; however, access differs depending on the income level of a country (Table 1) (). Italian guidelines specifically recommend liver biopsy with iron measurement by atomic absorption spectroscopy as the gold standard, with MRI as an accepted alternative. Italian patients over the age of 5 years with β-thalassemia and without a transfusion history must also have serum ferritin levels monitored 1–2 months apart to determine a baseline level before iron chelation can be initiated (). In children who are frequently transfused, Italian guidelines recommend that iron chelation can be initiated when they have received > 10 units of blood or if their serum ferritin level is ≥ 1,000 ng/mL (), which is also recommended by the 2021 Thalassemia International Federation guidelines ().
3.2 Blood transfusions
Blood transfusions are the primary treatment to suppress ineffective erythropoiesis and reduce anemia (Table 2), with guidelines recommending that a clinical assessment of the need for regular transfusions should quickly follow a confirmed genetic diagnosis of thalassemia. International guidelines for the management of TDT state that to initiate transfusion therapy, patients must satisfy the following criteria (). There must be a confirmed diagnosis of thalassemia, a Hb level of < 70 g/L on two occasions more than 2 weeks apart (excluding other causes), and/or the following clinical criteria irrespective of Hb level: significant symptoms of anemia, poor growth/failure to thrive, complications from excessive intramedullary hematopoiesis, and clinically significant extramedullary hematopoiesis.
For patients with TDT, lifelong regular blood transfusions are recommended every 2–5 weeks to maintain a pretransfusion Hb level of 95–105 g/L (). This transfusion regimen promotes normal growth in children and allows for a normal level of physical activity (). Maintaining the guideline-recommended Hb level may require shorter intervals between transfusions, but an appropriate interval between treatments must consider other factors, such as a patient’s school or work schedule, and fit to their lifestyle to prevent a negative effect on quality of life (QoL) (). However, maintaining an adequate supply of blood in countries where β-thalassemia is endemic is difficult, as many of these are LMICs that lack the volunteers, the resources, and the national organization of high-income countries. This can be seen in the overall volume of whole blood donated, where lower-income countries may have as much as 10-fold fewer donations per 1,000 of the population compared with higher-income countries (Egypt, 4.3 vs. Italy, 42.5; Table 1). Globally, only 12% of children born with TDβT received a RBC transfusion, many of whom live in lower-income countries ().
3.2.1 Transfusion-related complications
In a study of Italian patients with thalassemia, the most frequent transfusion-related clinical complication was iron-related heart disease, reported in 30% of patients, with many other common complications being endocrine in nature (). As a result of suboptimal monitoring and management, symptoms of comorbidities, such as endocrine disorders, may increase with cumulative iron exposure and can manifest in early adulthood in patients who are exposed to chronic transfusions without adequate chelation (). Reducing the intervals between transfusions may be necessary to maintain guideline-recommended Hb levels, but can cause patient discomfort and inconvenience. Increasing the exposure to allogeneic blood with short intervals between transfusions leads to the accumulation of excess iron in the heart, liver, and other organs; cardiac iron overload can have serious consequences, with a serum ferritin level > 1,000 ng/mL reported as an independent risk factor for death (). In addition to the excess iron from blood transfusions, patients with thalassemia have inappropriate increased absorption of iron from their diet as a result of hepcidin suppression (–). Furthermore, there is the risk of alloimmunization with RBC transfusions through the development of anti-RBC antibodies () and allergic, febrile, or delayed hemolytic transfusion reactions (), as well as the risk of transmission of blood-borne infections.
3.3 Management of transfusion-related complications
Chelation therapy (deferoxamine [desferrioxamine, Desferal], deferiprone, deferasirox) is used to remove the iron build-up resulting from blood transfusions and iron absorption through the gastrointestinal tract (). It must be taken regularly to be effective (), but factors impacting adherence include route of administration, side effects, and forgetfulness. Adherence to a medication that must be taken every day, sometimes multiple times per day, is very difficult for many patients to maintain (, ). Although chelation therapy may be available globally (Table 1), the cost is prohibitive in some countries. Worldwide, less than half of children born with TDβT receive adequate iron chelation therapy (). According to a 2008 WHO report, of the 100,000 patients living with regular transfusions, around 3,000 die annually in their teens or early adulthood from uncontrolled iron overload ().
Alloimmunization is not uncommon, with 25% of thalassemia patients in one study having positive alloantibodies () and 18% of patients in another study (). It depends on several factors, including the homogeneity of the donor–recipient population (). Blood antigen matching is performed to reduce alloimmunization () and Rh genotyping for the purpose of identifying genetic variants is possible, although cost prohibitive in many countries (). A systematic review of 41 studies determined that 78% of antibodies identified in patients with TDT were anti-Rh and anti-Kell antibodies; therefore, matching these antigens may reduce the risk of alloimmunization by approximately 80% (). In a Moroccan study over 9 years, the prevalence of RBC alloimmunization was 9%, with a univariate analysis indicating that a transfusion interval < 3 weeks was a significant risk factor (71% vs. 36% for intervals > 3 weeks; p = 0.01). As previously discussed, this may be due to increased exposure to allogeneic blood compared with longer intervals between transfusions ().
3.3.1 Patient management strategies
Management of patients with β-thalassemia in specialized treatment centers has a positive impact on life expectancy (); however, they are often only accessible to patients with TDβT who reside in high-income countries. Although many lower-income countries where thalassemia is endemic do possess specialized treatment centers to provide safe blood and proper care to patients (Table 1), they are often only present in the major cities, and in some cases, there may only be a single specialized center serving the whole country. In Morocco, most patients with thalassemia reside in rural areas (), and do not have the regular access to care that they require. Conversely, in Italy, there are several specialized centers across the country (). Patients treated at specialized centers have longer life expectancies (), as they are treated by a multidisciplinary team and provided with the best possible standard of care (Figure 3); however, longer life expectancy has associated complications, as older people are more likely to develop comorbidities that must be treated in tandem with their thalassemia (). In many parts of Asia, prognosis remains poor, as there is limited treatment availability and treatments are performed by non-specialized local hospitals; supportive treatments such as RBC transfusion are often the only available treatment (). In many Asian countries, treatment is only available to those who can afford it, particularly in the case of iron chelation (). Although blood transfusion may be widely available in these countries, access to chelators to manage iron overload are not (), leading to associated complications and, ultimately, death.
Figure 3
Luspatercept is a treatment for anemia in adults with β-thalassemia who require regular blood transfusions (Table 2). In the Phase III BELIEVE trial, luspatercept reduced the transfusion burden of patients with TDβT compared with placebo. Luspatercept has received approval for use in TDβT in both the US and Europe (, ); however, this treatment may not yet be covered by many national healthcare systems or private insurers. Another treatment, hydroxyurea, is an orally administered ribonucleotide reductase inhibitor approved to reduce the need for blood transfusions in sickle cell disease. This has the potential to reduce the cost of transfusion; however, there are inconsistent results in patients with TDβT and those receiving hydroxyurea should be closely monitored for response (). In addition, potential therapies in the pipeline, such as pyruvate kinase activators etavopivat and mitapivat, may decrease transfusion needs in patients with β-thalassemia (, ).
3.3.2 Safety of blood transfusions
Chronic blood transfusion comes with many risks, and many patients in lower-income countries are unable to access safe blood (). International guidelines recommend that blood should be obtained from “carefully selected voluntary, non-remunerated donors” to prevent transfusion-transmitted infections (). Two-thirds of countries have specific legislation on the safety and quality of transfused blood, but this only includes 39% of low-income countries (). Lower-income countries often have decentralized blood banking systems that rely heavily on non-governmental organizations, family replacement donations, and charities. This is often due to a lack of centralized systems, specialized centers, and voluntary donations, and improper screening (, ). The WHO recommends that all blood donations should be screened for infectious agents prior to use, and screening for the human immunodeficiency virus (HIV), hepatitis B (HBV), hepatitis C (HCV), and syphilis should be mandatory. Further testing for locally relevant infectious diseases, such as malaria or West Nile virus, may also be necessary (). Nearly all of the blood donated in high-income countries and upper-middle-income countries is screened (99.8% and 99.9%, respectively), but screening rates are only 83% and 76% in LMICs and low-income countries, respectively. This has led to a higher prevalence of transfusion-transmitted infections (TTIs) in lower-income than in higher-income countries (HIV: 0.7% vs. 0.002%; HBV: 2.8% vs. 0.02%; HCV: 1.0% vs. 0.007%; syphilis: 0.9% vs. 0.02%) (). Furthermore, LMICs often have difficulty in sourcing and storing sufficient volumes of blood, and these shortages may be addressed via unbanked directed blood transfusion, where donors undergo rapid TTI tests before transfusing blood to the recipient. There is concern that the use of rapid testing may lead to increased infection rates (); only 34% of blood laboratories in low-income countries undergo external quality assessment, compared with over 80% in high-income countries. Chronic transfusions required during the management of TDβT increase the risk of acquiring TTIs; in one study in Pakistan, older thalassemia patients had a significantly higher risk of HCV infection than thalassemia patients aged ≤ 10 years (22% vs. 8%; p = 0.005) (). This difference can, however, be attributed to better screening in younger people and the fact that HCV is also sexually transmitted (). Countries where thalassemia is prevalent have some of the highest rates of TTIs, such as HCV. The rates of thalassemia patients with HCV in Iran and Bangladesh are approximately 15% (), and an Indian study found a significant HCV viral load in 16% of chronically transfused patients with thalassemia (). In a study of almost 4,000 patients with thalassemia in Pakistan, HCV was present in the serum of 26% of patients assessed (). The introduction of serologic testing and the development of direct-acting antiviral agents has led to HCV being all but eradicated in higher-income countries, such as Italy (). Although the risk of acquiring TTIs, including HIV, HBV, HCV, and syphilis, is higher in LMICs than higher-income countries, it is decreasing globally and may reduce further as new technologies, such as pathogen inactivation systems for RBCs, become widely available ().
4 Unmet needs in transfusion-dependent β-thalassemia
As outlined, there are multiple facets to disease presentation in thalassemia, and most are only partially addressed by current treatment strategies. Despite improvements in treatment, disease- and transfusion-associated complications are still a challenge (). The burden of regular transfusions in TDT and the associated side effects, particularly iron overload, is central to this (), with a number of thalassemia-related complications, and subsequent healthcare resource utilization, positively correlated with increases in the number of units of RBCs transfused (). A study in the United States of America estimated that patients with TDβT required an average of 17 RBC transfusions annually with an annual healthcare cost of US$130,000/year compared with US$5,000/year in non-thalassemia controls; these costs were attributed to RBC transfusion and chelation therapy (). The incidence of comorbidities in patients with TDβT is higher than people without the disease and may be largely attributable to iron overload (). With respect to cancer incidence, the liver is a common site of tumor development in patients with thalassemia, possibly as a result of the stress caused by iron overload and infection with HBV/HCV, although overall cancer risk is not increased as a result of the presence of the hemoglobinopathy (). An Italian study assessing COVID-19 vaccinations reported that the immune response of patients with TDT resembled that of healthy elderly subjects, indicating that the immune system may prematurely age in these patients (). Poor physical health-related quality of life (HRQoL) in patients with β-thalassemia was positively associated with somatic comorbidities and depression score in an Iranian study. Variables associated with poor mental HRQoL were anxiety and depression scores (). In another Iranian study, all aspects of QoL were affected in adults with TDβT, with QoL correlating to laboratory findings. The authors concluded that managing patients’ laboratory indices may improve QoL and regular screening of QoL may allow for more efficient management of disease complications (). This impairment in QoL is not exclusive to LMICs, as patients with TDβT in Italy reported significantly lower general health and vitality as well as total psychological well-being than the general population (). In Sri Lanka, children with TDβT had lower mean HRQoL scores than healthy children, and splenectomy, short stature, under nutrition, and longer hospital stays were associated with lower QoL scores (). In Malaysia, HRQoL in children with TDT has improved since 2005, but psychosocial health was still lacking, with school functioning being the lowest dimension of this subscale (). In children with TDT in the United Arab Emirates, increasing age was associated with worse QoL scores, possibly due to older children suffering more from iron overload and having missed out on more school (). Despite a high burden on QoL in TDT, there is some evidence indicating that this may be higher in patients who do not require regular transfusion (), that is, non-transfusion-dependent thalassemia. A recent study found that anxiety/depression and perceived barriers were significant negative predictors of QoL in these patients, whereas a health-promoting lifestyle was a positive predictor. Where budgets are limited, the authors suggested that factors more strongly affecting QoL should be prioritized (). In addition, there are other burdens that may negatively impact the QoL of the patient. First, there are the financial costs for the treatment itself (, ), but there are also the costs associated with undergoing treatments, such as transport, and lost opportunities for the patient and their family (). Finally, the loss in productivity at work as well as the inability to do unpaid work may negatively impact the patient ().
Current curative measures utilizing stem cell transplants are limited and may be high risk, particularly in LMICs where the standard of care is suboptimal. As such, recent research has focused on improving the collection, preparation, testing, storage, transport, and administration of blood and blood components. The COVID-19 pandemic has led to a severe shortage of donated blood, with donor attendance falling by up to 30% and many hospitals unable to supply blood to the patients who need it most (, ), particularly in lower-income countries where supply is already limited (Table 1). In the case of patients with TDβT, there is a need to reduce the requirement for RBC transfusion or to extend the shelf life of RBCs to prevent supply issues and allow patients to receive the care they need. A reduction in the required transfusion frequency and volume may also reduce or delay iron overload and its effects on patient health and QoL.
5 Treatments in development
Many therapies and technologies are currently in development for TDT that attempt to address currently unmet needs (Table 3) (, ). There are therapeutic interventions in development that aim to increase Hb levels, with different combinations of chelators aiming to optimize the reduction in iron overload. In addition, there are several therapies that aim to resolve the underlying disease process, such as stem cell transplantation and gene therapy. Genome editing may help to reduce transfusion dependence; alteration of the BCL11A erythroid enhancer has been shown to induce long-term transfusion independence in patients with TDβT (), while mutation of α-globin enhancers has demonstrated benefits in patients with TDβT via a clinically significant knockdown of α-globin (). Furthermore, a technology in development in clinical trials is aiming to improve the quality of transfused blood via hypoxic storage of RBCs (). This may help to reduce the frequency of RBC transfusions and the overall transfusion burden by providing patients with cells of better quality.
Table 3
| Unmet need | Therapy | Clinical phase | Potential benefit |
|---|---|---|---|
| Addressing underlying disease process | Intrauterine blood transfusion for Hb Bart’s hydrops fetalis () | – | Reduce overall disease severity and improve survival in most severe thalassemia forms |
| Several drugs that induce production of fetal Hb are being investigated, including hydroxyurea for β-thalassemia () | II–III | ||
| Targeting α-globin expression to cure β-thalassemia () | |||
| Various kinds of stem-cell therapies/gene therapies: EDIT-301 [clustered regularly interspaced short palindromic repeats (CRISPR) gene-edited CD34+ hematopoietic stem/progenitor cells] NCT05444894 ET-01 (autologous CRISPR-Cas9-modified CD34+ human hematopoietic stem and progenitor cells) NCT04390971 NCT04925206 ST-400 (autologous CD34+ hematopoietic stem/progenitor cells that are genetically modified ex vivo at the erythroid-specific enhancer of the BCL11A gene) NCT03432364 NCT05145062 OTL-300 (autologous hematopoietic stem cells genetically modified with the GLOBE lentiviral vector encoding for the human beta-globin gene) NCT02453477 NCT03275051 LentiGlobin BB305 (autologous CD34+ cell-enriched population that contains cells transduced with LentiGlobin BB305 lentiviral vector encoding human βA-T87Q-globin) NCT03207009 NCT02906202 NCT02151526 CTX001 [autologous CRISPR-Cas9-modified CD34+ human hematopoietic stem and progenitor cells (hHSPCs) using CTX001] NCT03655678 NCT05356195 NCT05477563 Mismatched unrelated volunteer donor and/or haploidentical-related donor stem cell transplantation NCT03653338 | I/II – I I/II – I/II – III III I/II II/III III III I/II | ||
| Anemia | Thalidomide NCT03651102 () | II/III | Reduce anemia and associated symptoms by increasing hemoglobin levels/globin expression |
| PTG-300 NCT03802201 (TRANSCEND) Vamifeport NCT04938635 (VIT-2763) NCT04364269 (VITHAL) NCT04938635 | II II II II | ||
| Yisui Shengxue granule NCT01549080 | – | ||
| Sirolimus (inducer of fetal Hb) NCT03877809 (SIRTHALACLIN) NCT04247750 (THALA-RAP) | II II | ||
| Luspatercept NCT03342404 (BEYOND) NCT04143724 NCT04064060 NCT02604433 (BELIEVE) NCT05462548 | II II III III IV | ||
| AG-348 (mitapivat) NCT04770779 | III | ||
| Improving quality of blood transfusion/reducing iron overload | Leukoreduced packed RBCs NCT03992001 | IV | Improve Hb concentration with RBC transfusion and reduce anemia |
| Hemanext® oxygen reduction system (hypoxic RBC storage) NCT03301779 | II | Reduce overall frequency of transfusions. Use of anaerobically stored RBCs may reduce transfusion-related adverse events. Reduce the levels of markers of inflammation and hypoxia compared with non-anaerobically stored RBCs () | |
| Reducing iron overload | CN128 NCT04614779 Deferiprone (pediatric patients) NCT03591575 (START) Chelation combination therapies: Deferasirox + deferoxamine NCT00901199 Deferasirox + deferiprone NCT01709032 | II IV II I/II | Improve the efficacy of iron chelation therapy and reduce physiological consequences of iron overload, for example cardiac consequences |
Overview of therapies/technologies in clinical development for transfusion-dependent thalassemia.
CRISPR, clustered regularly interspaced short palindromic repeats; Hb, hemoglobin; NCT, National Clinical Trial; RBC, red blood cell.
6 Discussion
TDβT is a severe form of thalassemia that affects many people worldwide, with thousands of infants born annually eventually becoming dependent on transfusions in later life (, ). This multifaceted disorder is associated with a large disease burden, and the wide variety of symptoms require individualized management strategies and adequate resources. Patients with thalassemia have a high unmet need as a result of the effects of the disease and also the side effects of the primary management strategy, RBC transfusion. Most patients with thalassemia are in LMICs where the standard of care is suboptimal compared with higher-income countries. As these needs continue to go unmet throughout a patient’s life, both their physical and mental health are negatively affected, impacting both their life expectancy and their QoL as a whole.
Curative treatments are not yet available for every patient worldwide; they may be high risk and are expensive, regardless of availability. Iron chelation therapies and new treatments, such as luspatercept, are not widely available. Therefore, RBC transfusion with iron chelation currently remains the main treatment for most patients. However, the availability of a safe and adequate blood supply is suboptimal in many countries, particularly in those lower-income countries without bloodbanking infrastructure, which rely on the family of the patients and paid volunteers to maintain supply. In addition to the low volumes of available blood in these countries, there is a higher incidence of TTIs than in higher-income countries.
In conclusion, until curative modalities become available for all patients, modalities to optimize blood transfusion are needed to reduce anemia and its impact on physical and mental well-being; minimize transfusion-related reactions, side effects, alloimmunization, and TTIs; and reduce the psychosocial burden on both the patient and their caregivers. In addition, all patients need to have access to adequate chelation to reduce the sequelae associated with iron overload.
Statements
Author contributions
All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.
Conflict of interest
GG reports independent consultancy work for Hemanext, Inc. LO reports employment by and stock in Hemanext, Inc.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
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Summary
Keywords
anemia, hemoglobinopathies, transfusion-dependent beta thalassemia, unmet need, epidemiology, blood transfusion
Citation
Forni GL, Grazzini G, Boudreaux J, Agostini V and Omert L (2023) Global burden and unmet needs in the treatment of transfusion-dependent β-thalassemia. Front. Hematol. 2:1187681. doi: 10.3389/frhem.2023.1187681
Received
16 March 2023
Accepted
23 May 2023
Published
20 June 2023
Volume
2 - 2023
Edited by
Annarita Miccio, INSERM U1163 Institut Imagine, France
Reviewed by
Sachith Mettananda, University of Kelaniya, Sri Lanka; Zahra Pakbaz, University of California, Irvine, United States
Updates
Copyright
© 2023 Forni, Grazzini, Boudreaux, Agostini and Omert.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Laurel Omert, Laurel.Omert@hemanext.com
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.