IMR Press / FBE / Volume 14 / Issue 3 / DOI: 10.31083/j.fbe1403018
Open Access Review
Benefits and Risks in Polypathology and Polypharmacotherapy Challenges in the Era of the Transition of Thalassaemia from a Fatal to a Chronic or Curable Disease
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1 Postgraduate Research Institute of Science, Technology, Environment and Medicine Limassol, 3021 Limassol, Cyprus
*Correspondence: kontoghiorghes.g.j@pri.ac.cy (George J. Kontoghiorghes)
Academic Editor: Alessandro Poggi
Front. Biosci. (Elite Ed) 2022, 14(3), 18; https://doi.org/10.31083/j.fbe1403018
Submitted: 18 February 2022 | Revised: 25 April 2022 | Accepted: 26 April 2022 | Published: 12 July 2022
Copyright: © 2022 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.
Abstract

Beta thalassaemia major (TM), a potentially fatal haemoglobinopathy, has transformed from a fatal to a chronic disease in the last 30 years following the introduction of effective, personalised iron chelation protocols, in particular the use of oral deferiprone, which is most effective in the removal of excess iron from the heart. This transition in TM has been achieved by the accessibility to combination therapy with the other chelating drugs deferoxamine and deferasirox but also therapeutic advances in the treatment of related co-morbidities. The transition and design of effective personalised chelation protocols was facilitated by the development of new non-invasive diagnostic techniques for monitoring iron removal such as MRI T2*. Despite this progress, the transition in TM is mainly observed in developed countries, but not globally. Similarly, potential cures of TM with haemopoietic stem cell transplantation and gene therapy are available to selected TM patients but potentially carry high risk of toxicity. A global strategy is required for the transition efforts to become available for all TM patients worldwide. The same strategy could also benefit many other categories of transfusional iron loaded patients including other thalassaemias, sickle cell anaemia, myelodysplasia and leukaemia patients.

Keywords
thalassaemia major
iron overload
iron toxicity
organ damage
polypathology
polypharmacotherapy
1. Introduction

The thalassaemia diseases are haemoglobinopathies, the most common group of inherited diseases in humans. Adult haemoglobin in normal individuals is composed of two alpha and two beta polypeptide globin chains, each containing an iron molecule embedded in a protoporphyrin ring, which is responsible for the transport of oxygen to all cells of the body [1]. More than 200 mutations of the haemoglobin genes are known, causing a range of pathological abnormalities from asymptomatic to fatal states [1, 2].

Beta thalassaemia major (TM) is an autosomal recessive inherited haemoglobinopathy with serious pathological complications and a high morbidity and mortality rate [1, 2, 3]. In TM patients insufficient or none of the beta globin chains of haemoglobin are produced and the abnormal haemoglobin composed of alpha globin chains cannot deliver oxygen efficiently to the tissues. Beta thalassaemia major is a fatal disease if it is not treated. The main form of treatment of TM patients is chronic red blood cell (RBC) transfusions and iron chelation therapy [4, 5]. Bone marrow transplantation is also available for young TM patients in developed countries provided a compatible donor is found [6, 7].

Excess iron accumulated from chronic RBC transfusions is toxic to many organs and becomes fatal unless it is removed by chelating drugs. Iron overload toxicity in TM and other transfusional iron loaded conditions has one of the highest metal related morbidity and mortality rates globally [8].

The geographic distribution and prevalence of TM is in developing countries found in the Mediterranean, Middle East and South East Asia, where over 90% of TM patients are born [1, 2]. It is estimated that there are 100 million thalassaemia heterozygote asymptomatic carriers and more than 100,000 TM are born worldwide every year [1, 2]. As an example, the annual birth rate of TM patients in India is estimated at 9000 [9].

Thalassaemia is considered as orphan disease in the European Union (EU) and the United States due to the low number of patients compared to the total population, which is mainly of Caucasian origin [10]. The treatment of TM patients in the EU countries (e.g., Cyprus, Greece and Italy) is supported by the state, whereas in most other countries support is not available [10].

The survival prospects of a newborn TM is directly related to the treatment options available in each country. In countries without the ability to provide regular RBC transfusions, TM patients die from ineffective erythropoiesis and other related complications usually by the age of 2–7 years [1, 2]. In contrast, if regular RBC transfusions are available, survival in transfused TM patients is expected to increase to about 15–20 years [3]. In such cases, TM patients usually die from cardiac failure due to excess iron deposition in the myocytes and subsequent damage to myofibers [11, 12, 13].

The introduction of effective chelation therapy within a period of a few years of having the RBC transfusions, substantially increases the life expectancy of TM patients. There is an increasing number of TM patients who exceed 50 years of age, most of whom have previously adhered to effective chelation therapy protocols of subcutaneous (sc) deferoxamine (DF) and to oral deferiprone (L1), as well as effective combinations of these two drugs [4, 13, 14, 15]. In general, compliance with sc DF for the majority of TM patients is poor and the average life expectancy much shorter, e.g., the mean life span of TM patients in the United Kingdom before the introduction of L1 was estimated to be 30–35 years [16]. Following the introduction of L1 in 1999, an improvement in compliance and efficacy in iron removal and a reduction in the number of cardiac deaths was observed in many countries [17, 18, 19]. Further increase in compliance in relation to chelation therapy was anticipated following the introduction of oral deferasirox (DFRA) in 2007, which may benefit TM patients intolerant of or with complications to DF and L1 therapy [19, 20, 21, 22, 23, 24].

Overall, many aspects influence the morbidity and mortality rate of TM patients including the efficacy, toxicity and availability of chelating drugs [10, 14, 15, 16, 17]. Many other pathological effects in TM patients also need therapeutic intervention in addition to chelation therapy. Auxiliary therapeutics are being used in most TM patient cases in addition to iron chelating drugs for improving organ function and for treating other co-morbidities [15].

2. The Polypathology of Thalassaemia

There are many clinical complications arising from the main treatment of TM patients using chronic RBC transfusions and the removal of excess iron by chelation therapy, as well as other complications related to the underline disease. Similarly, many other clinical effects are observed as patients get older, which may be related to familial disorders, ageing or a combination of their effects and also side effects of different drugs and other therapeutic interventions. The treatments of each of the above mentioned complications are widely available to TM patients in developed countries. However, different conditions apply to TM patients in developing countries, where in most cases the patients receive irregular or no RBC transfusions or chelation therapy [1, 2, 9].

2.1 The Pathological Effects of Transfusional Iron Overload Toxicity in Thalassaemia

Regular RBC transfusions and iron chelation therapy is the mainstay therapy for the vast majority of TM patients worldwide. This form of therapy is also used for many other types of transfusion dependent thalassaemias and also for millions of patients with refractory anaemias such as sickle cell disease, myelodysplasia, aplastic anaemia and hematopoietic stem cell transplantation (HSCT) [6, 7, 8, 25].

Thalassaemia major patients are usually transfused every 1–4 weeks, with 1–3 packed units (1 unit = 200 mg of iron) of RBC in order to maintain haemoglobin levels above 9–10 mg/dL. This rate of transfusion maintains the normal physiological bodily functions and activities of TM patients, but at the same time causes the rapid increase in body iron accumulation and progresses to iron overload. These effects in TM patients are also found in other categories of transfused patients with refractory anaemias [6, 7, 8, 25].

Body iron levels in normal individuals are mainly regulated through iron absorption and the erythropoietic activity of the bone marrow. In TM patients the excess iron accumulated from transfusions cannot be excreted and it is stored in the cells of different organs in the form of ferritin and especially as haemosiderin [26, 27, 28]. The latter protein increases in concentration in many organs, particularly in the liver, as well as the heart and spleen of the transfused patients (Fig. 1) [28, 29, 30].

Fig. 1.

The major organs susceptible to iron overload toxicity and associated pathological effects in Thalassaemia major patients. The accumulation of iron in the organs is caused from chronic red blood cell transfusions. Similar toxic side effects of iron overload in affected organs are also observed in other categories of chronically transfused patients.

Iron overload toxicity in TM on the cellular level has been previously studied using electron microscopy [11, 12, 13, 27]. It has been shown that in iron overloaded conditions both cardiomyocytes and hepatocytes in TM patients contain iron loaded ferritin arrays, which are formed intracellularly mainly in primary lysosomes and also haemosiderin iron aggregates in secondary lysosomes [11, 12, 13, 27, 28]. Furthermore, ultrastructural observations of samples from heavily iron loaded TM patients suggest the presence of iron-laden lysosomes, which rupture into the cell sap causing intracellular damage. Similarly, several other forms of sub-cellular damage have been identified for example in cardiomyocytes of TM patients who suffered congestive cardiac failure [12, 13]. In this case the sub-cellular damage includes the presence of large cytoplasmic vacuoles, swollen mitochondria with loss of their cristae but with no iron deposits within them, substantial loss of myofilaments, an increase in the electron density of nuclei and also increased amounts of heterochromatin [12].

The rupture of iron-laden lysosomes into the cell sap following deposition of excess iron is considered to be the cause of the release of hydrolytic enzymes and also of potentially toxic forms of labile, redox active iron, which can catalyse the production of free radical cascades and cause further damage [31, 32, 33]. These damaging effects can progressively lead to ferroptosis and a vicious cycle of cellular, tissue and organ damage [34, 35, 36, 37, 38, 39].

Organ damage in iron overload is generally detectable when approximately 50–100 units of red blood cells have been transfused [3, 8, 28, 29]. The organ damage at the early stages can be reversible provided effective iron chelation therapy protocols are applied. In the absence of effective chelation therapy and following repeated transfusions, the organ damage caused by increasing iron load can progressively become irreversible, e.g., in liver fibrosis and cardiac failure.

The major cause of mortality in iron loaded TM patients is iron overload toxicity related cardiomyopathy [3, 8, 11, 16, 17]. Magnetic resonance imaging (MRI) diagnostic studies of iron load deposition in the heart of TM patients have suggested the existence of a correlation between cardiac damage and the level of iron overload [29, 30, 40, 41, 42, 43]. In particular, there is increased risk of congestive cardiac failure in TM patients with excess cardiac iron deposition levels [41, 42, 43].

In addition to the heart complications in TM patients, increased iron deposition and iron toxicity has also been observed in many other organs, affecting their function. These include liver, spleen and endocrine damage (Fig. 1) [29, 30]. Excess iron deposition and associated toxicity in organs can be prevented using effective chelation therapy and by achieving as well as maintaining normal iron levels from childhood [44].

2.2 Organs Susceptible to Iron Overload Toxicity Caused by Chronic Transfusions

Several organs have been identified as being susceptible to iron overload toxicity from chronic RBC transfusions and the extent of damage in each of these organs contributes to the overall morbidity and mortality rate observed in TM patients (Fig. 1). The diagnosis and extent of damage in these organs has been identified and monitored using mainly histopathological and magnetic resonance imaging (MRI) techniques, which can monitor structural feature changes in organs and also other tests related to the function of these organs, such as liver enzyme levels [13, 29, 30, 40, 41, 42, 43, 45, 46].

The major organs associated with an increased mortality due to iron overload damage in TM patients are the heart and to a lesser extent the liver (Fig. 1, Ref. [13]). In general, the level of cardiomyopathy and cardiac dysfunction appears to be related to the level of iron deposition in the heart and in particular severe cases of cardiac iron deposition, e.g., of MRI T2* with signal intensity less than 9 ms, the TM patients are in danger of congestive cardiac failure (Fig. 2) [13, 43]. Similarly, excess iron deposition in the liver, e.g., in severe siderosis can progressively cause hepatic cirrhosis, fibrosis and hepatocellular carcinoma (HCC), which can also lead to death [28, 47, 48, 49].

Fig. 2.

Magnetic resonance imaging (MRI) images of two iron loaded thalassaemia patients, showing differential iron loading of the heart and liver. (a) Right picture. Heavy haemosiderosis of the heart [T2* = 6.32 ms (normal T2* 19 ms)] and normal T2* of the liver (T2* = 19.2 ms). The top arrow shows the abnormal iron deposition in the interventricular septum of the heart of the patient, which is shown with low signal intensity (dark). The bottom arrow shows the liver of the patient with no iron deposition (normal). (b) Left picture. Heavy haemosiderosis of the liver [T2* = 1.2 ms (normal T2* 6.3 ms)] and normal T2* of the heart (T2* = 20.6 ms). The top arrow shows the interventricular septum of the heart of the patient with no iron deposition (normal) where the bottom arrow shows the heavy iron loading within the liver parenchyma, demonstrated as low signal intensity (dark). Adapted from [13].

Several other organs are affected from excess iron, including the pancreas, which is associated with diabetes mellitus and is widely occurring in TM patients [50]. Impaired or stunted growth and infertility associated with excess iron deposition in the pituitary gland is also observed, as well as hypoparathyroidism and hypogonadism caused by the malfunction of the thyroid and the gonads respectively, all of which are important side effects affecting many TM patients [51, 52, 53, 54].

Excess iron deposition appears to be at lower levels in the kidneys, skin, lungs and the brain of TM patients and accordingly their function is not affected to the same extent by iron toxicity in comparison to the heart, liver and other iron loaded organs. For example, a bronze colour appearance of the skin is observed in heavily iron loaded TM patients, which does not appear to be associated with any serious skin damage [55, 56, 57, 58].

In some TM patients the presence of excess focal deposited iron, irrespective of the total body iron load can also cause tissue damage. Excess iron has for example been observed in the joints of some TM patients using MRI T2* with associated knee and ankle complications [59]. It should be noted that focal iron deposition and associated complications have also been observed in the brain of patients with neurodegenerative diseases, such as Friedreich ataxia, Alzheimer’s and Parkinson’s diseases [60, 61, 62].

In addition to organ toxicity observed in TM patients as a result of excess iron deposition, pathological effects are also suspected from non-transferrin bound iron, which is able to catalyse the formation of free radicals leading to oxidative stress toxicity and progressively to biochemical, subcellular, cellular and tissue damage [63, 64, 65, 66, 67, 68]. All three chelating drugs and in particular L1 appear to inhibit effectively the iron catalysed free radical damage [69, 70, 71, 72, 73].

2.3 Pathological Effects in Thalassaemia Caused by Infections and Other Complications

Major clinical complications in TM are not directly related to iron overload toxicity but to several other factors including those caused by the underlying disease, transfusions from different blood donors, drugs and also many other common diseases affecting the general population. In most of these cases the treatments provided have different parameters and characteristics in comparison to the general population because of differences in the pathophysiology of TM patients.

Microbial infections are among the serious clinical complications affecting TM patients with estimated rate of 8.5 per 100 patient years and are becoming the major cause of death especially since the number of congestive cardiac failure incidences has dramatically declined in many countries following the introduction of effective chelation therapy protocols and primarily of L1 [16, 17, 18, 74, 75].

Although the level of iron overload and transferrin saturation are important parameters contributing to the growth and proliferation of microbes, many other pathological complications and factors are involved, some of which are similar to other categories of patients facing infection [75, 76, 77, 78, 79].

Thalassaemia major patients are subjected to various bacterial, fungal and viral infections. Many complications in TM patients include pneumonia, liver abscess, biliary tract and soft tissue infection, which are mostly caused by different bacteria species such as Klebsiella pneumonia, Streptococcus pneumonia, Escherichia coli, Salmonella typhi and Yersinia enterocolitica [74, 76]. Viral infections involving for example Human parvovirus B19 (HBV), Cytomegalovirus (CMV) and Human immunodeficiency virus (HIV), as well as fungal infections such as Mucormycosis or Zygomycoses and Pythium insidiosum are also common in TM patients. The main predisposing factors for infection in addition to iron overload in TM are transmission from transfusions, splenectomy, diabetes, liver derangement, reduced immunity and chronic diseases [74, 76, 80].

Infections and other clinical complications arising from chronic RBC transfusions in TM patients are also found in many other categories of regularly transfused patients with refractory anaemias. These additional complications can range from short term effects such as anaphylactic reactions to long term effects such as RBC antibodies arising from blood transfusions obtained from multiple blood donors. The latter effect makes blood selection for transfusions difficult, especially in older TM patients [81, 82]. Acute haemolytic reactions and delayed reactions are also frequent in patients with chronic transfusions [81, 82, 83, 84]. Some other side effects of transfusions may be very serious or even fatal, such as the accidental transfusion of the wrong blood type group, or rare cases like transfusion-related acute lung injury (TRALI) [85, 86]. Chronic RBC transfusions are also implicated in many other serious pathological effects such as cardiac hypertrophy and pulmonary hypertension, which are mainly observed in older TM patients [87, 88].

Many TM patients experience anaemia symptoms to a variable degree, which in general depends on the rate of RBC transfusions. In developing countries the absence or insufficient number of RBC transfusions can cause severe anaemia in TM patients, with many associated pathological changes and reduced survival. In such cases chronic haemolysis, bone marrow expansion and extramedullary erythropoiesis are observed, which can result in bone pain, deformities and fractures, facial abnormalities, as well as splenomegaly and hepatomegaly [2, 16].

Several other pathological effects are also observed in the older TM patient population, which are related to familial diseases such as diabetes and heart disease and also in ageing populations such as osteoporosis, musculoskeletal/joint problems and malignancy. In general these effects appear at a much younger age in TM patients in comparison to normal individuals of similar ages in the general population.

2.4 Clinical Complications Arising from the Toxic Side Effects of Chelating and Other Drugs

The need for daily chelation therapy for the treatment of iron overload, as well as many other drugs for the treatment of other pathological conditions in TM patients requires continuous vigilance for the possibility of toxic side effects. In this context, regular monitoring and prophylactic measures for chelating and other drug toxicity are generally recommended. Clinical examination and biochemical tests are regularly carried out to identify drug toxicities including tests for organ function such as liver enzyme and urine creatinine levels, blood cell counts, echocardiography, MRI, serum ferritin, serum iron and zinc levels [3, 16, 40, 45, 46].

The general toxic side effects of chelating and other drugs are listed in each drug’s label information following their regulatory approval. The monitoring of possible toxic side effects related to the daily use of DF, DFRA and L1 is important for the safety of TM patients (Fig. 3) [89, 90, 91]. In particular, the prospect of chelating drug toxicity increases in TM patients with low or normal iron stores [91]. Within this context, the use of DFRA is not recommended for iron loaded patients with serum ferritin lower than 500 μg/L [92, 93, 94, 95, 96]. Some toxic side effects have also been reported in iron loaded TM patients treated with DFRA, which however are less frequent than in non-iron loaded categories. These include renal, liver and bone marrow failure and agranulocytosis, skin rashes and gastric intolerance [92, 97, 98, 99]. Kidney function is regularly monitored in TM patients treated with DFRA and withdrawal of the drug is recommended for patients with persistent rise in serum creatinine levels [92].

Fig. 3.

The chemical structure of the iron chelating drugs used for the treatment of iron overload in Thalassaemia major patients. Deferiprone (L1), deferasirox (DFRA) and deferoxamine (DF) and their combinations are used for the treatment of thalassaemia and other transfusional iron loading conditions.

Similar limitations and restrictions apply in the use of DF in TM patients with low iron stores as those of DFRA, despite that the incidence of serious toxicity is much lower in the case of DF. The use of DF in non-heavily iron loaded TM patients or other categories of patients with normal iron stores is not recommended due to toxicity implications. Several toxicities were reported in different categories of patients using DF including cases of mucormycosis, acute respiratory distress syndrome and Yersinia enterocolitica. Furthermore, auditory and ocular toxicity has also been reported in non-heavily iron loaded TM patients using DF [89, 90, 100, 101, 102, 103].

Low toxicity has been observed in TM and other categories of patients with low or normal iron stores using L1 in thousands of patients in the last 25 years and also in studies in patient categories with normal iron stores, with an excess of 100 patients years [89, 90, 104]. The safety record of L1 in TM patients increased the prospect of its wider clinical use as a universal chelator/antioxidant in non-iron overloading diseases related to free radical pathology [33]. The chelator/antioxidant effects of L1 have been investigated in clinical trials involving many categories of patients including neurodegenerative, cardiovascular, renal, infectious diseases, cancer, AIDS and ageing [33, 60, 61, 62, 105, 106, 107, 108].

Several toxic side effects have been reported for L1, with the most serious those of agranulocytosis (less than 1%) and neutropenia (less than 5%) [89, 90, 104, 109]. Both toxicities are reversible and weekly or fortnightly mandatory blood count monitoring is recommended for prophylaxis for all patients using L1. Several other, less serious toxic side effects include gastric intolerance, joint pains and Zn deficiency [104, 109, 110, 111].

It appears that the rate of morbidity and mortality for each chelating drug is different and also the target organ of toxicity varies in each case [90]. Furthermore the iron complex of chelating drugs is less toxic than the non-bound chelator in all three drug cases.

The toxicity of the less frequently used drugs for the treatment of other co-morbidities in TM patients, in addition to iron chelation is rather rare and similar to that observed in other categories of patients. However, toxicity vigilance including drug interactions and prophylactic measures are important parameters for ensuring the safety of TM patients treated with chelating and also all other drugs.

3. The Polypharmacotherapy of Thalassaemia

The polypathology of TM requires the continuous biochemical and clinical monitoring of patients in specialised clinics, which includes the regular assessment of haemoglobin levels and arrangements for RBC transfusions every 1–4 weeks, as well as the adjustment of chelation therapy following serum ferritin estimations. Many more clinical and pharmacological interventions are also needed for the different co-morbidities and pathological effects related to the underlying condition, all of which contribute to the survival prospects and overall health status of TM patients.

Many different drugs are intermittently used by TM patients in addition to daily treatment by chelating drugs. The different pharmacological treatments help in improving the quality of life and in decreasing the overall morbidity and mortality of TM patients. In particular, the therapeutic approach used in the last two decades has significantly improved the life expectancy of TM patients, some of whom are grandparents and most are professionals contributing to many sectors of society [13, 15].

3.1 The Importance of Effective Iron Chelation Therapy Protocols in Thalassaemia

The main aim of chelation therapy in chronically transfused TM patients is the prevention or minimisation of iron overload toxicity and the decrease of the associated high mortality and morbidity rate [44]. This goal can only be achieved if effective chelation treatments are available, which can maintain the general body iron load and iron in the affected organs to normal or near normal levels [14, 90].

Despite the common goals for the substantial reduction or complete elimination of iron overload in TM patients, there is no consensus in the use of iron chelation protocols, which differ between countries and even clinics in each country [14, 90, 112]. In general, chelation treatment protocols in TM involve the administration of DF, L1 and DFRA, as well as different combinations of these chelating drugs (Fig. 3) [90, 113, 114, 115, 116, 117]. All drugs including the iron chelating drugs have different pharmacological activity including absorption, distribution, metabolism, elimination and toxicity (ADMET) characteristics, mode of action, efficacy, and cost [118]. Similarly, variable pharmacological activity of DF, L1, DFRA and their combinations are observed in TM patients, the availability and use of which affects the overall survival of TM patients in each country [90, 113, 114, 115, 116, 117].

The recommended doses for use of the chelating drugs in TM patients are 40–60 mg/kg/day for DF, 75–100 mg/kg/day for L1 and 20–40 mg/kg/day for DFRA [90]. Various dose protocols and combinations are used in the context of personalised therapies, which are based on variations in general body iron overload and also individual organ targeting effects [90, 113, 114, 115, 116, 117, 119]. A range of therapeutic protocols are selected for different categories of patients including intensive chelation, e.g., combinations of DF (40–60 mg/kg/day) and L1 (75–100 mg/kg/day) in heavily iron-loaded TM patients to intermittent withdrawal of chelation in less heavily iron-loaded TM patients [120, 121, 122, 123].

The most tolerable, safe and effective chelation protocol, which has been identified in achieving negative iron balance and normalisation of the iron stores in TM patients is that of the International Committee on Chelation (ICOC) combination of oral L1 (80–100 mg/kg/day) and sc DF (40–60 mg/kg/day, at least 3 days per week) [4, 13, 14, 15, 113, 114]. The time period required for achieving the normalisation of the iron stores in TM patients as assessed by MRI T2* and serum ferritin levels varies and depends mainly on the iron load of patients and the overall dose of the chelating drugs. For example, the complete elimination of iron overload in TM patients with initial serum ferritin of 700–4000 μg/L using the ICOC protocol was estimated to be about 6–30 months [120, 122, 123].

The importance of the selection of ICOC and similar protocols on TM patient survival has also been shown in epidemiological studies, which suggested that primarily the use of L1 and also its combination with DF can cause a substantial reduction in morbidity and mortality [15, 17, 124]. The ICOC and similar protocols appear to be effective therapeutic options in significantly reducing or eliminating gross iron overload and also for decreasing the associated high mortality and morbidity observed in TM. Overall, the role of L1 in reducing primarily excess cardiac iron and also excess body iron is considered as one of the major factors in the transition of TM from a fatal disease to a chronic disease [15, 125, 126, 127, 128].

The safety of L1 in TM patients with normal iron stores has also been confirmed following its introduction for the treatment of non-iron loaded patients by targeting focal toxic iron deposits, e.g., in Parkinson’s disease and Friedreich ataxia and also in diabetic and non-diabetic glomerular disease patients affected by toxic labile iron [60, 61, 62, 105, 106, 107, 108]. In particular, the long term safety of L1 has been shown in the glomerular disease patients using doses of 50–75 mg/kg/day for 6–9 months with no serious toxic side effects [105]. Similar findings from clinical trials on the safety of L1 have been observed in many other categories of non-iron loaded diseases including the anaemia of chronic disease, renal dialysis, infections and several other neurodegenerative diseases [89, 90].

3.2 Pharmacotherapies in Thalassaemia not Related to the Elimination of Excess Iron

Many other drugs are regularly used for the treatment of different pathologies in TM, in addition to the use of chelating drugs for the removal of excess iron. Most of these drugs are used for the prevention or treatment of abnormalities observed in the various organs and their function, some other drugs for microbial infections and immune reactions and many more for other abnormalities also affecting the general population.

Chronic RBC transfusions in TM are associated with clinical complications and side effects [129, 130, 131]. Most of the complications of RBC transfusions are related to reactions in response to blood from donors, which is contaminated with white blood cells and other antigenic factors [129, 132]. In such cases the treatment depends on the side effects and other co-morbidities of the patient. For example, mild allergic reactions such as itching and erythema are treated by corticosteroids and antihistaminic drugs. However, more intensive and complex therapies are required in severe allergic reactions which can cause anaphylaxis, hypotension and bronchospasm, or in delayed transfusion reactions, which may occur 1–2 weeks after transfusion and can cause anaemia, jaundice and fatigue. Acute haemolytic reaction is an additional side effect resulting from errors in blood typing and compatibility testing, which can cause fever, chills, shock, dyspnea, and haemoglobinuria. In such cases transfusion is stopped and patients are treated with intravenous fluids, diuretics and heparin [81, 82, 83, 84]. Alloimmunisation from transfusions and the occurrence of related alloantibodies causing reduction in haemoglobin levels is estimated to affect 10–20% of mainly splenectomised TM patients [81, 132, 133]. In addition, autoimmune haemolytic anaemia may occur in some patients with alloantibodies who can be treated with steroids, intravenous immunoglobulin and immunosuppressive drugs [84, 133]. Transfusion-related acute lung injury (TRALI) and transfusion-induced graft versus host disease are very rare cases in TM and other transfused patients but with very serious multi-pathological effects including fatalities, which require intensive and multidisciplinary treatment [85, 86, 133, 134].

Myocardial damage and dysfunction is the most serious toxic side effect of iron overloaded TM patients, which requires regular monitoring and follow up, as well as many and different drugs for improving cardiac function [43, 135, 136, 137, 138, 139]. Cardiac complications include arrhythmias, cardiac failure, pulmonary hypertension and peripheral vascular disease. Therapeutic approaches include anti-arrhythmic drugs such as beta-blockers, angiotensin converting enzyme (ACE) inhibitors such as ramipril, captopril and enalapril, aldosterone antagonists such as spironolactone and eplerenone, anticoagulants, cardiotonic agents, vasodilator agents and also diuretics [88, 135, 136, 137, 138, 139].

The liver complications in TM are mostly related to the level of iron overload, which may lead to cirrhosis, fibrosis and hepatomegaly. Liver damage and function are also affected by viral infections including chronic hepatitis B and C, and also fatty liver disease and hepatocellular carcinoma [48, 49, 140, 141, 142]. Hepatitis B is treated with interferon, the nucleoside analogs lamivudine and entecavir and the nucleotide analogs adefovir and tenofovir. Hepatitis C is treated with ribavirin and pegylated interferon and also bocepreviror and telaprevir [143, 144, 145, 146, 147]. There are also rare cases of hepatocellular carcinoma in TM, which are treated with chemotherapy and surgery [48, 49, 148, 149]. In a few cases of TM with severe liver damage, treatment with liver transplantation has also been considered and carried out.

Multiple clinical complications including infections and those related to splenomegaly and splenectomy, which occur in addition to iron overload toxicity, are also a major target of therapeutic interventions in TM [29, 47, 74, 80, 150, 151, 152, 153, 154, 155]. In general, TM patients prior to splenectomy are treated for immunoprophylaxis with vaccination against the pneumococcal, Haemophilus influenza and Neisseria meningitides viruses [156]. Splenectomised patients receive a number of prophylactic and other treatments including penicillin and other antibiotics for infections and sepsis, aspirin for thrombocytosis and anti-coagulant prophylaxis for hypercoagulability and thromboembolic complications [157, 158]. Further complications and therapies arise following splenectomy, such as increasing iron loading of other organs and particularly the liver and the heart [29, 47, 80, 159, 160]. In such cases, personalized chelation and other therapeutic protocols can be designed for overcoming individual associated health risk problems.

Endocrine damage is a major complication in young TM patients, which can lead to growth retardation and arrested puberty [50, 51, 52, 53, 54, 55]. In males, the management of the delayed puberty and hypogonadotrophic hypogonadism involves the intramuscular administration of depot-testosterone and in pubertal arrest the intramuscular administration of testosterone esters or topical testosterone gel. In females the treatment involves the administration of oral estradiol, low oestrogen and progesterone [161, 162, 163, 164]. In relation to hypothyroidism the treatment involves L-thyroxine and in cases of subclinical hypothyroidism and cardiomyopathy the drug amiodarone. In hypoparathyroidism management and also prophylaxis for prevention of acute and chronic complications of hypocalcemia, the affected patients receive oral vitamin D, calcium and synthetic human parathyroid hormone [164, 165, 166]. The management of osteoporosis and osteopenia involves calcium and vitamin D supplementation, hormonal replacement, prevention of hypogonadism, continuous hormonal replacement, and also the use of calcitonin and bisphosphonates [166, 167]. Lastly, the management of adrenal insufficiency involves treatment with glucocorticoids [164]. In many cases endocrine damage can be prevented, reversed or minimized using effective chelation protocols [168, 169, 170, 171].

In the majority of cases clinical complications with several co-morbidities can occur simultaneously as shown in Table 1 (Ref. [8, 14, 29, 30, 43, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 74, 80, 88, 90, 113, 114, 120, 121, 122, 123, 124, 125, 126, 127, 128, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170]), especially in older iron loaded TM patients, where multiple therapeutic drug interventions and other treatments are required in addition to chelation therapy [172]. Despite the complexity of such co-morbidities in TM patients, the clinical outcome in many cases has been improved with the introduction of effective iron chelation protocols and other new targeted therapeutics.

Table 1.Organ damage in Thalassaemia major and therapeutic interventions.
Organ and associated clinical complications Treatment Ref
Heart
Iron overload damage: L1 and combinations with DF and DFRA [8, 14, 30]
Cardiac failure. Arrhythmias. Arterial changes Anti-arrhythmic drugs. Aldosterone antagonists. ACE inhibitors. Anticoagulants, Diuretics. Cardiotonic agents. Vasodilator agents [43, 88, 90, 120, 121, 122, 123, 124, 125, 126, 127, 128, 135, 136, 137, 138, 139]
Complications unrelated to iron overload: Pulmonary hypertension. Arrhythmias and atrial Fibrillation. Thrombotic episodes. Cardiac function (restrictive or/and diastolic dysfunction/fibrosis). Arterial changes
Liver
Iron overload damage: Liver damage and malfunction, hepatomegaly cirrhosis and fibrosis DF, L1 and DFRA. Combinations of all three [29, 30, 48, 49, 113, 114]
Complications unrelated to iron overload: Hepatitis B (HBV) and C (HCV). Hepatocellular carcinoma (HCC). Fatty liver disease HBV: Interferon, nucleoside and nucleotide analog antiviral drugs. HCV: Pegylated interferon and antiviral drugs. HCC: Chemotherapy and surgery [120, 121, 122, 123, 124, 125, 126, 127, 128, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149]
Spleen
Iron overload damage: Spleen damage and malfunction. Splenomegaly DF, L1 and DFRA. Various combinations of all three drugs [29, 30, 47]
Spenectomy. Prior to splenectomy: Immunoprophylaxis with vaccines against viruses [74, 80]
Following splenectomy: Prophylaxis against infections and sepsis. Thrombocytosis. Hypercoagulability and thromboembolic complications Antibiotics. Aspirin. Anti-coagulant prophylaxis [150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160]
Endocrine glands
Iron overload damage: DF, L1 and DFRA. Various combinations of all three drugs from young age [29, 30]
Growth retardation and arrested puberty in young TM patients [50, 51, 52, 53, 54, 55, 56, 57, 58]
In males: Delayed puberty and hypogonadotrophic hypogonadism Intramuscular depot-testosterone Intramuscular testosterone esters or topical testosterone gel [120, 121, 122, 123, 124, 125, 126, 127, 128]
Pubertal arrest [161, 162, 163, 164, 165, 166, 167, 168, 169, 170]
In females: Oral estradiol, low oestrogen and progesterone
Hypothyroidism L-thyroxine
Subclinical hypothyroidism and cardiomyopathy Amiodarone
Hypoparathyroidism and hypocalcemia Vitamin D, calcium and parathyroid hormone
Osteoporosis and osteopenia Vitamin D, calcium, calcitonin, bisphosphonates, hormonal replacement
Diabetes mellitus Oral antidiabetic drugs, insulin (sc)
Adrenal insufficiency Glucocorticoids
ACE inhibitors, angiotensin converting enzyme inhibitors; DFRA, deferasirox; L1, deferiprone; DF, deferoxamine; HBV, Hepatitis B; HCV, Hepatitis C; HCC, hepatocellular carcinoma; sc, subcutaneous.
4. Future Prospects including Transplantation and Gene Therapies

Major efforts have been undertaken by governments and international organisations for the worldwide prevention of TM, a potentially fatal inherited disease prevalent in developing countries [1, 2, 9, 10, 15]. In the meantime, further research is needed on all aspects of the pathological effects and therapeutic interventions for the new born and existing TM patients.

Despite that HSCT from a matched family or unrelated donor, may offer a successful therapy for selected young TM patients who have no secondary organ damage due to iron overload, the risks of death and serious toxic effects are still high for the majority of the remaining patients [7, 173, 174, 175, 176, 177]. Further improvements on safety in HSCT transplantation and the introduction of safe gene therapy may offer a complete treatment for TM patients [7, 173, 174, 175, 176, 177, 178, 179].

There is increasing interest as well as many clinical trials in progress over the last 2 to 3 years concerning gene therapy and its comparison with allogeneic HSCT, both of which can potentially offer complete therapy for TM patients [6, 7, 8, 173, 174, 175, 176, 177, 178, 179, 180]. The risk/benefit assessment of these two HSCT methods and their comparison with the standard therapy of regular RBC transfusion and chelation therapy are likely to be the subject of future investigations.

Allogeneic HSCT in TM from human leukocyte antigen (HLA) matched siblings or unrelated bone marrow donors was initiated 40 years ago and is estimated to have been used so far in about 4000 TM patients worldwide [6, 7, 8, 173, 174, 175, 176, 177, 181]. This therapeutic method is subject to suitable donor availability and offers the complete treatment of TM especially for young TM children. The therapy has been developed for TM following many years of monitoring and investigations mainly on improving the transplant procedure and also treating the short and long term toxic side effects of transplantation including graft rejection, chimerism, graft versus host disease (GvHD), infections, myeloablative conditioning regimens, the use of matched or mismatched donors and in patients of different ages, iron loading and with different underlying co-morbidities [7, 8, 182, 183, 184, 185]. In this context, many different factors appear to influence the overall survival (OS) and thalassaemia –free survival (TFS) of HSCT TM patients in different countries and transplantation centers. For example, in a follow up of a maximum 30 years monitoring study, OS was estimated to be about 83% and TFS 78%. Furthermore, the probability of graft rejection was estimated to be about 7% and transplant-related mortality about 14%. Graft versus host disease was the major complication with grade II–IV acute and chronic incidence to range to about 24% and 13% respectively [186]. Similar results were obtained in other short and long term monitoring studies of HSCT TM patients [7, 182, 183, 184, 187]. Overall, it appears that in general young and non-iron loaded patients with non-underlying co-morbidities have the highest prospects of OS and TFS from the HSCT TM patients.

Genetically modified autologous HSCT via gene addition has recently received a conditional approval by the European Medicines Agency (EMA) for the treatment of TM patients [178, 179, 180]. This gene therapy option offers the potential for the treatment of all TM patients without the need of a bone marrow donor. The method is based on a gene addition using lentiviral vectors which can introduce a beta-globin gene into autologous hematopoietic stem cells. The product approved by EMA, betibeglogene autotemcel (beti-cel), has reached phase 3 trials with some promising results. Several other products and gene editing techniques are under investigation and development. Many clinical trials for these agents are ongoing and full assessment of the results is expected in the next few years [178, 179, 180, 188, 189, 190, 191, 192, 193, 194, 195].

Despite the initial encouraging results there are at least three major drawbacks, which are likely to limit the gene therapy option for TM patients and will require further research and development in the coming years. One of the major drawbacks is that most of the TM patients do not achieve transfusion independence, e.g., in a recent study six of nine patients failed to achieve this goal [180, 193, 196]. Another drawback is the risk of hematological malignancies due to different factors including insertional mutagenesis. Lastly, public expenditure concerns appear to limit the overall number of TM patients that can have access to gene therapy [180, 196].

Inducers of increased haemoglobin F production or other drugs than can cause reduction in the rate of RBC transfusion and subsequently to iron loading are important research areas for further improving the therapeutic prospects of TM [190, 197, 198, 199]. The anticancer and iron binding drug hydroxycarbamide (hydroxyurea) is widely used in thalassaemia indermedia for increasing HbF production but is not effective in TM [200, 201, 202]. Similarly, the recent introduction of erythropoietic biologics such as luspatercept (Reblozyl) has been considered for reducing RBC transfusions in TM and other haematological diseases [203, 204, 205]. Several studies have suggested that about 20% reduction in RBC could be achieved in some TM patients [203, 204, 205]. However, the use of luspatercept in TM is questionable, since even if haematopoiesis can be increased as suggested in other haematological patient categories, in the case of TM patients luspatercept can only increase the production of abnormal, non-functional haemoglobin [206]. Further studies are required to establish the mode of action and efficacy of luspatercept in TM. Similarly, serious concerns remain in other aspects of therapy, such as the safety and the availability of luspatercept and also of other biological therapies in TM and other diseases [206, 207].

Regular RBC transfusions and chelation therapy remains the mainstay, realistic therapy for the vast majority of TM patients. In general, iron overload toxicity is considered as an independent adverse prognostic factor in all diseases mainly because of the ability of iron to catalyse the excess production of free radicals and other reactive oxygen species, as well as to promote microbial infections. Many other categories of regularly transfused patients are affected from iron overload toxicity in addition to TM, including patients of allogeneic HSCT such as sickle cell anaemia, myelodysplasia, and leukaemia [8, 15, 208, 209, 210, 211]. Research efforts for the complete removal of excess iron and the achievement of normal iron stores is the ultimate aim for the treatment of iron toxicity in all these iron overload categories involving millions of patients [8, 14, 33, 44, 114].

Further improved therapeutic protocols, which can also decrease the overall morbidity and mortality in TM are expected from the introduction of new, personalised adjusted chelating drug combinations involving one to three drug combinations of L1, DF and DFRA as previously suggested [90, 212].

One of the major contributing factors that resulted in the increased survival and the quality of life of TM patients is the organisation of multidisciplinary specialised team protocols for monitoring and intervening in all the pathological effects involving each of the affected organs and their function [15, 172, 213].

New efforts are required for the supply of chelating drugs for the treatment of iron overloaded patients worldwide. These efforts could include clinical development of natural and synthetic investigational new chelating drugs, combinations with L1, DF and DFRA and targeted chelation protocols for optimal therapies [214, 215, 216, 217]. Similarly, advancements in the diagnosis and treatment of other co-morbidities, as well as improvements in the efficacy of polypharmaceutical treatment using new drugs could contribute further to the efforts in the transition of TM from a fatal to a chronic disease [15, 172, 193, 218, 219, 220, 221, 222]. Future research efforts and worldwide strategies targeting all comorbidities and the high mortality rate of TM in developing countries could signal the end of TM as a fatal disease worldwide.

5. Conclusions

The mainstay treatment of TM and other refractory anaemias is chronic RBC transfusions and chelation therapy. The introduction of effective personalised iron chelation therapy protocols involving mainly L1 and also DF, DFRA and their combinations, as well as new non-invasive diagnostic techniques for monitoring iron removal from major organs, resulted in the complete treatment of iron overload and the long term survival of TM patients in many developed countries. Similarly, new therapeutic approaches in relation to the polypathological and polypharmaceutical clinical challenges and the involvement of multidisciplinary specialist teams contributed to a great extent to the transition of TM from a fatal to a chronic disease in some developed countries. Future research efforts and worldwide strategies on all aspects of the polypathological clinical challenges, including the development of worldwide strategies for the supply of iron chelating and other drugs, as well as drug combinations could further improve the therapeutic outcomes of TM patients globally. Such efforts could also benefit many other categories of regularly transfused patients which are affected from iron overload toxicity including patients of allogeneic HSCT, sickle cell anaemia, myelodysplasia, and leukaemia. The complete removal of excess iron and the achievement of normal iron stores is the ultimate aim for the treatment of iron overload toxicity in TM and all other categories of chronically transfused patients.

Abbreviations

HSCT, allogeneic hematopoietic stem cell transplantation; ACE inhibitors, angiotensin converting enzyme inhibitors; DFRA, deferasirox; L1, deferiprone; DF, deferoxamine; HBV, Hepatitis B; HCV, Hepatitis C; HCC, hepatocellular carcinoma; HLA, human leukocyte antigen; MRI, magnetic resonance imaging; OS, overall survival; RBC, red blood cell; sc, subcutaneous; TFS, thalassaemia free survival; TM, beta thalassaemia major.

Author Contributions

GJK designed, wrote and edited the manuscript. AK reviewed the clinical aspects of Thalassaemia and polypharmacotherapy. MK reviewed the technical aspects and helped in the preparation of the manuscript.

Ethics Approval and Consent to Participate

Not applicable.

Acknowledgment

The authors would like to thank Christina N. Kontoghiorghe for reading and making comments on the manuscript.

Funding

This research received no external funding.

Conflict of Interest

The authors declare no conflict of interest.

Publisher’s Note: IMR Press stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References
[1]
Community control of hereditary anaemias: memorandum from a WHO meeting. Bulletin of the World Health Organization. 1983; 61: 63–80.
[2]
Weatherall DJ, Clegg JB. Inherited haemoglobin disorders: an increasing global health problem. Bulletin of the World Health Organization. 2001; 79: 704–712.
[3]
Zurlo M, De Stefano P, Borgna-Pignatti C, Di Palma A, Melevendi C, Piga A, et al. SURVIVAL and CAUSES of DEATH in THALASSAEMIA MAJOR. The Lancet. 1989; 334: 27–30.
[4]
Kontoghiorghes GJ. Advances in oral iron chelation in man. International Journal of Hematology. 1992; 55: 27–38.
[5]
Kontoghiorghes GJ, Eracleous E, Economides C, Kolnagou A. Advances in Iron Overload Therapies. Prospects for Effective Use of Deferiprone (L1), Deferoxamine, the New Experimental Chelators ICL670, GT56-252, L1NAll and their Combinations. Current Medicinal Chemistry. 2005; 12: 2663–2681.
[6]
Inamoto Y, Lee SJ. Late effects of blood and marrow transplantation. Haematologica. 2017; 102: 614–625.
[7]
Shenoy S, Angelucci E, Arnold SD, Baker KS, Bhatia M, Bresters D, et al. Current Results and Future Research Priorities in Late Effects after Hematopoietic Stem Cell Transplantation for Children with Sickle Cell Disease and Thalassemia: a Consensus Statement from the second Pediatric Blood and Marrow Transplant Consortium International Conference on Late Effects after Pediatric Hematopoietic Stem Cell Transplantation. Biology of Blood and Marrow Transplantation. 2017; 23: 552–561.
[8]
Kontoghiorghes GJ. How to manage iron toxicity in post-allogeneic hematopoietic stem cell transplantation? Expert Review of Hematology. 2020; 13: 299–302.
[9]
Verma IC. Burden of genetic disorders in india. The Indian Journal of Pediatrics. 2000; 67: 893–898.
[10]
Kontoghiorghe CN. World health dilemmas: Orphan and rare diseases, orphan drugs and orphan patients. World Journal of Methodology. 2014; 4: 163.
[11]
Kyriacou K, Michaelides Y, Senkus R, Simamonian K, Pavlides N, Antoniades L, et al. Ultrastructural pathology of the heart in patients with beta-thalassemia major. Ultrastructural Pathology. 2000; 24: 75–81.
[12]
Kolnagou A, Michaelides Y, Kontos C, Kyriacou K, Kontoghiorghes GJ. Myocyte Damage and Loss of Myofibers is the Potential Mechanism of Iron Overload Toxicity in Congestive Cardiac Failure in Thalassemia. Complete Reversal of the Cardiomyopathy and Normalization of Iron Load by Deferiprone. Hemoglobin. 2008; 32: 17–28.
[13]
Kontoghiorghes GJ. New targeted therapies and diagnostic methods for iron overload diseases. Frontiers in Bioscience. 2018; 10: 1–20.
[14]
Kolnagou A, Kontoghiorghes GJ. Effective Combination Therapy of Deferiprone and deferoxamine for the Rapid Clearance of Excess Cardiac IRON and the Prevention of Heart Disease in Thalassemia. The Protocol of the International Committee on Oral Chelators. Hemoglobin. 2006; 30: 239–249.
[15]
Kolnagou A. Transition of Thalassaemia and Friedreich ataxia from fatal to chronic diseases. World Journal of Methodology. 2014; 4: 197.
[16]
Modell B, Khan M, Darlison M. Survival in β-thalassaemia major in the UK: data from the UK Thalassaemia Register. The Lancet. 2000; 355: 2051–2052.
[17]
Telfer P, Coen PG, Christou S, Hadjigavriel M, Kolnakou A, Pangalou E, et al. Survival of medically treated thalassemia patients in Cyprus. Trends and risk factors over the period 1980–2004. Haematologica. 2006; 91: 1187–1192.
[18]
Au WY, Lee V, Lau CW, Yau J, Chan D, Chan EY, et al. A synopsis of current care of thalassaemia major patients in Hong Kong. Hong Kong Medical Journal. 2011; 17: 261–266.
[19]
Maggio A, Filosa A, Vitrano A, Aloj G, Kattamis A, Ceci A, et al. Iron chelation therapy in thalassemia major: a systematic review with meta-analyses of 1520 patients included on randomized clinical trials. Blood Cells, Molecules, and Diseases. 2011; 47: 166–175.
[20]
Kontoghiorghes GJ. Do we need more iron-chelating drugs? The Lancet. 2003; 362: 495–496.
[21]
Piga A, Galanello R, Forni GL, Cappellini MD, Origa R, Zappu A, et al. Randomized phase II trial of deferasirox (Exjade, ICL670), a once-daily, orally-administered iron chelator, in comparison to deferoxamine in thalassemia patients with transfusional iron overload. Haematologica. 2006; 91: 873–880.
[22]
Galanello R, Piga A, Forni GL, Bertrand Y, Foschini ML, Bordone E, et al. Phase II clinical evaluation of deferasirox, a once-daily oral chelating agent, in pediatric patients with beta-thalassemia major. Haematologica. 2006; 91: 1343–1351.
[23]
Galanello R, Origa R. Once-daily oral deferasirox for the treatment of transfusional iron overload. Expert Review of Clinical Pharmacology. 2008; 1: 231–240.
[24]
Anonymous. Deferasirox: for iron overload: only a third-line option. Prescrire International. 2007; 16: 196.
[25]
Gratwohl A, Pasquini MC, Aljurf M, Atsuta Y, Baldomero H, Foeken L, et al. One million haemopoietic stem-cell transplants: a retrospective observational study. The Lancet Haematology. 2015; 2: e91–e100.
[26]
Kontoghiorghes GJ, Kontoghiorghe CN. Iron and chelation in biochemistry and medicine: New approaches to controlling iron metabolism and treating related diseases. Cells. 2020; 9: 1456.
[27]
Iancu TC. Ferritin and hemosiderin in pathological tissues. Electron Microscopy Reviews. 1992; 5: 209–229.
[28]
Iancu TC, Neustein HB, Landing BH. The Liver in Thalassaemia Major: Ultra-Structural Observations. Ciba Foundation Symposium 51-Iron Metabolism. 1977; 293–316.
[29]
Papakonstantinou O, Alexopoulou E, Economopoulos N, Benekos O, Kattamis A, Kostaridou S, et al. Assessment of iron distribution between liver, spleen, pancreas, bone marrow, and myocardium by means of R2 relaxometry with MRI in patients with β-thalassemia major. Journal of Magnetic Resonance Imaging. 2009; 29: 853–859.
[30]
Kolnagou A, Natsiopoulos K, Kleanthous M, Ioannou A, Kontoghiorghes GJ. Liver iron and serum ferritin levels are misleading for estimating cardiac, pancreatic, splenic and total body iron load in thalassemia patients: factors influencing the heterogenic distribution of excess storage iron in organs as identified by MRI T2*. Toxicology Mechanisms and Methods. 2013; 23: 48–56.
[31]
Halliwell B. Free radicals, antioxidants, and human disease: where are we now? Journal of Laboratory and Clinical Medicine. 1992; 119: 598–620.
[32]
Ďuračková Z. Some Current Insights into Oxidative Stress. Physiological Research. 2010; 59: 59–69.
[33]
Kontoghiorghes GJ, Kontoghiorghe CN. Prospects for the introduction of targeted antioxidant drugs for the prevention and treatment of diseases related to free radical pathology. Expert Opinion on Investigational Drugs. 2019; 28: 593–603.
[34]
Cabon L, Martinez-Torres A-C, Susin SA. Programmed cell death comes in many flavors. Medecine Sciences. 2013; 29: 1117–1124.
[35]
Speer RE, Karuppagounder SS, Basso M, Sleiman SF, Kumar A, Brand D, et al. Hypoxia-inducible factor prolyl hydroxylases as targets for neuroprotection by “antioxidant” metal chelators: from ferroptosis to stroke. Free Radical Biology and Medicine. 2013; 62: 26–36.
[36]
Feng H, Stockwell BR. Unsolved mysteries: How does lipid peroxidation cause ferroptosis? PLoS Biology. 2018; 16: e2006203.
[37]
Shah R, Shchepinov MS, Pratt DA. Resolving the Role of Lipoxygenases in the Initiation and Execution of Ferroptosis. ACS Central Science. 2018; 4: 387–396.
[38]
Hao S, Liang B, Huang Q, Dong S, Wu Z, He W, et al. Metabolic networks in ferroptosis. Oncology Letters. 2018; 15: 5405–5411.
[39]
Tang D, Chen X, Kang R, Kroemer G. Ferroptosis: molecular mechanisms and health implications. Cell Research. 2021; 31: 107–125.
[40]
MAVROGENI S, GOTSIS E, MARKUSSIS V, TSEKOS N, POLITIS C, VRETOU E, et al. T2 relaxation time study of iron overload in b-thalassemia. Magnetic Resonance Materials in Biology, Physics, and Medicine. 1998; 6: 7–12.
[41]
Anderson L. Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload. European Heart Journal. 2001; 22: 2171–2179.
[42]
Kolnagou A, Economides C, Eracleous E, Kontoghiorghes GJ. Low Serum Ferritin Levels are Misleading for Detecting Cardiac Iron Overload and Increase the Risk of Cardiomyopathy in Thalassemia Patients. the Importance of Cardiac Iron Overload Monitoring Using Magnetic Resonance Imaging T2 and T2*. Hemoglobin. 2006; 30: 219–227.
[43]
PENNELL DJ. T2* Magnetic Resonance and Myocardial Iron in Thalassemia. Annals of the New York Academy of Sciences. 2005; 1054: 373–378.
[44]
Kontoghiorghes GJ. The aim of iron chelation therapy in thalassaemia. European Journal of Haematology. 2017; 99: 465–466.
[45]
Kontoghiorghes G, Sheppard L, Aldouri M, Hoffbrand AV. 1,2-DIMETHYL-3-HYDROXYPYRID-4-one, an ORALLY ACTIVE CHELATOR for TREATMENT of IRON OVERLOAD. The Lancet. 1987; 329: 1294–1295.
[46]
Kontoghiorghes GJ, Aldouri MA, Hoffbrand AV, Barr J, Wonke B, Kourouclaris T, et al. Effective chelation of iron in beta thalassaemia with the oral chelator 1,2-dimethyl-3-hydroxypyrid-4-one. British Medical Journal. 1987; 295: 1509–1512.
[47]
Kolnagou A, Michaelides Y, Kontoghiorghe CN, Kontoghiorghes GJ. The importance of spleen, spleen iron, and splenectomy for determining total body iron load, ferrikinetics, and iron toxicity in thalassemia major patients. Toxicology Mechanisms and Methods. 2013; 23: 34–41.
[48]
Borgna-Pignatti C, Garani MC, Forni GL, Cappellini MD, Cassinerio E, Fidone C, et al. Hepatocellular carcinoma in thalassaemia: an update of the Italian Registry. British Journal of Haematology. 2014; 167: 121–126.
[49]
Fragatou S, Tsourveloudis I, Manesis G. Incidence of Hepatocellular Carcinoma in a Thalassemia Unit. Hemoglobin. 2010; 34: 221–226.
[50]
Angelopoulos NG, Zervas A, Livadas S, Adamopoulos I, Giannopoulos D, Goula A, et al. Reduced insulin secretion in normoglycaemic patients with beta-thalassaemia major. Diabetic Medicine. 2006; 23: 1327–1331.
[51]
Angelopoulos NG, Goula A, Rombopoulos G, Kaltzidou V, Katounda E, Kaltsas D, et al. Hypoparathyroidism in transfusion-dependent patients with β-thalassemia. Journal of Bone and Mineral Metabolism. 2006; 24: 138–145.
[52]
Vullo C, Sanctis V, Katz M, Wonke B, Hoffbrand AV, BAGNI B, et al. Endocrine Abnormalities in Thalassemia. Annals of the New York Academy of Sciences. 1990; 612: 293–310.
[53]
Angelopoulos NG, Goula A, Katounda E, Rombopoulos G, Kaltzidou V, Kaltsas D, et al. MARKERS of BONE METABOLISM in EUGONADAL FEMALE PATIENTS with β-THALASSEMIA MAJOR. Pediatric Hematology and Oncology. 2007; 24: 481–491.
[54]
Tolis GJ, Vlachopapadopoulou E, Karydis I. Reproductive health in patients with beta-thalassemia. Current Opinion in Pediatrics. 1996; 8: 406–410.
[55]
Jeong HK, An JH, Kim HS, Cho EA, Han MG, Moon JS, et al. Hypoparathyroidism and Subclinical Hypothyroidism with Secondary Hemochromatosis. Endocrinology and Metabolism. 2014; 29: 91.
[56]
Sudmantaitė V, Čelutkienė J, Glaveckaite S, Katkus R. Difficult diagnosis of cardiac haemochromatosis: a case report. European Heart Journal - Case Reports. 2020; 4: 1–6.
[57]
Skandalis K, Vlachos C, Pliakou X, Gaitanis G, Kapsali E, Bassukas ID. Higher Serum Ferritin Levels Correlate with an Increased Risk of Cutaneous Morbidity in Adult Patients with β-Thalassemia: a Single-Center Retrospective Study. Acta Haematologica. 2016; 135: 124–130.
[58]
Shirota T, Shinoda T, Aizawa T, Mizukami T, Katakura M, Takasu N, et al. Primary hypothyroidism and multiple endocrine failure in association with hemochromatosis in a long-term hemodialysis patient. Clinical Nephrology. 1992; 38: 105–109.
[59]
Economides CP, Soteriades ES, Hadjigavriel M, Seimenis I, Karantanas A. Iron deposits in the knee joints of a thalassemic patient. Acta Radiologica Short Reports. 2013; 2: 1–5.
[60]
Boddaert N, Le Quan Sang KH, Rötig A, Leroy-Willig A, Gallet S, Brunelle F, et al. Selective iron chelation in Friedreich ataxia: biologic and clinical implications. Blood. 2007; 110: 401–408.
[61]
Martin-Bastida A, Ward RJ, Newbould R, Piccini P, Sharp D, Kabba C, et al. Brain iron chelation by deferiprone in a phase 2 randomised double-blinded placebo controlled clinical trial in Parkinson’s disease. Scientific Reports. 2017; 7: 1398.
[62]
Zorzi G, Zibordi F, Chiapparini L, Bertini E, Russo L, Piga A, et al. Iron-related MRI images in patients with pantothenate kinase-associated neurodegeneration (PKAN) treated with deferiprone: Results of a phase II pilot trial. Movement Disorders. 2011; 26: 1755–1759.
[63]
Galaris D, Pantopoulos K. Oxidative Stress and Iron Homeostasis: Mechanistic and Health Aspects. Critical Reviews in Clinical Laboratory Sciences. 2008; 45: 1–23.
[64]
Halliwell B, Gutteridge JMC. The antioxidants of human extracellular fluids. Archives of Biochemistry and Biophysics. 1990; 280: 1–8.
[65]
Young IS. Antioxidants in health and disease. Journal of Clinical Pathology. 2001; 54: 176–186.
[66]
Rahman K. Studies on free radicals, antioxidants, and co-factors. Clinical Interventions in Aging. 2007; 2: 219.
[67]
Hershko C, Graham G, Bates GW, Rachmilewitz EA. Non-Specific Serum Iron in Thalassaemia: an Abnormal Serum Iron Fraction of Potential Toxicity. British Journal of Haematology. 1978; 40: 255–263.
[68]
Leitch HA, Fibach E, Rachmilewitz E. Toxicity of iron overload and iron overload reduction in the setting of hematopoietic stem cell transplantation for hematologic malignancies. Critical Reviews in Oncology/Hematology. 2017; 113: 156–170.
[69]
Kontoghiorghes GJ, Jackson MJ, Lunec J. In Vitro Screening of Iron Chelators Using Models of Free Radical Damage. Free Radical Research Communications. 1986; 2: 115–124.
[70]
Mostert LJ, Van Dorst JALM, Koster JF, Van Eijk HG, Kontoghiorghes GJ. Free Radical and Cytotoxic Effects of Chelators and their Iron Complexes in the Hepatocyte. Free Radical Research Communications. 1987; 3: 379–388.
[71]
Timoshnikov VA, Kobzeva TV, Polyakov NE, Kontoghiorghes GJ. Inhibition of Fe2+- and Fe3+- induced hydroxyl radical production by the iron-chelating drug deferiprone. Free Radical Biology and Medicine. 2015; 78: 118–122.
[72]
Timoshnikov VA, Kichigina LA, Selyutina OY, Polyakov NE, Kontoghiorghes GJ. Antioxidant activity of deferasirox and its metal complexes in model systems of oxidative damage: comparison with deferiprone. Molecules. 2021; 26: 5064.
[73]
Timoshnikov VA, Selyutina OY, Polyakov NE, Didichenko V, Kontoghiorghes GJ. Mechanistic Insights of Chelator Complexes with Essential Transition Metals: Antioxidant/Pro-Oxidant Activity and Applications in Medicine. International Journal of Molecular Sciences. 2022; 23: 1247.
[74]
Rahav G, Volach V, Shapiro M, Rund D, Rachmilewitz EA, Goldfarb A. Severe infections in thalassaemic patients: prevalence and predisposing factors. British Journal of Haematology. 2006; 133: 667–674.
[75]
Weinberg ED. Iron availability and infection. Biochimica Et Biophysica Acta (BBA) - General Subjects. 2009; 1790: 600–605.
[76]
Kontoghiorghes GJ, Kolnagou A, Skiada A, Petrikkos G. The Role of Iron and Chelators on Infections in Iron Overload and Non Iron Loaded Conditions: Prospects for the Design of New Antimicrobial Therapies. Hemoglobin. 2010; 34: 227–239.
[77]
Kontoghiorghe CN, Kolnagou A, Kontoghiorghes GJ. Potential clinical applications of chelating drugs in diseases targeting transferrin-bound iron and other metals. Expert Opinion on Investigational Drugs. 2013; 22: 591–618.
[78]
Mahroum N, Alghory A, Kiyak Z, Alwani A, Seida R, Alrais M, et al. Ferritin – from iron, through inflammation and autoimmunity, to COVID-19. Journal of Autoimmunity. 2022; 126: 102778.
[79]
Kontoghiorghes GJ, Weinberg ED. Iron: Mammalian defense systems, mechanisms of disease, and chelation therapy approaches. Blood Reviews. 1995; 9: 33–45.
[80]
Cullingford GL, Watkins DN, Watts ADJ, Mallon DF. Severe late postsplenectomy infection. British Journal of Surgery. 1991; 78: 716–721.
[81]
Thompson AA, Cunningham MJ, Singer ST, Neufeld EJ, Vichinsky E, Yamashita R, et al. Red cell alloimmunization in a diverse population of transfused patients with thalassaemia. British Journal of Haematology. 2011; 153: 121–128.
[82]
Spanos T, Karageorga M, Ladis V, Peristeri J, Hatziliami A, Kattamis C. Red Cell Alloantibodies in Patients with Thalassemia. Vox Sanguinis. 1990; 58: 50–55.
[83]
Rebulla P, Modell B. Transfusion requirements and effects in patients with thalassaemia major. The Lancet. 1991; 337: 277–280.
[84]
Ameen R, Al-Shemmari S, Al-Humood S, Chowdhury RI, Al-Eyaadi O, Al-Bashir A. RBC alloimmunization and autoimmunization among transfusion-dependent Arab thalassemia patients. Transfusion. 2003; 43: 1604–1610.
[85]
Vlaar AP, Juffermans NP. Transfusion-related acute lung injury: a clinical review. The Lancet. 2013; 382: 984–994.
[86]
Kolnagou A, Kontoghiorghe CN, Kontoghiorghes GJ. Transfusion-related acute lung injury (TRALI) in two thalassaemia patients caused by the same multiparous blood donor. Mediterranean Journal of Hematology and Infectious Diseases. 2017; 9: e2017060.
[87]
Morris CR, Kim H, Trachtenberg F, Wood J, Quinn CT, Sweeters N, et al. Risk factors and mortality associated with an elevated tricuspid regurgitant jet velocity measured by Doppler-echocardiography in thalassemia: a Thalassemia Clinical Research Network report. Blood. 2011; 118: 3794–3802.
[88]
Vlahos AP, Koutsouka FP, Papamichael ND, Makis A, Baltogiannis GG, Athanasiou E, et al. Determinants of Pulmonary Hypertension in Patients with Beta-Thalassemia Major and Normal Ventricular Function. Acta Haematologica. 2012; 128: 124–129.
[89]
Kontoghiorghes GJ, Neocleous K, Kolnagou A. Benefits and Risks of Deferiprone in Iron Overload in Thalassaemia and other Conditions. Drug Safety. 2003; 26: 553–584.
[90]
Kontoghiorghe CN, Kontoghiorghes GJ. Efficacy and safety of iron-chelation therapy with deferoxamine, deferiprone, and deferasirox for the treatment of iron-loaded patients with non-transfusion-dependent thalassemia syndromes. Drug Design, Development and Therapy. 2016; 10: 465–481.
[91]
Kontoghiorghes GJ, Kolnagou A, Peng C, Shah SV, Aessopos A. Safety issues of iron chelation therapy in patients with normal range iron stores including thalassaemia, neurodegenerative, renal and infectious diseases. Expert Opinion on Drug Safety. 2010; 9: 201–206.
[92]
Exjade (deferasirox) tablets for oral suspension. prescribing information. 2011. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021882s010lbl.pdf (Accessed: 5 February 2022).
[93]
Kontoghiorghes GJ. A record number of fatalities in many categories of patients treated with deferasirox: loopholes in regulatory and marketing procedures undermine patient safety and misguide public funds? Expert Opinion on Drug Safety. 2013; 12: 605–609.
[94]
Chuang G, Tsai I, Tsau Y, Lu M. Transfusion-dependent thalassaemic patients with renal Fanconi syndrome due to deferasirox use. Nephrology. 2015; 20: 931–935.
[95]
Maximova N, Gregori M, Simeone R, Sonzogni A, Zanon D, Boz G, et al. Total body irradiation and iron chelation treatment are associated with pancreatic injury following pediatric hematopoietic stem cell transplantation. Oncotarget. 2018; 9: 19543–19554.
[96]
Fucile C, Mattioli F, Marini V, Gregori M, Sonzogni A, Martelli A, et al. What is known about deferasirox chelation therapy in pediatric HSCT recipients: two case reports of metabolic acidosis. Therapeutics and Clinical Risk Management. 2018; 14: 1649–1655.
[97]
Al-Khabori M, Bhandari S, Al-Huneini M, Al-Farsi K, Panjwani V, Daar S. Side effects of Deferasirox Iron Chelation in Patients with Beta Thalassemia Major or Intermedia. Oman Medical Journal. 2013; 28: 121–124.
[98]
Dee CMA, Cheuk DKL, Ha S, Chiang AK, Chan GC. Incidence of deferasirox-associated renal tubular dysfunction in children and young adults with beta-thalassaemia. British Journal of Haematology. 2014; 167: 434–436.
[99]
Naderi M, Sadeghi-Bojd S, Valeshabad AK, Jahantigh A, Alizadeh S, Dorgalaleh A, et al. A Prospective Study of Tubular Dysfunction in Pediatric Patients with Beta Thalassemia Major Receiving Deferasirox. Pediatric Hematology and Oncology. 2013; 30: 748–754.
[100]
Boelaert JR, Fenves AZ, Coburn JW. Deferoxamine Therapy and Mucormycosis in Dialysis Patients: Report of an International Registry. American Journal of Kidney Diseases. 1991; 18: 660–667.
[101]
Orton RB, de Veber LL, Sulh HM. Ocular and auditory toxicity of long-term, high-dose subcutaneous deferoxamine therapy. Canadian Journal of Ophthalmology. 1985; 20: 153–156.
[102]
Cases A, Kelly J, Sabater F, Torras A, Griño C, Lopez-Pedret J, et al. Ocular and Auditory Toxicity in Hemodialyzed Patients Receiving Desferrioxamine. Nephron. 1990; 56: 19–23.
[103]
Ioannides AS, Panisello JM. Acute respiratory distress syndrome in children with acute iron poisoning: the role of intravenous desferrioxamine. European Journal of Pediatrics. 2000; 159: 158–159.
[104]
Cohen AR, Galanello R, Piga A, De Sanctis V, Tricta F. Safety and effectiveness of long-term therapy with the oral iron chelator deferiprone. Blood. 2003; 102: 1583–1587.
[105]
Rajapurkar MM, Hegde U, Bhattacharya A, Alam MG, Shah SV. Effect of deferiprone, an oral iron chelator, in diabetic and non-diabetic glomerular disease. Toxicology Mechanisms and Methods. 2013; 23: 5–10.
[106]
Saxena D, Spino M, Tricta F, Connelly J, Cracchiolo BM, Hanauske A-R, et al. Drug-based lead discovery: the novel ablative antiretroviral profile of deferiprone in HIV-1-infected cells and in HIV-infected treatment-naive subjects of a double-blind, placebo-controlled, randomized exploratory trial. PLoS ONE. 2016; 11: e0154842.
[107]
Mohanty D, Ghosh K, Pathare AV, Karnad D. Deferiprone (L1) as an adjuvant therapy for Plasmodium falciparum malaria. Indian Journal of Medical Research. 2002; 115: 17–21.
[108]
Leftin A, Zhao H, Turkekul M, de Stanchina E, Manova K, Koutcher JA. Iron deposition is associated with differential macrophage infiltration and therapeutic response to iron chelation in prostate cancer. Scientific Reports. 2017; 7: 11632.
[109]
Hoffbrand AV, Bartlett AN, Veys PA, O’Connor NTJ, Kontoghiorghes GJ. AGRANULOCYTOSIS and THROMBOCYTOPENIA in PATIENT with BLACKFAN-DIAMOND ANAEMIA during ORAL CHELATOR TRIAL. The Lancet. 1989; 334: 457.
[110]
Ceci A, Baiardi P, Felisi M, Cappellini MD, Carnelli V, De Sanctis V, et al. The safety and effectiveness of deferiprone in a large-scale, 3-year study in Italian patients. British Journal of Haematology. 2002; 118: 330–336.
[111]
Kontoghiorghes GJ. Present status and future prospects of oral iron chelation therapy in thalassaemia and other diseases. The Indian Journal of Pediatrics. 1993; 60: 485–507.
[112]
Kontoghiorghe CN, Kontoghiorghes GJ. New developments and controversies in iron metabolism and iron chelation therapy. World Journal of Methodology. 2016; 6: 1.
[113]
Kontoghiorghes GJ, Kolnagou A. Effective new treatments of iron overload in thalassaemia using the ICOC combination therapy protocol of deferiprone (L1) and deferoxamine and of new chelating drugs. Haematologica. 2006; 91: ELT04–ELT04.
[114]
Kontoghiorghes GJ. Chelation protocols for the elimination and prevention of iron overload in thalassaemia. Frontiers in Bioscience. 2018; 23: 1082–1098.
[115]
Totadri S, Bansal D, Bhatia P, Attri SV, Trehan A, Marwaha RK. The deferiprone and deferasirox combination is efficacious in iron overloaded patients with β-thalassemia major: a prospective, single center, open-label study. Pediatric Blood & Cancer. 2015; 62: 1592–1596.
[116]
Cassinerio E, Orofino N, Roghi A, Duca L, Poggiali E, Fraquelli M, et al. Combination of deferasirox and deferoxamine in clinical practice: an alternative scheme of chelation in thalassemia major patients. Blood Cells, Molecules, and Diseases. 2014; 53: 164–167.
[117]
Elalfy MS, Adly AM, Wali Y, Tony S, Samir A, Elhenawy YI. Efficacy and safety of a novel combination of two oral chelators deferasirox/deferiprone over deferoxamine/deferiprone in severely iron overloaded young beta thalassemia major patients. European Journal of Haematology. 2015; 95: 411–420.
[118]
Dézsi L, Vécsei L. Clinical implications of irregular ADMET properties with levodopa and other antiparkinson’s drugs. Expert Opinion on Drug Metabolism & Toxicology. 2014; 10: 409–424.
[119]
Binding A, Ward R, Tomlinson G, Kuo KHM. Deferiprone exerts a dose‐dependent reduction of liver iron in adults with iron overload. European Journal of Haematology. 2019; 103: 80–87.
[120]
Kolnagou A, Kleanthous M, Kontoghiorghes GJ. Reduction of body iron stores to normal range levels in thalassaemia by using a deferiprone/deferoxamine combination and their maintenance thereafter by deferiprone monotherapy. European Journal of Haematology. 2010; 85: 430–438.
[121]
Farmaki K, Tzoumari I, Pappa C, Chouliaras G, Berdoukas V. Normalisation of total body iron load with very intensive combined chelation reverses cardiac and endocrine complications of thalassaemia major. British Journal of Haematology. 2010; 148: 466–475.
[122]
Kolnagou A, Kontoghiorghe C, Kontoghiorghes G. Prevention of Iron Overload and Long Term Maintenance of Normal Iron Stores in Thalassaemia Major Patients using Deferiprone or Deferiprone Deferoxamine Combination. Drug Research. 2017; 67: 404–411.
[123]
Kolnagou A, Kleanthous M, Kontoghiorghes GJ. Efficacy, Compliance and Toxicity Factors are Affecting the Rate of Normalization of Body Iron Stores in Thalassemia Patients Using the Deferiprone and Deferoxamine Combination Therapy. Hemoglobin. 2011; 35: 186–198.
[124]
Telfer PT, Warburton F, Christou S, Hadjigavriel M, Sitarou M, Kolnagou A, et al. Improved survival in thalassemia major patients on switching from desferrioxamine to combined chelation therapy with desferrioxamine and deferiprone. Haematologica. 2009; 94: 1777–1778.
[125]
Maggio A, Vitrano A, Lucania G, Capra M, Cuccia L, Gagliardotto F, et al. Long-term use of deferiprone significantly enhances left-ventricular ejection function in thalassemia major patients. American Journal of Hematology. 2012; 87: 732–733.
[126]
Filosa A, Vitrano A, Rigano P, Calvaruso G, Barone R, Capra M, et al. Long-term treatment with deferiprone enhances left ventricular ejection function when compared to deferoxamine in patients with thalassemia major. Blood Cells, Molecules, and Diseases. 2013; 51: 85–88.
[127]
Pennell DJ, Udelson JE, Arai AE, Bozkurt B, Cohen AR, Galanello R, et al. Cardiovascular Function and Treatment in β-Thalassemia Major. Circulation. 2013; 128: 281–308.
[128]
Pepe A, Meloni A, Rossi G, Cuccia L, D’Ascola GD, Santodirocco M, et al. Cardiac and hepatic iron and ejection fraction in thalassemia major: Multicentre prospective comparison of combined Deferiprone and Deferoxamine therapy against Deferiprone or Deferoxamine Monotherapy. Journal of Cardiovascular Magnetic Resonance. 2013; 15: 1.
[129]
Klein HG, Spahn DR, Carson JL. Red blood cell transfusion in clinical practice. the Lancet. 2007; 370: 415–426.
[130]
Cazzola M, Stefano PD, Ponchio L, Locatelli F, Beguin Y, Dessì C, et al. Relationship between transfusion regimen and suppression of erythropoiesis in β-thalassaemia major. British Journal of Haematology. 1995; 89: 473–478.
[131]
Cazzola M, Borgna-Pignatti C, Locatelli F, Ponchio L, Beguin Y, Stefano P. A moderate transfusion regimen may reduce iron loading in beta- thalassemia major without producing excessive expansion of erythropoiesis. Transfusion. 1997; 37: 135–140.
[132]
Spinella PC, Dressler A, Tucci M, Carroll CL, Rosen RS, Hume H, et al. Survey of transfusion policies at us and Canadian children’s hospitals in 2008 and 2009. Transfusion. 2010; 50: 2328–2335.
[133]
Brand A. Immunological aspects of blood transfusions. Transplant Immunology. 2002; 10: 183–190.
[134]
Naveen KN, Kabbin GM, Kulkarni V, Pai VV, Rao R. Transfusion induced Graft versus host disease – Case report in a 2year child. Transfusion and Apheresis Science. 2012; 47: 17–19.
[135]
Cogliandro T, Derchi G, Mancuso L, Mayer MC, Pannone B, Pepe A, et al. Guideline recommendations for heart complications in thalassemia major. Journal of Cardiovascular Medicine. 2008; 9: 515–525.
[136]
Singer ST, Kuypers FA, Styles L, Vichinsky EP, Foote D, Rosenfeld H. Pulmonary hypertension in thalassemia: Association with platelet activation and hypercoagulable state. American Journal of Hematology. 2006; 81: 670–675.
[137]
DERCHI G, FORNI GL. Therapeutic Approaches to Pulmonary Hypertension in Hemoglobinopathies: Efficacy and Safety of Sildenafil in the Treatment of Severe Pulmonary Hypertension in Patients with Hemoglobinopathy. Annals of the New York Academy of Sciences. 2005; 1054: 471–475.
[138]
Cheung YF, Chan GCF, Ha SY. Effect of deferasirox (ICL670) on arterial function in patients with beta-thalassaemia major. British Journal of Haematology. 2008; 141: 728–733.
[139]
Wood JC, Enriquez C, Ghugre N, Otto-Duessel M, Aguilar M, Nelson MD, et al. Physiology and Pathophysiology of Iron Cardiomyopathy in Thalassemia. Annals of the New York Academy of Sciences. 2005; 1054: 386–395.
[140]
Di Marco V, Capra M, Angelucci E, Borgna-Pignatti C, Telfer P, Harmatz P, et al. Management of chronic viral hepatitis in patients with thalassemia: recommendations from an international panel. Blood. 2010; 116: 2875–2883.
[141]
Badawy SM, Payne AB, Hulihan MM, Coates TD, Majumdar S, Smith D, et al. Concordance with comprehensive iron assessment, hepatitis a vaccination, and hepatitis B vaccination recommendations among patients with sickle cell disease and thalassaemia receiving chronic transfusions: an analysis from the Centers for Disease Control haemoglobinopathy blood safety project. British Journal of Haematology. 2021; 195: e160–e164.
[142]
Mazzucco W, Chiara di Maio V, Bronte F, Fabeni L, Pipitone RM, Grimaudo S, et al. Phylogenetic analysis in the clinical risk management of an outbreak of hepatitis C virus infection among transfused thalassaemia patients in Italy. Journal of Hospital Infection. 2021; 115: 51–58.
[143]
Ruiz I, Fourati S, Ahmed-Belkacem A, Rodriguez C, Scoazec G, Donati F, et al. Real-world efficacy and safety of direct-acting antiviral drugs in patients with chronic hepatitis C and inherited blood disorders. European Journal of Gastroenterology & Hepatology. 2021; 33: e191–e196.
[144]
Lai ME, Origa R, Danjou F, Leoni GB, Vacquer S, Anni F, et al. Natural history of hepatitis C in thalassemia major: a long-term prospective study. European Journal of Haematology. 2013; 90: 501–507.
[145]
Triantos C, Kourakli A, Kalafateli M, Giannakopoulou D, Koukias N, Thomopoulos K, et al. Hepatitis C in patients with β-thalassemia major. a single-centre experience. Annals of Hematology. 2013; 92: 739–746.
[146]
Kalafateli M, Kourakli A, Gatselis N, Lambropoulou P, Thomopoulos K, Tsamandas A, et al. Efficacy of Interferon A-2b Monotherapy in B-Thalassemics with Chronic Hepatitis C. Journal of Gastrointestinal and Liver Diseases. 2015; 24: 189–196.
[147]
Sinakos E, Kountouras D, Koskinas J, Zachou K, Karatapanis S, Triantos C, et al. Treatment of chronic hepatitis C with direct-acting antivirals in patients with β-thalassaemia major and advanced liver disease. British Journal of Haematology. 2017; 178: 130–136.
[148]
Maakaron JE, Cappellini MD, Graziadei G, Ayache JB, Taher AT. Hepatocellular carcinoma in hepatitis-negative patients with thalassemia intermedia: a closer look at the role of siderosis. Annals of Hepatology. 2013; 12: 142–146.
[149]
Mancuso A. Hepatocellular carcinoma in thalassemia: a critical review. World Journal of Hepatology. 2010; 2: 171.
[150]
Adamkiewicz T v, Berkovitch M, Krishnan C, Polsinelli C, Kermack D, Olivieri NF. Infection Due to Yersinia enterocolitica in a Series of Patients with β-Thalassemia: Incidence and Predisposing Factors. Clinical Infectious Diseases. 1998; 27: 1362–1366.
[151]
Attina’ G, Triarico S, Romano A, Maurizi P, Mastrangelo S, Ruggiero A. Role of Partial Splenectomy in Hematologic Childhood Disorders. Pathogens. 2021; 10: 1436.
[152]
Ud-naen S, Tansit T, Kanistanon D, Chaiprasert A, Wanachiwanawin W, Srinoulprasert Y. Defective cytokine production from monocytes/macrophages of E-beta thalassemia patients in response to Pythium insidiosum infection. Immunobiology. 2019; 224: 427–432.
[153]
Sakran W, Levin C, Kenes Y, Colodner R, Koren A. Clinical spectrum of serious bacterial infections among splenectomized patients with hemoglobinopathies in Israel: a 37-year follow-up study. Infection. 2012; 40: 35–39.
[154]
Chan GC, Chan S, Ho PL, Ha SY. Effects of chelators (deferoxamine, deferiprone and deferasirox) on the growth of Klebsiella pneumoniae and Aeromonas hydrophila isolated from transfusion-dependent thalassemia patients. Hemoglobin. 2009; 33: 352–360.
[155]
Choudhury S. R, Rajiv C, Pitamber S, Akshay S, Dharmendra S. Management of splenic abscess in children by percutaneous drainage. Journal of Pediatric Surgery. 2006; 41: e53–e56.
[156]
Sari TT, Akib AAP, Gatot D, Roswita Harahap A, Bardosono S, Hadinegoro SRS. Pneumococcal vaccination for splenectomized patients with thalassemia major in Indonesia. Vaccine. 2017; 35: 4583–4586.
[157]
Bahoush G, Nojoomi M. A Study on the Efficacy of Empirical Antibiotic Therapy for Splenectomized Children with Fever. Journal of Medicine and Life. 2020; 13: 151–155.
[158]
Tahir F, Ahmed J, Malik F. Post-splenectomy sepsis: a review of the literature. Cureus. 2020; 12: e6898.
[159]
Aessopos A, Farmakis D, Deftereos S, Tsironi M, Polonifi A, Moyssakis I, et al. Cardiovascular effects of splenomegaly and splenectomy in β-thalassemia. Annals of Hematology. 2005; 84: 353–357.
[160]
Aydinok Y, Bayraktaroglu S, Yildiz D, Alper H. Myocardial Iron Loading in Patients with Thalassemia Major in Turkey and the Potential Role of Splenectomy in Myocardial Siderosis. Journal of Pediatric Hematology/Oncology. 2011; 33: 374–378.
[161]
De Sanctis V, Soliman A, Elsedfy H, Skordis N, Kattamis C, Angastiniotis M, et al. Growth and endocrine disorders in thalassemia: the international network on endocrine complications in thalassemia (i-CET) position statement and guidelines. Indian Journal of Endocrinology and Metabolism. 2013; 17: 8.
[162]
Ngim CF, Lai NM, Hong JYH, Tan SL, Ramadas A, Muthukumarasamy P, et al. Growth hormone therapy for people with thalassaemia. Cochrane Database of Systematic Reviews. 2020; 5: CD012284.
[163]
Tan K, Lum S, Yahya A, Krishnan S, Jalaludin M, Lee W. Prevalence of growth and endocrine disorders in Malaysian children with transfusion-dependent thalassaemia. Singapore Medical Journal. 2019; 60: 303–308.
[164]
Dhouib NG, Khaled M ben, Ouederni M, Besbes H, Kouki R, Mellouli F, et al. Growth and endocrine function in Tunisian thalassemia major patients. Mediterranean journal of hematology and infectious diseases. 2018; 10: e2018031.
[165]
de Sanctis V, Soliman A, Candini G, Campisi S, Anastasi S, Iassin M. High prevalence of central hypothyroidism in adult patients with β-thalassemia major. Georgian Medical News. 2013; 222: 88–94.
[166]
Soliman A, de Sanctis V, Yassin M. Vitamin D status in thalassemia major: an update. Mediterranean Journal of Hematology and Infectious Diseases. 2013; 5: e2013057.
[167]
de Sanctis V, Soliman AT, Elsedfy H, Yassin M, Canatan D, Kilinc Y, et al. Osteoporosis in thalassemia major: an update and the I-CET 2013 recommendations for surveillance and treatment. Pediatric Endocrinology Reviews. 2013; 11: 167–180.
[168]
Tolis G, Politis C, Kontopoulou I, Poulatzas N, Rigas G, Saridakis C, et al. Pituitary somatotropic and corticotropic function in patients with beta-thalassemia on iron chelation therapy. Birth Defects Original Article Series. 1987; 23: 449–452.
[169]
Sanctis VD, Soliman A, Yassin M. Iron overload and glucose metabolism in subjects with β-thalassaemia major: an overview. Current Diabetes Reviews. 2013; 9: 332–341.
[170]
Farmaki K, Angelopoulos N, Anagnostopoulos G, Gotsis E, Rombopoulos G, Tolis G. Effect of enhanced iron chelation therapy on glucose metabolism in patients with β-thalassaemia major. British Journal of Haematology. 2006; 134: 438–444.
[171]
Platis O, Anagnostopoulos G, Farmaki K, Posantzis M, Gotsis E, Tolis G. Glucose metabolism disorders improvement in patients with thalassaemia major after 24-36 months of intensive chelation therapy. Pediatric Endocrinology Reviews. 2004; 2: 279–281.
[172]
Borgna-Pignatti C, Gamberini MR. Complications of thalassemia major and their treatment. Expert Review of Hematology. 2011; 4: 353–366.
[173]
Oikonomopoulou C, Goussetis E. HSCT remains the only cure for patients with transfusion-dependent thalassemia until gene therapy strategies are proven to be safe. Bone Marrow Transplantation. 2021; 56: 2882–2888.
[174]
Di Bartolomeo P, Santarone S, Di Bartolomeo E, Olioso P, Bavaro P, Papalinetti G, et al. Long‐term results of survival in patients with thalassemia major treated with bone marrow transplantation. American Journal of Hematology. 2008; 83: 528–530.
[175]
Hongeng S, Pakakasama S, Chuansumrit A, Sirachainan N, Sura T, Ungkanont A, et al. Reduced intensity stem cell transplantation for treatment of class 3 Lucarelli severe thalassemia patients. American Journal of Hematology. 2007; 82: 1095–1098.
[176]
Issaragrisil S, Visudhisakchai S, Suvatte V, Chandanayingyong D, Piankijagum A, Mahasandana C, et al. Bone marrow transplantation for thalassemia in Thailand. Bone Marrow Transplantation. 1993; 12: 42–44.
[177]
Andreani M, Nesci S, Lucarelli G, Tonucci P, Rapa S, Angelucci E, et al. Long-term survival of ex-thalassemic patients with persistent mixed chimerism after bone marrow transplantation. Bone Marrow Transplantation. 2000; 25: 401–404.
[178]
Locatelli F, Thompson AA, Kwiatkowski JL, Porter JB, Thrasher AJ, Hongeng S, et al. Betibeglogene Autotemcel Gene Therapy for Non–β0/β0 Genotype β-Thalassemia. New England Journal of Medicine. 2022; 386: 415–427.
[179]
Payen E. Efficacy and Safety of Gene Therapy for β-Thalassemia. New England Journal of Medicine. 2022; 386: 488–490.
[180]
Leonard A, Bertaina A, Bonfim C, Cohen S, Prockop S, Purtill D, et al. Curative therapy for hemoglobinopathies: an International Society for Cell & Gene Therapy Stem Cell Engineering Committee review comparing outcomes, accessibility and cost of ex vivo stem cell gene therapy versus allogeneic hematopoietic stem cell transplantation. Cytotherapy. 2022; 24: 249–261.
[181]
Sagoo P, Gaspar HB. The transformative potential of HSC gene therapy as a genetic medicine. Gene Ther. 2021 May 26.
[182]
Li C, Mathews V, Kim S, George B, Hebert K, Jiang H, et al. Related and unrelated donor transplantation for β-thalassemia major: results of an international survey. Blood Advances. 2019; 3: 2562–2570.
[183]
Huang C, Qu Y, Liu S, Nie S, Jiang H. Hematopoietic stem cell transplantation for thalassemia major using HLA fully-matched and mismatched donor grafts. Translational Pediatrics. 2021; 10: 1552–1565.
[184]
Lüftinger R, Zubarovskaya N, Galimard J, Cseh A, Salzer E, Locatelli F, et al. Busulfan–fludarabine- or treosulfan–fludarabine-based myeloablative conditioning for children with thalassemia major. Annals of Hematology. 2022; 101: 655–665.
[185]
Chaya W, Anurathapan U, Rattanasiri S, Techasaensiri C, Pakakasama S, Apiwattanakul N. Bloodstream bacterial infections in thalassemic pediatric and adolescent patients after hematopoietic stem cell transplantation. Pediatric Transplantation. 2022; 26: e14168.
[186]
Caocci G, Orofino MG, Vacca A, Piroddi A, Piras E, Addari MC, et al. Long-term survival of beta thalassemia major patients treated with hematopoietic stem cell transplantation compared with survival with conventional treatment. American Journal of Hematology. 2017; 92: 1303–1310.
[187]
Ahmed SO, El Fakih R, Elhaddad A, Hamidieh AA, Altbakhi A, Chaudhry Q, et al. Strategic priorities for hematopoietic stem cell transplantation in the EMRO region. Hematology/Oncology and Stem Cell Therapy. 2021. (in press)
[188]
Magrin E, Semeraro M, Hebert N, Joseph L, Magnani A, Chalumeau A, et al. Long-term outcomes of lentiviral gene therapy for the β-hemoglobinopathies: the HGB-205 trial. Nature Medicine. 2022; 28: 81–88.
[189]
Boulad F, Maggio A, Wang X, Moi P, Acuto S, Kogel F, et al. Lentiviral globin gene therapy with reduced-intensity conditioning in adults with β-thalassemia: a phase 1 trial. Nature Medicine. 2022; 28: 63–70.
[190]
Langer AL, Esrick EB. Β-Thalassemia: evolving treatment options beyond transfusion and iron chelation. Hematology. 2021; 2021: 600–606.
[191]
Thompson AA, Walters MC, Kwiatkowski J, Rasko JE, Ribeil JA, Hongeng S, et al. Gene therapy in patients with transfusion-dependent b-thalassemia. New England Journal of Medicine. 2018; 378: 1479–1493.
[192]
Rattananon P, Anurathapan U, Bhukhai K, Hongeng S. The Future of Gene Therapy for Transfusion-Dependent Beta-Thalassemia: The Power of the Lentiviral Vector for Genetically Modified Hematopoietic Stem Cells. Frontiers in Pharmacology. 2021; 12: 730873.
[193]
Constantinou V, Papayanni P, Mallouri D, Batsis I, Bouinta A, Papadopoulou D, et al. Case study of betibeglogene autotemcel gene therapy in an adult Greek patient with transfusion‐dependent β‐thalassaemia of a severe genotype. British Journal of Haematology. 2022; 196: 1401–1404.
[194]
Makis A, Voskaridou E, Papassotiriou I, Hatzimichael E. Novel Therapeutic Advances in β-Thalassemia. Biology. 2021; 10: 546.
[195]
Frangoul H, Altshuler D, Cappellini MD, Chen Y, Domm J, Eustace BK, et al. CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia. New England Journal of Medicine. 2021; 384: 252–260.
[196]
Thuret I, Ruggeri A, Angelucci E, Chabannon C. Hurdles to the Adoption of Gene Therapy as a Curative Option for Transfusion-Dependent Thalassemia. Stem Cells Translational Medicine. 2022. (in press)
[197]
Ovsyannikova G, Balashov D, Demina I, Shelikhova L, Pshonkin A, Maschan M, et al. Efficacy and safety of ruxolitinib in ineffective erythropoiesis suppression as a pretransplantation treatment for pediatric patients with beta‐thalassemia major. Pediatric Blood & Cancer. 2021; 68: e29338.
[198]
Madan U, Bhasin H, Dewan P, Madan J. Improving Ineffective Erythropoiesis in Thalassemia: a Hope on the Horizon. Cureus. 2021; 5: e18502.
[199]
Manolova V, Nyffenegger N, Flace A, Altermatt P, Varol A, Doucerain C, et al. Oral ferroportin inhibitor ameliorates ineffective erythropoiesis in a model of β-thalassemia. Journal of Clinical Investigation. 2019; 130: 491–506.
[200]
Italia KY, Jijina FJ, Merchant R, Panjwani S, Nadkarni AH, Sawant PM, et al. Response to hydroxyurea in β thalassemia major and intermedia: Experience in western India. Clinica Chimica Acta. 2009; 407: 10–15.
[201]
Banan M. Hydroxyurea treatment in β-thalassemia patients: to respond or not to respond? Annals of Hematology. 2013; 92: 289–299.
[202]
Konstantinou E, Pashalidis I, Kolnagou A, Kontoghiorghes GJ. Interactions of Hydroxycarbamide (Hydroxyurea) with Iron and Copper: Implications on Toxicity and Therapeutic Strategies. Hemoglobin. 2011; 35: 237–246.
[203]
Schmid H, Jelkmann W. Investigational therapies for renal disease-induced anemia. Expert Opinion on Investigational Drugs. 2016; 25: 901–916.
[204]
Fenaux P, Kiladjian JJ, Platzbecker U. Luspatercept for the treatment of anemia in myelodysplastic syndromes and primary myelofibrosis. Blood. 2019; 133: 790–794.
[205]
Piga A, Perrotta S, Gamberini MR, Voskaridou E, Melpignano A, Filosa A, et al. Luspatercept improves hemoglobin levels and blood transfusion requirements in a study of patients with β-thalassemia. Blood. 2019; 133: 1279–1289.
[206]
Kontoghiorghes GJ. Questioning Established Theories and Treatment Methods Related to Iron and Other Metal Metabolic Changes, Affecting All Major Diseases and Billions of Patients. International Journal of Molecular Sciences. 2022; 23: 1364.
[207]
Kontoghiorghes GJ, Kolnagou A, Fetta S, Kontoghiorghe CN. Conventional and Unconventional Approaches for Innovative Drug Treatments in COVID-19: Looking Outside of Plato’s Cave. International Journal of Molecular Sciences. 2021; 22: 7208.
[208]
Isidori A, Borin L, Elli E, Latagliata R, Martino B, Palumbo G, et al. Iron toxicity – its effect on the bone marrow. Blood Reviews. 2018; 32: 473–479.
[209]
Angelucci E, Pilo F. Management of iron overload before, during, and after hematopoietic stem cell transplantation for thalassemia major. Annals of the New York Academy of Sciences. 2016; 1368: 115–121.
[210]
Germing U, Schroeder T, Kaivers J, Kündgen A, Kobbe G, Gattermann N. Novel therapies in low- and high-risk myelodysplastic syndrome. Expert Review of Hematology. 2019; 12: 893–908.
[211]
Cremers EMP, de Witte T, de Wreede L, Eikema D, Koster L, van Biezen A, et al. A prospective non-interventional study on the impact of transfusion burden and related iron toxicity on outcome in myelodysplastic syndromes undergoing allogeneic hematopoietic cell transplantation. Leukemia & Lymphoma. 2019; 60: 2404–2414.
[212]
Kontoghiorghes GJ. A New Era in Iron Chelation Therapy: the Design of Optimal, Individually Adjusted Iron Chelation Therapies for the Complete Removal of Iron Overload in Thalassemia and other Chronically Transfused Patients. Hemoglobin. 2009; 33: 332–338.
[213]
Anie KA, Massaglia P. Psychological therapies for thalassaemia. Cochrane Database of Systematic Reviews. 2014; 2014: CD002890.
[214]
Allan DS, Parquet MDC, Savage KA, Holbein BE. Iron Sequestrant DIBI, a Potential Alternative for Nares Decolonization of Methicillin-Resistant Staphylococcus aureus, is Anti-infective and Inhibitory for Mupirocin-Resistant Isolates. Antimicrobial Agents and Chemotherapy. 2020; 64: e02353-19.
[215]
Kontoghiorghe CN, Kolnagou A, Kontoghiorghes GJ. Phytochelators intended for clinical use in iron overload, other diseases of iron imbalance and free radical pathology. Molecules. 2015; 20: 20841–20872.
[216]
Irto A, Cardiano P, Chand K, Cigala RM, Crea F, de Stefano C, et al. Bifunctional 3-Hydroxy-4-Pyridinones as Potential Selective Iron (III) Chelators: Solution Studies and Comparison with Other Metals of Biological and Environmental Relevance. Molecules. 2021; 26: 7280.
[217]
Kontoghiorghes GJ. New chelation therapies and emerging chelating drugs for the treatment of iron overload. Expert Opinion on Emerging Drugs. 2006; 11: 1–5.
[218]
Barbouti A, Lagopati N, Veroutis D, Goulas V, Evangelou K, Kanavaros P, et al. Implication of dietary iron-chelating bioactive compounds in molecular mechanisms of oxidative stress-induced cell ageing. Antioxidants. 2021; 10: 491.
[219]
Mangia A, Bellini D, Cillo U, Laghi A, Pelle G, Valori VM, et al. Hepatocellular carcinoma in adult thalassemia patients: an expert opinion based on current evidence. BMC Gastroenterology. 2020; 20: 251.
[220]
Brock JH, Licéaga J, Kontoghiorghes GJ. The effect of synthetic iron chelators on bacterial growth in human serum. FEMS Microbiology Letters. 1988; 47: 55–60.
[221]
Aessopos A, Kati M, Farmakis D, Polonifi E, Deftereos S, Tsironi M. Intensive chelation therapy in β-thalassemia and possible adverse cardiac effects of desferrioxamine. International Journal of Hematology. 2007; 86: 212–215.
[222]
Cohen AR. Iron chelation therapy: you gotta have heart. Blood. 2010; 115: 2333–2334.
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