The History of Deferiprone (L1) and the Paradigm of the Complete Treatment of Iron Overload in Thalassaemia
Received: October 29, 2019
Accepted: December 18, 2019
Mediterr J Hematol Infect Dis 2020, 12(1): e2020011 DOI 10.4084/MJHID.2020.011
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(L1) was originally designed, synthesised and screened in vitro and in
vivo in 1981 by Kontoghiorghes G. J. following his discovery of the
novel alpha-ketohydroxypyridine class of iron chelators (1978-1981),
which were intended for clinical use. The journey through the years for
the treatment of thalassaemia with L1 has been a very difficult one
with an intriguing turn of events, which continue until today. Despite
many complications, such as the extensive use of L1 suboptimal dose
protocols, the aim of chelation therapy- namely, the complete removal
of excess iron in thalassaemia major patients, has been achieved in
most cases following the introduction of specific L1 and
L1/deferoxamine combinations. Many such patients continue to maintain
normal iron stores. Thalassemia has changed from a fatal to chronic
disease; also thanks to L1 therapy and thalassaemia patients are active
professional members in all sectors of society, have their own families
with children and grandchildren and their lifespan is approaching that
of normal individuals. No changes in the low toxicity profile of L1
have been observed in more than 30 years of clinical use and
prophylaxis against the low incidence of agranulocytosis is maintained
using mandatory monitoring of weekly white blood cells’ count.
Thousands of thalassaemia patients are still denied the
cardioprotective and other beneficial effects of L1 therapy. The safety
of L1 in thalassaemia and other non-iron loaded diseases resulted in
its selection as one of the leading therapeutics for the treatment of
Friedreich’s ataxia, pantothenate kinase-associated neurodegeneration
and other similar cases. There are also increasing prospects for the
application of L1 as a main, alternative or adjuvant therapy in many
pathological conditions including cancer, infectious diseases and as a
general antioxidant for diseases related to free radical pathology.
Thalassaemia is endemic in some countries such as Cyprus, where 1 in 6 persons is an asymptomatic thalassaemia heterozygote carrier, and about 1 in 1000 is a thalassaemia major and intermedia patient. The prevention and treatment programmes for thalassaemia and especially chelation therapy impose a great financial burden on the health budget of many countries.[1,3]
The standard form of treatment of transfusion dependent thalassaemia (TDT) is regular red blood cell (RBC) transfusions every 1-4 weeks accompanied by daily chelation therapy. Multiple transfusions cause increased iron deposition and damage to the liver, heart, spleen and other organs. Iron overload in thalassaemia has the highest rate of morbidity and mortality of metal related intoxication in humans. Iron chelation therapy in thalassaemia and other transfusional iron loading conditions is carried out worldwide using the generic drugs deferoxamine (DF), deferiprone (L1) and deferasirox (DFRA). The combination of chelating drugs and especially the L1/DF combination, is also widely used in the vast majority of thalassaemia patients in Cyprus and also in some other countries.[5,6]
There is no worldwide consensus in the use of iron chelating drugs or of related protocols in transfusional iron loaded patients. In most cases, the selection of chelation therapy and related protocols is generally ‘random’ and based on subjective and other criteria and non specific aim. As a result, the selection and use of iron chelating drugs vary from country to country and from clinic to clinic.
The main aim of iron chelation therapy in thalassaemia and other iron loaded conditions is the achievement and maintenance of normal iron stores, in which case patients are devoid of iron overload toxic side effects. This aim, including the long term prevention of iron overload, can be accomplished using effective and safe chelation protocols, involving mainly L1 and L1/DF combinations.
Some of the unique pharmacological properties and characteristics of L1 such as the ability to penetrate most organs and remove effectively excess iron from the heart has resulted in a substantial reduction in the mortality rate of thalassaemia.[4-6,9,10] Furthermore, the ability of L1 to remove excess iron from the brain has resulted in the development of L1 as one of the leading pharmaceuticals in the treatment of Friedreich’s ataxia, pantothenate kinase-associated neurodegeneration (PKAN), and other cases of neurodegeneration with brain iron accumulation.[11-13]
Design, Development, and Cost of Deferiprone
The project on chelation was initiated at the University of Essex, UK, while working on haemoglobins in 1979 and was partly supported by the British Technology Group (BTG) and the UKTS.[14,15]
Following a fundamental new approach on iron chelation design and testing, a new group of iron chelators was discovered by one of the authors- namely Kontoghiorghes G J (GJK), and as a result, the new classes of alpha-ketohydroxyridines including 1,2-dimethyl-3-hydroxypyrid-4-one (L1) were synthesised and tested at Essex University and University College Medical School London (UCH), UK.[15,16] The latter was selected by GJK and members of UKTS because of the in vivo and clinical testing facilities.[15-18]
The discovery and iron removal effects of L1 could not be published for 5 years due to “embargo” on publications by BTG, and in 1985 the UKTS sponsored the continuation of the chelation project at the Royal Free Hospital Medical School (RF) London, UK from where the first publications of the iron removal effects of L1 in comparison to parenteral DF in animals were reported.[19-22]
A significant invention at the RF in 1986 was also the one-step novel synthesis of L1 and L1 analogues, instead of the 4-step synthesis invented in 1981, which overturned the BTG patent monopoly in many countries. The one-step synthetic method is currently utilised by all manufacturers of L1 worldwide and make L1 less expensive than DF and DFRA.[23-27] Deferiprone became a generic drug about 15 years ago, and by comparison, its sale price in India, Iran and Thailand is about 5-10 times cheaper than that sold in western countries.[23-27]
A fierce competition against L1 and related controversies were in process from the time of the L1 discovery until today. For example, more than 60 patents were filed worldwide since the discovery of L1 and other alpha-ketohydroxyridines. The first patent application was filed in 1982.[15,28] However, due to ‘policy changes’, BTG has submitted the remaining patents under the names of the inventor (GJK) and co-inventors using an alphabetical order format.[29,30]
An analogue of L1, namely 1,2-diethyl-3-hydroxypyrid-4-one (EL1NEt or CP 94) was promoted by BTG sponsored studies at Essex University and UCH.[31-35] However, based on further studies and clinical trials in thalassaemia patients, EL1NEt was later abandoned.[36-39] Similarly, Ciba Geigy (now Novartis) the then manufacturers of DF have also carried out animal toxicity studies with L1 and reached the conclusion that L1 was toxic. However, the evaluation methods used for L1, as well as the comparative toxicity data obtained previously with DF questioned Ciba Geigy’s conclusions. Similar controversies continue until today.[42-45]
Despite the opposition from different groups, the academic initiative and strategy for the development of L1 in academic institutions continued and included the general phase I to V studies as described for most other drugs.
The First Clinical Trials with Deferiprone and Today’s Implications
In the first two clinical studies, different divided or single daily doses of L1 were administered to 11 patients (10-110 mg/kg/day) to assess efficacy and tolerability.[46,47] All doses caused a net increase of urinary iron excretion (UIE), which was proportional to the dose of L1 and the iron load of the patients (Figure 2). Doses of 75-110 mg/kg/day were identified to cause negative iron balance with an increase in UIE greater than 25-33 mg, which was equivalent to that caused by DF and higher than the intake of iron from RBC transfusions. No increase in urinary excretion of other essential metals (Ca, Zn and Mg) or other toxic side effects were reported.[46,47]
International multicentre clinical trials were organised, following the initial clinical trials in London and L1 was supplied in different university clinical centres worldwide e.g. Italy, Switzerland, The Netherlands, Germany, etc. The production of L1 for clinical trials was later carried out by private companies in India, Switzerland, The Netherlands and Canada etc.
In 1989 the first episode of agranulocytosis was reported, as well as episodes of neutropenia, masculoskeletal and joint pains, gastric intolerance, and zinc deficiency in the RF, which were also confirmed by other centres.[48-51] In the same year, no similar agranulocytosis episodes were observed in a total of 125 other patients who received L1 in 8 other countries, as reported in the first international conference on oral chelation (1st ICOC) at the RF. In this context, a mandatory weekly blood count was introduced for prophylaxis against agranulocytosis and neutropenia similar to the drug clozapine.
An application proposing a name for L1 in 1991 by the inventor (GJK), resulted in the adoption by the World Health Organisation (WHO) of the INN name deferiprone (WHO drug information list 67, volume 2 of 1992).
There was no interest from major pharmaceutical companies for the commercial development of L1.[5,40] Within this context, India played a leading role in the pharmaceutical development of L1. A collaborative project initiated between a parent of a thalassaemia patient of the Indian pharmaceutical generic company Cipla with one of us (GJK), led to the pharmaceutical preparation of L1 and also the initiation of clinical trials in India.[21,50] The first in the world regulatory approval for L1 was in India and L1 became available to Indian thalassaemia patients in 1995 (Table 1).[49,50] At a later stage, BTG licensed the L1 patents to the generic pharmaceutical company Apotex, Canada and L1 received regulatory approval from the EU in 1999 and many other countries worldwide and also from the USA in 2011.
|Table 1. Deferiprone (L1)- the journey across the years.|
No formal animal or other preclinical toxicology studies were carried out on L1 by either Cipla or Apotex. The absence of such data put L1 at a disadvantage as a second line iron chelating drug in comparison to DF and DFRA. However, animal toxicology data are generally of a similar level of toxicity for all three drugs and in clinical practice, L1 is widely used to the same extent as the other two chelating drugs. In many cases, L1 is regarded as the first line iron chelating drug because of its unique properties and especially its cardioprotective effects.[5-10]
With regards to safety, long term studies, and continuous clinical monitoring involving thousands of thalassaemia and other categories of patients in the last 30 years have confirmed the low toxicity of L1.[50,51] The most severe toxic side effects of L1 still remain the same until today and are all controllable, manageable, and reversible. These include reversible agranulocytosis (1% >) and neutropenia (5% >), while less serious toxic side effects include gastric intolerance, masculoskeletal and joint pains and zinc deficiency.[50,51] Toxicity vigilance and prophylactic measures are essential steps for ensuring the safety of L1 and the other chelators. For example, zinc supplements are used for prophylaxis for patients on long term treatment with L1, DF and the L1/DF combination.
Agranulocytosis is the most severe toxic side effect of L1 and mandatory monitoring of weekly white blood cell count is an essential prophylactic measure for its prevention during L1 therapy. Similarly, temporary withdrawal of L1 is necessary during the sore throat and other infections. The cause of agranulocytosis is still unknown but in almost all the cases, this L1 toxicity was transient and all the patients recovered following treatment with granulocyte-colony stimulating factor (G-CSF). The time of recovery of the neutrophil count in patients treated with G-CSF varies between a few days to 7 weeks.[21,48] The mechanism of L1 induced agranulocytosis is thought to be related to an L1-related immune response against white cell progenitors since re-challenge on the same patients with L1 results in another episode of agranulocytosis. The patients with this L1 toxic side effect have to switch to DF or DFRA chelation.
Mechanisms of Chelation and Prevention of Iron Toxicity by Deferiprone
The pharmacokinetics, metabolism and route of iron elimination of L1 have also been determined (Figure 3).[21,52-54] Deferiprone is readily absorbed within minutes from the stomach, metabolised to a glucuronide conjugate, cleared from the plasma within 6-8 hours, and excreted in the urine in the form of L1 iron complex, L1 glucuronide conjugate and free L1 (Figure 3).[16,21,52-54] No increase in iron excretion was detected in the faeces of iron loaded thalassaemia patients treated with L1 (Figure 4).[53,55]
Iron mobilisation by L1 depends on the iron load of the patients and the dose of L1 (Figure 4). The increase of UIE in non iron loaded patients is only a few mg, which by comparison, is a small fraction of what is excreted in iron loaded patients.[21,53]
Iron chelation and mobilisation by L1 have been shown to occur from all the iron pools in cells including ferritin and haemosiderin and also from transferrin and NTBI in plasma (Figure 5).[4,21,22,56] In contrast to the other chelating drugs, only L1 can cause the mobilisation of iron from transferrin and prevent the accumulation of excess iron in cells (Figure 5).[4,21,22,56]
Many factors can affect the rate of accumulation and deposition of iron in the organs of transfused iron loaded patients, with the rate of RBC transfusions being the primary factor (Table 2). Similarly, many factors can affect the rate of iron removal from regularly transfused patients with the most important being the efficacy of the iron chelation protocol (Table 2). In this context, the selected chelating drugs and dose protocols, as well as other related effects, can influence the outcome of chelation therapies (Table 3).[57,88]
|Table 2. Factors affecting the iron load and iron removal in transfused patients.|
|Table 3. Comparison of the mode of action and effects of chelating drugs.|
There are many variables in the properties and mode of action of chelating drugs and the selection of any chelation protocol could have a direct effect on the mortality and morbidity of thalassaemia patients (Table 3).[5-10,57-60] Optimum iron chelation therapies in the context of personalised medicine in thalassaemia patients take into consideration the most effective and less toxic monotherapy or combination therapy protocols. In this context, for each patient, the dose protocols are adjusted with regards to the iron load and the efficacy/tolerability of the chelation therapy. The benefits from the selection of a chelation protocol could easily be assessed by monitoring the levels of the iron load and also organ function. For example, the removal of excess toxic iron in thalassaemia patients by L1, and the L1/DF combination is accompanied with improvement of cardiac function, such as elevation of left ventricular ejection fraction (LVEF), endothelial function, etc.[9,10,62] Improvements have also been observed in some other haematological conditions using L1 but the mechanisms have not yet been fully clarified.[63-65]
Recent Developments on Iron Chelation Metabolic Pathways
However, the relatively recent routine introduction of new diagnostic techniques such as Magnetic Resonance Imaging (MRI) T2 and T2* which identify the level of iron load in the heart, liver, spleen and other organs of thalassaemia and other iron overloaded patients, has not only increased our understanding of transfusional and other iron overload metabolic pathways but also the differential effect of chelating drugs in iron removal from various organs.[60,69-73]
The recent diagnostic procedures, and especially MRI T2 and T2* in the determination of iron deposition in organs, have increased the prospects of improved chelating drug targeting therapies of iron overload toxicity, as well as the introduction of personalised chelation regimens in thalassaemia and other iron overload metabolic disorders. Furthermore, based on these diagnostic findings the complete treatment of iron overload by removing all excess iron safely from the heart, liver and other organs of regularly TDT patients using L1, the L1/DF or other chelator combinations can nowadays be precisely monitored (Figure 6). In addition, the safe long term maintenance of normal iron stores in thalassaemia patients and prevention of chelating drug toxicity can also be regularly assessed using monthly monitoring of serum ferritin levels, as well as yearly or half yearly MRI T2 and T2* measurements.
The promising results in the treatment of iron overload in thalassaemia encouraged investigations for the use and development of chelating drugs in many other clinical conditions. Such initiatives were within the broad context of the risk/benefit assessment of therapeutic outcomes in each condition because of the absence of other effective therapeutic approaches. Most efforts were mainly focused on the use of L1 as a universal antioxidant in non iron overload diseases such as neurodegenerative, cardiovascular, renal, infectious diseases, as well as other diseases including cancer and ageing.[74,75]
Recent developments involving the prospects of the broader use of chelating drugs have been investigated in clinical trials and clinical developments in many of these clinical conditions.[74,75] In particular, the introduction of L1 for the treatment of non iron loaded patients with focal toxic iron deposits e.g. in Friedreich ataxia and toxic labile iron e.g. in diabetic and non-diabetic glomerular disease, is a reflection of the antioxidant and safety potential of L1.[11-13,74,75] As in many other cases of drug development, the prospects of introduction of L1 and other chelating drugs in these diseases are based on commercial and not ethical criteria.
The Paradigm of the Complete Treatment of Iron Overload in Thalassaemia
With the introduction of intramuscular and then subcutaneous and intravenous DF in the early 1960’s, it became evident that the rate of iron removal by DF was not sufficient to compensate for the body iron intake from RBC transfusions in the vast majority of thalassaemia major patients mainly due to severe complications with the parenteral administration of DF.[66,67,74] Furthermore, serious complications were also observed such as neurotoxic and other toxic side effects during the use of DF in low iron loaded thalassaemia patients and also other categories of patients with normal iron stores.[66,74]
As a result of the DF limitations, no clear strategies have become available or promoted in the last 50 years for the complete elimination of excess iron and the normalisation of the iron stores in thalassaemia and other patients.
It has been estimated previously that in the absence of chelation therapy the mean survival of thalassaemia major patients was about 20 years, and the primary cause of death was congestive cardiac failure.[5,66,74] Results from a UK registry indicate that with the introduction of DF the mean survival of thalassaemia major patients has increased to about 35 years. Recently, with the introduction of L1, the mortality rate of thalassaemia major patients has decreased substantially and mean survival is approaching that of normal individuals.[5,77]
It appears that the primary aim of chelation therapy in thalassaemia major and possibly other chronically transfused patients, i.e. the removal of all excess iron and inhibition/prevention of iron toxicity, as well as the associated tissue and organ damage can now be accomplished in most cases.[8,77] This aim became foreseeable and applicable very recently especially in patients that followed the ICOC protocol using L1 and L1/DF combinations.[8,73,77] Furthermore, the secondary aim of chelation therapy in chronically transfused patients i.e. the safe maintenance of normal iron stores, has also been achieved using lower dose ICOC protocols of L1 monotherapy and L1/DF combinations.[8,73,77]
The Achievement and Maintenance of Normal Iron Stores in Thalassaemia
The normalisation of the iron stores in thalassaemia major and other chronically transfused patients was not considered as a possible option following the introduction of DF and later DFRA, mainly because DFRA and DF were not sufficiently effective in removing all excess iron but also because in both cases there was a high risk of toxicity in non heavily iron loaded patients with serum ferritin lower than 500 μg/L, as described in their drug label information.
Another limiting factor for not achieving normal iron stores was that no such aim had been proposed in the medical literature until recently or was described in the drug label information of L1, DF, and DFRA. It appears that overall insufficiently effective and suboptimal chelating drug dose protocols are generally used even today by most thalassaemia and other clinics, despite that the normalisation of the iron stores should be a primary aim for thalassaemia and other multitransfused patients. In most of these cases, chelating drug combinations are required for achieving normal iron stores.
Individual drug monotherapies are described and recommended by the chelating drug manufacturers in all three chelating drug label information, while chelating drug combinations are not described and are clearly excluded as a form of therapy. The prospect of chelating drug combinations and precisely the L1/DF combination was an academic initiative and suggested as early as 1987 and repeated in 1992[46,79] It was then mainly recommended for patients with toxicity or efficacy complications of either DF or L1.[46,79]
The dilemma of how to control iron load and over-chelation following the achievement of normal iron stores has been demonstrated in several studies using the ICOC and similar protocols of tailor-made administration of L1 and L1/DF combinations and by regular monitoring of iron store levels.[8,78]
The first report of the normalisation of the iron stores in iron loaded thalassaemia major patient was described following the replacement of DF with L1 due to congestive cardiac failure caused by cardiac iron overload during DF therapy. Several other reports followed, indicating that the use of selected combinations of L1 and DF could achieve the normalisation of the iron stores in iron loaded thalassaemia major patients.[81-83] In particular, the ICOC protocol of L1 (80–100 mg/kg/day) and subcutaneous DF (40–60 mg/kg/day, at least 3 days per week) was identified as the most tolerable and effective chelation therapy protocol for achieving negative iron balance (Figure 6, Table 3).[33,81]
Continuous monitoring of the iron stores, e.g. monthly serum ferritin assessment, is required for regularly transfused patients who have achieved normal iron stores. Furthermore, continuous adjustment of iron chelation dose protocols is necessary for maintaining the normal iron stores without the prospect of excess chelation toxicity. Different dose protocols of L1, DF, and L1/DF combination, are required for maintaining normal iron stores within the context of personalised medicine. In some cases of low serum ferritin in thalassaemia major patients, withdrawal of chelation therapy may be necessary for avoiding iron deficiency.[83,84]
In addition to the more significant clinical benefits for thalassaemia patients from the maintenance of normal iron stores, there is also a substantial reduction in the cost of chelation therapy since much lower doses of chelators are generally used by comparison to iron loaded paients.[58,83]
Future Prospects of Iron Chelation Therapy
The same aim and approach for the normalisation of the iron stores and the reduction of excess iron toxicity in thalassaemia major could be used in many other haematological conditions of iron overload including myelodysplasia, post-allogenic stem cell trans-plantation, non-transfusion dependent thalassaemia (NTDT), non-venesected idiopathic haemochromatosis, transfused cancer cases etc. Effective iron chelation therapy protocols within the context of personalised medicine and risk/benefit assessment could be used in each of these cases, similar to the ICOC protocol. In most of these cases, tolerant and active combination protocols of 1-3 chelating drugs may be used for effective and rapid clearance of excess iron.[81-83]
The interaction between chelating drugs and chelating drugs with other drugs used for other therapeutic effects of the underlying diseases needs further investigations. Similarly, the therapeutic and toxic effects of drugs with chelating potential such as hydroxycarbamate (hydroxyurea) and iron also need further investigation.
The clinical application of iron chelating drugs and other chelators is likely to increase in the future involving the treatment of many other diseases in addition to transfusional iron overload and focal iron deposit toxicities.[11-13,74,86] Initial clinical trials in several non iron loaded diseases with L1 are encouraging and promising.[87-90] Most of these future applications include infectious diseases by withholding iron from microbes, intervention in iron metabolic pathways associated with cancer, HIV and other diseases, detoxification of environmental and diagnostic metals, and inhibition of excess toxic free radical production involved in many diseases of free radical pathology.[74,75,87-91] In particular, with regards to the latter, iron chelation therapy using L1 has been considered for the reduction of anticancer drug toxicity such as doxorubicin, for ophthalmic toxicity and neurotoxicity and also many other related applications.[92-95]
The selection of therapeutic protocols for thalassaemia and other diseases involving chelating drugs is crucial because it affects risk/benefit assessment and therapeutic outcome, as well as morbidity and mortality of hundreds of thousands of patients.[96-99] The present state of generally ‘random’ selection of chelating drug protocols does not appear to benefit the patients. In this context, the high efficacy and safety of the ICOC L1/DF combination protocol should be considered as a first line chelation treatment for the vast majority of thalassaemia patients.[8,81,83] This proposition is supported by recent detailed monitoring findings in the improvement in cardiac iron depletion rate and cardiac function by L1 and L1/DF over other therapies.[60,100] Advances in the constant monitoring of iron deposition in critical organs like heart, liver, and pancreas by MRI T2* has recently allowed improvement in the tailoring iron chelation therapy and the selection of the more appropriate chelation regimens in different clinical cases, thus reducing overall patient mortality and morbidity.[101-103]
The limitations in the use of L1 and the L1/DF combination in some countries may constitute an irregular action by health policy decision makers and also negligence in relation to the well being of thalassaemia patients. This policy appears to be controversial, especially considering that drug combinations are widely used not only in other haematological conditions but also in many other diseases.
Similar controversies apply in the risk/benefit assessment for the use of chelating drugs not only in transfusion-dependent thalassemia (TDT) but in patients with non -transfusion dependent thalassaemia (NTDT) intermedia, idiopathic haemochromatosis, myelodyplasia, sickle cell disease, post-transplanted sickle cell disease and thalassaemia as well as many other categories of patients.[78,104-110]
With regards to personalised medicine, the characterisation of the iron metabolic or toxicity or other related targets is necessary for designing the appropriate therapeutic strategies in each condition and each patient, which can result in the optimisation of chelating drug protocol or other therapeutic interventions.[111-117] In this context, the mechanisms of iron release from ferritin and haemosiderin, as well as other molecular or cellular mechanisms are of particular interest.[118,119]
Changes in the therapeutic strategies are necessary under special circumstances such as pregnancy, splenomegaly, and infections and also when considering the possible introduction of erythropoietic biological or other emerging therapies.[120-123] Similar considerations are in progress regarding other clinical issues such as the early initiation of chelation therapy using L1 in thalassaemia children from about one year of age and also the initiation of combination therapies.[124-127] There are different criteria and opinions regarding the latter, with the ICOC L1/DF combination, for example, to be available, safe and flexible in all the patient categories and cases depending on the iron load levels and the rate of body iron intake from transfusions, whereas for other groups of investigators different restrictions are imposed in the use of combination protocols (Figure 6).[9,57,58,73,81-83,99,100,103,128]
The academic debates on the efficacy, toxicity, historical, and other aspects of L1, DF and DFRA and their combinations are likely to continue in the forthcoming years. Such debates are mostly focused on past practises of ineffective therapies and not issues associated with the current “golden era” period of iron chelation therapy in thalassaemia, namely the achievement and maintenance of normal iron stores.[81-83,128-131]
The molecular, therapeutic, and other properties of L1 as a potent chelator and antioxidant with access to most tissues and organs make it a unique pharmaceutical with broad spectrum clinical applications.[75,95] This prospect/dilemma is similar to that of the introduction of L1 as the first oral iron chelating drug about 30 years ago and needs further investigations to be confirmed. Within this context, specific therapeutic strategies have to be designed based on a risk/benefit assessment for each condition and each patient. The aim and targets of such therapeutic strategies need to be defined and evaluated in a manner similar to the case of the paradigm of the complete treatment of iron overload in thalassaemia using L1 and selected L1/DF combinations.[58,81-83]
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