Iron Chelation Therapy for Patients with Myelodysplastic Syndrome

Chronic blood transfusions are necessary for patients with hereditary anemia such as thalassemia, and for patients with myelodysplastic syndrome (MDS) who become anemic and transfusion-dependent. A common consequence of chronic transfusion is iron accumulation that can lead to organ damage. While there is general agreement regarding the value of iron chelation therapy to reduce the detrimental effects of iron overload in thalassemia major, the same is not true for MDS. The malignant nature of the disease and the relatively high cost of iron chelation therapy make cost-effectiveness an issue of great concern. Furthermore, the positive assessment of a drug's cost-effectiveness in one country does not necessarily justify its use in another country. More prospective studies are needed to identify the best iron chelator for patients with MDS as well as to identify those patients who will benefit most from iron chelation therapy.     

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

A new era in iron chelation therapy began with the successful removal of excess iron load and the maintenance of normal iron stores in thalassemia patients using the International Committee on Chelation (ICOC) protocols. This achievement was based on two phases, firstly the introduction of deferiprone (L1) (80–100 mg/kg/day) and deferoxamine (DFO) (40–60 mg/kg at least 3 days per week) combination therapy, which appears to progressively remove all excess storage iron and thereafter by the introduction of L1 monotherapy that can maintain physiological range levels of serum ferritin, cardiac and liver magnetic resonance imaging (MRI) T2*. This new development is likely to change current practices and set a new gold standard in the treatment of transfusional iron loaded patients leading to an increased survival and the change of thalassemia from a fatal to a chronic disease. A major aspect of the improved therapies is the ability of L1 to mobilize and remove excess cardiac iron and reduce congestive cardiac failure, which is the main cause of death in thalassemia patients. Further, new developments include the use of alternating sequential chelation therapies and selected dose protocols with L1, DFO and deferasirox (DFRA) for overcoming toxicity and efficacy complications observed in some patients treated with monotherapies or combination therapies. The selection and adjustment of dose protocols is crucial for providing optimum chelation therapy for each individual patient.     

Ethical Issues and Risk/Benefit Assessment of Iron Chelation Therapy: Advances with Deferiprone/Deferoxamine Combinations and Concerns about the Safety,Efficacy and Costs of Deferasirox

New developments in the area of iron and other metal metabolism and toxicity and the effects and uses of chelators have been presented at the 16th International Conference on Chelation (ICOC), Limassol, Cyprus in October 2006. Marketing practices by pharmaceutical companies, contradictory policies by regulatory authorities and ineffective policies by health authorities deprive thousands of thalassemia and other transfused patients of life saving iron chelating drugs and of efficacious chelation treatments. Thousands of patients were using deferasirox (DFRA) worldwide a few months after the European Union (EU) authorities, and about 1 year after the Food and Drugs Administration (FDA), proceeded to its accelerated approval with no sufficient evidence that the drug was efficacious, especially for clearing excess cardiac iron, and also safe.

Cases of fatal, acute, irreversible renal and liver failure, fatal agranulocytosis and other toxicities have recently been reported with DFRA. The FDA has not yet approved deferiprone (L1) depriving thousands of patients of potentially life saving treatment. The high cost of DFRA at 60 euros/g, L1 at 5.5 euros/g and deferoxamine (DFO) at 8.3 euros/g, diminishes the prospects of universal chelation therapy, especially for patients in developing countries. The safety and efficacy record of L1, DFO, and their combination in particular, appear to provide universal solutions in the treatment of transfusional iron overload, and also in reducing mortality because of their ability to clear rapidly and effectively excess cardiac iron.     

Uses and Limitations of Serum Ferritin,Magnetic Resonance Imaging T2 and T2* in the Diagnosis of Iron Overload and in the Ferrikinetics of Normalization of the Iron Stores in Thalassemia Using the International Committee on Chelation Deferiprone/Deferoxamine Combination Protocol

Excess cardiac iron deposition leads to congestive cardiac failure and accounts for more than 70% of deaths in thalassemia major patients. In three separate studies involving 145 thalassemia patients, serum ferritin and magnetic resonance imaging (MRI) relaxation times T2 and T2* have been compared for assessing iron load levels during chelation treatment. In two studies, variable levels of cardiac iron load have been detected by T2 and T2* in patients treated with deferoxamine (DFO), which, however, were unrelated to serum ferritin. In most cases, similar range levels from normal to severe cardiac iron load could be identified by both the T2 and T2* methods. However, in a few cases there were substantial differences in the levels detected between the two methods. In the third study, the ferrikinetics of the normalization of the iron stores during the International Committee on Chelation (ICOC) deferiprone (L1)/DFO combination protocol was followed up using T2 and T2* and serum ferritin. Iron deposits were found not to be proportionally distributed between the liver and the heart or uniformly distributed within each organ. Iron mobilization in each patient varied and iron deposits in each organ were cleared at different rates. Despite some limitations, the application of the MRI relaxation times T2 and T2* offers the best diagnostic methods for iron overload estimations in most organs and especially the heart. These MRI methods and serum ferritin could also be used for the ferrikinetics of iron mobilization and removal during chelation therapy and the normalization of the iron stores during the ICOC L1/DFO combination protocol. There is a need to standardize the two MRI relaxation times T2 and T2* methods and identify the factors causing the differences between them.     

The proceedings of the 19Th international conference on chelation held in London, United Kingdom: major changes in iron chelation therapy in the last 25 years using deferiprone (L1) has resulted in the complete treatment of iron overload

Major advances were presented at the 19th International Conference on Chelation (ICOC) in London, UK including changes in iron chelation therapy that led to the complete treatment of transfusional iron overload. The first oral iron chelation results in animals using deferiprone (L1) were published in 1985, and effective iron removal in thalassemia and myelodysplasia patients were reported 2 years later. The results of multicenter clinical trials of L1 were presented at the 1st ICOC in London, UK in 1989. Long-term use of L1 resulted in the reduction of the mortality rate in thalassemia patients due to the effective removal of all excess iron from the heart. In 2008, specific combinations of L1 and deferoxamine (DFO) were reported to cause the complete removal of excess iron load and the achievement of normal range body iron store levels (NRBISL) in thalassemia patients. Patients with NRBISL were identified to require lower doses of L1 for the maintenance of negative iron balance. The introduction of deferasirox (DFRA) may benefit patients not tolerating L1, DFO or their combination. A simple, inexpensive synthesis of L1 has encouraged its manufacture in developing countries for the benefit of patients who could not afford the expensive imported chelating drugs or formulations.     

Iron status and treatment modalities in transfusion-dependent patients with myelodysplastic syndromes

Transfusion dependency and iron overload are common among patients with myelodysplastic syndromes (MDS) treated with red blood cell (RBC) transfusions. Transfusion dependency is associated with leukemic progression and shorter survival. Guidelines recommend iron chelation therapy to manage iron overload, however little is known about the chelation patterns in daily clinical practice. The objective of this multicenter, retrospective, cross-sectional, observational study was to evaluate iron status and its management in transfusion-dependent MDS patients. A total of 193 patient records from 29 centers were eligible for inclusion. Median patient age was 76, and median age at diagnosis of MDS was 74. Patients had received an average of 13.4?±?7.6 RBC units in the past 4?months; 44% had received more than 50 units since their MDS diagnosis. Medium serum ferritin was 1,550???g/L. Ninety patients (46.6%) received iron chelation therapy with either deferoxamine (41%), deferasirox (36%), and deferoxamine followed by deferasirox (23%). There were no statistically significant differences between chelated and nonchelated patients in terms of International Prognostic Scoring System (IPSS), French-American-British (FAB), and/or World Health Organization (WHO) status, though chelated patients had received more RBC transfusions (p?=?0.014). Iron chelation therapy may be underutilized in transfusion-dependent patients. Undertreatment can be reduced by complementing sound clinical judgment with the generally accepted guidelines of a serum ferritin level >1,000???g/L and/or two or more RBC transfusions per month for the past year; considering patients on the basis of their IPSS, FAB, and/or WHO status; and individually tailored treatment regimens. Prospective randomized trials are necessary to establish causally the efficacy of iron chelation therapy in MDS.     

The effect of iron chelation therapy on overall survival in sickle cell disease and β‐thalassemia: A systematic review

Red blood cell transfusions have become standard of care for the prevention of life‐threatening anemia in patients with β‐thalassemia and sickle cell disease (SCD). However, frequent transfusions can lead to accumulation of iron that can result in liver cirrhosis, diabetes mellitus, arthritis, arrhythmias, cardiomyopathy, heart failure, and hypogonadotropic hypogonadism. Iron chelation therapy has been shown to reduce serum ferritin levels and liver iron content, but limitations of trial design have prevented any demonstration of improved survival. The objective of this systematic review was to investigate the impact of iron chelation therapy on overall and event‐free survival in patients with β‐thalassemia and SCD. Eighteen articles discussing survival in β‐thalassemia and 3 in SCD were identified. Overall iron chelation therapy resulted in better overall survival, especially if it is instituted early and compliance is maintained. Comparative studies did not show any significant differences between available iron chelation agents, although there is evidence that deferiprone is better tolerated than deferoxamine and that compliance is more readily maintained with the newer oral drugs, deferiprone and deferasirox. Iron chelation therapy, particularly the second‐generation oral agents, appears to be associated with improved overall and event‐free survival in transfusion‐dependent patients with β‐thalassemia and patients with SCD.     

Ethical issues and risk/benefit assessment of iron chelation therapy: advances with deferiprone/deferoxamine combinations and concerns about the safety, efficacy and costs of deferasirox

New developments in the area of iron and other metal metabolism and toxicity and the effects and uses of chelators have been presented at the 16th International Conference on Chelation (ICOC), Limassol, Cyprus in October 2006. Marketing practices by pharmaceutical companies, contradictory policies by regulatory authorities and ineffective policies by health authorities deprive thousands of thalassemia and other transfused patients of life saving iron chelating drugs and of efficacious chelation treatments. Thousands of patients were using deferasirox (DFRA) worldwide a few months after the European Union (EU) authorities, and about 1 year after the Food and Drugs Administration (FDA), proceeded to its accelerated approval with no sufficient evidence that the drug was efficacious, especially for clearing excess cardiac iron, and also safe. Cases of fatal, acute, irreversible renal and liver failure, fatal agranulocytosis and other toxicities have recently been reported with DFRA. The FDA has not yet approved deferiprone (L1) depriving thousands of patients of potentially life saving treatment. The high cost of DFRA at 60 euros/g, L1 at 5.5 euros/g and deferoxamine (DFO) at 8.3 euros/g, diminishes the prospects of universal chelation therapy, especially for patients in developing countries. The safety and efficacy record of L1, DFO, and their combination in particular, appear to provide universal solutions in the treatment of transfusional iron overload, and also in reducing mortality because of their ability to clear rapidly and effectively excess cardiac iron.     

Assessment of Iron Overload in Very Young Children with Limited Thalassemia Care Resources in South China

Southern China has one of the world’s largest population of patients needing transfusions. Transfusion and chelation are not uniformly available and no magnetic resonance imaging (MRI) assessment data exists to date. A total of 153 young β-thalassemia major (β-TM) patients were assessed using a validated 1.5T scanner in Hong Kong, People’s Republic of China (PRC). Their median age was 13 (range 7 to 30), and most patients were young (22.0% age <10, 73.0% age <15, 88.0% age <18). Erratic health care made estimation of total transfusion and chelation exposure impossible. Despite their early age, 24.0% had severe cardiac hemosiderosis [T2*<10 milliseconds (ms)], at ages as early as 8 years old. Median heart iron was 1.68?mg/g dry weight (range 0.19–7.66) and increased with age (p?=?0.017), while liver iron was 22.2?mg/g dry weight (range 3.15 to 39.2). Serum ferritin levels were poor predictors of heart and liver, or pancreatic R* and pituitary R* values. Magnetic resonance imaging scans are needed to screen very young β-TM patients with immediate risk of premature cardiac death in developing nations and triage them to more intensive treatment. This is particularly important in countries with a large number of patients and limited resources. Our data suggests that in developing countries, there is no lower limit for thalassemia MRI scanning programs.     

Treating iron overload in patients with non‐transfusion‐dependent thalassemia

Despite receiving no or only occasional blood transfusions, patients with non‐transfusion‐dependent thalassemia (NTDT) have increased intestinal iron absorption and can accumulate iron to levels comparable with transfusion‐dependent patients. This iron accumulation occurs more slowly in NTDT patients compared to transfusion‐dependent thalassemia patients, and complications do not arise until later in life. It remains crucial for these patients' health to monitor and appropriately treat their iron burden. Based on recent data, including a randomized clinical trial on iron chelation in NTDT, a simple iron chelation treatment algorithm is presented to assist physicians with monitoring iron burden and initiating chelation therapy in this group of patients. Am. J. Hematol. 88:409–415, 2013. © 2013 Wiley Periodicals, Inc.     

Thalassemia Major: Transplantation or Transfusion and Chelation

Thalassemia is the most common monogenic hematologic disease that affects millions in the world and kills thousands of patients every year.Without transfusion or transplantation, patients with thalassemia major are expected to die within months of diagnosis. However, long-term transfusion and chelation therapy is highly challenging for many developing countries where the disease is prevalent, representing a major and unsustainable health burden.Stem cell transplantation is the only cure for thalassemia. It has witnessed major developments that have made it less toxic, more successful, and feasible for a larger number of patients with diverse comorbidities and from a wider range of donors. Advances in human leukocyte antigen typing have greatly refined alternate donor selection with results of matched unrelated donors similar to matched sibling donors.Novel strategies such as haploidentical and cord blood transplantation have increased the possibility of patients with no healthy donor to get a better opportunity to survive and avoid chronic transfusion complications.Cost-effectively, transplantation should be considered the primary treatment of choice in the presence of a suitable related or unrelated donor and at centers with a satisfactory experience in the field of transplantation and particularly, in managing those with thalassemia. Despite some complications such as graft-versus-host disease and late conditioning effects, the overall improvement in the quality of life of thalassemia is difficult to deny.Unfortunately, the number of transplants for thalassemia represents only a minority of all transplants conducted globally and the essential requirement for transplants for thalassemia in limited-resources countries should mandate the transplant societies, including Worldwide Network for Blood and Marrow Transplantation, to collaborate to help initiate and support specialized transfusion and transplant programs for managing thalassemia.     

Iron mobilization from transferrin and non-transferrin-bound-iron by deferiprone. Implications in the treatment of thalassemia, anemia of chronic disease, cancer and other conditions

Iron mobilization from transferrin is one of the most important screening methods for the selection of chelators intended for clinical use in the treatment of iron overload in thalassemia and other conditions. In vitro and in vivo screening of approved and experimental chelating drugs has shown that only the alpha-ketohydroxypyridines deferiprone (L1) and 1-allyl-2 methyl-3-hydroxypyrid-4-one (L1NAll), are effective in the mobilization of iron from transferrin. Iron mobilization from transferrin and non-transferrin-bound-iron (NTBI) can be used to optimize existing chelation therapy protocols for the treatment of iron loaded patients. New chelation strategies involving L1 and its combination with deferoxamine (DFO) and other chelators can be used to increase iron excretion and reduce or prevent excess iron deposition in the heart and other vital organs of iron loaded patients by comparison to monotherapies. Deferiprone and its combinations may also have potential applications in the treatment of cancer, the anemia of chronic disease and other conditions.     

Health related quality of life in Middle Eastern children with beta-thalassemia

ABSTRACT: BACKGROUND: Thalassemia is a common disorder worldwide with a predominant incidence in Mediterranean countries, North Africa, the Middle East, India, Central Asia, and Southeast Asia. Whilst substantial progress has been made towards the improvement of Health related quality of life (HRQoL) in western countries, scarce evidence-based data exists on HRQol of thalassemia children and adolescents living in developing countries. Patients and methods We studied 60 thalassemia children from Middle Eastern countries with a median age of 10 years (range 5 to 17 years). HRQoL was assessed with the Pediatric Quality of Life Inventory (PedsQL) 4.0. The Questionnaire was completed at baseline by all patients and their parents. The agreement between child-self and parent-proxy HRQoL reports and the relationship between HRQoL profiles and socio-demographic and clinical factors were investigated. RESULTS: The scores of parents were generally lower than those of their children for Emotional Functioning (mean 75 vs 85; p = 0.002), Psychosocial Health Summary (mean 70.3 vs 79.1; p = 0.015) and the Total Summary Score (mean 74.3 vs 77.7 p = 0.047). HRQoL was not associated with ferritin levels, hepatomegaly or frequency of transfusions or iron chelation therapy. Multivariate analysis showed that a delayed start of iron chelation had a negative impact on total PedsQL scores of both children (p = 0.046) and their parents (p = 0.007). CONCLUSIONS: The PedsQL 4.0 is a useful tool for the measurement of HRQoL in pediatric thalassemia patients. This study shows that delayed start of iron chelation has a negative impact on children's HRQOL.     

Update on Thalassemia Treatment in Taiwan,Including Bone Marrow Transplantation,Chelation Therapy,and Cardiomyopathy Treatment Effects

Over the past few decades, Taiwan has seen striking improvements in the life expectancy of its 400 registered β-thalassemia major (β-TM) patients due mainly to adequate transfusion regimens and effective iron chelation therapy. Since 1995, Taiwanese citizens have enjoyed universal health care through National Health Insurance (NIH), receiving comprehensive treatment at minimal cost. In 1984, a national program for thalassemia prevention, control, and hematopoietic stem cell transplantation (HSCT) was initiated. Recent data show 1- and 2-year event-free survival rates of 85 and 78%, respectively. Chelation agents like deferoxamine (DFO), deferiprone (L1) and deferasirox (DFRA) are available in Taiwan, and therapy is tailored to individuals based on drug availability and tissue distribution of iron load. Intensive chelation regimens combining L1 and DFO are recommended in patients with cardiac complications, while DFRA has been found to be effective in reducing serum ferritin, with acceptable side effects. Here, we report advances in thalassemia treatment in Taiwan and suggest treatment guidelines.     

Electrocardiographic Presentation,Cardiac Arrhythmias,and Their Management in β‐Thalassemia Major Patients

Beta‐thalassemia major (β‐TM) is a genetic hemoglobin disorder characterized by an absent synthesis of globin chains that are essential for hemoglobin formation, causing chronic hemolytic anemia. Clinical management of thalassemia major consists in regular long‐life red blood cell transfusions and iron chelation therapy to remove iron introduced in excess with transfusions. Iron deposition in combination with inflammatory and immunogenic factors is involved in the pathophysiology of cardiac dysfunction in these patients. Heart failure and arrhythmias, caused by myocardial siderosis, are the most important life‐limiting complications of iron overload in beta‐thalassemia patients. Cardiac complications are responsible for 71% of global death in the beta‐thalassemia major patients. The aim of this review was to describe the most frequent electrocardiographic abnormalities and arrhythmias observed in β‐TM patients, analyzing their prognostic impact and current treatment strategies.     

Iron Mobilization From Transferrin And Non-Transferrin-Bound-Iron by Deferiprone. Implications in the Treatment of Thalassemia,Anemia of Chronic Disease,Cancer and Other Conditions

Iron mobilization from transferrin is one of the most important screening methods for the selection of chelators intended for clinical use in the treatment of iron overload in thalassemia and other conditions. In vitro and in vivo screening of approved and experimental chelating drugs has shown that only the α-ketohydroxypyridines deferiprone (L1) and 1-allyl-2 methyl-3-hydroxypyrid-4-one (L1NAll), are effective in the mobilization of iron from transferrin. Iron mobilization from transferrin and non-transferrin-bound-iron (NTBI) can be used to optimize existing chelation therapy protocols for the treatment of iron loaded patients. New chelation strategies involving L1 and its combination with deferoxamine (DFO) and other chelators can be used to increase iron excretion and reduce or prevent excess iron deposition in the heart and other vital organs of iron loaded patients by comparison to monotherapies. Deferiprone and its combinations may also have potential applications in the treatment of cancer, the anemia of chronic disease and other conditions.     

Outcomes, utilization, and costs among thalassemia and sickle cell disease patients receiving deferoxamine therapy in the United States

Deferoxamine mesylate (DFO) reduces morbidity and mortality associated with transfusional iron overload. Data on the utilization and costs of care among U.S. patients receiving DFO in typical clinical practice are limited however. This was a retrospective study using a large U.S. health insurance claims database spanning 1/97-12/04 and representing 40 million members in >70 health plans. Study subjects (n = 145 total, 106 sickle cell disease [SCD], 39 thalassemia) included members with a diagnosis of thalassemia or SCD, one or more transfusions (whole blood or red blood cells), and one or more claims for DFO. Mean transfusion episodes were 12 per year. Estimated mean DFO use was 307 g/year. Central venous access devices were required by 20% of patients. Cardiac disease was observed in 16% of patients. Mean total medical costs were $59,233 per year including $10,899 for DFO and $8,722 for administration of chelation therapy. In multivariate analyses, potential complications of iron overload were associated with significantly higher medical care costs. In typical clinical practice, use of DFO in patients with thalassemia and SCD receiving transfusions is low. Administration costs represent a large proportion of the cost of chelation therapy. Potential complications of iron overload are associated with increased costs.     

Sequential alternating deferiprone and deferoxamine treatment compared to deferiprone monotherapy: main findings and clinical follow-up of a large multicenter randomized clinical trial in -thalassemia major patients

In β-thalassemia major (β-TM) patients, iron chelation therapy is mandatory to reduce iron overload secondary to transfusions. Recommended first line treatment is deferoxamine (DFO) from the age of 2 and second line treatment after the age of 6 is deferiprone (L1). A multicenter randomized open-label trial was designed to assess the effectiveness of long-term alternating sequential L1-DFO vs. L1 alone iron chelation therapy in β-TM patients. Deferiprone 75 mg/kg 4 days/week and DFO 50 mg/kg/day for 3 days/week was compared with L1 alone 75 mg/kg 7 days/week during a 5-year follow-up. A total of 213 thalassemia patients were randomized and underwent intention-to-treat analysis. Statistically, a decrease of serum ferritin level was significantly higher in alternating sequential L1-DFO patients compared with L1 alone patients (p = 0.005). Kaplan-Meier survival analysis for the two chelation treatments did not show statistically significant differences (log-rank test, p = 0.3145). Adverse events and costs were comparable between the groups. Alternating sequential L1-DFO treatment decreased serum ferritin concentration during a 5-year treatment by comparison to L1 alone, without significant differences of survival, adverse events or costs. These findings were confirmed in a further 21-month follow-up. These data suggest that alternating sequential L1-DFO treatment may be useful for some β-TM patients who may not be able to receive other forms of chelation treatment.     

Effects of Chelation Therapy on Cardiac Function Improvement in Thalassemia Patients: Literature Review and the Taiwanese Experience

The iron chelators deferoxamine (DFO) and deferiprone (L1) have demonstrated their ability to normalize cardiac function in patients with iron overload-induced cardiac disease. However, conventional chelation with subcutaneous DFO fails to prevent iron deposition in two-thirds of thalassemia major patients, placing them at risk of heart failure and its complications. Deferiprone appears to be more effective in cardiac iron removal. The detection and management of heart complications have improved dramatically over the last 7 years. Non invasive techniques of quantifying iron burden via magnetic resonance imaging (MRI) have been validated. A better understanding of cardiac pathophysiology and improved ability to detect at-risk populations are yielding better outcomes and reduced morbidity.

We continue to appraise readily available bedside tools for monitoring thalassemia patients with heart complications, and here we summarize studies from the literature and our own findings. Deferiprone chelation was found to be of statistically significant benefit in upgrading cardiac function and reducing iron accumulation. The use of echocardiography and MRI to closely monitor cardiac functions associated with iron overload complications and mortality has proved quite practical.     

The challenges of adherence and persistence with iron chelation therapy

Due to advances in medical sciences, many chronic diseases that formerly resulted in early death can now be effectively managed with long-term treatment regimens. Patients with potentially fatal anemias, for example, can be treated with ongoing blood transfusions and iron chelation therapy. Ensuring adherence and persistence is challenging, as the benefits of therapy are not perceived immediately. Poor adherence severely compromises the effectiveness of treatment and, therefore, improving compliance in terms of quality of life and health economics is critical. Although adherence to chelation therapy is generally poor, the availability of oral iron chelators may help to improve patient compliance. For chronic conditions such as thalassemia major, even when oral chelation therapy is available, support by an integrated team including a clinical psychologist and nurse specialist working with the treatment center is recommended to achieve optimal results.