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Iron overload is inevitable in patients who are transfusion dependent. In young children with transfusion-dependent thalassemia (TDT), current practice is to delay the start of iron chelation therapy due to concerns over toxicities, which have been observed when deferoxamine was started too early. However, doing so may increase the risk of iron accumulation that will be manifested as toxicities later in life. This study investigated whether deferiprone, a chelator with a lower affinity for iron than deferoxamine, could postpone transfusional iron overload while maintaining a good safety profile. Recently diagnosed TDT infants (N = 64 their age ranged from 10 to 18 (median 12) months, 54.7% males; receiving ≤6 transfusions; serum ferittin (SF) >400 to < 1000 ng/mL were randomized to "early start deferiprone" (.ES-DFP) at a low dose (50 mg/kg/day) or to "delay chelation" (DC), and remained in the study until their serum ferritin (SF) level reached ≥1000 μg/L. 61 patients continued the study Levels of transferrin saturation (TSAT) and labile plasma iron (LPI) were measured as well. By approximately 6 months postrandomization, 100% of the subjects in DC group had achieved SF > 1000 µg/L and TSAT > 70% compared with none in the ES-DFP group. LPI level > 0.6 µM was observed in 97% vs. 40% of the DS and ES groups, respectively, (P < 0.001). The time to reach SF > 1000 µg/L was delayed by 6 months in the ES-DFP group (P < 0.001) without escalating DFP dose. No unexpected, serious, or severe adverse events were seen in the ES-DFP group., (© 2017 Wiley Periodicals, Inc.)

With repeated blood transfusions, patients with thalassemia major rapidly become loaded with iron, often surpassing hepatic metal accumulation capacity within ferritin shells and infiltrating heart and endocrine organs. That pathological scenario contrasts with the physiological one, which is characterized by an efficient maintenance of all plasma iron bound to circulating transferrin, due to a tight control of iron ingress into plasma by the hormone hepcidin. Within cells, most of the acquired iron becomes protein-associated, as once released from endocytosed transferrin, it is used within mitochondria for the synthesis of protein prosthetic groups or it is incorporated into enzyme active centers or alternatively sequestered within ferritin shells. A few cell types also express the iron extrusion transporter ferroportin, which is under the negative control of circulating hepcidin. However, that system only backs up the major cell regulated iron uptake/storage machinery that is poised to maintain a basal level of labile cellular iron for metabolic purposes without incurring potentially toxic scenarios. In thalassemia and other transfusion iron-loading conditions, once transferrin saturation exceeds about 70%, labile forms of iron enter the circulation and can gain access to various types of cells via resident transporters or channels. Within cells, they can attain levels that exceed their ability to chemically cope with labile iron, which has a propensity for generating reactive oxygen species (ROS), thereby inducing oxidative damage. This scenario occurs in the heart of hypertransfused thalassemia major patients who do not receive adequate iron-chelation therapy. Iron that accumulates in cardiomyocytes forms agglomerates that are detected by T2* MRI. The labile forms of iron infiltrate the mitochondria and damage cells by inducing noxious ROS formation, resulting in heart failure. The very rapid relief of cardiac dysfunction seen after intensive iron-chelation therapy in some patients with thalassemia major is thought to be due to the relief of the cardiac mitochondrial dysfunction caused by oxidative stress or to the removal of labile iron interference with calcium fluxes through cardiac calcium channels. In fact, improvement occurs well before there is any significant improvement in the total level of cardiac iron loading. The oral iron chelator deferiprone, because of its small size and neutral charge, demonstrably enters cells and chelates labile iron, thereby rapidly reducing ROS formation, allowing better mitochondrial activity and improved cardiac function. Deferiprone may also rapidly improve arrhythmias in patients who do not have excessive cardiac iron. It maintains the flux of iron in the direction hemosiderin to ferritin to free iron, and it allows clearance of cardiac iron in the presence of other iron chelators or when used alone. To date, the most commonly used chelator combination therapy is deferoxamine plus deferiprone, whereas other combinations are in the process of assessment. In summary, it is imperative that patients with thalassemia major have iron chelators continuously present in their circulation to prevent exposure of the heart to labile iron, reduce cardiac toxicity, and improve cardiac function., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Over the last 20 years, the management of thalassemia major has improved to the point where we predict that the patients' life expectancy will approach that of the normal population. These outcomes result from safer blood transfusions, the availability of three iron chelators, new imaging techniques that allow organ-specific assessment of the degree of iron overload and improvement in the treatment of hepatitis. The ability to prescribe any of the three chelators, as well as their combinations, has led to a more effective reduction of the total body iron. The ability to determine the amount of iron in the liver and heart by MRI has allowed the prescription of the most appropriate chelation regime for the patient and has allowed the reconsideration of 'the comfort zones'. Thus, normalizing iron stores not only prevents new morbidities but also reverses many complications, such as cardiac failure, hypothyroidism, hypogonadism, impaired glucose tolerance and Type 2 diabetes, therefore improving survival and patients' quality of life. Furthermore, outcomes should continue to improve in the future. Starting relatively intensive chelation in younger children may prevent short stature and abnormal pubertal maturation, as well as other iron-related morbidities. In addition, further information should become available on the use of other combinations in chelation treatment, some of which have only been used in a very limited fashion so far. New safe oral chelators may also become available that may offer additional ease of use. All these advances in management do require absolute cooperation and understanding on behalf of children's parents and subsequently the adult themself. Only with such cooperation can normal long-term survival be achieved as it is likely that adherence to treatment is the primary barrier to longevity.

In general, in women with transfusion-dependent thalassemia, during pregnancy, iron chelation therapy is ceased. We report a splenectomized patient, who was an excellent complier with chelation therapy, who before embarking on a pregnancy showed no evidence of iron overload, with normal cardiac, thyroid function and glucose metabolism. Laboratory findings showed ferritin 67 microg/L, myocardial T(2)* of 34 ms and liver magnetic resonance imaging (MRI) liver iron concentration of 1 mg/g dry weight. She became pregnant by in vitro fertilization in October 2006, delivery occurred in June 2007. She breast fed for 2 months. After 12 months without iron chelation, ferritin was 1583 microg/L. Quantitative MRI showed myocardial T(2)* of 27 ms, that the liver iron concentration had increased to 11.3 mg/g dry weight, indicative of moderate to heavy iron load. This case demonstrates that iron overload can develop rapidly and that physicians caring for patients with transfusion-dependent thalassemia should be particularly alert to any discontinuation of chelation therapy over time.

The effect of iron chelation using subcutaneous desferrioxamine on the iron-overloaded heart was studied prospectively over 4 years in 23 asymptomatic patients (mean age 13.2 +/- 5.3 years) with thalassaemia major and transfusion-dependent anaemia. The haemoglobin was maintained greater than 10 g/dl by transfusion and chelation therapy to achieve a negative iron balance. Chelation was closely supervised to ensure compliance. Despite an increase in calculated iron load due to transfusion from 34 +/- 27 g to 63 +/- 28 g, there was a sequential fall in serum ferritin levels from 3148 +/- 1956 ng/ml to 2228 +/- 1825 ng/ml (P less than 0.05). Abnormalities of left ventricular (LV) function, assessed by radionuclide angiography, were present at rest or during exercise in 18 of 23 patients (78%) prior to therapy. Normal LV function was restored in 11 of these 18 patients, five continuing to have abnormal function and two dying. There was a significant increase in resting LVEF from 50 +/- 8% to 57 +/- 6% (P less than 0.01). Peak exercise LVEF rose from 51 +/- 11% to 65 +/- 7% (P less than 0.001). We conclude that the common subclinical abnormalities of LV function induced by iron overload in unchelated patients with thalassaemia major can be reversed with long-term subcutaneous infusions of desferrioxamine.

The results are described of 200 antenatal diagnostic tests for haemoglobinopathies performed on samples of fetal blood obtained during the second trimester of pregnancy. Haemoglobin A synthesis in the fetus was measured by incorporation of tritiated leucine in vitro and separation of the globin chains on CM23 columns. The range of HbA synthesis detected was 3.5-8.0% in normal fetuses, 2.0-5.0% in fetuses with thalassaemia trait, and less than 1.6% in fetuses with thalassaemia major. There were eight cases in which other haemoglobinopathies were diagnosed. 29% of the pregnancies were terminated because thalassaemia major was diagnosed, and 9.5% of the remaining healthy fetuses were lost for obstetric reasons. Follow up has been possible for 96% of the 124 surviving babies and three misdiagnoses have come to light; one false positive (0.5%) and two false negatives (1%). These figures represent a first effort at antenatal diagnosis for haemoglobinopathies and it is likely that they will improve with the passage of time.

An 18-month-old boy with beta-thalassaemia major underwent bone-marrow transplantation with marrow from his 30-month-old brother. The brother was HLA-identical, mixed-lymphocyte culture non-reactive and had thalassaemia minor. The patient was "conditioned" with busulphan and cyclophosphamide before transplantation and received methotrexate to prevent graft-versus-host disease. Immediately after the transplant, complications arose, which included mild graft-versus-host disease, gastrointestinal bleeding and fever. The boy is alive 18 months after transplantation, is leading a normal life, is receiving no therapy and has a normally functioning donor marrow with thalassaemia minor. Bone-marrow transplantation may be considered as alternative therapy in patients with beta-thalassaemia who are young, and who have no organ dysfunction or iron overload. Chronic transfusion and chelation therapy and its problems must be weighed against the 13% risk of mortality and the 73% chance of a normal life that are associated with transplantation. Older patients, who have received multiple blood transfusions, have iron overload or have organ dysfunction, have a low survival rate after transplantation and this therapy is inappropriate for such patients.

Seven hundred and ninety-five people, (96% of whom were of Greek origin) were screened for thalassaemia trait. A prevalence rate of 7.1% for beta-thalassaemia carriers was found. The red cells of individuals with the alpha-1-thalassaemia, beta-thalassaemia, and haemoglobin Lepore traits all had a mean corpuscular volume (MCV) of less than 76 fL and a mean corpuscular haemoglobin (MCH) of less than 25 pg, thus confirming the usefulness of these indices as a preliminary thalassaemia screening test. However, in three of the six people provisionally diagnosed as having delta-beta-thalassaemia trait, an overlap of MCV and MCH values with the normal range occurred. Community attitudes to the survey and its implications are discussed.

Exercise radionuclide angiography was used to assess the incidence of subclinical abnormalities of left ventricular function in 23 asymptomatic patients with thalassemia major. Left ventricular ejection fraction (LVEF) at rest was normal in 18 patients and abnormal in 5. A normal LVEF response during exercise was shown in only 5 of the patients with normal resting left ventricular function. A normal response during exercise occurred more often in those patients who had received a smaller transfusional iron load and had a lower serum ferritin level (p less than 0.05). Twelve of the twenty-three patients were receiving chelation therapy with subcutaneous deferoxamine. Ejection fraction at rest was normal in 11 of these patients. During exercise a normal ventricular response was shown in 4 patients. After 1 year of intensive chelation therapy in these 12 patients, left ventricular function was reassessed. A normal exercise response was seen in an additional 4 patients; 3 of these showed an increase in peak exercise LVEF, and in the remaining patient no change of peak exercise LVEF was shown. The response during exercise was unchanged in 3 patients and had deteriorated in 1 patient.

Haemoglobin synthesis was studied in fetal blood samples obtained at 17 to 20 weeks' gestation in 22 women at risk of carrying a fetus with homozygous beta-thalassaemia. A presumptive diagnosis of homozygous beta-thalassaemia was made in four cases, and the pregnancy was terminated. An inconclusive answer was obtained in one case, and the patient also chose to have her pregnancy terminated. Two fetuses were lost as a result of the procedure. Of the remaining 15 pregnancies, 13 proceeded to term and two to 36 weeks; in each case a normal infant or one heterozygous for beta-thalassaemia was delivered. Current efforts should be directed towards improving the blood sampling technology so that fetal blood sampling can be used widely in those countries where thalassaemia is a major problem.

We describe here the first case of classical homozygous beta-thalassaemia in a part-Aboriginal child. The child came from Bourke, New South Wales, and is the product of a consanguineous mating. His great-great-grandfather was a camel driver from Sri Lanka who settled in western New South Wales. From the family studies, we have found that there are now 17 carriers of beta-thalassaemia in the Aboriginal community in northwestern New South Wales, and it is anticipated that more part-Aboriginal children with thalassaemia major will be identified. The presence of numerous carriers of beta-thalassaemia in the Aboriginal population would suggest that care should be taken in the administration of iron for the treatment of anaemias found in Aboriginal children.

We compared red cell exchange transfusions (RC Ex) on the Aminco Celltrifuge (continuous flow cell separator) with conventional transfusions in 17 patients aged between 7 and 24 years who have transfusion dependent homozygous beta-thalassaemia and two other patients with chronic transfusion dependent anaemias aged 20 and 22. We aimed to return the youngest cohort of cells ('Neocytes') from both donor blood and the patient and to discard older cells ('gerocytes'). Using RC Ex, red cell transfusion requirement was reduced by 30%, reducing significantly the iron load, and the transfusion interval was increased by 43%. There is a great demand by the patients to continue this therapy as they have appreciated the immediate benefit of reduced hospitalization.