Table of Contents

HK J Paediatr (New Series)
Vol 1. No. 1, 1996

HK J Paediatr (New Series) 1996;1:14-22

Feature Article

Recent Progress in the Management of Thalassaemia

NF Olivieri, DJ Weatherall


Keyword : Classification; Management; Thalassaemia syndromes


Introduction

The thalassaemias, the commonest monogenic diseases, are frequently encountered in paediatric practice throughout the Mediterranean region, the Middle East, the Indian subcontinent and Southeast Asia. Over recent years a great deal has been learnt about their genetics, pathophysiology and molecular pathology, work that has led to genuine improvements in their prevention and management.

In this review we shall concentrate on the more practical clinical aspects of the prevention and management of the β thalassaemias. Because recent work in this field has attracted a very large literature it will be impossible for us to cite original references. Readers who wish to explore it in more detail are referred to the list of recent articles that are cited at the end of this paper.

The Nature and Classification of the Thalassaemias

The thalassaemias are a heterogeneous collection of inherited disorders of haemoglobin synthesis, all characterised by a reduction in one or other of the globin chains that constitute adult haemoglobin. Normal adults have two haemoglobins, a major component, Hb A, that consists of a pair of α chains and a pair of β chains (α2β2), and a minor component, Hb A2 which is made up of α chains and δ chains (α2δ2). In fetal life the main haemoglobin is Hb F that consists of α chains and γ chains (α2γ2). In the embryo there are a different α-like and γ/β-like chains called ζ and ε. During normal human development α chain synthesis is activated early during fetal life and α chains combine with γ chains to produce Hb F and, after birth, with β chains to make Hb A.

There are two main classes of thalassaemia called α and β thalassaemia, that result from defective α or β chain synthesis respectively. There are rarer forms in which both β and δ chain production is reduced, δβ thalassaemia, or in which ε, γ, δ and β chain production is defective, εγδβ thalassaemia.

β-thalassaemia

In some forms of β thalassaemia no β globin chains are produced whereas in others some β chains are made, but at a lower rate than normal. These conditions are called β0 and β+ thalassaemia respectively. Using a similar nomenclature the α thalassaemias can be also divided into α+ and α0 thalassaemias.

It is now known that over 100 different mutations of the β globin genes can produce the clinical picture of β thalassaemia. In some cases these completely inactivate these genes leading to the phenotype of β0 thalassaemia. But there are many that only partially reduce the output of β chains and hence give rise to the phenotype of β+ thalassaemia of varying severity. In clinical practice many children are encountered who are compound heterozygotes for different β thalassaemia mutations.

All the β thalassaemias are characterised by imbalanced globin chain synthesis. The excess of α globin chains that result from defective β chain production are unstable and precipitate in the red cell precursors, leading to their premature destruction in the bone marrow or, later, in the blood. The resulting anaemia stimulates increased erythropoietin production, expansion of the ineffective bone marrow, and hence skeletal deformities and a hypermetabolic state. Probably due to the marked erythroid expansion and ineffective erythropoiesis there is a modest increase in fetal haemoglobin production; red cell precursors that synthesise γ chains are at a selective advantage because they combine with α chains to produce Hb F and hence there is less chain imbalance. This accounts, at least to some extent, for the elevation of Hb F seen in β thalassaemia.

These pathophysiological changes can be corrected by regular blood transfusion that, in effect, switches off the dyserythropoietic bone marrow. However, the administration of regular transfusion results in progressive iron loading that, if not corrected, leads to widespread damage of the liver, endocrine glands and myocardium.

The clinical course of β thalassaemia is remarkably variable. Some children die in the first year or two of life if not transfused while others may grow and develop quite normally with satisfactory haemoglobin levels; others are more severely affected though not transfusion dependent. These milder forms of β thalassaemia are called β thalassaemia intermedia. Although their pathophysiology is not fully understood it is clear that at least in some cases they result from the co-inheritance of α thalassaemia, which reduces the amount of a chain excess, or the coinheritance of genes that potentiate fetal haemoglobin production.

α thalassaemia

The inheritance of α thalassaemia is more complicated because normal individuals have two α globin genes per haploid genome (on each parental chromosome); their genotype can be written αα/αα. The α+ thalassaemias result from the loss of one of the linked pair of α globin genes, either by deletion (-α/αα or-α/-α) or by a mutation that reduces the output of one of the pair of a globin genes (αTα/αα or αTα/αTα). On the other hands, the α0 thalassaemias result from deletions that remove both α globin genes (--/αα or --/--).

There are many different forms of α thalassaemia, but in clinical practice the two most important are the haemoglobin Bart's hydrops syndrome and haemoglobin H disease. Haemoglobin Bail's is homotetramer of γ chains (γ4) while Hb H is its adult counterpart (β4). The haemoglobin Bart's hydrops syndrome usually results from the homozygous inheritance of α0 thalassaemia and hence affected children make no α globin chains and have the genotype --/--. Haemoglobin H disease usually results from the compound heterozygous state for α0 and α+ thalassaemia and hence has the genotype --/-α. However, in Southeast Asia haemoglobin H disease often results from the compound heterozygous state for α0 thalassaemia and a form of α+ thalassaemia in which one of the a globin genes is almost entirely inactivated by an unusual mutation that results in the production of low levels of a haemoglobin variant called haemoglobin Constant Spring; the genotype is, therefore, --/αCSα.

Haemoglobin Bail's hydrops fetalis syndrome is usually characterised by the stillbirth of a severely hydropic fetus with in some but not all cases other fetal abnormalities. This condition is also associated with a high frequency of maternal toxaemia of pregnancy and post-partum haemorrhage due to delivery of a massively hypertrophied placenta. Haemoglobin H disease runs a very variable course, in some cases with severe anaemia but in many with a moderate anaemia and splenomegaly that are compatible with normal survival.

The inheritance of thalassaemia with structural haemoglobin variants

Many different thalassaemia syndromes result from the co-inheritance of either α or β thalassaemia with structural haemoglobin variants. Globally, the most important condition of this kind is haemoglobin E thalassaemia. This disorder occurs at a very high frequency throughout Bangladesh, Burma, Malaysia, Indonesia and Thailand though it is much less common in Chinese populations. It has a remarkably variable clinical phenotype; in some cases it is as severe as homozygous β thalassaemia major while in others it behaves like a moderate to mild form of thalassaemia intermedia. Although some of the reasons for this clinical variability are similar to those described above for the intermediate forms of β thalassaemia this is not the whole story; a great deal more needs to be learnt about the pathophysiology of this extremely important disease.

A Comprehensive Programme for the Prevention and Management of Thalassaemia

The management of thalassaemia requires expertise ranging from the bedside to the basic science laboratory backed up by competent diagnostic services and access to skills in the identification of individual mutations.

This service should be able to cover the identification of carriers for all the common forms of α and β thalassaemia, adequate genetic counselling, the provision of a prenatal diagnosis programme, and clinical staff with expertise in handling thalassaemia throughout childhood and into adult life. The latter requires the interaction of specialists who have personal long-term care for these children with a whole range of paediatric and medical sub-specialities.

Carrier detection and prenatal diagnosis

In societies in which prenatal diagnosis and termination of affected pregnancies is acceptable it is possible to offer prenatal diagnosis to potential parents of thalassaemic children. It is beyond the scope of this review to describe this aspect of thalassaemia control in detail.

The most practical approach to the control of thalassaemia is to set up a comprehensive screening programme in the antenatal clinic. Providing that iron deficiency is excluded most forms of thalassaemia can be identified initially by the finding of small hypochromic red cells using electronic cell counters. In such cases it is important to determine the type of thalassaemia; the vast majority of β thalassaemias are associated with a raised Hb A2 level. If the Hb A2 value is normal and the red cell indices are typically thalassaemic the most likely diagnosis is α thalassaemia, either the carrier state for α0 thalassaemia or the homozygous state for α+ thalassaemia. In populations in which α thalassaemia is common it is very important to distinguish between these two possibilities; this can only be done with certainty by globin gene mapping.

Once the diagnosis of thalassaemia is established in a mother the father should be tested and the couple counselled about the likely outcome of a particular pregnancy.

There have been considerable advances in the prenatal detection of thalassaemia over the last 15 years. Although this can be achieved by fetal blood or amniocentesis sampling late in the second trimester it is preferable to carry out chorion villus sampling towards the end of the first trimester. Extensive experience with this procedure suggests that it results in a low fetal loss and, if not done too early, carries little risk to the fetus. It should be emphasised however that there have only been a few large series of long-term follow-up of babies who have been born following chorion villus sampling.

There is a variety of methods for detecting particular mutations in fetal DNA. In recent years most of these have involved the use of the polymerase chain reaction, a method for rapidly amplifying regions of DNA that contain the mutations that are being sought. It is now possible to carry out a prenatal diagnosis within a few hours of receiving a sample. It is important to check the sample for maternal tissue contamination and non-paternity. If these precautions are taken the error rate should be extremely low, less than one percent in most large series. All babies born after this procedure should have their haemoglobin type checked at six months.

The Management of β Thalassaemia

The last three decades have witnessed dramatic changes in the management of patients homozygous for β thalassaemia. Regular transfusion programs now eliminate the complications of anaemia and compensatory bone marrow expansion and permit normal growth and development throughout childhood. Over the last fifteen years, developments in chelating therapy have further improved the prognosis.

Medical management of β thalassaemia major

The initial assessment of the child homozygous for β thalassaemia is focused around the requirement for regular transfusions. Many patients who are homozygous or doubly heterozygous for mutations within the β globin gene nonetheless maintain haemoglobin concentrations of 7-10 g/dL without regular transfusions, except during periods of infection or surgery. As mentioned earlier, such patients are said to have thalassaemia "intermedia", a clinical term which describes only the transfusion status of the patient. The clinical spectrum of patients with thalassaemia "intermedia" is considerable. Many patients have mild or moderate, well-compensated anaemia, attain normal growth, puberty and fertility, and enjoy a good quality of life without transfusions. Alternatively, growth retardation and bone marrow expansion may be observed and indicate the need for regular transfusions. In thalassaemia "intermedia" unsuppressed erythropoiesis results in increased plasma iron turnover and an increase in gastrointestinal iron absorption; cardiac, hepatic and endocrine iron-related dysfunction are usually observed several years later in these patients than in those with transfused homozygous β thalassaemia.

In every child homozygous for β thalassaemia, monthly assessment should include a complete history and physical examination with particular emphasis on assessment of growth, with height, weight and spleen size carefully recorded at each visit. Parental reassurance and education should be begun at the initial visit, and reinforced at each subsequent one. Parents should be informed as to the expectations of survival for their child, with the awareness that the outlook for this disease has been favorably altered with programs of early, regular red cell transfusions and iron chelation therapy. At this time, if parents are interested in pursuing bone marrow transplantation as a therapeutic alternative, HLA-typing to determine the possibility of this option should be arranged. On an annual basis, monitoring of iron-related complications and of the efficacy and toxicity of chelation therapy should be instituted (Table).

Transfusion

Adoption of a regimen to maintain pre-transfusion haemoglobins concentrations of approximately 9.5 g/dL, usually requiring the administration of 15 cc per kilogram of red cells (packed to a haematocrit of 75%) every four weeks, results in a significant reduction in transfusion requirement, and improved control of body iron burden when compared to the results of a regimen under which baseline haemoglobin concentrations exceed 11.0 g/dL ("supertransfusion"). Individualization of transfusion regimens for each patient is necessary. Pre-transfusion haemoglobin levels and volumes of packed cells administered should be recorded at each visit to permit yearly calculation of transfusion requirements and hence the indications, if any, for splenectomy.

Studies of the use of neocytes, or young red blood cells, to reduce transfusional iron loading in thalassaemia have demonstrated extensions of transfusion interval between approximately 13% and 25%, but are achieved at the costs of an increased transfusion load, augmented demands on blood supply, and a five-fold increase in preparation costs over those of standard concentrates. Hence, the use of neocytes currently has a very small impact on the management of most chronically transfused patients.

Splenectomy

In patients in whom yearly transfusion requirements exceed 200 mL per kilogram body weight, splenectomy will significantly diminish red cell requirements and iron accumulation. Because of the risk of post-splenectomy infection with encapsulated organisms in young children, splenectomy should usually be delayed until the age of at least five years. Prior to splenectomy, immunization with 23-valent pneumococcal vaccine and Haemophilus influenza type B vaccine, if not administered previously, is recommended; after splenectomy, compliance with longterm prophylactic penicillin should be monitored.

Table Evaluation of the Patient with Thalassaemia

Initial
  • History and physical examination
  • CBC; Hb electrophoresis
  • α/non-α globin chain synthesis ratio
  • Red cell phenotype
  • Serum iron, total iron binding capacity
  • Serum ferritin concentration
  • RBC and serum folate
  • Total and direct bilirubin
  • Serum ALT
  • Hepatitis screen
  • Initiation of hepatitis B vaccine series
  • Parental counselling and education
  • HLA testing, if BMT desired
Monthly
  • History and physical examination
  • CBC
  • Parental counselling
  • Compliance review [if receiving iron chelation therapy]
Q6 months
  • Serum ALT
  • Serum ferritin concentration
Q12-18 months
Age <10 years
Liver
  • Biopsy
  • Hepatitis screen
  Endocrine
  • Serum Ca++ PO4, Mg++, Zn++, PTH, TSH
  Monitoring of DFO toxicity:

Audiogram

Opthlamologic examination
Radiographs of spine, wrists, knees
Bone age

Age >10 years Liver
  • Biopsy
  • MRI
  • Hepatitis screen
Heart
  • Cardiology consultation
  • Exercise radionuclide angiography/ dolbutamine stress test
  • 24-hour Holter monitoring
  • MRI
Endocrine
  • Endocrinology consultation
  • Fasting blood glucose
  • Serum Ca++ PO4, Mg++, Zn++, PTH, TSH
  • GnRH stimulation test
  • MRI of anterior pituitary
Monitoring of DFO toxicity as above

Complications of longterm transfusions

Hepatitis

Iron-induced liver damage in thalassaemia may be influenced by infection with the viruses responsible for hepatitis B and C. Hepatitis C is the most frequent cause of hepatitis in children with thalassaemia and frequently leads to liver failure or hepatocellular carcinoma in patients who have acquired the virus through transfusions. Trials of interferon-alpha in thalassaemia suggest that reduction in both body iron burden and viral load are required for improvement in hepatic damage, and that the effectiveness of anti-viral therapy may depend to a significant degree on that of iron chelating therapy.

Iron overload

The most important consequence of life-saving transfusions in thalassaemia is the inexorable accumulation of iron within tissues, causing progressive organ dysfunction that is fatal if untreated. The only iron chelating agent currently available for clinical use is deferoxamine B, a trihydroxamic acid produced by Streptomyces pilosus, with a high affinity and relatively high specificity for ferric iron.

Deferoxamine is poorly absorbed orally and is rapidly metabolized, conferring on the drug its principal disadvantage the requirement for prolonged parenteral infusions to maintain plasma drug concentrations and achieve long-term effectiveness. Regimens of 10 to 12 hours infusions of deferoxamine, 25 to 75 mg deferoxamine/kg, introduced in the mid 1970s, have been widely adopted for transfusion-dependent children.

Complications of iron overload and the impact of iron chelating therapy

The heart

In the absence of chelating therapy, myocardial disease remains the most severe, life-limiting complication of transfusional iron overload. In irregularly transfused, unchelated children, conduction disturbances, recurrent pericarditis and congestive failure are observed by the mid-teens; survival following the development of cardiac failure is less than one year.

The liver

Although the liver has reportedly a larger capacity to accumulate iron without toxicity, transfusion-associated viral infection and other insults may act synergistically with iron in accelerating the development of hepatic fibrosis and cirrhosis, and liver disease remains the commonest cause of death in thalassaemic patients over 15 years of age.

Growth and sexual maturation

Poor pubertal growth and impairment of sexual maturation in 60 to 80 percent of patients with thalassaemia major have been attributed to iron-induced selective central hypogonadism, interference by hepatic iron with the production of IGF-1, or both. Alternatively, zinc deficiency, hyposecretion of adrenal androgen, deferoxamine administration, and delay in pubertal development itself, may impair growth in thalassaemia major.

Glucose tolerance

Diabetes mellitus has been variably attributed to impaired insulin secretion due to chronic pancreatic iron overload or to insulin resistance as a result of iron deposition within liver or skeletal muscle, and has been linked temporally to episodes of acute viral hepatitis in some patients. In most studies there is a direct relationship between the occurrence of diabetes, and both the severity and duration of iron overload, and a late age at the start of chelation therapy.

Endocrine function

The most common endocrine abnormalities observed in modern cohorts of patients with thalassaemia include hypogonadotropic hypogonadism, growth hormone deficiency, and diabetes mellitus. Variable incidences of hypothyroidism, hypoparathyroisim, and low levels of adrenal androgen secretion, with normal glucocorticoid reserve, have also been reported.

The benefits of iron chelating therapy

Prevention of iron-induced morbidity and mortality

Studies supporting the beneficial effects of iron chelating therapy with deferoxamine have emerged over the last decade. Two recent trials, both of over 10 years duration, have demonstrated unequivocally that long-term deferoxamine prevents the complications of iron overload, and improves survival, in patients with thalassaemia major. Both trials have shown that the magnitude of the body iron burden is the principal determinant of the severity of iron toxicity and of clinical outcome. One series reported that all deaths, and an increased incidence of cardiac disease and diabetes mellitus, occurred among patients who had begun chelation therapy relatively later in life and had used less deferoxamine in relation to their transfusional iron load. In a second study, the proportion of serum ferritin measurements exceeding 2500 mg/L emerged as the most significant factor associated with cardiac-disease-free survival in thalassaemia. Patients with fewer than 33% of serum ferritin levels exceeding 2500 mg/L had an estimated cardiac-disease-free survival of 100% after 10 years of chelation therapy, and 91% after 15 years; in contrast, patients in whom most serum ferritin determination exceeded 2500 mg/L had significantly reduced cardiac disease free survival after 10 and 15 years. A positive impact of early, regular deferoxamine therapy on sexual maturation and fertility have also been reported over the past ten years.

Reversal of iron-induced complications

In parallel with the prevention of complications, the reversibility of severe iron-induced hepatic and cardiac disease in patients treated with deferoxamine has been demonstrated in several reports. Improvements in established thyroid dysfunction and in glucose intolerance, though not in established pituitary failure have also been reported during deferoxamine treatment in thalassaemia major.

Assessment of body iron indirectly

Serum or urinary estimates of body iron burden

The measurement of serum ferritin is the most commonly used indirect estimate of body iron stores. Interpretation of serum ferritin concentration may be complicated by ascorbate deficiency, acute infection, chronic inflammatory disorders, acute and chronic liver damage, haemolysis, and ineffective erythropoiesis, all common in thalassaemia major. Only approximately 57% of variability in serum ferritin concentration is accounted for by changes in body iron burden. Therefore, the convenience of this screening test does not justify its use in the accurate determination of body iron burden. A similarly poor correlation between urinary iron excretion and hepatic iron quantiation is observed, in part because the relative amounts of iron excreted into stool and urine varies with body iron burden and erythroid activity.

Imaging of tissue iron

The use of computed tomography, magnetic resonance imaging (MRI), and nuclear resonance scattering from manganese-56 have been used to evaluate hepatic iron in patients with iron overload. MRI is the only method that images cardiac and anterior pituitary iron stores. Serial MRI studies have demonstrated changes consistent with a reduction of cardiac iron and pituitary iron, and have confirmed biopsy-demonstrated changes in hepatic iron concentration in chelated patients over one to two years. Large studies demonstrating a precise correlation between iron assessed by MRI and reference methods of iron quantitiation are awaited.

Assessment of organ function

Electro- or resting echo-cardiograms may be normal late in the course of iron-related cardiac disease, and are not useful in the evaluation of cardiac iron loading. Decreased left ventricular contractile reserve in asymptomatic patients may be demonstrated during exercise multi-gated cardiac radionuclide angiography (MUGA), or by low-dose dobutamine stimulation testing; either may be useful in the diagnosis of early iron-related cardiac disease. Stimulation with GnRH infusion is useful in the evaluation of the reserve of the iron-loaded pituitary.

Assessment of body iron directly

Measurement of hepatic iron

It is the most quantitiative, specific, and sensitive means of assessing the body iron burden, and of evaluating the inflammatory activity and presence of fibrosis within the liver. The most accurate technique for determination of iron stores is quantitiation of iron by wet weight in liver biopsy specimens. Superconducting magnetic susceptometry of hepatic iron stores (SQUID) offers a non-invasive method for quantitiation of hepatic iron; this instrument has been validated as a method of providing measurements of hepatic iron quantitiatively equivalent to those obtained by chemical analysis of tissue obtained at biopsy.

Initiation of therapy

Uncertainties as to the optimal age for the start of chelation therapy continue to exist. Reports of abnormal linear growth and metaphyseal dysplasias observed in children treated with intensive deferoxamine prior to the age of three years, not uniformly evident by serum ferritin concentration or liver function testing, suggest that low-dose chelation therapy may be indicated early in the clinical course of transfused patients with thalassaemia. Because of the imprecision of serum ferritin concentrations, it is recommended that initiation of chelation therapy should be based on the quantitiation of hepatic iron concentration obtained after one year of regular transfusions. Liver biopsy under ultrasound guidance is a safe procedure in children, with a negligible complication rate in patients aged less than five years. Hepatic storage iron concentration should be maintained between 3 and 5 milligrams per gram dry weight tissue. If liver biopsy is refused, therapy with subcutaneous deferoxamine, not exceeding 25 mg/kg body weight per 24 hours in children under three years of age, should be initiated after one year of regular transfusions. Although ascorbate supplementation results in a marked improvement in deferoxamine-induced iron excretion, ascorbate administration may aggravate the toxicity of iron. While ascorbate supplementation is therefore discouraged in patients with thalassaemia, the observation of loss of sustained efficacy of deferoxamine should prompt determination of tissue ascorbate concentrations. If these are reduced, 100 mg ascorbic acid should be administered during infusions of deferoxamine.

Balance between effectiveness and toxicity of deferoxamine

A common feature of most toxicities induced by deferoxamine is the use of high doses, or standard doses in the presence of a relatively modest body iron burden. Deferoxamine-induced toxicity can be avoided by regular, precise assessment of body iron burden using the reference method of hepatic iron concentration, with maintenance of hepatic iron concentration between 3 and 5 milligrams per gram dry weight tissue. Especially if hepatic iron is not quantitated, a "toxicity index" defined as the mean daily dose of deferoxamine (mg/kg) divided by the serum ferritin concentration in ug/L should be calculated on a regular basis for each patient, and should not exceed 0.025. Doses of deferoxamine should never exceed 50 mg/kg/24 hours, even in heavily iron loaded patients treated with intravenous regimens. Regular evaluation of deferoxamine toxicity is strongly recommended in all patients maintained on any dose of deferoxamine.

Chelation in thalassaemia "intermedia"

In patients with thalassaemia "intermedia", iron loading is less accelerated than in regularly transfused patients and may be treated with twice weekly standard dose-deferoxamine. Iron loading in thalassaemia "intermedia" has been shown to be rapidly reduced during treatment with the orally active iron chelating agent deferiprone, as described below.

Alternatives to subcutaneous deferoxamine

Intravenous deferoxamine

Regimens of intravenous ambulatory deferoxamine administered through implantable venous access ports induce rapid reduction of body iron burden. Protocols that infuse continuous deferoxamine, and in which the infusion site is accessed on a weekly basis by medical personnel, eliminate reliance on the patient and improve compliance.

Other forms of deferoxamine; HES-DFO

New, high-molecular-weight chelators, synthesized by attaching deferoxamine to hydroxyethyl starch polymer, have iron affinity and specificity identical to deferoxamine, but have a vascular retention half-life up to 30 times longer than that of standard deferoxamine. Their use may make it possible to replace some or all of nightly deferoxamine infusions with single short-term infusions, improving compliance and, therefore, effectiveness of chelation therapy. The feasibility of this approach is presently under investigation.

Orally active iron chelating agents

The orally active iron chelating agent with the broadest clinical experience is 1,2-dimethyl-3-hydroxypyrid-4-one (Li; CP020; DMHP; deferiprone), a member of the 3-hydroxypyridin-4-one class of bidentate iron chelators, patented in 1982 as an alternative to deferoxamine. Animal studies, which may have underestimated the long term effectiveness of deferiprone in humans, have reported variable efficacy of removal of iron. Early studies reported deferiprone-induced urinary iron excretion that, if sustained, would be predicted to induce net negative iron balance in individuals with thalassaemia major. Formal dose response studies demonstrated that 75 milligrams deferiprone per kilogram body weight was the minimum daily dose associated with excretion of iron sufficient to achieve such balance. While several studies support the conclusion that the short term efficacy of deferiprone is inferior to that of deferoxamine, the long term effectiveness of deferiprone may be sufficient to maintain net negative iron balance in many transfused patients over several years, as described below.

Results of longterm prospective trials of deferiprone have provided information on the effectiveness and toxicity of deferiprone therapy in humans. Sustained changes in serum ferritin concentration have been reported in several studies. Results from a 5-year prospective trial in Toronto demonstrated that deferiprone can reduce or maintain serum ferritin concentrations in the range associated with cardiac-disease-free survival in the longterm trial of deferoxamine-treated patients described above. Evidence that deferiprone could reduce tissue iron was provided by study of a patient with thalassaemia "intermedia," in whom gastrointestinal iron loading had resulted in accumulation of cardiac and hepatic iron; hepatic iron concentration normalized in this patient over nine months of deferiprone therapy. This observation was soon followed by a report of significant decline in hepatic iron concentration to levels associated with prolonged complication-free survival in deferoxamine-treated patients, over five years of deferiprone therapy. As documented by this study, excellent compliance with deferiprone improves the long-term effectiveness of chelating therapy; hence, the inferior efficacy of deferiprone relative to that of deferoxamine appears less important in long term studies.

Toxicity studies of deferiprone at doses between 200 and 400 mg/kg/day (more than two to four times the doses used clinically) reported dose-dependent bone marrow atrophy and pancytopenia, gastrointestinal lesions, adrenal, thymic and gonadal atrophy, embryotoxicity, and growth retardation in rodents and dogs. Most of these adverse effects have never been observed in patients treated with deferiprone. The most common complication has been arthralgia, primarily of the large joints, with a reported incidence varying between 33% to 38%. The joint pain, swelling and muscle stiffness usually resolve after dose reduction or discontinuation of therapy. No clinical or laboratory evidence of systemic lupus erythematosus have been consistently observed and the etiology remains elusive. Aspiration of synovial fluid and arthroscopy show no evidence of an inflammatory or allergic reaction. One of us has hypothesized that chelators-induced shifts of iron from other tissues to the synovium may result in tissue damage, accelerated by free radicals produced during incomplete complexation of iron and deferiprone.

Concerns regarding an adverse effect of deferiprone on immunologic function have been raised in a single case report from one center in India, the significance of which remains unclear. Results of formal prospective studies of immunologic function in patients treated with deferiprone over three years have not differed from those of normal controls, nor from those of a cohort of age-matched, deferoxamine-treated patients. Uneventful recovery from varicella zoster and from pneumococcal meningitis have been reported during longterm deferiprone therapy. At present, therefore, there exists no evidence of altered immunity or increased risk of opportunistic infection in humans receiving deferiprone.

The most serious adverse effect has been severe neutropenia or agranulocytosis. To date, this complication has been observed in a total of thirteen patients with no previous history of bone marrow suppression; no deaths have been reported. Observed as early as six weeks and as late as 21 months after commencement of deferiprone, neutropenia has varied in duration between seven and 124 days after drug withdrawal, and appears to be fully reversible. The mechanism by which neutropenia occurs is unknown. In vitro studies of murine hematopoieses have shown that growth of granulocyte/macrophage colonies is inhibited in a dose-dependent manner by both deferoxamine and deferiprone, and that toxicity of both chelators is abrogated by addition of saturating concentrations of iron. There is no evidence for increased in vitro sensitivity of the myeloid precursors, nor of antibody-mediated inhibition of growth of normal marrow. This complication should be considered the most serious adverse effect associated with deferiprone therapy, and may limit the widespread application of this drug.

Less serious adverse effects associated with the administration of deferiprone have included nausea, dermatologic changes associated with declines in serum zinc concentration, transient liver enzyme abnormalities.

The development of deferiprone has been unorthodox. Initial studies in several countries were conducted without the full animal toxicology studies required for human use by the United States Food and Drug Administration, a body whose regulatory decisions are followed closely by those of several countries. Representatives of this body await data from a randomized trial comparing therapy with deferiprone with deferoxamine, and one designed to examine the incidence of serious adverse effects of deferiprone, prior to licensing of deferiprone in the United States. These trials are ongoing in Canada, Italy and a single center in the United States, supported by Apotex Pharmaceuticals, Canada, and will be completed in 1997. In 1995, deferiprone was licensed for sale in India.

Bone marrow transplantation

While iron chelation therapy has dramatically improved the outlook for patients with thalassaemia major, thalassaemia-free survival has also been achieved in many patients undergoing bone marrow transplantation from an HLA identical donor. Hence many families and clinicians are inevitably confronted with the choice between these two forms of treatment. The excellent results reported by the bone marrow transplantation group from Pesaro, Italy, in patients defined as Class I has underlined the benefits of good early medical care in all patients homozygous for β thalassaemia. In the Pesaro series, a patient with a history of regular chelation therapy, and no evidence of hepatomegaly or of hepatic fibrosis, has a 85-93% five year disease free survival following bone marrow transplantation. Several other factors render the the choice between medical and "surgical" therapy for severe thalassaemia difficult for clinicians and families. One includes the increased expectation of survival under "medical" management, comparable to that with achieved with bone marrow transplantation in Class I patients. A second consideration is that that five-year survival in patients with thalassaemia who have undergone bone marrow transplantation in North America appears much lower than that reported from Pesaro. Third, the late complications of bone marrow transplantation for thalassaemia major are not fully known. In support of marrow transplantation, the procedure renders patients not merely cardiac disease free, but also thalassaemia free. Moreover, the long-term cost of transfusion and chelation therapy greatly exceeds the cost of bone marrow transplantation. Finally, regular administration of deferoxamine is difficult and may be associated with toxicity, and if compliance with this difficult regimen falters, survival rates for "medically treated" patients should be expected to decline. For the heavily iron-loaded patient who is poorly compliant with deferoxamine, the poor long-term prognosis with medical therapy may therefore favor bone marrow transplantation, even if the patient already has hepatic enlargement or fibrosis, findings that negatively affect the outcome of transplantation.

Experimental therapies

A means of reversing the switch from fetal to adult haemoglobin production, which unfortunately occurs on schedule in patients homozygous for β thalassaemia, would be of great benefit in the treatment of this disorder. In the vast majority, the upstream γ globin genes are intact and, at least potentially, fully functional, and if they could be reactivated, haemoglobin F synthesis could be maintained during adult life, eliminating the phenotype of the disease entirely. The regulation of fetal haemoglobin synthesis in the β-haemoglobinopathies is a subject of great theorectical and practical signficance. During the last decade, studies in vitro, in experimental animals and in patients with these disorders have identified several compounds that increase fetal haemoglobin production, including 5-azacytidine, cytarabine, vinblastine, hydroxyurea, recombinant human erythropoietin and the butyric acid compounds. The only agent to which consistent hematological responses, with substantial increases in total haemoglobin concentration, have been reported in thalassaemia is 5-azacytidine. Studies with arginine butyrate and sodium phenylbutyrate have shown early promise in patients homozygous for β thalassaemia; trials to determine the factors that influence response are ongoing. Small studies have reported variable increases in haemoglobin concentration during administration of high doses of recombinant human erythropoietin. Combination therapy with hydroxyurea and erythropoietin has increased fetal haemoglobin production in some studies, while no responses have been reported in others. Adverse effects of these agents are reported as minimal. While these findings are promising, several issues related to administration of these agents in patients with thalassaemia remain unresolved. The importance of the usefulness of combination therapies, the effect of dose and dosing regimen, the requirement for iron supplementation, the risks of bone marrow expansion and myelosuppression, and the potential risk of malignancy with the use of cytotoxic agents all remain unanswered.

Conclusions

With the increased safety of red cell transfusions, the promise of orally active iron chelating agents, and reports of the usefulness of compounds to augment fetal haemoglobin, prolonged survival and major improvements in the quality of life may be anticipated for patients with thalassaemia over the next decade.

Suggested Reading

General reading

Olivieri NF. Iron chelation therapy and thalassemia. In: Kelton JG, Brain M, editors. Current Therapy in Hematology/Oncology, 5th ed.1995:80-9.

Brittenham GM. Disorders of iron metabolism: deficiency and overload. In: Hoffman R, Benz E, Shattil S, Furie B, Cohen H, editors. Hematology: Basic Principles and Practice. New York: Churchill Livingstone, 1994:492-523.

Weatherall DJ. The Thalassemias. In: Stamatoyannopoulos G, Nienhuis AW, Majerus PW, Varmus H, editors. The molecular basis of blood diseases. 2nd ed. Philadelphia: WB Saunders. 1994:157-95.

Weatherall DJ. The molecular basis for phenotypic variability of the common thalassaemias. Mol Med Today 1995;1:15-20.

Weatherall DJ. The thalassemias. In: Beutler E, Lichtman MA, Coller BS, Kipps TJ, editors. Williams Hematology 5th ed. New York: McGraw-Hill Inc. In press.

Morbidity and mortality in thalassemia major

Zurlo MF, De Stefano P, Borgna-Pignatti C, et al. Survival and causes of death in thalassemia major. Lancet 1989;2:27-30.

Bronspiegel-Weintrob N, Olivieri NF, Tyler BJ, Andrews DF, Freedman MH, Holland FJ. Effect of age at the start of iron chelation therapy on gonadal function in beta-thalassemia major. N Engl J Med 1990;323:713-9.

Brittenham GM, Griffith PM, Nienhuis AW, et al. Efficacy of deferoxamine in preventing complications of iron overload in patients with thalassemia major. N Engl J Med 1994;331:467-573.

Olivieri NF, Nathan DG, MacMillan JH, et al. Survival in medically treated patients with homozygous β thalassemia. N Engl J Med 1994;331:574-8.

The assessment of body iron burden

Brittenham GM, Farrell DE, Harris JW, et al. Magnetic-susceptibility measurement of human iron stores. N Engl J Med 1982;307:1671-5.

Brittenham GM, Cohen AR, McLaren CE, et al. Hepatic iron stores and plasma ferritin concentration in patients with sickle cell anemia and thalassemia major. Am J Hematol 1993;42:81-5.

Hepatitis C infection

Clemente MG, Congia M, Lai ME, et al. Effect of iron overload on the response to recombinant interferon-alfa treatment in transfusion-dependent patients with thalassemia major and chronic hepatitis C. J Pediatr 1994;125:123-8.

Deferoxamine toxicity

DeVirgilis S, Congia M, Frau F, et al. Deferroxamine-induced growth retardation in patients with thalassemia major. J Pediatr 1988;113:661-9.

Porter JB, Huehns R. The toxic effects of desferrioxamine. Clinical Haematology J 1989;2:459-74.

Porter JB, Jaswon MS, Huehns ER, East CA, Hazell JWP. Desferrioxamine ototoxicity: evaluation of risk factors in thalassaemic patients and guidelines for safe dosage. Br J Haematol 1989;73:403-9.

Hartkamp MJ, Babyn PS, Olivieri NF. Spinal deformities in deferoxamine-treated beta-thalassemia major patients. Ped Radiol 1993;23:525-8.

Orally active iron chelators

Brittenham GM. Development of iron-chelating agents for clinical use. Blood 1992;80:569-74.

Al-Refaie FN, Wonke B, Hoffbrand AV, Wickens DG, Nortey P, Kontoghiorghes GJ. Efficacy and possible adverse effects of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) in thalassemia major. Blood 1992;80:592-9.

Olivieri NF, Brittenham GM, Matsui D, et al. Iron-chelation therapy with oral deferiprone in patients with thalassemia major. N Engl J Med 1995;332:918-22.

Al-Refaie FN, Hershko C, Hoffbrand AV, Olivieri NF, Tondury P, Wonke B. Results of long-term deferiprone (L1) therapy: a report by the International Study Group on Oral Iron Chelators. Br J Haematol 1995;91:224-9.

Olivieri NF. Long term therapy with deferiprone. In: C Hershko, guest editor. Iron Chelating Therapy. Acta Haematologica 1996. In press.

Bone marrow transplantation in thalassemia

Lucarelli G, Galimberti M, Polchi P, et al. Bone marrow transplantation in adult thalassemia. Blood 1992;80:1603-7.

Lucarelli G, Galimberti M, Polchi P, et al. Marrow transplantation in patients with thalassemia responsive to iron chelation therapy. N Engl J Med 1993;329:840-4.

Mariotti E, Agostini A, Angelucci E, Lucarelli G, Sgarbi E. Echocardiographic study in ex-thalassemic patients with iron overload, preliminary observations during phlebotomy therapy. Bone Marrow Transplant 1993;12:106-7.

De Sanctis V, Galimberti M, Lucarelli G, et al. Pubertal development in thalassaemic patients after allogenic bone marrow transplantation. Eur J Pediatr 1993;152:993-7.

Muretto P, Del Fiasco S, Angelucci E, De Rosa F, Lucarelli G. Bone marrow transplantation in thalassemia: modifications of hepatic iron overload and associated lesions after long-term engrafting. Liver 1994;14:14-24.

Erer B, Angelucci E, Lucarelli G, et al. Hepatitis C virus infection in thalassemia patients undergoing allogeneic bone marrow transplantation. Bone Marrow Transplant 1994;14:369-72.

Reactivation of fetal hemoglobin

Perrine SP, Ginder GD, Faller DV, et al. A short-term trial of butyrate to stimulate fetal-globin-gene expression in the β-globin disorders. N Engl J Med 1993;328:81-6.

Collins AF, Pearson HA, Giardina P, McDonagh KT, Brusilow SW, Dover GJ. Oral sodium phenylbutyrate therapy in homozygous beta thalassemia. Blood 1995;85:43-9.

Sher GD, Ginder G, Little JA, Wang SY, Dover G, Olivieri NF. Extended therapy with arginine butyrate in patients with thalassemia and sickle cell disease. N Engl J Med 1995;332:1606-10.

Olivieri NF. Erythropoietin therapy in inherited anemias. In: Biology of hematopoietic growth factors and their use in children, Int J Ped Hem One 2:105-16.

Olivieri NF. Clinical experience with reactivation of fetal hemoglobin in the beta hemoglobinopathies. In: Thalassemia. Seminars in Hematology 1996. In press.

 
 

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