Transfusions
The goals of transfusion therapy are correction of anemia, suppression of erythropoiesis and inhibition of gastrointestinal iron absorption, which occurs in non transfused patients as a consequence of increased, although ineffective, erythropoiesis. The decision to start transfusion in patients with confirmed diagnosis of thalassemia should be based on the presence of severe anemia (Hb < 7 g/dl for more than two weeks, excluding other contributory causes such as infections). However, also in patients with Hb > 7 g/dl, other factors should be considered, including facial changes, poor growth, evidence of bony expansion and increasing splenomegaly. When possible, the decision to start regular transfusions should not be delayed until after the second- third year, due to the risk of developing multiple red cell antibodies and subsequent difficulty in finding suitable blood donors. Several different transfusional regimens have been proposed over the years, but the most widely accepted aims at a pre-transfusional Hb level of 9 to 10 g/dl and a post-transfusion level of 13 to 14 g/dl. This prevents growth impairment, organ damage and bone deformities, allowing normal activity and quality of life [
3,
4]. The frequency of transfusion is usually every two to four weeks. Shorter intervals might further reduce the overall blood requirement, but are incompatible with an acceptable quality of life. The amount of blood to be transfused depends on several factors including weight of the patient, target increase in Hb level and hematocrit of blood unit. Appropriate graphs and formulae to calculate the amount of blood to be transfused are available [
3]. In general, the amount of transfused RBC should not exceed 15 to 20 ml/kg/day, infused at a maximum rate of 5 ml/kg/hour, to avoid a fast increase in blood volume. To monitor the effectiveness of transfusion therapy, some indices should be recorded at each transfusion, such as pre- and post-transfusion Hb, amount and hematocrit of the blood unit, daily Hb fall and transfusional interval. These measurements enable two important parameters to be calculated: red cell requirement and iron intake. Dedicated computerized programs (Webthal) are available to monitor transfused thalassemia patients accurately [
34]. Although red cell transfusions are lifesavers for patients with thalassemia, they are responsible for a series of complications and expose the patients to a variety of risks. Iron overload is the most relevant complication associated with transfusion therapy. Other adverse events associated with red cell transfusions are summarized in Table
2.
Table 2
Transfusion-dependent complications.
Iron overload | |
Infections | |
|
Known
|
| - Viral (HIV, HCV, HBV, HTLVI, West Nile virus) |
| - Bacterial |
| - Parasitic |
|
Rare
|
| - Creutzfeld-Jacob disease |
| - Emerging and new pathogens |
Hemolytic reactions | |
|
Acute hemolytic reactions
|
|
Delayed hemolytic reactions
|
|
Autoimmune hemolytic anemia
|
Non-Hemolytic reactions | |
|
Allergic and anaphylactic reactions
|
|
Febrile non-hemolytic reactions
|
|
Transfusion-related acute lung injury (TRALI)
|
|
Transfusion-associated graft-versus-host disease
|
|
Circulatory overload
|
|
Post-transfusion purpura
|
Assessment and treatment of Iron overload
Patients maintained on a regular transfusion regimen progressively develop clinical manifestations of iron overload: hypogonadism (35-55% of the patients), hypothyroidism (9-11%), hypoparathyroidism (4%), diabetes (6-10%), liver fibrosis, and heart dysfunction (33%) [
35,
36]. Iron status should be accurately assessed in order to evaluate its clinical relevance, the need for treatment, and the timing and monitoring of chelation therapy. The iron status of multitransfused patients can be assessed by several methods. Serum ferritin has in general been found to correlate with body iron stores [
37]. However, as a single value it is not always reliable because, being an acute-phase reactant, it is influenced by other factors such as inflammatory disorders, liver disease, malignancy. Despite this, serial measurements of serum ferritin remain a reliable and the easiest method to evaluate iron overload and efficacy of chelation therapy. Determination of liver iron concentration in a liver biopsy specimen shows a high correlation with total body iron accumulation and is considered the gold standard for the evaluation of iron overload [
38]. However, liver biopsy is an invasive technique with the possibility (though low) of complications. Moreover, we should consider that the presence of hepatic fibrosis, which commonly occurs in individuals with iron overload and HCV infection, and heterogeneous liver iron distribution can lead to possible false negative results [
39]. In recent years, nuclear magnetic resonance imaging (MRI) techniques for assessing iron loading in the liver and heart have been introduced [
40‐
43]. R2 and T2* parameters have been validated for liver iron concentration. Cardiac T2* is reproducible, transferable between different scanners, correlates with cardiac function, and relates to tissue iron concentration. Clinical utility of T2* in monitoring patients with siderotic cardiomyopathy has been demonstrated [
44,
45]. Calibration of T2* in the heart will be available in the near future. Magnetic biosusceptometry (SQUID), is another option for a reliable measurement of hepatic iron concentration [
46]; however, magnetic susceptometry is presently available only in a limited number of centers worldwide.
As the body has no effective means for removing iron, the only way to remove excess iron is to use iron binders (chelators), which allow iron excretion through the urine and/or stool. As a general rule, patients should start iron chelation treatment once they have had 10-20 transfusions or when ferritin levels rise above 1000 ng/ml [
3]. The first drug available for treatment of iron overload was
deferoxamine (DFO), an exadentate iron chelator that is not orally absorbed and thus needs parenteral administration, usually as a subcutaneous 8- to 12-hour nightly infusion, 5-7 nights a week. Average dosage is 20-40 mg/kg body weight for children and 30-50 mg/kg body weight for adults [
3,
4]. In high risk cases, continuous administration of DFO via an implanted delivery system (Port-a-cath) or subcutaneously, at doses between 50 and 60 mg/kg per day, were the only options to intensify the chelation treatment before the advent of the combined therapy with DFO and deferiprone [
44]. Implanted delivery systems are associated with risk of thrombosis and infection. With DFO, iron is excreted both in faeces (about 40%) and in urine. The most frequent adverse effects of DFO are local reactions at the site of infusion, such as pain, swelling, induration, erythema, burning, pruritus, wheals and rash, occasionally accompanied by fever, chills and malaise. Other complications, mainly associated with high doses of DFO in young patients and low ferritin values are:
-
sensorineural hypoacusia, particularly at high frequencies
-
ocular toxicity (night-blindness, blurred vision, decreased visual acuity, impairment of colour vision, cataract and other disturbances of the eye)
-
retarded growth and skeletal changes with a disproportionately short trunk and dysplasia of the long bones
-
infections by Yersinia Enterocolitica, and other pathogens (Klebsiella Pneumoniae).
It is therefore important to monitor patients receiving DFO regularly with audiometric and ophthalmologic tests and with regular evaluation of growth and bone changes.
The use of DFO decreases morbidity and mortality among those who are able to comply with regular prolonged infusions [
47]. However, because of the side effects and the inconvenient parenteral administration, a consistent proportion of patients is non-compliant, limiting the usefulness of this chelator [
35].
The orphan drug
deferiprone (DFP) is an orally active iron chelator which has emerged from an extensive search for new treatment of iron overload. Comparative studies have shown that this chelator, at doses of 75-100 mg/kg/day may be as effective as DFO in removing body iron [
48]. Retrospective and prospective studies have shown that DFP monotherapy is significantly more effective than deferoxamine in decreasing myocardial siderosis in thalassemia major [
49‐
51]. Agranulocytosis is the most serious side effect associated with the use of DFP, occurring in about 1% of the patients [
48]. More common but less severe side effects are gastrointestinal symptoms, arthralgia, zinc deficiency, and fluctuating liver enzymes. Retrospective studies have shown that DFP treatment is associated with reduced cardiac morbidity and mortality [
50,
52,
53]. DFO and DFP can be used in combination to achieve levels of iron excretion that cannot be achieved by either drug alone without increasing toxicity [
54‐
59]. Reversal of severe iron-related heart failure with DFO and DFP combination has been reported in many patients [
44,
60‐
62]. The effect of combined therapy versus DFO monotherapy on myocardial iron overload was evaluated in a prospective, randomized, placebo controlled trial, which showed a statistically significant improvement in myocardial T2* with the combined treatment as compared with DFO and placebo treatment [
63]. Combination therapy should be considered as an alternative to continuous intravenous DFO monotherapy when an intensive chelation is required.
Deferasirox (DFX) is a once-daily, orally administered iron chelator that a large program of clinical trials has shown to be effective in adults and children [
64,
65]. It received European Union marketing authorization as an orphan drug from the EMEA in 2002 and was authorized for marketing in most countries in 2006. The recommended starting dose of DFX for most patients is 20 mg/kg/day, although this can be modified to 10 or 30 mg/kg/day depending on the number of transfusions a patient is receiving and whether the therapeutic goal is to decrease or maintain body iron levels. The most frequent adverse events reported during treatment with DFX include transient, mild-to-moderate gastrointestinal disturbances and skin rash. These events rarely require drug discontinuation and most resolve spontaneously. Mild, usually nonprogressive increases in serum creatinine (generally within the upper limit of normal) has been observed in approximately a third of patients. Creatinine levels returned spontaneously to baseline in most of patients and data from up to 3.5 years of treatment in more than 1000 patients have confirmed that creatinine increase is non progressive [
66]. However, cases of renal failure have been reported following the postmarketing use of DFX [
67].
(S)-3'-(OH)-desazadesferrithiocin-polyether, magnesium salt is an oral once a day iron chelator expected to excrete iron mainly in the stools, evaluated in experimental models. Orphan designation of this medicine has been granted in the United States of America and Europe for treatment of chronic iron overload in patients with transfusion-dependent anemias. Recently, three main practice guidelines for the management of iron overload in thalassemia major have been published and are available online [
3,
68,
69].
Bone marrow and cord blood transplantation
Bone marrow transplantation (BMT) remains the only definitive cure currently available for patients with thalassemia. The outcome of BMT is related to the pretransplantation clinical conditions, specifically the presence of hepatomegaly, extent of liver fibrosis, history of regular chelation and hence severity of iron accumulation. In patients without the above risk factors, stem cell transplantation from an HLA identical sibling has a disease-free survival rate over 90% [
80]. The major limitation of allogenic BMT is the lack of an HLA-identical sibling donor for the majority of affected patients. In fact, approximately 25-30% of thalassemic patients could have a matched sibling donor. BMT from unrelated donors has been carried out on a limited number of individuals with beta-thalassemia. Provided that selection of the donor is based on stringent criteria of HLA compatibility and that individuals have limited iron overload, results are comparable to those obtained when the donor is a compatible sib [
81]. However, because of the limited number of individuals enrolled, further studies are needed to confirm these preliminary findings. If BMT is successful, iron overload may be reduced by repeated phlebotomy, thus eliminating the need for iron chelation. Chronic graft-versus-host disease (GVHD) of variable severity may occur in 5-8% of individuals.
Cord blood transplantation from a related donor offers a good probability of a successful cure and is associated with a low risk of GVHD [
82,
83]. For couples who have already had a child with thalassemia and who undertake prenatal diagnosis in a subsequent pregnancy, prenatal identification of HLA compatibility between the affected child and an unaffected fetus allows collection of placental blood at delivery and the option of cord blood transplantation to cure the affected child [
84]. On the other hand, in cases with an affected fetus and a previous normal child, the couple may decide to continue the pregnancy and pursue BMT later, using the normal child as the donor.
Management of thalassemia intermedia
Treatment of individuals with thalassemia intermedia is symptomatic [
4,
85]. As hypersplenism may cause worsening anemia, retarded growth and mechanical disturbance from the large spleen, splenectomy is a relevant aspect of the management of thalassemia intermedia. Risks associated with splenectomy include an increased susceptibility to infections mainly from encapsulated bacteria (
Streptococcus Pneumoniae, Haemophilus Influenzae and Neisseria Meningitidis) and an increase in thromboembolic events. Prevention of post-splenectomy sepsis includes immunization against the above mentioned bacteria and antibiotic prophylaxis as well as early antibiotic treatment for fever and malaise. Because of the elevated prevalence of cholelithiasis and the risks of cholecystitis in splenectomised patients, the gallbladder should be inspected during splenectomy and removed in case with or to prevent gallstones. Treatment of extramedullary erythropoietic masses, detected by magnetic resonance imaging, is based on radiotherapy, transfusions, or hydroxycarbamide. Once leg ulcer has developed, it is very difficult to manage. Regular blood transfusions, zinc supplementation and pentoxifylline, and the use of an oxygen chamber have been proposed for ulcer treatment. Hydroxycarbamide also has some benefit, either alone or with erythropoietin. Recently promising results have been obtained with platelet derived growth factor. Since patients with thalassemia intermedia have a high risk of thrombosis, exacerbated by splenectomy, it is important to be aware of thrombotic complications. Recommended treatment options include proper anticoagulation prior to surgical or other high-risk procedures, platelet anti-aggregating agents in case of thrombocytosis (platelet count higher than 700,000/mm
3) and low molecular weight heparin in patients with documented thrombosis. Because individuals with thalassemia intermedia may develop iron overload from increased gastrointestinal absorption of iron or from occasional transfusions, chelation therapy is started when the serum ferritin concentration exceeds 300 ng/ml or when iron overload is demonstrated by direct or indirect methods [
86]. Supplementary folic acid can be prescribed to patients with thalassemia intermedia to prevent deficiency from hyperactive bone marrow.
Lifestyle and diet in beta-thalassemia
If the disease is fully compensated by ideal treatment, an individual with thalassemia major can enjoy a near-normal lifestyle and experience normal physical and emotional development from childhood to adulthood, including parenthood.
Patients with thalassemia do not have specific dietary requirements, unless they have special prescriptions. Patients already have a heavy treatment schedule and it is counterproductive to add further restrictions without the likelihood of clear benefit. During growth, a normal energy intake with normal fat and sugar content is recommended. During adolescence and adult life, a diet low in highly refined carbohydrates may be useful in preventing or delaying the onset of impaired glucose tolerance or diabetes. There is no clear evidence that a specific diet is beneficial in preventing or managing liver disease, unless at late stages. Increased iron absorption from the intestinal tract is characteristic of thalassemia. The amount depends on the degree of erythropoiesis, the Hb level and other potential independent factors. Drinking a glass of black tea with meals reduces iron absorption from food, particularly in thalassemia intermedia [
85]. However, there is no evidence that iron-poor diets are useful in thalassemia major; only foods very rich in iron (such as liver, many baby foods, breakfast cereals and multivitamin preparations contain added iron, along with other vitamin supplements) should be avoided. Since many factors in thalassemia promote calcium depletion, a diet containing adequate calcium (e.g. milk, cheese, dairy products and kale) is always recommended. However, nephrolithiasis is seen in some adults with thalassemia major, and calcium supplements should not be given unless there is a clear indication; instead a low oxalate diet should be considered.
Patients with thalassemia who remain untransfused or are on low transfusion regimens have increased folate consumption and may develop a relative folate deficiency. Supplements (1 mg/day) may be given if this occurs. Patients on high transfusion regimens rarely develop this condition, and usually have no need for supplements.
Iron overload causes vitamin C to be oxidized at an increased rate, leading to vitamin C deficiency in some patients. Fifty mg of vitamin C in children <10 years and 100 mg >10 years at the time of DFO infusion may increase the 'chelatable iron' available in the body, thus increasing the efficacy of chelation. However there is currently no evidence supporting the use of vitamin C supplements in patients on DFP, DFX or combination treatment. Vitamin C may increase iron absorption from the gut, labile iron and hence iron toxicity and may therefore be particularly harmful to patients who are not receiving DFO, as iron mobilized by the vitamin C will remain unbound, causing tissue damage.
The effectiveness and safety of vitamin E supplementation in thalassemia major has not been formally assessed and it is not possible to give recommendations about its use at this time.
Patients with thalassemia should be discouraged from consuming alcohol, as it can facilitate the oxidative damage of iron and aggravates the effect of HBV and HCV on liver tissue.
In general, physical activity must always be encouraged unless there is a precise secondary medical condition. Conditions requiring special attention include splenomegaly, severe heart disease and osteoporosis.
There is no reason for patients with thalassemia to skip or delay standard recommended vaccinations. To prevent and minimize the risk of infection, immunization with the pneucococcal, Haemophilus Influenza and meningococcal vaccines is recommended about two weeks before splenectomy and after surgery.
It is now universally recognized that thalassemia, like other chronic diseases, has important psychological implications. The way in which the family and the patient come to terms with the disease and its treatment will have a critical effect on the patient's survival and quality of life, and a general acceptance by the patient of his/her own condition constitutes the key to normal development from childhood to adulthood. A key role for treating physicians and other health care professionals is to help patients and families to face up to the difficult demands of treatment, while maintaining a positive role.
Therapies under investigation
Induction of HbF synthesis can reduce the severity of beta-thalassemia by improving the imbalance between alpha and non-alpha globin chains. Several compounds including 5-azacytidine, decytabine, and butyrate derivatives gave encouraging results in clinical trials [
87]. These agents induce Hb F by different mechanisms not yet well defined. Their potential in the management of beta-thalassemia syndromes is under investigation.
A butyrate derivative, 2,2-Dimethylbutyric acid, sodium salt has received orphan designation for betathalassemia in the United States of America and in Europe.
The efficacy of hydroxycarbamide treatment in individuals with thalassemia is still unclear. Hydroxycarbamide has been used as experimental treatment in patients with thalassemia intermedia to reduce extramedullary masses, to increase Hb levels, and, in some cases, to improve leg ulcers. A good response, correlated with particular polymorphisms in the beta globin cluster (i.e., C>T at -158 G gamma), has been reported in individuals with transfusion dependence [
88,
89]. However, controlled and randomized studies are needed to establish the role of hydroxycarbamide in the management of thalassemia major.
The possibility of correction of the molecular defect in hematopoietic stem cells by transfer of a normal gene via a suitable vector or by homologous recombination is being actively investigated [
90]. The most promising results in the mouse model have been obtained with lentiviral vectors [
90,
91]. In 2009, orphan designation was granted by the European Commission for autologous haematopoietic stem cells transduced with lentiviral vector encoding the human beta globin gene for the treatment of beta-thalassemia major and intermedia.
Prognosis
Prognosis of thalassemia minor subjects is excellent. An increased risk for cholelithiasis, especially in association with the Gilbert mutation has been demonstrated [
92]. Patients with thalassemia intermedia who do not usually have severe hemosiderosis are less prone to cardiac problems [
11]. However, pulmonary hypertension, thromboembolic complications, overwhelming postsplenectomy sepsis, and the development of hepatocarcinoma may reduce survival in this group of patients. The prognosis of betathalassemia major was very grim before there was any treatment available. With no treatment, the natural history was for death by age five from infections and cachexia. The first advance in treatment was the initiation of episodic blood transfusions when the patient was having a particularly bad time. With the advent of this type of therapy, survival was prolonged into the second decade, but it soon became evident that the treatment that saved lives in children caused death from cardiac disease in adolescence or early childhood. Prognosis for individuals with betathalassemia major has dramatically improved with the advent of DFO. However, many transfusion-dependent patients continued to develop progressive accumulation of iron. This can lead to tissue damage and eventually death, particularly from cardiac disease. Advances in red cell transfusion, and the introduction of new iron chelators and chelation regimes have further prolonged survival in recent years.
Assessment of myocardial siderosis and monitoring of cardiac function combined with intensification of iron chelation have converted a once universally fatal disease to a chronic illness and an excellent long-term prognosis is expected for children who have been chelated since a very young age [
93,
94].
Bone marrow transplantation is at present the only available definitive cure for patients with thalassemia major.