Iron Chelation in Thalassemia Major

Abstract

Purpose

Iron chelation has improved survival and quality of life of patients with thalassemia major. there are currently 3 commercially available iron-chelating drugs with different pharmacokinetic and pharmacodynamic activity. The choice of adequate chelation treatment should be tailored to patient needs and based on up-to-date scientific evidence.

Methods

A review of the most recent literature was performed.

Findings

The ability of the chelators to bind the redox active component of iron, labile plasma iron, is crucial for protecting the cells. Chelation therapy should be guided by magnetic resonance imaging that permits the tailoring of therapy according to the needs of the patient because different chelators preferentially clear iron from different sites. Normal levels of body iron seem to decrease the need for hormonal and cardiac therapy.

Implications

The 3 chelators currently available have different benefits, different safety profiles, and different acceptance on the part of the patients. Good-quality, well-designed, randomized, long-term clinical trials continue to be needed.

Introduction

The β-thalassemia syndromes are a group of hereditary blood disorders characterized by reduced or absent β-globin synthesis, resulting in variable phenotypes ranging from severe anemia to clinically asymptomatic individuals. Thalassemia major (TM) is the homozygous, transfusion-dependent form. The worldwide annual incidence of symptomatic individuals is estimated at 1 in 100,000.¹

The clinical forms of thalassemia that do not require regular transfusions for survival are the non–transfusion-dependent thalassemias, including β-thalassemia intermedia, hemoglobin E β-thalassemia, and hemoglobin H disease.

The anemia of TM becomes symptomatic in early childhood, usually between 6 months and 2 years of age, and requires regular blood transfusions. A regimen maintaining pretransfusion hemoglobin concentrations of 9.5 to 10.5 g/dl prevents the main complications of the disease (delayed growth and puberty, facial anomalies, hepatosplenomegaly) at the price of a mean intake of approximately 0.40 mg/kg per day of iron. A patient who receives 25 to 30 U of blood a year, by the third decade of life, in the absence of chelation, will accumulate >70 g of iron.

In addition to the iron transfused, iron absorption from the gut contributes to the iron burden. Iron absorption is the main cause of iron overload in thalassemia intermedia. In fact, the high erythropoietic drive causes severe hepcidin deficiency that, in turn, results in hyperabsorption of dietary iron.

Non–transferrin-bound iron (NTBI), and in particular its redox active component labile plasma iron (LPI), appears in plasma when approximately 70% of transferrin is saturated. LPI is believed to be responsible for catalyzing the formation of reactive radicals in the circulation of iron overloaded individuals, inducing peroxidative injury to the phospholipids of lysosomes and mitochondria, as indicated in vitro and in experimental animal studies.² In addition to transfusional iron load, ineffective erythropoiesis is considered to be responsible for the generation of NTBI.

Iron, if untreated, causes considerable morbidity in most organs and ultimately leads to death.³ Even osteoporosis appearing in adolescents and adults is thought to be related to iron overload, and the molecular basis for this phenomenon is now unfolding.⁴ Heart disease, however, is the most serious consequence of iron overload and represents the first cause of death in more than half of the patients.⁵ Iron is believed to enter into cardiomyocytes via the L-type Ca2+ channels.⁶

The distribution of iron loading in various organs depends in part on differences in iron-regulatory proteins. The liver can take up iron rapidly from the circulation via both transferrin- and non–transferrin-mediated processes and, similarly, can unload it via the iron exporter ferroportin, which is abundant in liver cells. The heart and endocrine glands, like the pancreas, conversely tend to take up iron only when there is circulating NTBI, whose level increases when the liver is loaded. The unloading from the heart, which contains very little ferroportin, is 4 times slower.⁷

Other hemoglobinopathies and chronic hemolytic anemias (eg, sickle cell disease, congenital dyserythropoietic anemias, and Blackfan-Diamond anemia) may also require iron chelation.

Accurate assessment of the iron accumulated is necessary to evaluate iron overload and need and efficacy of chelation therapy. Transfusional iron intake should be monitored on an ongoing basis when trying to achieve neutral or negative iron balance. Serum ferritin testing is widely available and is the least expensive way of measuring iron stores. Despite the fact that it is an acute-phase reactant and can be influenced by inflammation, liver disease, and vitamin C status, ferritin remains a satisfactory parameter of liver iron concentration (LIC) and a good predictor of cardiac response to chelation.⁸ It has recently been proven to be a predictive factor for progression to endocrine dysfunction, allowing intensification of chelation and reversal of hypothyroidism.⁹

The use of magnetic resonance imaging (MRI) to measure tissue iron has had a remarkable effect on the assessment of the efficacy of iron chelators and the understanding of the pathophysiology of iron overload. The results can be reported as R2 and R2* or as their reciprocal T2 and T2*.10, 11, 12 T2* cardiovascular magnetic resonance provides robustly validated, reproducible measurements of myocardial iron. T2* values of the interventricular septum >20 msec are considered normal, whereas values <10 msec are considered a sign of severe accumulation.¹² A validated MRI, multisection, multiecho T2* technique for global and segmental measurement of iron overload in the heart is in use in most Italian centers.¹¹

The liver represents the primary iron storage site; therefore, measurement of LIC reflects total body iron stores. Liver biopsy used to be considered the gold standard for measuring LIC. However, this is an invasive procedure, and MRI is used instead whenever possible. LIC, however, does not consistently correlate with cardiac iron and therefore cannot be the only parameter used to predict the risk of cardiac disease.¹² MRI of the pituitary gland and pancreas are now often being performed. The results are predictive of hypogonadism and, for pancreas, of β-cell toxicity and cardiac iron loading.13, 14 Other devices also based on magnetic iron detection are available in a few centers.

To prevent hemosiderosis, iron needs to be chelated and excreted in an amount equal or greater than that introduced by transfusion. In addition, the circulating LPI needs to be bound by a chelator to prevent free radical formation and lipid peroxidation. Three iron chelating agents are currently commercially available: deferoxamine (DFO), deferiprone (DFP), and deferasirox (DFX).

DFO^* is the first chelating agent that became available. It was introduced in clinical use in the 1960s and was approved by the Food and Drug Administration in 1982. It has a large molecular weight and a short plasma half-life and therefore requires subcutaneous administration by means of a portable pump or intravenous administration in case of cardiac dysfunction and gross iron overload. The suggested dose is 40 to 50 mg/kg per day at least 5 times a week for 8 to 10 hours. DFO is mainly excreted through urine, although some patients may reach a 40% fecal excretion. On cessation of DFO infusion, NTBI reappearance is rapid, and therefore the protection is incomplete.

DFO has been found to be efficacious in reducing the iron burden and in improving organ function and even survival. However, with the introduction of cardiac magnetic resonance, myocardial siderosis, often associated with left ventricular dysfunction, was found in two-thirds of TM patients treated with deferoxamine.¹⁵

Subcutaneous administration of the drug, which is cumbersome and even painful, has a negative effect on adherence to therapy. The most common adverse effects of DFO are local redness and soreness at the site of infusion. Systemic allergic reactions and, rarely, anaphylaxis may occur, requiring change of chelator or desensitization. Vision and hearing impairment have been reported with high doses of DFO.¹⁶

In children, stunted linear growth has been reported when patients were given DFO before 2 years of age.¹⁷ Deficiency in trace elements secondary to DFO treatment may play a role in growth impairment and auditory and visual toxic effects.¹⁸ Yersinia and Klebsiella infections seemed to be favored by DFO treatment. Therefore, fever and gastrointestinal symptoms are an indication to temporarily discontinue use of DFO.19, 20

DFP,^†‡§ the first oral alternative to DFO, was introduced in Europe at the end of a large, nonrandomized, multicenter trial.²¹ It was approved by the European Medicines Evaluation Agency in 1999 and in 2011 by the US Food and Drug Administration as a second-line therapy. It is indicated in patients >6 years of age with inadequate response or contraindications to other chelators. The recommended dosage is 75 to 100 mg/kg per day in 3 subdoses. DFP is easily absorbed from the gut and, a peak concentration is reached in the plasma 45 minutes after ingestion. Half-life is approximately 2 to 3 hours. The drug is excreted in the urine within 3 to 4 hours after having been glucuronidated in the liver. In addition to being administered as monotherapy, DFP is frequently given in combination with DFO.²²

Response to treatment appears to be greater at higher baseline ferritin levels.²³ Significant differences observed in the genotypic distribution of UGT1A6 polymorphisms can explain variable response in terms of efficacy but not in the appearance of adverse reactions.²⁴ The most frequent adverse effects are gastrointestinal discomfort (nausea, abdominal pain, vomiting, diarrhea). These symptoms are usually mild to moderate and tend to improve with time. The most severe adverse effects are neutropenia and agranulocytosis. In a prospective, multicenter study, the overall frequency of agranulocytosis was 0.5%, and the incidence was 0.2 per 100 patient-years. Milder neutropenia occurred in 8.5% of patients.²³

DFX^‖ is the most recently approved chelator for transfusional hemosiderosis (US Food and Drug Administration, 2005; European Medicines Evaluation Agency, 2006) in patients ≥2 years of age. It is administered orally once a day, usually in the morning, half an hour away from meals, at a dose varying from 10 to 40 mg/kg daily, depending on the transfusional load. DFX is absorbed through the gut, and peak plasma levels are reached at approximately 4 to 6 hours, with a half-life of approximately 14 to 16 hours, allowing a once daily administration. The drug is mainly excreted through feces. Patients with inadequate response were found by pharmacokinetic studies to have significantly lower drug exposure compared with controls.²⁵ DFX is the most commonly used chelator in the United States.²⁶

The US Food and Drug Administration has recently approved DFX tablets that can be swallowed whole. The most common adverse effects reported are related to gastrointestinal symptoms, including nausea, vomiting, and abdominal pain. A rash can develop, usually within the first month of treatment. It is usually mild to moderate and resolves spontaneously, without drug therapy discontinuation or dose adjustment. In more severe cases, DFP treatment can be temporarily interrupted.²⁷

Approximately one-third of patients develop increases in serum creatinine, defined as >33% above baseline on 2 separate occasions. In a 5-year follow-up study, this event was reported in 6.7% of the patients.²⁷ In two-thirds of cases the creatinine level returns to normal without dose adjustment. Nevertheless, DFX treatment requires close monitoring of the renal function. The adverse effects of the 3 chelators in use are reported in the Table.

Long-term experience has revealed that combined chelation with DFP and DFO rapidly reduces liver iron, serum ferritin, and, more importantly, myocardial siderosis and improves left ventricular ejection fraction.³³ Balance studies have found an additive effect of the 2 drugs, probably because they access different pools of iron. When given in combination, DFP enhances DFO’s ability to chelate iron by rapidly accessing and shuttling NTBI fractions that are otherwise only slowly available to DFO.³⁴

Several studies have reported concordant results.³⁵ A striking effect on cardiac death and therefore on overall survival was observed in Cyprus after the year 2000 when DFO monotherapy was substituted with combination therapy. Results of multivariate analysis indicated that combined chelation was the only independent factor associated with improved survival.³⁶ In a 7-year, multicenter randomized clinical trial, no deaths occurred with DFP alone or with the combined use of DFP and DFO, whereas one death occurred with alternating therapy and 10 with DFO monotherapy.³⁷ Farmaki et al³⁸ reported reversal of hypothyroidism and abnormalities in glucose tolerance and a decreased need for testosterone after normalization of iron stores with intensive combined iron chelation. This combination may be lifesaving in a deteriorating patient. Combination therapy does not increase the risk of adverse effects from either chelator.

Two of the 3 available chelators can be combined to increase their efficacy and improve adherence. In fact, metabolic iron balance studies found in 6 patients that DFX and DFO used on the same day had a synergistic effect in 2 patients and an additive effect in 3 others.³⁹

A few trials have reported beneficial effects on heart and liver hemosiderosis when DFX and DFO40, 41 or DFX plus DFP were given on the same day.42, 43 Combination of DFP and DFX reversed cardiac dysfunction and endocrine complications in a small series of Greek patients.⁴⁴ Balocco et al,⁴⁵ who alternated DFP and DFX, were able to avoid adverse effects of both drugs in patients who had previously developed arthralgia or neutropenia with DFP and proteinuria or severe skin reaction with DFX.