Key points

Introduction

Transfusions are increasingly being used in the management of blood disorders in children. Regular red cell transfusions have been used to alleviate the severe anemia and suppress ineffective erythropoiesis in patients with thalassemia major for many years, and are increasingly being used in the management of children with sickle cell disease (SCD). In SCD, the goal of regular transfusions generally is to reduce the hemoglobin S level to less than 30% to 50% to prevent or treat disease complications, such as stroke. An estimated 1000 to 2000 individuals with thalassemia and 100,000 individuals with SCD live in the United States, and therefore patients with SCD account for a larger proportion of transfused individuals. Other hematologic disorders treated with transfusions include bone marrow failure syndromes, such as Diamond-Blackfan anemia (DBA), and hemolytic anemias, such as pyruvate kinase deficiency.

The monitoring and treatment guidelines for transfusional iron overload generally have been derived from the experience with patients with thalassemia and are described herein. However, differences in transfusional iron loading and its clinical manifestations between patients with thalassemia and other blood disorders are becoming better understood. These differences and the implications for clinical management are discussed where applicable.

Introduction

Transfusions are increasingly being used in the management of blood disorders in children. Regular red cell transfusions have been used to alleviate the severe anemia and suppress ineffective erythropoiesis in patients with thalassemia major for many years, and are increasingly being used in the management of children with sickle cell disease (SCD). In SCD, the goal of regular transfusions generally is to reduce the hemoglobin S level to less than 30% to 50% to prevent or treat disease complications, such as stroke. An estimated 1000 to 2000 individuals with thalassemia and 100,000 individuals with SCD live in the United States, and therefore patients with SCD account for a larger proportion of transfused individuals. Other hematologic disorders treated with transfusions include bone marrow failure syndromes, such as Diamond-Blackfan anemia (DBA), and hemolytic anemias, such as pyruvate kinase deficiency.

The monitoring and treatment guidelines for transfusional iron overload generally have been derived from the experience with patients with thalassemia and are described herein. However, differences in transfusional iron loading and its clinical manifestations between patients with thalassemia and other blood disorders are becoming better understood. These differences and the implications for clinical management are discussed where applicable.

How transfusions lead to iron overload

Typical regular transfusion regimens involve the administration of 10 to 15 mL/kg of packed red blood cells every 3 to 5 weeks. Each milliliter of pure packed red cells (hematocrit 100%) contains just more than 1 mg of iron. Humans do not have the physiologic ability to excrete excess iron, and therefore chronic red cell transfusion therapy leads to progressive iron accumulation. Chelation therapy is necessary to prevent iron accumulation and/or to remove excess iron. In children with SCD, exchange transfusion also may be used, which limits transfusional iron loading and may obviate the need for chelation.

Toxicity of iron

Free iron is toxic; therefore, iron is usually bound to proteins within the body. For example, iron in plasma is bound to transferrin, a transport protein. However, transferrin becomes saturated in iron overload states, leading to the presence of non–transferrin-bound iron (NTBI) forms. Labile plasma iron (LPI), a form of NTBI, is taken up into cells and causes oxidative damage. The heart, liver, and endocrine organs are most susceptible to iron-related injury.

Cardiac toxicity, including congestive heart failure and atrial and ventricular arrhythmias, is the leading cause of death related to iron overload in patients with thalassemia major. Iron-related heart disease generally does not become evident until the teen years in patients with thalassemia who are poorly chelated. Furthermore, iron-associated cardiac disease is uncommon in transfused individuals with SCD, even at older ages. However, children with DBA and sideroblastic anemias may be at risk for iron-related heart disease at younger ages.

Hepatic toxicity from iron overload includes inflammation, fibrosis, and cirrhosis. It is important to vaccinate children against hepatitis A and B viruses and to counsel against alcohol abuse to avoid exposure to additional hepatotoxins. Iron also damages endocrine organs, leading to growth failure, growth hormone deficiency, delayed puberty, hypogonadotropic hypogonadism, impaired glucose metabolism and insulin-dependent diabetes mellitus, osteopenia, hypothyroidism, and hypoparathyroidism. In a registry of North American patients with thalassemia, almost half of patients in the 16- to 24-year-old age group had developed endocrinopathies. Iron-associated endocrinopathies are less common in patients with SCD than in those with thalassemia, but may occur at earlier ages in patients with DBA. Good control of iron burden in children is important because organ damage likely results from cumulative exposure to iron.

Evaluation of iron overload

Several different tests can be used to monitor the degree of iron overload. Measured with a simple blood test, the serum ferritin level is the easiest and least expensive test to obtain. Although the ferritin level correlates with total body iron burden in patients receiving chronic transfusions, the utility of the test is limited because infection, inflammation, and ascorbate deficiency can either raise or lower serum ferritin levels, altering the ability to accurately predict iron stores. In particular, the serum ferritin may not correlate well with the degree of transfusional iron loading in patients with SCD. Ferritin levels also do not predict cardiac iron loading accurately.

The liver iron concentration (LIC) correlates well with total iron burden in transfusion associated iron overload, and levels greater than 15 mg of iron per gram (Fe/g) dry weight (dw) of liver are associated with increased morbidity and mortality. However, LIC does not adequately predict cardiac iron levels due to differential rates of iron loading and unloading in these organs. Before the validation of noninvasive imaging techniques, liver biopsy was considered the best method for determining LIC. Biopsy also enables direct assessment of histology, which is helpful in assessing tissue injury from iron, infections such as hepatitis C, and chelator-related toxicity. However, the risks of the procedure limit its acceptability to patients and providers, and noninvasive imaging techniques have superseded liver biopsy for the estimation of liver iron.

The superconducting quantum interference device (SQUID) is one noninvasive technique for estimating LIC, but given that few SQUID scanners exist worldwide, the use of this technique is impractical for many patients. Magnetic resonance imaging (MRI) is more widely available, and liver iron estimation by R2 and R2* techniques correlates well with LIC determined by biopsy. The presence of iron in hepatocytes or cardiomyocytes causes the tissues to darken more rapidly on MRI than non–iron-loaded tissue. R2 and R2* represent the rate of tissue relaxation (darkening), and the values typically are converted into milligrams of Fe/g dw tissue on clinical reports. MRI has now become the primary monitoring tool for both liver and cardiac iron.

The ability to estimate cardiac iron using T2* MRI techniques has revolutionized the care of patients with transfusional iron overload. Cardiac T2* can predict the risk of developing heart disease, allowing intensification of therapy that may prevent this outcome. T2*, the reciprocal of R2* (1000/R2*), reflects the half-life of tissue darkening, and thus lower values are worse. Cardiac T2* greater than 20 ms is normal, white values less than 10 ms indicate severe cardiac iron loading. In one multicenter cohort study, 98% of patients who developed heart failure had T2* less than 10 ms in the year prior. Patients with cardiac T2* less than 6 ms were at highest risk, with a 47% chance of developing heart failure within a year of the T2* study. In addition, most (83%) cardiac arrhythmias occurred with T2* values less than 20 ms. Thus, cardiac T2* values that decrease to less than 20 ms indicate the presence of cardiac iron loading and a need for better chelation.

Abnormal cardiac T2* is uncommon in children with thalassemia in the first decade of life, but increased cardiac iron was reported to be detectable in 24% of children between 9.5 and 15.0 years old and 36% of children 15 to 18 years old in one study. Regularly transfused patients with SCD have a lower risk of cardiac iron loading, even at older ages. Therefore, beginning cardiac T2* surveillance around 10 years old in children with thalassemia major is generally recommended, whereas monitoring in children with SCD often may be postponed until the teen years. In contrast, chronically transfused children with DBA may be at increased risk for early cardiac disease, and T2* monitoring beginning at 5 years old may be warranted.

MRI also may detect iron loading in endocrine organs. Abnormal pancreatic iron levels (R2* >100 MHz) are associated with an increased risk of glucose dysregulation, and pituitary iron loading and volume loss are associated with an increased risk of hypogonadism. These MRI techniques need to be studied further and currently are not in widespread clinical use.

Goals of iron chelation

Chelation therapy is used to limit iron loading from ongoing transfusions and to remove excess accumulated iron. Chelators also bind and detoxify NTBI forms and protect susceptible organs from oxidative injury. Chelation therapy can prevent and reverse iron-associated cardiac disease, and with aggressive chelation, some endocrinopathies may improve.

Chelation therapy should be started in children 2 years of age or older, after 1 to 2 years of chronic transfusions, and when the serum ferritin level is greater than 1000 ng/mL on 2 separate measurements obtained when the child is well. Chelation therapy is dosed to maintain the liver and cardiac iron in an acceptable range and to match ongoing transfusional iron intake; with increasing transfusional iron intake, higher doses of chelator are needed. Target ranges for LIC and cardiac T2* results are shown in Fig. 1 . Traditionally, the goal has been to keep the LIC between 2 and 7 mg/g dw, ferritin between 500 and 1500 ng/mL, and cardiac T2* greater than 20 ms. Some centers have shown improvement in endocrinopathies and other iron-related toxicities in adult patients using more aggressive chelation regimens to achieve normal body iron stores. This approach has not been studied in growing children.

Chelation recommendations for various cardiac and liver iron levels. The green area indicates optimal liver and cardiac iron levels; current chelation can be continued. The gray area indicates low iron stores with an increased risk of chelator toxicity. Children should be monitored closely for chelator-associated toxicities, and chelator dose should be reduced if these occur. The yellow area shows moderate cardiac and liver iron burden, with concern for an increased risk of iron-associated toxicity. If the iron levels are not improving from prior studies, adherence should be addressed and/or chelation intensified. The red area denotes iron levels that are unacceptably high; adherence should be addressed and chelation intensified. Combination chelation should be considered because of the increased risk of cardiac morbidity and mortality.

Pharmacologic strategies

Three chelators are currently approved by the FDA, each with varying properties.

Deferoxamine

Deferoxamine was the only available chelator for more than 30 years. The drug has poor oral bioavailability and a short half-life ; thus, deferoxamine is given as a continuous infusion of 25 to 40 mg/kg given over 8 to 12 hours, 5 to 7 days per week either subcutaneously or intravenously. Daily administration of higher doses (50–60 mg/kg/d) over longer durations of up to 24 hours often is used for patients with evidence of significant cardiac iron loading (cardiac T2* <10 ms) or iron-related cardiac toxicity. Deferoxamine induces both urinary and fecal iron excretion. This chelator effectively removes hepatic and cardiac iron and can prevent, and even reverse, iron-related cardiac complications.

Adverse effects associated with the use of deferoxamine are described in Table 1 . Some adverse effects, including audiologic, ophthalmologic, and growth and bone toxicities, are dose-related and may be minimized through adjusting the deferoxamine dose based on the degree of iron loading. In addition, deferoxamine often is not started until 3 years of age, and lower doses (25–30 mg/kg/d) are used in young children to minimize side effects. Acute neurotoxicity and pulmonary toxicity have been reported with doses of 10 to 20 mg/kg/h, and these high doses generally are not recommended.

Table 1

Chelator adverse effects, monitoring, prevention, and treatment recommendations

Chelator	Adverse Effect	Monitoring	Prevention	Treatment
DFO	Local reaction	Examine infusion sites at each visit	Rotate infusion sites; use more dilute concentration of DFO	For severe reactions, may consider addition of hydrocortisone to infusion
	Audiologic: tinnitus, high-frequency hearing loss	Audiologic examination annually	Maintain ratio of DFO (mean dose in mg/kg/day)/ferritin <0.025; limit exposure to loud noises, such as high volume on headphones	Hold/reduce dose
	Ophthalmologic: visual loss and/or changes in visual acuity, color vision changes, retinal opacities and pigment changes, delayed visual evoked potentials, optic neuritis	Ophthalmologic examination annually	Maintain ratio of DFO (mean dose in mg/kg/day)/ferritin <0.025	Hold/reduce dose
	Bony deformities	Growth velocity and seated height twice yearly; consider knee radiographs	Avoid use in children <3 y; administer low doses (25–30 mg/kg/d) to growing children	Hold/reduce dose
	Increased risk of infection with Yersinia , Klebsiella	Blood cultures if indicated	Hold DFO with unexplained fever	Antibiotic therapy if cultures positive
	Neurotoxicity	Neurologic examination	Avoid very high doses	Hold/reduce dose
	Pulmonary toxicity	NA	Avoid very high doses	Hold/reduce dose
DFP	Neutropenia (ANC 500 to <1500 × 10 9 /L) and agranulocytosis (ANC <500 × 10 9 /L)	Complete blood cell count with white blood cell differential weekly and with febrile events	Avoid concomitant use of medications that may cause cytopenias; avoid use in children with history of unexplained neutropenia or bone marrow failure syndromes	Hold drug GCSF may be administered in setting of neutropenia/agranulocytosis and infection
	GI symptoms	Query for nausea, vomiting, diarrhea	Increase dose gradually	Administer with food Supportive care (eg, antiemetic) Symptoms often improve with continued drug administration
	Arthralgia and arthropathy	Routine joint examinations; for arthralgia or arthropathy of large joints persisting after discontinuing DFP, consider radiograph or MRI	NA	Supportive care (eg, nonsteroidal anti-inflammatory agents); hold/reduce dose if persistent symptoms
	Elevated hepatic enzymes	Hepatic enzymes at least quarterly	NA	Generally resolves without dose adjustment Hold/reduce dose if persists
	Decreased plasma zinc	Plasma zinc concentration at least annually	NA	Zinc supplementation
DFX	Audiologic: high-frequency hearing loss	Audiologic examination annually	Avoid high doses in children with low iron burden; limit exposure to loud noises	Hold/reduce dose
	Ophthalmologic: cataracts, lenticular opacities, retinal disorders, elevations in intraocular pressure	Ophthalmologic examination annually	Avoid high doses in children with low iron burden	Hold/reduce dose
	Rash	Physical examination	NA	For mild or moderate, may continue current dose For more severe, may hold and then restart drug at lower dose Short course of oral steroids may be considered
	GI symptoms	Query for nausea, vomiting, diarrhea, abdominal pain	Patients with lactose intolerance may experience more GI symptoms because of presence of lactose in drug manufacturing	Supportive care (eg, Lactaid or antidiarrheal agent) Reduce dose Divide dose (twice daily) Symptoms may improve over time
	Elevated hepatic enzymes; rare reports of hepatic failure	Hepatic enzymes and bilirubin 2 wk after starting DFX and then monthly	NA	Hold for transaminase that are consistently rising or >5x upper limit Reduce dose; discontinue if hepatic failure
	Nephrotoxicities: elevated creatinine, proteinuria, renal Fanconi syndrome	Creatinine, urinalysis, electrolytes monthly	NA	Hold/reduce dose if creatinine abnormal or persistent proteinuria Hold for Fanconi syndrome and discontinue if recurs with rechallenge
	GI bleeding	Monitor for dark or bloody stools	Avoid concomitant use of steroids, nonsteroidal anti-inflammatory medications, and anticoagulants if possible	Hold drug Gastroenterology referral
	Cytopenias	Monitor complete blood count at least quarterly	NA	Hold drug

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