Iron overload is the major cause of morbidity for thalassemia patients. Even nontransfused patients develop iron overload secondary to increased intestinal absorption of dietary iron. Iron overload is a leading cause of mortality and organ injury.
Iron overload occurs very rapidly in patients who are on chronic transfusion programs. Since humans have no mechanism other than sloughing of the mucosa of their gastrointestinal tracts or menstruation to excrete excess iron, patients who are being transfused every three or four weeks gain 0.5 mg/kg per day of iron in excess of natural losses. Patients who are not on a transfusion regimen are also prone to iron overload due to significantly increased intestinal absorption of iron secondary to ineffective erythropoiesis.
The only treatment options for removing excess iron are phlebotomy and chelation. While phlebotomy is a very effective way of removing iron, it is not appropriate for patients with thalassemia except after bone marrow transplantation. Thalassemia patients who are not transfusion dependent cannot maintain an adequate hemoglobin level and become symptomatic after phlebotomy. Outpatient exchange transfusion can be used in selected cases to decrease iron intake, but it is not effective by itself in rapidly reducing heavy iron loads and would not be appropriate by itself in the face of cardiac iron loading. The primary treatment for iron overload in thalassemia is chelation, which is described below.
Iron is very toxic to tissue. Under normal circumstances, in humans, iron is transported bound to a carrier protein called transferrin. Transferrin transports iron into certain tissues. Because the iron is bound to this protein, other tissues are protected from the toxic effects of free iron. Patients on chronic transfusion rapidly acquire much more iron than can be bound by transferrin, and free iron levels increase in the blood. This free iron, or so called non-transferrin bound iron, is directly toxic to the heart and other tissues.
There are two goals of iron chelation therapy: the binding of toxic non-transferrin bound iron in the plasma and the removal of iron from the body. Detoxification of excess iron is probably the most important function of chelation therapy. It is clear that certain symptoms of iron overload, such as cardiac arrhythmia and heart failure, can be improved well before local tissue levels of iron have decreased by the continual presence of a chelator in the plasma.
It is useful to think about the toxicity of iron according to the following relation:
Toxicity = [tissue iron] x [patient- and tissue-specific factors] x [time]
Generally, time is measured in years. Thus, it takes three to ten years of chronic exposure to high levels of iron before measurable organ dysfunction occurs. Fortunately, this means that there is time to implement treatment strategies to reduce iron loading. However, depending upon the organ, it can take a long time to significantly reduce iron, so the best strategy is acting early and, in fact, trying to prevent significant iron loading from the start.
New equipment -- such as the quantitative MRI for iron and the ferritometer (SQUID) -- has enabled providers to measure the amount of iron in the organs and also look at the relationship between excess iron, time, and patient- and tissue-specific factors. Such factors include transfusion regimen; weekly chelation; differences of transport of iron into various organs; genetic differences in antioxidant defense mechanisms; and disease-specific differences in inflammation and metabolism. It is now clear that there is a tremendous range of variability in end organ toxicity among patients who seemingly have the same amount of tissue iron. From a clinical standpoint, this means that end organ function, as well as tissue iron concentration, must be serially monitored during the management of chronic iron overload.
In general, significant iron loading of the liver can be detected after about six months of monthly transfusions, while cardiac loading takes about eight to ten years. The liver loads linearly with time, whereas the heart remains devoid of iron for years. However, once it starts, iron loading of the heart is very rapid. Evidence of liver damage can occur after about four years of transfusions. The onset of cardiac dysfunction is more complex and less well understood. Quantitative cardiac iron, determined by MRI, is reported by T2*. The lower the number, the more the iron. A cardiac T2* greater than 20 ms is not associated with iron-induced cardiac dysfunction. A cardiac T2* between 10 and 20 ms indicates excess iron in the heart and represents a warning for potential cardiac dysfunction. If the T2* is less than 10 ms, the risk of cardiac dysfunction is high, and treatment should be considered emergent.
Under full chelation with deferoxamine, about 50 percent of liver iron can be removed in four to six months. It takes about 17 months to remove half of the heart iron.
In general, chelation should be started as soon as the patient becomes significantly iron loaded. Since removal of iron from normal tissues can result in toxicity from over-chelation, it is important to delay the start of chelation until the patient is significantly iron loaded. Since iron loading occurs much faster than toxicity develops, this delay will not put the patient in danger.
General recommendations for treatment with iron chelation are presented in Table 5.1. The decision points are based on total amount of blood transfused, ferritin levels, and degree of iron loading based on liver iron concentration (LIC). Liver iron is measured by biopsy, MRI, or SQUID.
Chelation therapy should be started after about one year of chronic transfusions. This correlates with a serum ferritin of approximately 1,000 ng/mL. LIC is the best measure of total iron loading. LIC should be at least 3,000 µg/g dry weight before starting chelation. The general guidelines for iron chelation are gradually changing. Many experts are increasing the therapy in order to maintain a lower steady-state body iron store. While long-term prospective data is limited on these aggressive protocols, it is felt that more aggressive therapy may be more effective in preventing iron-induced organ injury. This needs to be balanced with the drug toxicity. While the standard recommendations have been to maintain a ferritin between 1,000 and 2,500 ng/mL, several programs are aiming to maintain serum ferritin at 500 ng/mL in adult patients.
In infants, chelation therapy may be delayed beyond the first year because of known toxicity of chelators in young children.
Starting a daily regimen of chelation therapy, whether oral or parenteral, represents a significant commitment and disruption of lifestyle. Before commencement of chelation, the patient and family should be taught about the reasons for the treatment, as well as how to prepare and take the medication. A continued education and support program involving the nurse practitioner, a child life specialist, and social workers can enhance acceptance and compliance with this kind of chronic therapy.
The adequate assessment of iron stores before the initiation of therapy is important; it allows determination of efficacy and appropriate dosing. Prior to the availability of MRI and SQUID, quantitative liver iron measurements were determined by liver biopsy. This method remains acceptable when MRI or SQUID is not accessible. However, noninvasive, quantitative liver iron assessments by MRI or SQUID performed at an experienced center are as accurate and less prone to measurement error and should be used in place of biopsy whenever possible. While most MRI machines are capable of making these measurements, they require special software modification and calibration to produce accurate and reliable results.
|Liver iron concentration (LIC)||Ferritin||Recommended chelation||Monitoring||Comments|
|<3,000 µg/g||<1,000 ng/mL||Lower the dose at <1,000 ng/mL and hold medication at <500 ng/mL||Monitor ferritin monthly; start reduced-dose chelation when ferritin goes up to 500 ng/mL and full dose at 1,000 ng/mL, depending on age and risk factors.|
|3,000 to 7,000 µg/g||1,000 to 2,500 ng/mL||Maintain existing therapy||Monitor ferritin every 3 months||Note changes in trends. More aggressive therapy may be indicated, depending on organ dysfunction.|
|> 7,000 µg/g||> 2,500 ng/mL||Intensive chelation||Monitor ferritin every 2 to 3 months, and check LIC within 6 months.||Intensive chelation consists of at least 12 hours of deferoxamine per day, 7 days per week, or maximum tolerated deferasirox, as well as consideration of combination therapy.|
|Excess cardiac iron without cardiac dysfunction; T2* <20 ms||Intensive chelation||Monitor ferritin every 2 to 3 months, and check LIC within 6 months; monitor cardiac function within 6 months||Intensive chelation consists of at least 12 hours of deferoxamine per day, 7 days per week. Combination therapy with deferiprone or maximum tolerated deferasirox is recommended.|
|Iron-induced cardiomyopathy, T2* <20 ms; or T2* <10 ms without cardiomyopathy||Maximum chelation: 24-hour deferoxamine therapy in combination with deferiprone (alternatively, in combination with deferasirox—limited combination data available).||Monitor intensively with cardiology consultation and iron chelation specialist.|
NOTES: Ferritin may be a misleading measurement; liver iron is the much more accurate one. Young children may have more toxicity with chelators and may need dose adjustment.
Therapeutic index (TI) is often used in determining the deferoxamine dose when ferritin is analyzed. The therapeutic index is equal to the mean daily dose (mg/kg) / serum ferritin (mg/l). The target is to maintain the value of TI at under 0.025. The mean daily dose of deferoxamine is calculated by multiplying the dose administered in each treatment by the total number of doses administered per week, then dividing by seven—the number of days in a week. Ferritin measurements should be accompanied by periodic LIC measurements.
Consultation with thalassemia specialists should be considered in dose adjustments.
Nontransfused or intermittently transfused patients should receive chelation therapy and have their iron stores closely monitored. Their dosing should be modified on an individual basis with consultation.
LIC refers to dry weight, which is the standard method for reporting liver iron by liver biopsy and MRI. The wet weight conversion, which is a direct measurement determined by SQUID, is achieved using a divisor of 5 to 6.
The best iron chelation regimen is the one the patient is compliant with. Compliance with chelation therapy is the critical factor in treating iron overload. In the United States, there are three FDA-approved iron chelators: deferoxamine (Desferal), deferasirox (Exjade), and deferiprone (L1)
Deferoxamine (Desferal, DFO) is the most studied iron chelator. It has an excellent safety and efficacy profile and has shown a dramatic effect on increasing survival rates and decreasing morbidity.
Deferoxamine has a poor oral bioavailability. It is administered subcutaneously, intravenously, or occasionally intramuscularly. It has a short half-life, necessitating administration at least eight to twelve hours daily, five to seven days per week. Generally, iron is removed much more efficiently when deferoxamine is infused over a longer period of time. It also can be given intravenously 24 hours per day when indicated. The primary—if not the only—reason deferoxamine is ineffective in some patients is poor compliance.
Deferoxamine is effective in chelating non-transferrin bound iron and can reverse cardiac arrhythmias and left-ventricular dysfunction, although, combination chelation therapy is usually recommended for patients with cardiac dysfunction.
The dosing of deferoxamine depends upon the weight of the patient, the degree of iron overload, and the presence of iron-related cardiotoxicity. Side effects of deferoxamine and chelators in general are greater in patients with limited iron stores and in children under two to three years of age. For this reason, deferoxamine treatment is usually withheld until after two years of age.
Ascorbic acid (vitamin C) increases the excretion of iron in the presence of deferoxamine. It is started after the initial month of deferoxamine therapy. It is given orally in the dose of 2 to 4 mg/kg per day (100 to 250 mg) and taken soon after the deferoxamine infusion has been initiated. Patients should be cautioned against excessive ascorbate intake when deferoxamine is not being infused. Ascorbate releases iron and has been associated with increased cardiac damage when taken in the absence of an iron chelator.
Subcutaneous deferoxamine should be administered at 30 to 60 mg/kg for eight to fifteen hours, five to seven days or nights per week. Deferoxamine should run over a minimum of six hours (or longer) at a maximum of 15 mg/kg per hour.
High doses of deferoxamine—more than 4 to 6 mg over 24 hours—should not be given. Increasing the dose beyond this point can cause deferoxamine toxicity. Overall survival is related to the number of hours per week that deferoxamine is infused. Deferoxamine is more effective when a lower dose is circulated through the body over a longer period of time than when a higher dose is circulated over a short period of time. Therefore, time of exposure is more important than total dose once doses of 60 mg/kg per day are being utilized.
Starting at a lower number of days per week and advancing to five to seven may help the family adapt to and accept the new therapy. Treatment seven days a week should be the goal.
A small-gauge needle in the thigh or abdomen is usually used. It is important that the needle be long enough to go through the dermis. Intradermal infusion is painful and results in blisters, swelling, and reactions. The sites should be rotated to prevent reaction and fat necrosis. (Also see Section 7.6, regarding treatment suggestions for local reactions.)
Additional intravenous deferoxamine can be given during each transfusion. However, its efficacy is limited, and toxicity is significant when given over a short period of time. By itself, this mode of administration is inadequate for control of iron overload, and additional daily dosing as described above is always necessary.
Deferoxamine at 60 mg/kg per day, 24 hours per day, 7 days per week, may be indicated with patients with severe hemosiderosis and vital organ dysfunction. Patients with a T2* less than 10 ms or a liver iron greater than 30 mg/g dry weight are candidates for this therapy. If the patient has cardiac arrhythmia or left-ventricular dysfunction, this therapy is mandatory and must be emergently started. Deferoxamine can be administered intravenously using a central line. The intravenous therapeutic dose is 60 mg/kg per day. In such high risk patients, combination therapy with deferiprone—or alternatively, deferasirox—should be utilized. If the patient has symptomatic cardiac disease due to iron, a cardiologist with special expertise in cardiac iron overload should be consulted. Certain standard cardiac treatments recommended by cardiologists unfamiliar with iron overload can be deleterious to a patient in heart failure due to iron overload.
The oral iron chelator deferasirox (Exjade) is taken as a dispersible tablet once a day. It was approved in North America in November 2005 for the treatment of transfusional iron overload. The clinical experience is not as great as with deferoxamine. However, the drug has been used in thousands of patients and has been shown to be an effective iron chelator and to have an acceptable safety profile. It has become the most common iron chelator used in North America and many parts of the world because of its once-per-day oral dosage.
Deferasirox has good oral bioavailability and a long half-life suitable for once-daily dosing. In general, deferasirox appears similar to deferoxamine in lowering liver iron and serum ferritin levels in a dose-dependent manner. The starting dose is 20 mg/kg per day. The dose is often increased to 30 mg/kg per day, and in certain cases, to 40 mg/kg per day. After starting therapy, increase the dose by 5 to 10 mg/kg every three to six months based on iron stores. A dose of 20 mg/kg per day is effective in establishing negative iron balance in some patients. However, a higher dose of 30 to 35 mg/kg per day is usually required to establish negative iron balance. Recent data indicates that deferasirox in doses of at least 30 mg/kg per day significantly improves cardiac iron. Toxicities like skin rash, nausea, and diarrhea are dose-related, so starting at 20 mg/kg per day and working upward can help develop tolerance to the medication, even though the patient will likely require a higher dose at some later point. Ferritin is usually the most frequent parameter used to monitor efficacy. It is important to check ferritin with each transfusion and use the average change from three to five measurements to judge efficacy. (Also see Section 6, on monitoring iron overload.)
The safety profile of deferasirox is similar in pediatric and adult patients. In studies of deferasirox in children less than two years old, the medication appears to be safe, but the studies are limited. The most common side effects include gastrointestinal symptoms such as nausea and vomiting, diarrhea, and abdominal pain; mild skin rash is the second-most common side effect. These side effects often resolve with time and are dose-related. If gastrointestinal symptoms are significant, the dose can be lowered or stopped and then gradually increased. Dividing the same dose into twice-daily administration may decrease these side effects.
The most serious side effect with deferasirox is potential kidney damage; a mild nonprogressive rise in serum creatinine is seen in about one-third of patients. The dose should be lowered if there is an increase in serum creatinine that exceeds 33 percent of the baseline or greater than the upper limit of normal on two consecutive tests. Creatinine levels should be monitored monthly and repeated more frequently if rises are noted. Renal tubular problems, including severe renal tubular acidosis, have been seen.
Deferasirox is a dispersible tablet that can be suspended in water, apple juice, or orange juice. It should be taken on an empty stomach 30 minutes before or after eating. Recent data suggests that taking deferasirox with food is acceptable in patients who have difficulty with deferasirox on an empty stomach.
As with deferoxamine, deferasirox doesn’t work if the patient does not take it. While there is improved quality of life with the oral chelator, compliance remains a problem. If a patient seems to not be responding, compliance should be the first issue addressed. Even though it is a once-daily dose, the preparation of the liquid takes time and planning. The drug is suspended in the liquid and has a chalky texture. Some patients let it settle before drinking, discarding the scum (the actual drug) at the bottom. Others describe forgetting to put the tablet in liquid in the morning before their shower so when they are ready for school or work, the drug is not ready, and they skip it. It may take some creativity on the part of the team to help the patient get past some of these barriers. As with deferoxamine, some patients have a serious psychological aversion to taking the medicine and may need professional counseling. Addressing compliance issues is probably one of the most important advantages of having a comprehensive team to help the patient with a chronic disease.
Deferiprone (L1, Ferriprox) has been approved for use in several countries for many years and recently received FDA approval for patients who are not effectively chelated with standard therapy. Deferiprone reduces or maintains total body iron stores in the majority of patients. Studies suggest that deferiprone may be more effective than deferoxamine in reducing cardiac iron. Deferiprone in combination with deferoxamine may decrease the risk of cardiac disease and improve cardiac function. Studies in Europe suggest that deferiprone, particularly in combination with deferoxamine, is beneficial in patients with iron cardiomyopathy and cardiac dysfunction. The standard therapeutic daily dose is 75 mg/kg given three times daily and may be increased to 100 mg/kg three times a day in high-risk patients.
The major side effects of deferiprone include gastrointestinal symptoms, joint pain, and neutropenia. Due to the risk of agranulocytosis and associated rare deaths, weekly white blood cell counts are required for all patients receiving this drug. Zinc deficiency may occur particularly with deferiprone and require supplementation.
|Agent||Route||Half-life of drug (hours)||Schedule||Clearance||Side effects and toxicity|
|Deferoxamine (Desferal)||Slow infusion: intravenous or subcutaneous||0.5||Eight to 24 hours||Renal, hepatic||Dermatological, ocular, auditory|
|Deferasirox (Exjade)||Oral||12 to 16||Once daily||Hepatobiliary||Gastrointestinal, renal, hepatic|
|Deferiprone (L1)||Oral||2 to 3||Three times per day||Renal, cardiac||Hematological (neutropenia, agranulocytosis), arthropathic|
Some patients have particularly high iron loads, a high presence of cardiac iron, or other organ toxicity that may require more aggressive treatment. There are many ways to approach these patients, and treatments need to be tailored to achieve reduction of iron in a way that is acceptable to each patient. With the availably of several chelators, a number of new approaches have been suggested. There is no extensive experience with any of them. Some are presented below.
An aggressive chelation regimen is recommended when liver iron is greater than 20 mg/g dry weight, or cardiac T2* is less than 20. A higher—but not a toxic—dose of deferoxamine is recommended. Intensification of treatment can be accomplished by administering continuous intravenous deferoxamine (via a central intravenous line, if possible) in the hospital or in an outpatient/day unit. A minimum of 72 hours continuous, one to two times a month, in addition to regular use of subcutaneous deferoxamine has been recommended to increase iron removal. The continuous regimen alone may control liver iron concentration but will allow development of cardiac iron. Intravenous treatment is given at 50 to 100 mg/kg per day (with a maximum dose of 6 g per day). This regimen should be continued until the ferritin level is less than 2,000 ng/mL on two consecutive occasions. Alternative regimens include daily intravenous administration of deferoxamine, or continuous deferoxamine via percutaneous line or an indwelling venous access device. In all such treatment, high-dose, continuous treatments require careful monitoring for signs of toxicity.
Combination therapy of deferoxamine and deferasirox is presently being studied in North America. In over 30 patients followed for over one year, combination therapy appeared safe and effective in lowering body and cardiac iron. Larger multicenter trials are now underway.
Combination therapy with deferoxamine and deferiprone is increasingly being used worldwide. Treatment protocols include both sequential and simultaneous administration of both drugs. Pilot studies show that sequential therapy (for example, three days of deferoxamine and four days of deferiprone) appears to improve compliance and maintain iron levels. Simultaneous therapy (both drugs daily) improves cardiac function better than either drug alone. Careful monitoring for increased side effects is imperative.