Page 653 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 40 Thalassemia Syndromes 555

phase reactant and may be influenced by inflammation, vitamin C
Benefits of Iron Chelation Therapy
deficiency, hepatitis, and other infectious states. Transferrin satura-
More than 30 years of experience using iron chelation therapy with tion is not very useful in evaluating the severity of iron overload in
deferoxamine in thalassemia major patients have demonstrated that: patients with thalassemia because the massive IE usually results in a
1. Liver iron concentrations can be maintained at normal or mildly transferrin saturation greater than 60% even in the absence of iron
elevated levels. overload. 142
2. Hepatic fibrosis is slowed or prevented.
3. The risk of iron-induced cardiac disease, including heart failure
and serious arrhythmias, is markedly decreased. Deferoxamine
4. Normal growth and sexual development are common but not
universal. Deferoxamine mesylate is a naturally occurring hexadentate sidero-
5. Long-term survival is substantially improved. These benefits are
directly related to compliance and generally require the prolonged phore isolated from cultures of Streptomyces pilosus introduced in
administration of daily iron chelation therapy. 1960. Deferoxamine has a high molecular weight of approximately
6. Long-term safety and efficacy studies of the oral iron chelators 600 g/mol, is poorly absorbed by the gastrointestinal tract, and is
deferiprone and deferasirox are ongoing, and new formulations rapidly removed from the plasma. It has a relatively short half-life of
are in development. 8 to 10 minutes, which necessitates intravenous or subcutaneous
administration. It is highly specific for iron and is associated with
143
relatively low toxicity. Deferoxamine enters cells, chelates iron, and
appears in the serum and bile as the iron chelate product, ferrox-
144
“labile iron pool” 122,123 and from nontransferrin-bound plasma amine. Deferoxamine chelates iron released by the RES after the
145
iron. 124,125 catabolism of senescent RBCs and is excreted in the urine. Unbound
deferoxamine is absorbed by the hepatic parenchymal cells and che-
lates iron from the intracellular pool which is excreted in bile.
Assessment of Iron Stores Approximately one-half to two-thirds of the iron excreted in response
146
to deferoxamine is in the stool, with the remainder in the urine.
Because excess transfusional iron cannot be actively excreted, it is These proportions vary from patient to patient and at different levels
deposited in the macrophages of the reticuloendothelial system of iron overload, dose of deferoxamine, and endogenous erythropoi-
(RES). When the RES is overwhelmed, iron spills over into paren- etic activity. 147
chymal tissue, generating free radical damage with cellular membrane Iron excretion after the administration of deferoxamine is propor-
lipid peroxidation and leading to end-organ dysfunction, especially tional to body iron stores. To achieve negative iron balance, the
of the liver, endocrine system, and myocardium. chelating agent must cause the daily excretion of 0.3–0.6 mg/kg of
Chelation therapy is initiated after approximately 10 to 25 units iron. In the 1960s, deferoxamine was initially administered by daily
of blood have been transfused, serum ferritin levels are above intramuscular injections of 0.5 g, which led to reduced rates of
1000 mg/mL, and liver iron concentration (LIC) is greater than 3 mg hepatic iron accumulation and hepatic fibrosis in patients with thalas-
Fe/g dry weight. semia. 148,149 However, intramuscular injections proved to be too
Measurement of LIC by biopsy provides a direct assessment of painful and were insufficient to achieve negative iron balance. In the
tissue iron loading and reflects total body iron stores but liver biopsy mid-1970s, it was demonstrated that iron excretion with deferox-
requires a skilled technician, at least 1 mg of tissue at least 2.5 cm in amine at 20–60 mg/kg/d was markedly enhanced and negative iron
length with five portal tracts, and has the risk of hemorrhage and balance was attained by continuous, prolonged 24-hour intravenous
sampling error. The use of magnetic resonance imaging (MRI) to or 8- to 12-hour subcutaneous infusions administered via a light-
estimate hepatic and cardiac iron in patients with transfusional sid- weight battery-operated or balloon-driven pump. 150,151 In addition,
erosis has largely replaced liver biopsy for LIC quantification. MRI maintaining normal ascorbic acid levels optimizes iron excretion
with proton transverse relaxation rates (R2) with spin-echo imaging, because it increases tissue iron turnover in the plasma.
signal intensity ratios, and gradient-echo T2* is currently the pre- A pump infuses an aqueous solution of deferoxamine through a
ferred method to assess LIC. 126–130 Direct comparisons with hepatic small 27-gauge butterfly needle placed under the skin of the abdomen,
152
tissue samples demonstrate significant correlations (r = 0.97) with thigh, or extremities. Most patients use the pump during sleep.
biopsy-measured LICs. 127,129–133 . Values between 3 and 7 mg Fe/g dry Bolus subcutaneous injections of deferoxamine used twice daily
weight appear to be associated with minimal toxicity, while LIC levels induce levels of urinary iron excretion comparable with subcutaneous
greater than 15 mg Fe/g dry weight are associated with a greater risk infusions and may prove helpful as a respite from overnight infusions
134
of iron-induced heart disease. Experience with cardiac MRI sug- in some patients not adherent to prolonged infusions. 153,154 In patients
gests that changes in T2* reflect levels of iron in the heart and may who are poorly compliant with subcutaneous therapy, administration
predict adverse changes in cardiac function. Cardiac T2* values are of deferoxamine in normal or higher doses can be accomplished
135
predictive of arrhythmias and cardiac value over 1 year. Cardiac intravenously by means of a deep line indwelling catheter, external-
MRI T2*-directed treatment results in improved chelation and iron ized venous catheter, or subcutaneous port. Continuous intravenous
136
stores. MRI assessment of iron overload cannot be used in patients administration of deferoxamine is particularly useful for rapidly
with pacemakers or those who are claustrophobic. Future MRI use lowering the total iron burden and is used for reversal of cardiac
may involve the quantification of iron concentration of endocrine morbidity (e.g., cardiac arrhythmias or left ventricular dysfunction).
glands to predict or monitor dysfunction. 137–139 Complications of indwelling catheters, including infection and
Measurements of LIC by magnetic susceptometry using a super- thrombosis rates, have been reported at 1.2 and 0.5 per 1000 catheter
conducting quantum interference device (SQUID) also correlate well days, respectively, in patients treated over 1 to 5 years.
with biochemical measurements of tissue iron. 140,141 At present, The optimal age for beginning parenteral or oral iron chelation
measurement of tissue iron by SQUID is limited to the liver, and the therapy in patients with thalassemia has not been established with
instruments are available in only a few sites in the United States of certainty. The surprisingly high LICs that have been found in some
America and Europe. Importantly, the SQUID is not an enclosed patients with thalassemia within the first 2 to 3 years of transfusion
space, so claustrophobia is not an issue. therapy, occasionally accompanied by histologic finding of fibrosis,
Serum ferritin levels are safe, inexpensive, and readily available, provided the rationale for the early initiation of deferoxamine iron
and serial measurements are predictive both of critical complications chelation. 155,156 Regular deferoxamine chelation therapy begun after
such as iron-induced heart disease and of adverse effects of chelation the age of 3 to 5 years seems capable of removing previously stored
104
therapy such as impairment of vision and hearing. However, single iron and preventing iron-induced liver disease. Data show that
ferritin levels may correlate poorly with LIC because it is an acute deferoxamine started by the age of 2 to 4 years forestalls significant