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752 Part VI: The Erythrocyte Chapter 48: The Thalassemias: Disorders of Globin Synthesis 753

be controlled, at least in part, by including 5 to 10 mg hydrocortisone maintained at less than 1500 mcg/L. The value of hepatic iron concentra-
in the infusion. Probably of greatest concern is neurosensory toxic- tion assessment was discussed earlier in “Abnormal Iron Metabolism.”
ity, which has been documented in up to 30 percent of cases. Toxicity Newer noninvasive approaches to assessing body iron burden have been
causes high-frequency hearing loss that may become symptomatic. 262,263 developed. There is now strong evidence that, with adequate calibra-
In a few cases, the toxicity did not respond to discontinuation of the tion, the measurement and mapping of liver iron concentrations using
drug, and permanent hearing loss resulted. Ocular toxicity has been magnetic resonance imaging (MRI) is an extremely effective approach
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reported. Symptoms include visual failure, night and color blindness, for the regular assessment of the effectiveness of chelation therapy.
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and field loss. Reversal of symptoms after discontinuation of the drug Similarly, there have been advances in the noninvasive estimation of
has been reported. Deferoxamine may cause bone changes and growth myocardial iron using T2* MRI. Evidence obtained using this approach
retardation, sometimes associated with bone pain. Body measurements suggests that there may be a variable correlation between hepatic and
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characteristically show a reduced crown-pubis–to–pubis-heel ratio. cardiac iron concentrations. Clearly functional cardiologic studies
These changes may be associated with radiologic abnormalities of the should be combined with assessment of cardiac iron levels, particularly
vertebral column. These complications can be prevented by exercising the ejection fraction, pulmonary artery pressure, and other parameters
extreme care in monitoring patients receiving long-term deferoxamine of cardiac activity. The true value of these new approaches to assessing
therapy. Young children or individuals from whom most of the iron has myocardial iron levels and function still require further study by pro-
been removed by chelation are at particularly high risk. Formal audi- spective controlled trials.
ometry and ophthalmologic examinations at 6-month intervals are Increasing evidence indicates children maintained at a high hemo-
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recommended. globin level do not develop hypersplenism. However, enlargement of
Because of the practical difficulties of a nightly subcutaneous the spleen with increased transfusion requirements occurs commonly
infusion of deferoxamine there has been an intensive search for effec- in patients maintained at a lower hemoglobin level. Splenectomy should
tive oral chelating drugs. Two of these agents are currently available, be performed if transfusion requirements increase dramatically or pain
deferiprone (Ferriprox, L1) and deferasirox. The extensive literature on develops because of the size of the spleen. Because of the risk of over-
these agents has been reviewed. 265–267 Deferiprone is administered at a whelming pneumococcal infections, splenectomy should not be per-
dosage of 75 mg/kg in three daily doses. Unfortunately there have been formed in children younger than age 5 years. Patients should receive
limited numbers of long-term trials comparing its efficacy with deferox- a pneumococcal vaccine prior to the procedure. They then should be
amine, but overall it appears to be less effective than deferoxamine at placed on prophylactic oral penicillin after the operation. Haemophilus
maintaining safe body iron levels. Its administration is accompanied by influenzae type B and meningococcal vaccines also are recommended.
a number of complications, the most important of which is neutrope- Children with severe thalassemia are still prone to other infec-
nia and, in some cases, agranulocytosis with some fatalities. Hence it tions. Presentation with abdominal pain, diarrhea, and vomiting should
is recommended that patients receiving this agent have a weekly white always suggest an infection with a member of the Yersinia class of bacte-
cell count. It also causes arthritis which varies in severity and between ria. Empirical treatment should start immediately with either an amino-
different ethnic groups. However, by virtue of its membrane-crossing glycoside or a cotrimoxazole. Transfusion-transmitted virus infection
capacity it has been suggested that it may be more effective in remov- is common in some populations. All chronically transfused patients
ing cardiac iron (Chap. 43). Unfortunately, to date, all the studies that should be tested annually for hepatitis C, hepatitis B, and HIV. Patients
suggest that it may reduce the frequency of cardiac complications in with serologic evidence of chronic active hepatitis should be considered
transfusion-dependent thalassemics have been retrospective and there for treatment.
are no long-term controlled data available. It is currently suggested that As mentioned earlier in “Abnormal Iron Metabolism,” subtle
it should be used in combination with desferrioxamine, particularly for endocrine deficiencies are increasingly recognized, particularly those
its cardiac-iron sparing effect; again, long-term prospective data are associated with growth retardation and hypogonadism. These patients
required. require expert endocrinologic assessment and replacement therapy
The initial studies of deferasirox were promising and suggested when appropriate.
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that this agent in doses of 5 or 10 mg/kg per day, or higher in those
who are heavily iron-loaded, was as effective as desferrioxamine in con-
taining adequate hepatic iron levels. Preliminary clinical studies also STEM CELL TRANSPLANTATION
showed that this agent may be effective for removing excess cardiac By 1997, more than 1000 marrow transplants had been performed at
iron. Recent followup data have confirmed these early observations. three centers in Italy. 273–276 Based on this experience and on later data,
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The most frequent adverse reactions to deferasirox included gastroin- the prognosis evidently depended on the adequacy of iron chelation up
testinal disturbances, transient rashes, and a nonprogressive increase in to the time of transplantation. Hence, patients were divided into three
serum creatinine. It is still too early to be sure about the overall effec- classes: class I patients had a history of adequate iron chelation and nei-
tiveness of this agent, however, or to assess its long-term safety. ther liver fibrosis nor hepatomegaly; class II patients had one or two
Because of the extremely well-documented data showing long- of these characteristics; and class III patients had all three character-
term survival of patients adequately treated with deferoxamine, 268–270 istics. Among children in class I who had undergone transplantation
this agent is still recommended as a first-line choice for management early in the course of the disease, disease-free survival was assessed at
of transfusion-dependent thalassemia. However, particularly in view of 90 to 93 percent at 5 years, with a 4 percent risk of mortality related
problems of compliance and the promising trial results of deferasirox, to the procedure. For class II patients, the intermediate-risk group, the
this drug is also being used increasingly as a first line form of treatment. survival and disease-free survival rates were 86 percent and 82 percent,
Further long-term follow up data regarding its efficacy are still required respectively. For class III, the high-risk group, the survival and disease-
however. free survival rates were 62 percent and 51 percent, respectively. Apart
Careful monitoring of the degree of iron accumulation during from the immediate complications of severe infection in the posttrans-
chelation therapy is absolutely vital. The simplest approach, partic- plantation period, most of the problems were related to development
ularly in countries where most sophisticated technology is not avail- of acute or chronic graft-versus-host disease. The overall frequency of
able, is a regular estimation of the serum ferritin level, which should be mild to severe grades ranges from 27 to 30 percent. Modification of
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