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

preparative drug regimens has reduced the frequency of drug toxicity. include various cytotoxic drugs, erythropoietin, and several different
The occurrence of mixed chimerism may be a risk factor for graft-ver- butyrate analogues. Overall, these agents, used alone or in combination,
sus-host disease. No case of hematologic malignancy has been observed have produced some small effects on fetal hemoglobin production, but
in the longest followup of patients between 15 and 20 years after trans- the results of these trials have been disappointing. Some notable excep-
plantation. Recent experience has fully confirmed these pioneering tions were seen, however, particularly several cases of homozygosity
278
studies and suggests that patients without matched donors could ben- or compound heterozygosity for hemoglobin Lepore in which use of
efit from haploidentical mother-to-child transplantation. The current either a combination of sodium phenylbutyrate and hydroxyurea or
status of blood stem cell therapy is discussed further in Chap. 23. hydroxyurea alone produced a spectacular rise in hemoglobin F pro-
duction. In the case of two homozygotes for hemoglobin Lepore, the
GENERAL CARE necessity for further transfusion was eliminated. This finding raises
283
Management of thalassemia requires a high standard of general pediat- the intriguing possibility that certain mutations, possibly deletions of
ric care. Infection should be treated early. If the diet is deficient in folate, the β-globin gene cluster, are more susceptible to this type of approach.
supplements should be given. Supplementation probably is unneces- Recent progress in searching for genetic targets for modifying fetal
42
sary in children maintained on a high-transfusion regimen. Particular hemoglobin synthesis has been reviewed recently.
attention should be paid to the ear, nose, and throat because of chronic The other experimental approach involves somatic gene therapy.
sinus infection and middle-ear diseases resulting from bone deformity Currently, the therapy is mainly directed at gene transfer into potential
284
of the skull. Similarly, regular dental surveillance is essential because hematopoietic stem cells using retroviral vectors. Other approaches
poorly transfused thalassemic children have a variety of deformities of also are being taken, including attempts at the restoration of normal
285
the maxilla and poorly developed teeth. In the later stages of the illness, splicing in cases of splicing mutations and use of trans-splicing
286
when iron loading becomes the major feature, endocrine replacement ribozymes to correct β-globin gene transcripts. However, studies
therapy may be necessary. Symptomatic treatment for metabolic bone using murine models with recombinant lentiviral vectors suggest that
disease and cardiac failure also may be needed. sustained, high-level globin gene expression may be possible, at least
in this experimental system. 287,288 There continues to be slow progress
toward somatic-cell gene therapy as applied to the hemoglobin disor-
THERAPIES OF SPECIAL TYPES OF ders, with at least one apparent success and future plans for several
289
THALASSEMIA clinical trials.
Hemoglobin H disease usually requires no specific therapy, although
splenectomy may be of value in cases associated with severe anemia and PROGNOSIS
splenomegaly. 7,9,10 Because splenectomy may be followed by a higher
incidence of thromboembolic disease than occurs in splenectomized The prognosis for patients with severe forms of β-thalassemia who
children with β-thalassemia, the spleen should be removed only in are adequately treated by transfusion and chelation has improved dra-
7
cases of extreme anemia and splenomegaly. Oxidant drugs should not matically over the years. Three large studies investigated the influence
be given to patients with hemoglobin H disease. The management of of effective long-term desferrioxamine use on the development of car-
symptomatic sickle cell thalassemia follows the lines described for sickle diac disease. 268–270 In one study, patients who had maintained sustained
cell anemia (Chap. 49). reduction of body iron, as estimated by a serum ferritin level less than
Thalassemia intermedia presents a particularly complex therapeu- 2500 mcg/L over 12 years of followup, had an estimated cardiac disease-
tic problem. Whether a child with a steady-state hemoglobin level of free survival rate of 91 percent. This finding is in contrast to patients in
6 to 7 g/dL should be transfused is difficult to determine with certainty. whom most determinations of serum ferritin level exceeded this value,
Probably the best compromise is to watch such children very closely in whom the estimated cardiac disease-free survival rate was less than 20
during the first years of life. If they grow and develop normally and no percent. In a second study, the relationship between survival and total-
signs of bone changes are evident, they should be maintained without body iron burden was measured directly using hepatic storage iron val-
transfusion. If, however, their early growth pattern is retarded or their ues. Patients who had maintained hepatic iron concentrations of at least
activity is limited because of their anemia, they should be placed on 15 mg of iron per gram of liver, dry weight, had a 32 percent probability
a regular transfusion regimen. If hypersplenism plays a role in their of survival to age 25 years. No cardiac disease developed in patients who
anemia as the children grow older, splenectomy should be performed. maintained hepatic iron levels below this threshold. These and other stud-
Because many of these patients have significant iron loading from the ies provide unequivocal evidence that adequate transfusion and chelation
gastrointestinal tract, regular estimations of serum iron and ferritin are associated with longevity and good quality of life. On the other hand,
should be obtained and chelation therapy instituted when appropriate. poor compliance or unavailability of chelating agents still are associated
with a poor prospect of survival much beyond the second decade.
EXPERIMENTAL APPROACHES TO TREATMENT
Two main experimental approaches are being pursued in the search for PREVENTION
more effective therapy of the thalassemias: (1) reactivation or augmen- In parts of the world where the incidence of thalassemia is high, the dis-
tation of fetal hemoglobin production and (2) somatic gene therapy. ease places an immense economic burden on society. For example, if all
The main rationale for employing agents that have been used in the thalassemic children born in Cyprus were treated by regular blood
attempts to increase hemoglobin F production is based on the obser- transfusions and iron-chelating therapy, it was estimated that within 15
vation that patients recovering from cytotoxic drug therapy or during years the total medical budget of the island would be required to treat
other periods of erythroid expansion may reactivate hemoglobin F syn- this single disease. Clearly, this approach was not feasible, so consid-
290
thesis. In addition, the observation that butyrate analogues might have erable effort was directed toward developing programs for prevention of
a stimulating effect on hemoglobin F production has led to a number the different forms of thalassemia.
of studies of their potential for management of thalassemia. A number The goal of prevention can be achieved in two ways. The first is pro-
of clinical trials have been performed. 279–282 Agents that have been used spective genetic counseling, that is, screening total populations while

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