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Chapter 40 Thalassemia Syndromes 563

intermedia show a significant association between disease severity TABLE Indications to Initiate Regular Transfusion Therapy in
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and transfusion-free survival related to Hb F expression. An addi- 40.3 Nontransfusion-Dependent Thalassemia
tional locus highlighted by GWAS is the intergenic interval between
HBS1L and MYB. 400–403 More recently, it has been demonstrated that Declining hemoglobin with enlargement of the spleen
knockdown of c-Myb was associated with decreased expression of growth failure
404
KLF1. In conclusion, new key regulators of the globin switch have poor school performance
been identified that may be used to develop new and more powerful
drugs aimed at increasing Hb F synthesis. Pregnancy
Surgery
β-Globin Gene Transfer decreased exercise tolerance
failure of secondary sexual development
Cure of thalassemia by genetic transfer of the normal β-globin gene bony changes
into the pluripotent hematopoietic stem cell awaits further advances frequent hemolytic crisis (hemoglobin H disease)
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in molecular biology but is a goal of the foreseeable future. β-Globin
gene transfer and expression has been accomplished in thalassemia poor quality of life
murine models, which have demonstrated that retroviral vectors, Primary prevention and management of the following
specifically lentiviral vectors, are capable of transferring the human 1. thrombotic or cerebrovascular disease
β-globin gene sequences and its promoter regions into murine stem
cells 406,407 and into long-term repopulating hematopoietic cells of 2. pulmonary hypertension/heart failure
primates and humans. 408,409 Studies of safe and efficient specific tar- 3. extramedullary hematopoiesis
geting vectors in humans are ongoing. 410 4. leg ulcers
A total of seven thalassemia patients have been treated in three
published clinical trials of gene therapy. A phase I human gene
therapy clinical trial for hemoglobinopathies was initiated in France
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in 2007. This trial used a lentiviral vector that expresses an adult Certain patients have a milder clinical phenotype because they have
β-globin gene flanked by two copies of the 250-base-pair core of the coinherited a form of α-thalassemia or because they carry one (or
cHS4 chromatin insulator implanted in the U3 region of the 3′ long two) β-thalassemia chromosome(s) with a greater than usual potential
terminal repeat. After gene transfer, the patient became transfusion for high levels of γ-globin gene expression. 12–14
independent. However, the therapeutic Hb in this patient contrib- The ability to maintain a Hb level compatible with comfortable
uted only one-third of the total Hb synthesized; the embryonic and survival in the absence of regular transfusions is the generally accepted
fetal Hbs accounted equally for the remaining Hb. Therefore, the criterion for the diagnosis of thalassemia intermedia. In other words,
success of this first trial was made possible by the additive effect of distinguishing between thalassemia major and thalassemia interme-
transgenic β-globin chains synthesized by the vector and those (fetal dia, which in turn is the distinction between initiating a regular
and adult) made by the patient’s cells. Thus, without the support transfusion program or not, requires consideration of the Hb level
of endogenous Hbs, the gene transfer would not have allowed this and the quality of life (Table 40.3). These two parameters do not
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patient to become transfusion independent. Several clinical trials have a predictable relationship. Patients with thalassemia and Hb
of CD34+ modified autologous cells with lentiviral β-globin vectors levels of 7 g/dL may be relatively symptom free, but patients with
413
are currently ongoing and published results are eagerly awaited. Hb levels of 9 g/dL may have numerous problems related to IE.
It remains unclear the optimal method for stem cell mobilization Thus, the assessment of the patient rather than the Hb level alone is
and leukapheresis, whether granulocyte colony-stimulating factor or essential in deciding who does not require regular transfusions and
plerixafor are safe in thalassemia, and the appropriate long-term therefore, by definition, has thalassemia intermedia. Some nontrans-
follow-up strategies will be important. Alternatively, somatic cells fused patients have normal growth and sexual development, few
reprogrammed to induced pluripotent stem cells (iPSCs) might also medical problems, and normal or near-normal survival rates. However,
provide a possible new approach to treat β-thalassemia and sickle others develop disfiguring facial changes, markedly delayed growth
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cell disease. Currently, robust generation of iPSCs requires the and sexual maturation, heart failure, severe osteoporosis, repeated
introduction and integration of genes encoding the transcriptional fractures, arthritis, and massive splenomegaly. Calling the condition
factors OCT3/4, SOX2 with either KLF4 and c-MYC or NANOG of this latter group “thalassemia intermedia” implies a milder disease
414
and LIN28. 415–417 Ye and coworkers have shown that iPSCs can than thalassemia major but, in fact, the patients’ quality of life does
be generated from cells derived from skin fibroblasts, amniotic not compare favorably with the quality of life of patients with thalas-
fluid, or chorionic villus sampling of patients with β-thalassemia semia major. Nonetheless, many families and physicians are reluctant
and subsequently differentiated into hematopoietic cells that to initiate a chronic transfusion program because of concern about
synthesized Hb. Multiple clinical trials are currently underway using the risks of long-term transfusion therapy and the inevitable need for
both gene therapy and genome editing technologies as curative iron chelation therapy. If the decision is made to manage the patient
approaches for thalassemia major. initially without regular transfusions, regular reassessments of the
patient’s clinical condition, including appearance, growth, and
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development, and bone expansion are crucial. Short-term transfu-
Thalassemia Intermedia sion therapy may be useful during pregnancy or in the management
of cardiac and other serious complications. The need for regular
Approximately 10% of patients with homozygous β-thalassemia transfusions often develops in adults with thalassemia intermedia
exhibit a phenotype characterized by intermediate hematologic because of a further decline in the Hb level or a growing intolerance
1–4
severity. The balance of globin chain synthesis is better than in of the anemia. 424
typical thalassemia major because of a less severe defect in β-globin Even in the absence of regular transfusions, many patients develop
chain synthesis, a decrease in α-globin chain synthesis as well as progressive iron overload because of increased absorption of dietary
β-globin chain synthesis, or an increase in γ-globin chain synthesis. iron induced by IE and, in many cases, the intermittent administra-
For example, homozygous β-thalassemia in African Americans, Por- tion of RBC transfusions. By the third or fourth decade, the total
tuguese, and other populations may be relatively mild, at least for the iron burden may attain the levels seen in transfusion-dependent
425
first two decades of life. 418–420 Homozygotes or mixed heterozygotes for patients. Ferritin levels may underestimate the degree of tissue iron
forms of β-thalassemia associated with normal Hb A 2 and normal Hb loading in thalassemia intermedia, and assessment of LIC is more
F (silent carrier state) also tend to have mild to moderate disease. 421,422 helpful in determining the need for chelation therapy. Deferoxamine,