206 SURAKSHA AGRAWAL
predict GvHD and transplant outcome as unrelated people will have the same combination
compared to other methods like mixed lymphocyte of HLA types is very low. This problem is being
culture assay etc. solved by establishing registries containing large
HLA-A, B, and C locus antigens are numbers of volunteers who have had HLA typing
determined by a complement-dependent by blood tests and who have agreed to be
lymphocytotoxicity assay with a minimum of 144 available as a marrow donor if they have the same
to 216 different HLA alloantisera and monoclonal type of HLA molecules as someone who needs a
antibodies. These reagents, collectively, can transplant. A patient’s chance of finding a donor
identify over 60 different HLA antigens. HLA- who has the same combination of HLA types is
DR alloantigens are defined using DNA-based greatly increased by having a large number of
procedures. Currently, more than 200 HLA-DRB1 people in the registry. Even with registries
alleles or groups of alleles can be identified. For containing millions of donors, however, some
molecular typing genomic DNA is first isolated patients are not able to find a donor who is
and then amplified by the polymerase chain perfectly matched for all HLA molecules. In this
reaction (PCR) using several pairs of situation, transplantation must be done with a
oligonucleotide primers. donor whose HLA molecules are not all the same
It is highly desirable to evaluate all first as those of the recipient, even though this
degree blood relatives of the patient’s family, increases the chance of rejection or GvHD after
including parents, at the same time so that direct the transplantation.
comparisons of the data can be performed. It is
absolutely essential to identify the racial SOURCES OF STEM CELLS
background of the family and the relationship of
each member in relation to the patient. With this Majority of stem cell transplantations in
information, HLA genotyping results (with HLA thalassemias were performed by using HLA-
haplotype assignments) can be provided to the compatible sibling donor bone marrow. In recent
clinician, together with a narrative interpretation years, the source of stem cells have been extended
of the extent of HLA compatibility. to include peripheral blood stem cell (PBSC) and
The immune response against HLA cord blood stem cells (CBSC) for transplantation.
molecules can cause two types of problems after Since the first successful transplantation of CBSC
a bone marrow transplant. When the immune in a patient with Fanconi’s anemia (Gluckman et
system of the recipient responds against HLA al. 1989), more than 600 cord bloods have been
molecules of the donor, rejection can occur. used as a source of hemotopoietic stem cells for
When this happens, the normal marrow from the transplantation to treat a variety of malignant
donor is destroyed. Recent studies have shown and nonmalignant hematologic disorders.
that HLA-A, HLA-B, and HLA-C molecules of (Gluckman et al. 1989; Gluckman et al. 1997;
the donor are more likely to cause rejection than Rubinstein et al. 1998; Kelly et al. 1997).
HLA-DR or HLA-DQ molecules. When immune
cells of the donor respond against HLA PROGNOSTIC FACTORS FOR
molecules of the recipient, graft-versus-host OUTCOME AFTER BMT
disease (GvHD) can occur. When this happens,
the skin, liver, stomach and intestines of the The risk of BMT using an HLA-identical
recipient are injured. Recent studies have shown sibling donor could be predicted according to
that HLA-DR and HLA-DQ molecules of the the presence or absence of only three criteria:
recipient are more likely to cause GvHD that of hepatomegaly, evidence of portal fibrosis in the
HLA-A, HLA-B, and HLA-C molecules. The role liver on biopsy, and inadequate iron chelation
of HLA-DP molecules in marrow transplantation therapy (Lucarelli et al. 1990). Patients with none
is not yet known. of these risk factors can be categorized as class
The best way to prevent rejection and GVHD I, with one or two of these risk factors as class II,
is to ensure that the donor and recipient have and with all the three risk factors as class III.
the same types of HLA molecules. Because there When such type of analysis was performed in a
are so many different kind of HLA molecules, large series of patients it was seen that disease-
and because each kind of HLA molecule can have free survival was 94%, 77% and 53% in class I, II
many different types, the chance that any two and III, respectively (Lucarelli et al. 1990).
STEM CELL TRANSPLANTATION IN THALASSEMIA 207
CONDITIONING REGIMENS (<8 years) regain a normal growth rate after BMT,
while older children and children in class III,
Most BMT centers use a combination of especially those who developed chronic GvHD,
busulfan and cyclophosphamide for the often have severely impaired growth (Lucarelli
conditioning regimen, with cyclosporine +/- short et al. 1990). There are evidences that gonadal
course methotrexate as graft-versus host disease function of some patients who have undergone
(GVHD) prophylaxis. The most widely used BMT for thalassemia is impaired, but it is not
regimen is a total dose of 14 mg/kg of clear how much of this effect is a result of
cyclophosphsmide over the next 4 days (Lucarelli previous iron overload or a consequence of the
et al. 1990; Galimberti et al. 1997). This regimen is preparatory regimen (Giardini et al 1995). Indeed,
the most appropriate for patients with class I and successful pregnancy following BMT for
II disease. For those higher risk patients in class thalassemic, as well as following BMT got other
III (particularly for patients >17 years), a lower hematological disorders using busulfan/
dose of cylocphosphamide (120 – 160 mg/kg) is cylophosphamide conditioning, has been
recommended in order to reduce transplant reported, and no increase in congenital anomalies
related mortality (Lucarelli et al. 1996), although of the resultant offspring has yet been seen (De
this is likely to be at the expense of an increased Sanctis et al. 1991; Borgna-Pignatti et al. 1996).
chance of graft rejection. On the other hand, to
overcome the risk of graft rejection in poor-risk CONCLUSION
class III patients, some centers use either 16 mg/
kg or 600 mg/m2 of busulfan especially in children The beneficial results of stem cell
with markedly expanded abnormal erythropoiesis transplantation from HLA identical family
(Lucarelli et al. 1996; Issargrisil et al. 1997). The members for patients with severe thalassemia are
addition of antilymphocyte globulin (ALG) / clear. Class I patients have a very high probability
antithymocyte globulin (ATG) or Campath to the of cure with a very low early and late morbidity
pre-BMT preparative regimen effectively have and mortality. Delay of transplantation until the
reduced the rate of graft rejection in many trials patient is in a risk category beyond class I
(Galimberti et al. 1997; Krishnamorrthy et al. 1999; substantially reduces the probability of transplant
Souillet et al. 1995; Roberts et al. 1995). success and jeopardizes the reversibility of liver
and cardiac damage. It is reasonable to suggest
LONG-TERM CONSEQUENCES that patients with β-thalassemia who have HLA-
identical donors should be transplanted as soon
For thalassemic patients who have as possible. Umbilical cord blood (UCB) has been
undergone BMT and acquired normal shown to be capable of reconstituting the bone
hematologic status post transplant, the term marrow of the patient with thalassemia after
“exthalassemic after transplant” has been myeloablated pre-conditioning treatment. The
proposed by Lucarelli (Lucarelli et al. 1996). The major advantage of UCB over other sources of
long-term consequences in these ex-thalassemics stem cells is the ability to cross HLA barriers,
include both the complications associated with and there is evidence of less GVHD. The use of
the underlying disease and those that arise from related –donor UCB stem cells with HLA
the allogeneic stem cell transplantation. Virtually mismatches at one to three antigens needs to be
all “ex-thalassemic” patients have moderate- considered. It would be worth while to do a
severe iron overload (Li et al. 1997). In order to prospective study to evaluate the role of UCB
prevent progressive cardiac and hepatic damages stem cell transplantation in the treatment of the
in patients who maintain high levels of iron thalassemias and hemoglobinopathies.
overload, it is now recommended that these REFERENCES
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