Page 1787 - Hematology_ Basic Principles and Practice ( PDFDrive )

C H A P T E R 103

OVERVIEW AND CHOICE OF DONOR OF HEMATOPOIETIC

STEM CELL TRANSPLANTATION

Helen E. Heslop

Since the first hematopoietic stem cell transplants (HSCTs) were Other determinants include minor histocompatibility antigens,
performed more than 50 years ago, this modality has become a which are naturally processed peptides derived from normal cellular
well-established therapeutic option for many hematologic malignan- proteins that can stimulate an MHC-restricted response when dif-
cies as well as for bone marrow (BM) failure states, immune deficien- ferent polymorphisms are present in donor and recipient. Natural
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cies, and inborn errors of metabolism (Table 103.1). The wider killer (NK) cells may also contribute to alloreactivity, particularly in
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application of allogeneic transplantation has been possible because of the setting of haploidentical transplantation (Chapter 101). There
increased knowledge of the genetic basis of histocompatibility and is also increasing evidence that genetic loci outside of the MHC
advances in molecular methodology to more accurately type donors may influence the risk of transplant complications such as infection
and recipients. In addition, the development of large donor registries or regimen-related mortality, and several groups have undertaken
and cord blood banks has expanded access to transplant as well as genome-wide association assays to define genetic variants that might
increasing the likelihood that a recipient will find a well-matched predict these complications. 6
donor. 3
Over the last 20 years, there has also been identification of addi-
tional sources of stem cells so that BM, peripheral blood (PB), and Donor Choice
umbilical cord blood (UCB) are all widely used in clinical practice
to provide long-term hematopoietic reconstitution. The increasing The choice of donor for an allogeneic HSCT depends on several
use of reduced-intensity conditioning regimens has made transplant factors, including donor choices, the urgency of the transplant, and
an option for older patients and patients with comorbidities. Finally, the patient’s disease status. The optimal donor is a matched sibling
there have been improvements in graft-versus-host disease (GVHD) sharing HLA class I and HLA class II alleles, but because each child
prophylaxis and supportive care during the period of hematopoietic inherits one set of paternal and one set of maternal HLA antigens,
and immune suppression after transplant. Allogeneic HSCT should the likelihood of any sibling matching is only 25%. For patients who
therefore be considered for patients in whom this procedure is likely lack such donors, other options include a closely matched unrelated
to result in superior long-term disease-free survival (DFS) compared or cord donor or a haploidentical family member. Development of
with other therapeutic modalities. Potential candidates must also have high-resolution molecular tissue typing methods and establishment
a suitable source of hematopoietic stem cells (HSCs) available at an of large donor registries have facilitated transplants from closely
appropriate time in the course of the disease. HLA-matched unrelated donors. These volunteer donors are healthy
This chapter provides an overview of HSCT procedures, includ- individuals between 18 and 60 years of age who fulfill eligibility
ing conditioning regimens, selection of donor and HSC source, requirements similar to those applied to blood donors. With increas-
and common early and late posttransplant complications. These ing registry size, the chance of finding a donor has increased, so that
topics are discussed in depth in Chapters 104 to 109, and the disease more than 70% of Caucasian patients can identify an HLA-A, B, C,
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specific indications are discussed in the relevant disease chapters (see and DRB1 allele-matched unrelated donor. The likelihood of finding
Table 103.1 for details). Technical aspects of transplant, including a donor matching at these eight loci (or 10 loci if matching at DQB1
HSC harvesting and cell processing, are discussed in Chapters 95 is also included) varies for different ethnic groups and is less for
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and 97. groups with more polymorphism of HLA antigens. The initial
results of transplantation from unrelated donors were inferior to those
seen after matched sibling transplantation because of increased inci-
ALLOGENEIC TRANSPLANTATION dences of graft rejection and of GVHD caused by the greater genetic
disparity. Over the past decade, though, results have gradually
Allogeneic transplant is a potential treatment for patients with improved in both single-center and multicenter registry studies,
relapsed or high-risk hematologic malignancy as well as for patients reflecting better donor–recipient matching and advances in GVHD
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with inherited and acquired disorders of the hemopoietic and prophylaxis and supportive care. A recent study has examined donor
immune systems. The goal is to replace the recipient’s hemopoietic characteristics that predict outcome and found that after adjustment
and immune systems with normal HSCs from a closely matched for patient disease and comorbidities when the donor was a 10/10
donor whose hematopoietic stem and progenitor cells obtained from match, there was a significantly improved survival if the donor was
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donor BM or other sources can home to the recipient’s hematopoietic young (aged 18–32 years). Indeed for every 10-year increment in
microenvironment and engraft. The major criteria for choosing an donor age, there was a 5.5% increase in the hazard ratio for overall
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allogeneic donor is the degree of histocompatibility between the mortality. Overall donor age is the most important factor after
donor and recipient because the risks of both graft rejection and donor–recipient HLA match when selecting an unrelated donor.
of GVHD increase with the degree of genetic disparity. The most For a patient who lacks a matched sibling or 10/10 matched
important determinant of alloreactivity is matching at loci in the unrelated donor, the options are a mismatched unrelated donor, a
major histocompatibility complex (MHC) that includes human haploidentical donor, or a cord, and each choice has benefits and
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leukocyte antigens (HLA), encoded by class I (HLA-A, HLA-B, and disadvantages (Table 103.2). One limitation of unrelated donor
HLA-C) and class II (HLA-DR, HLA-DQ, and HLA-DP) genes. transplant is the time required to identify and screen an unrelated
HLA molecules were originally defined by serology, but molecular donor, which can be up to 3–6 months. Cord units by contrast can
testing is now routine because gene sequencing has revealed multiple be obtained within 1 week of identifying a suitable matched unit
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alleles for most serologically defined specificities (see Chapter 105). while almost everyone has a haploidentical donor who is usually
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