Page 1804 - Hematology_ Basic Principles and Practice ( PDFDrive )

C H A P T E R 105

UNRELATED DONOR HEMATOPOIETIC CELL TRANSPLANTATION

Effie W. Petersdorf and Claudio Anasetti

The outcomes of unrelated donor hematopoietic cell transplantation growth in registry size worldwide has increased the chances that
(HCT) have greatly improved as a result of better understanding of well-matched donors can be identified. The NMDP registers 52,000
the diversity of genes that give rise to host-versus-graft (HVG) and new donors each month (http://www.bethematch.org). Today, more
graft-versus-host (GVH) allorecognition. Development of robust than 10.5 million donors are available through the NMDP, and
typing methods that define functional variation of human leukocyte more than 25 million donors are available through international
antigen (HLA) genes have greatly accelerated understanding of cooperative agreements with registries around the world (http://
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gene−gene interactions that lead to graft failure, graft-versus-host www.worldmarrow.org). With this database of 25 million donors,
disease (GVHD), and graft-versus-leukemia (GVL). Continued North American white patients have a 75% chance of identifying an
growth of registries of volunteer donors worldwide now provides the unrelated donor matched at HLA-A, HLA-B, HLA-C, and HLA-
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potential for identifying suitable donors for up to 75% of white DRB1 (HLA “8/8”). This number increases to 97% if the donor
patients in need of a transplant. The major challenges are to increase selection criteria are relaxed to accommodate one HLA mismatch
the safety and efficacy of unrelated donor HCT therapy through (HLA “7/8”). The situation is not as favorable for patients of non-
improved prevention and treatment of GVHD while leveraging European white background. For African Americans, the likelihood
control of leukemia through GVL effects. For unrelated HCT to be of finding an HLA 8/8–matched donor is only 19% but improves to
more widely applied to patients of diverse ethnic and racial back- 76% with HLA 7/8 donors. These statistics emphasize that although
grounds, more information on permissible HLA mismatches is the total number of donors is climbing, the challenges for the future
needed so that mismatched donors can be safely used when matched remain achieving the ideal optimal registry size and composition to
donors are not available. This chapter chronicles genotyping methods improve the odds that every patient in need of a transplant has at
used for donor selection and the clinical results of unrelated donor least one suitable donor.
HCT in the era of DNA typing for HLA genes. The availability of HLA-matched donors is only one potential
barrier to transplantation for patients. In a single center study of 531
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DONOR IDENTIFICATION AND LIKELIHOOD OF patients who initiated a search for an unrelated donor, an 8/8
HLA-A, HLA-B, HLA-C, HLA-DRB1−matched donor was avail-
TRANSPLANTATION able for 54% of these patients; a further 30% had a donor with a
single HLA mismatch, and 16% had no suitable donor. Factors that
The field of unrelated donor HCT has witnessed a rapid growth over increased the chances of a patient undergoing unrelated donor
the past 25 years. Data from the Center for International Bone transplantation included race (white patients are more likely; p = .03),
Marrow Transplant Research (CIBMTR) show that among all allo- younger age (p = .01), lower disease risk (p = .005), and availability
geneic transplantations performed in the United States, the number of an HLA 8/8–matched donor (p = .005; Box 105.1). The reasons
of transplants from unrelated donors has exceeded that from related for patients not pursuing transplant can be varied, but most often are
donors since 2006 (http://www.CIBMTR.org). Similar statistics caused by disease progression, alternative treatment plan choices, and
from the European Group for Blood and Marrow Transplantation medical ineligibility. Having a suitable donor not only allowed
show that 52% of all allogeneic transplants are performed with patients to reach transplantation but also improved the overall survival
unrelated donors (http://www.ebmt.org). The primary indications of patients with good performance status, compared with not having
for unrelated donor HCT are acute myeloid leukemia, myelodysplas- a suitable donor. 3
tic syndrome/myeloproliferative disorders, acute lymphoblastic leu-
kemia, non-Hodgkin lymphoma, and other nonmalignant disorders.
Between 2002 and 2006, patients older than 60 years of age com- DONOR EVALUATION AND SELECTION
prised the fastest growing group of transplant recipients as a result of
the introduction of nonmyeloablative and reduced-intensity condi- Selection of unrelated donors includes consideration for the level of
tioning regimens (http://www.CIBMTR.org). the HLA tissue-type match with the recipient and the presence of
Unrelated HCT has been made feasible by the establishment of recipient antidonor HLA antibodies, which place the patient at high
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registries of volunteer donors worldwide. The Anthony Nolan Appeal risk for nonengraftment in the setting of HLA mismatching. One
was the first effort to demonstrate the feasibility of donor recruit- of the earliest studies to highlight the importance of anti-HLA
ment. Now known as the Anthony Nolan Research Institute, this antibodies in nonengraftment found an over twofold higher risk of
registry was the first to promote access to HLA-matched bone marrow graft failure after haploidentical related donor transplantation when
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(BM) donors for patients around the world. In the United States, the patient possessed antidonor lymphocytoxic antibodies. More
early efforts for donor recruitment were spearheaded by individual recently, anti−HLA-DP antibodies were associated with graft failure
centers. Growing interest in unrelated donor HCT led the US after transplantation from otherwise HLA-A, HLA-B, HLA-C,
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Congress to authorize the creation of a national registry comprising HLA-DR, HLA-DQ−matched unrelated donors. The increased
a network of donor centers, transplant centers, and a national coor- utilization of cord blood sources for stem cells in transplantation has
dinating center through the Transplant Act of 1984. Two years later, prompted evaluation of the role of anti-HLA antibodies in cord
a federal contract to establish a national registry was awarded to the blood, and the experience has paralleled that of unrelated donor
National Marrow Donor Program (NMDP). In the Netherlands, transplantation. 7–11 Collectively, this experience has led to the formu-
Professor Jon J. van Rood led the Europdonor Foundation in the lation of strategies for antibody screening before allogeneic
collection of HLA data from donor registries around the world and transplantation. 12
in the formation of a database of HLA phenotypes known as Bone Evaluation of unrelated donors includes a screening medical
Marrow Donors Worldwide (http://www.bmdw.org). Continued history, physical examination, and laboratory testing for risks

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