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Unrelated Donor StemCell Transplantation: The Role of the National Marrow Donor Program

Unrelated Donor StemCell Transplantation: The Role of the National Marrow Donor Program

Approximately 70% of patients
with life-threatening diseases
treatable with allogeneic blood
stem cell transplantation do not have
matched related donors. The National
Marrow Donor Program (NMDP) was
established in 1986 to provide human
leukocyte antigen (HLA)-matched,
volunteer unrelated donors for these
patients. The NMDP performs this
task by maintaining a registry of more
than 4.9 million volunteer donors of
marrow and peripheral blood stem
cells (PBSC) and 12 cord blood banks
containing more than 25,000 units of
umbilical cord blood.

Background

The NMDP is a nonprofit organization
that operates the congressionally
mandated National Bone Marrow
Donor Registry under contract from
the Health Resources Services Administration,
a division of the US Department
of Health and Human
Services. The NMDP Registry is the
largest, most diverse registry of potential
hematopoietic stem cell donors
in the world. To carry out its mission
of providing HLA-matched stem cells
for patients, the NMDP operates a
worldwide network of medical organizations
that cooperate together to locate,
procure, and transport stem cells
to waiting patients.

The wide range of medical organizations
in the NMDP network are
shown in Table 1. The NMDP also
provides resources for patients and physicians,
collects patient outcome data,
and conducts research to improve the
outcomes of stem cell transplantation.

A graphic representation of the
NMDP network is shown in Figure 1.
The national coordinating center of the
NMDP, located in Minneapolis, Minnesota,
houses the computerized NMDP
registry of unrelated stem cell donors,
including data on the inventories of
NMDP-affiliated cord blood banks.
Searches of the NMDP Registry for
HLA-matched donors or umbilical
cord blood units are accomplished
through secure electronic communications
between the NMDP and its
network of donor centers, apheresis
centers, collection centers, transplant
centers, and HLA laboratories.

The NMDP Registry
Stem cell transplants, whether related
or unrelated, require precise
HLA matching between donor and
patient. Because HLA antigens are
inherited, patients are more likely to
find a matching donor within their
own racial or ethnic communities. To
provide patients of every ethnic community
a better chance at finding a
matched donor, the NMDP has ongoing
recruitment programs to bring
more African-American, American
Indian/Alaska Native, Asian/Pacific
Islander, and Hispanic donors to the
NMDP Registry. Currently, approximately
31% of the volunteer donors
listed in the NMDP Registry are from
racial and ethnic minority groups.

NMDP Cord Blood Program
The NMDP currently lists more than
25,000 units of donated umbilical cord
blood from a growing partnership with
cord blood banks. The addition of cord
blood banks to the NMDP Network
was vital to provide more transplant
options for patients. All cord blood units
at NMDP cord blood banks are listed
in the NMDP Registry and are automatically
included in every patient
search. The NMDP's cord blood program
is a clinical trial developed in
1998 under an Investigational New
Drug application (IND) with the US
Food and Drug Administration (FDA).
The NMDP continues to work with
existing cord blood banks to establish
new contacts and list more cord blood
units in the NMDP Registry.

NMDP Office of Patient Advocacy
The NMDP's Office of Patient
Advocacy (OPA) works with patients
to remove barriers to obtaining an unrelated
donor transplant. The OPA
connects patients to transplant-related
resources, helps patients find a transplant
center, and assists them with
financial and insurance matters. In
addition, the OPA assists patients, their
families, and physicians with any concerns
or questions they may have regarding
an NMDP-facilitated search
and stem cell transplant.

NMDP Research Program
The NMDP collects detailed medical
data on patients who receive a
transplant from an NMDP donor.
These data are part of a comprehensive
research database the NMDP
maintains to assist medical researchers
in the field of unrelated stem cell
transplantation. The NMDP research
program develops and promotes research
aimed at increasing opportunities
for and improving outcomes of
unrelated donor stem cell transplants.
NMDP resources available to researchers
include:

  • The largest database of HLAtyped
    individuals in the world (more
    than 4.9 million volunteer donors).
  • Outcome, histocompatibility
    data, donor search, and donation sideeffects
    data on approximately 90% of
    the more than 16,000 unrelated donor
    stem cell transplants the NMDP has
    coordinated since 1987.
  • The largest unrelated stem cell
    donor and recipient HLA database in
    the world (more than 7,600 paired
    samples).

The NMDP, in collaboration with
the International Bone Marrow Transplant
Registry (IBMTR) and the
EMMES Corporation, recently received
a 5-year NIH grant to coordinate a newly
established Blood and Marrow Transplant
Clinical Research Network.

Funding for this network is being
provided by both the National Heart,
Lung and Blood Institute and the National
Cancer Institute. When the network
begins operations, a data coordinating
center will manage a national
network of centers performing clinical
trials focused on hematopoietic stem
cell transplantation. Additional goals
of the network include developing
consensus guidelines for diagnosing,
monitoring, and grading important
transplant-related end points, and the
development and use of novel study
designs to increase the efficiency and
scientific validity of clinical trials in
blood and marrow transplantation.

The NMDP and Unrelated Donor
Stem Cell Transplantation

Approximately 75% of the stem
cell transplants facilitated by the
NMDP are for patients with some
form of leukemia. Indications for unrelated
donor stem cell transplant are
constantly changing. Since 1999,
NMDP-facilitated transplants for
adults with acute myelogenous leukemia have increased 66%, and transplants
for myelodysplastic syndromes
have increased by 50%. Since the
development of imatinib mesylate
(Gleevec) to treat chronic myelogenous
leukemia (CML), NMDP-facilitated
transplants for CML have
decreased by 45%.

Current research is exploring the
use of reduced-intensity (nonmyeloablative)
regimens in allogeneic stem
cell transplantation. This has resulted
in an increase in the number of stem
cell transplants for non-Hodgkin's
lymphoma, multiple myeloma, and
hemoglobinopathies such as sickle cell
disease.[1,2] Researchers are also investigating
the use of stem cell transplantation
in breast cancer[3,4] and
renal cell carcinoma.[3,5] Table 2
shows the diseases for which unrelated
stem cell donor transplants have
been performed by transplant centers
in the NMDP Network

Obtaining an NMDP-Facilitated
Stem Cell Transplant

Initiating a preliminary search of
the NMDP Registry to locate an HLAmatched
donor or umbilical cord
blood is free and available to any physician.
Interpreting the results of a
preliminary search and efficiently
moving forward through the many
steps to a transplant requires an understanding
of the clinical aspects of
stem cell transplantation and knowledge
of the operations of the NMDP.

The HLA System
Lymphocytes differentiate between
self and nonself cells by examining the
HLA antigens expressed on the surface
of cells. To prevent graft rejection and
other posttransplant complications,
stem cell donors and recipients must be
closely HLA matched.[6]

The HLA antigens are encoded on
the short arm of human chromosome 6,
on a segment called the major histo-
compatibility complex (MHC). There
are 3.5 million bases in the MHC, but
only a small number are currently
matched in stem cell transplantation.
The relevant portions of the MHC are
further divided into two regions-
class I and class II. Class I antigens
(HLA-A, -B, and -C) and class II
antigens
(HLA-DRB1, -DP, and -DQ)
are the antigens most frequently examined
when matching potential stem
cell donors and transplant recipients.

The NMDP requires that donors and
patients have no more than a one-antigen
mismatch at the HLA-A, -B or
-DRB1 locations. Because there are two
HLA antigens at each of these three
locations, a perfect match is referred to
as a 6 of 6 match, and a one-antigen
mismatch is termed a 5 of 6 match.
Using this terminology, the NMDP will
allow a 5/6 match or a 6/6 match for
marrow and peripheral blood stem cell
transplants, but not a 4/6 match or less.

The NMDP will allow a 4/6 match
for cord blood transplants, provided
the mismatched antigens are not at
the same loci. This less stringent HLA
matching for cord blood is permitted
because of the lowered immunologic
competence of cord blood T cells.[7-9]
Some transplant centers require additional
matching at the HLA-C, -DP,
and/or DQ loci. Newer DNA-based
methods of HLA typing have proven
to be more accurate than serologic
methods and have largely superseded
them.[10]

Impact of HLA Match
on Transplant Outcome

In allogeneic stem cell transplantation,
the degree of donor/recipient
HLA match is an important factor in
engraftment, the development of graftvs-
host disease (GVHD), and overall
survival.[11,12] The association of HLA
class I allele disparity with graft failure
was examined by the Seattle group, who
retrospectively analyzed data from 21
patients experiencing graft failure and
42 case-matched controls. Complete allele-
level matching for class I was identified
in 45% of controls and 10% of graft
failure cases.[13]

The effect of the number of HLA disparities
was subsequently studied in unrelated-
donor stem cell transplant for
CML patients. Among allele-matched
donors/recipients and donors/recipients
mismatched for a single class I allele,
the graft failure rate was 2%. When two
or more class I disparities at HLA-A, -B,
and/or -C were present, the graft failure
rate increased to 29%.[14]

In unrelated-donor stem cell transplantation,
the risk of clinically significant
GVHD is also influenced by
the extent of HLA disparity between
the donor and recipient. GVHD is a
potentially life-threatening complication
involving an immunologic reaction
in recipients that is mediated by
the transplanted T cells.

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