Finding the Perfect Donor
Brian Zikmund-Fisher was 28 years-old when he learned that he
needed a bone marrow transplant. Diagnosed with myelodysplasia just three
months before he and his wife, Naomi, were to celebrate the birth of their
first child, Zikmund-Fisher began his search for an unrelated bone marrow
donor.
“I expected the process to be straightforward,” recalls
Zikmund-Fisher. “I assumed that you just checked the donor registry,
identified the best few candidates, called them in to be sure, and you were
done.” Unfortunately for Zikmund-Fisher, the donor search process turned
out to be far more complicated.
Although Zikmund-Fisher’s initial search of the National
Marrow Donor Program Registry yielded 800 potential donors, that number quickly
diminished when more sophisticated DNA-based testing revealed that most were
not a suitable donor for him. It was not until 12 months later that
Zikmund-Fisher found his “perfect” match.
Twenty years ago, many of the rejected donors might have been
deemed a suitable donor for Zikmund-Fisher. But today’s technology enables
doctors to detect subtle genetic differences between donors and
patients—differences that can significantly influence the outcome of the
transplant. For this reason, most transplant centers today no longer rely
solely on the older “serological” tests that were once used to
identify a suitable unrelated donor, but now use sophisticated DNA-based tests
(also called molecular testing or high resolution typing) to determine whether
a donor and the patient are a good match.
What Are They Matching?
On the surface of most of our cells lies a set of proteins called
Human Leukocyte Antigens (HLA). Like a fingerprint, these proteins enable our
immune system to distinguish between cells that belong in our body and cells
that do not. If immune system cells encounter a cell with the wrong
“fingerprint”, they orchestrate an immune system attack to destroy
it.
Five different HLA proteins on the surface of the cells are
believed to play an important role in stem cell transplantation. Each protein
is made from a small section of chromosome (the genetic code everyone carries
in the cells of their body) called an allele (pronounced uh-léel). The
locations or loci of the alleles on the chromosome are referred to as HLA-A,
HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1. If an unrelated donor and patient have the
same two alleles at HLA-A, HLA-B, HLA-C, HLA-DR1 and HLA-DQ1, the donor is
considered a “ten out of ten” or “perfect” match.¹,
²
Finding a perfectly matched donor reduces the risk of developing
graft rejection and acute graft-versus-host disease (GVHD). Graft rejection
occurs when the patient’s immune system perceives the donor’s cells
as foreign matter that should be destroyed. Graft-versus-host disease is a
condition in which the donor’s cells perceive the patient’s organs
and tissues as foreign material that should be destroyed.
Making the Match
The original method used to test whether donors and patients were
HLA-matched was serological testing. Serological testing picks up differences
in the HLA proteins on the surface of cells, but cannot identify the specific
gene that creates those differences. Serological tests can distinguish between
28 different HLA-A genes, 59 HLA-B genes and 21 HLA-C genes.
In contrast, high-resolution DNA-based tests, called allele level
typing, can distinguish between hundreds of different genes that generate HLA
proteins on the cell surface. But while allele level typing is more precise, it
is also more time-consuming and expensive. For these reasons, some transplant
centers use high resolution DNA testing only if the potential donor is
unrelated.
Less sophisticated DNA-based testing, called low resolution or
intermediate resolution DNA testing, is often used to screen a large pool of
donors. If an HLA-matched donor is identified, allele level typing is then
performed. In order to speed up the search process, the National Marrow Donor
Program requires patients to have high resolution typing at DRB1 and
intermediate level typing at HLA-A and HLA-B before beginning a donor search.
High resolution DNA-based testing is less critical when the
potential donor is a sibling with the same biological parents as the patient.
Children inherit HLA alleles from their parents in linked strands called
haplotypes—one strand from the mother, the other from the father. Since
there are only two possible strands of alleles that can be inherited from each
parent, serological or low resolution DNA testing is usually sufficient to
determine if a patient’s sibling is an HLA match.
Typing the Pool of Unrelated Donors
The early goal of most registries of unrelated donors was to
enroll as many donors as possible in a rapid, cost-effective manner. Thus, most
of the donors recruited by the National Marrow Donor Program (NMDP) between
1987 and 1991 were only typed at HLA-A and HLA-B. HLA-DR typing was done later,
at the patient’s expense, after a preliminary search of the NMDP database
identified donors who were HLA-A and HLA-B matched.
However, enrollment in the donor registries has far exceeded
anyone’s expectations and today some patients, like Zikmund-Fisher, find
hundreds of HLA-A and HLA-B matched donors in the preliminary search. Paying to
have each one DR-typed is prohibitively expensive and time-consuming.
“So many of the people we met during transplant had
transplants with mis-matched donors because they didn’t have time to
DR-type all the donors who were preliminary matches at HLA-A and HLA-B,”
says Naomi Zikmund-Fisher. “If all donors in the registry were DR-typed,
more people would have a chance of finding a perfect match.”
The Zikmund-Fishers have “put their money where their mouth
is” by creating the Brian Zikmund-Fisher Fund to raise money for
DR-typing. To date, the couple has raised over $90,000 - enough to DR-type
approximately 3,000 donors in the National Marrow Donor Program registry.
Since 1992, the National Marrow Donor Program (NMDP) has also
stepped up efforts to expand the pool of HLA-DR typed donors in the registry by
DR-typing newly enrolled donors, as well as a subset of donors already enrolled
in the registry. Currently, 61% of the 4.3 million NMDP volunteer donors have
been DR-typed using DNA-based typing methods.
“Since HLA types are inherited, patients are more likely to
find a matched donor from within their own racial/ethnic group,” notes
Chatchada Karanes MD, Medical Director of the National Marrow Donor
Program’s Search and Transplant Services Department. “For this
reason, NMDP has made a concerted effort over the past few years to recruit
more minority donors into the registry. Currently 55 percent of donors in the
registry are Caucasian, 8 percent are African-American, 6.1 percent are
Asian/Pacific Islander, 8.3 percent are Hispanic, 1.3 percent are Native
American, 1.5 percent are of multiple ethnic backgrounds, and 19.4 percent are
of unknown origin.”
Beyond HLA Typing
While DNA-based typing enables doctors to more precisely identify
the HLA types of donors and patients, not everyone will be able to find a
perfectly matched donor. In many cases, it will be necessary for a patient to
be transplanted with stem cells from a donor whose HLA-type is very similar,
but not identical to the patient’s.
If a patient has the luxury of selecting between two or more
donors, several other factors will enter into the equation. Younger donors are
usually preferred over older donors. Donors who have not been exposed to the
cytomegalovirus (CMV) are optimal. Some studies suggest that gender is
important. Male patients who are transplanted with stem cells from a female
donor appear to have an increased risk of developing chronic GVHD.
DNA-based testing has become an important tool in the battle to
control graft-versus-host disease and eliminate graft-rejection. As more people
with rare HLA-types are identified and enrolled in the donor registries, the
prospects of finding a “perfect” match will increase for all people,
regardless of race or ethnic background. 
¹ If the donor is the patient’s sibling, HLA-typing is
often only done at the HLA-A, HLA-B and HLA-DR loci. A donor who matches at
these three loci is referred to as a six out of six match.
² The NMDP
requires unrelated donors to be at least a five out of six antigen match.
Depending on the urgency of a transplant, the age of the patient and the number
of potential donors in the registry, a transplant center will decide to wait
for a perfectly matched donor or proceed to transplant with a mismatched
unrelated donor. |
