Darrell J. Triulzi, M.D., Medical Director
The number of hematopoietic stem cell transplants performed to treat
neoplastic diseases has dramatically increased in the past few years. The underlying
rationale for stem cell transplants is that the major barrier to successful treatment of
chemotherapy sensitive cancers is an inability to administer sufficient quantities of
cytotoxic agents. A principal limitation is the toxicity of these drugs for bone marrow
precursors: If administered in doses high enough to eradicate the malignant cells, fatal
marrow aplasia will result. Transplants of normal stem cells can rescue patients after
intensive cytoreductive therapy.
There are two general types of transplants: those in which the patient
serves as his own stem cell donor (autologous transplant) and those in which the stem
cells are obtained from another donor (allogeneic). The initial experience with allogeneic
hematopoietic stem cell transplants relied exclusively on HLA matched stem cells obtained
from a siblings bone marrow. The probability that a patient with a transplantable
disease will match with a sibling is approximately 1:4. Thus, a major limited pool of
compatible donor-recipient pairs.
For patients that require allogeneic transplants and do not have an HLA
matched sibling, several alternatives are now possible. The most likely source of stem
cells would be a matched unrelated donor. Although the likelihood that any two individuals
will have identical HLA types is quite small (approximately 1:10-20,000), a match may well
be identified if there is a sufficiently large pool of prospective donors. To locate such
donors, organizations such as the National Marrow Donor
Program (NMDP) have been established to maintain a computerized list of HLA types.
NMDP maintains typing information on more than 1.5 million individuals. Since the
formation of the registry in 1987, they have been able to locate matched donors to
facilitate over 3,000 transplants. Central Blood Bank serves
as the NMDPs regional resource for entering donors into the registry as well as
coordinating the collection of donor marrow for transplantation. Currently, more than
5,700 local residents have been registered and 16 have served as marrow donors.
HLA-matched siblings differ at minor histocompatibility loci. These
differences can result in an immunological reaction between donor lymphocytes and host
cells resulting in graft vs. host disease (GVHD). The severe forms of GVHD are often
fatal. A major factor associated with severe GVHD is the age of the recipient; in fact,
the incidence of fatal disease in patients greater than 45-55 years is sufficiently great
that most centers will not transplant older patients.
The immunological differences between donor and recipient in an
allogeneic transplant can also have a beneficial effect. The donors immune cells may
be induced to react against and kill residual tumor cells. This has been described for
transplants performed to treat acute leukemia; as such, it has been termed a graft vs.
leukemia effect. This type of reaction can eliminate small numbers of residual tumor cells
which survive the high dose chemotherapy, thus increasing the likelihood of a cure.
Allogeneic stem cell transplantation can also involve an HLA-mismatched
or partially matched donor. In these circumstances, the marrow must be manipulated to
remove T-lymphocytes prior to transplant. It is the presence of these lymphocytes that
causes GVHD and, in the case of a non-HLA identical transplant, the histocompatibility
differences are sufficiently great that the recipient may develop fatal disease. Various
techniques can be used to remove most of the T-lymphocytes. However, T-cell depleted
mismatched transplants have a higher risk of either graft failure or the development of a
If marrow transplants were exclusively restricted to age eligible
individuals with an HLA-matched sibling or a matched unrelated donor, the procedure would
be more of a curiosity than a realistic therapeutic option. However, the demonstrated
utility of autologous transplants, in which the patient is the donor of his own stem
cells, has greatly expanded the clinical utility of rescue procedures. Initially,
autologous transplants were performed using cells harvested directly from the marrow; more
recently, many of these procedures have used stem cells collected from the peripheral
blood by leukapheresis. Regardless of the stem cell source, the procedure requires that
the patient be treated with high dose chemotherapy to eradicate the malignancy. The stored
stem cells are then reinfused into the patient, where they repopulate the marrow and
One of the problems with an autologous transplant is the possibility
that the graft itself may contain residual tumor cells. To circumvent this possibility,
several approaches have been used to deplete tumor cells. In diseases such as leukemia and
lymphoma, cells are harvested at a time that the patient is in a drug-induced remission.
However, even these collections may contain a small number of viable tumor cells. Because
of this possibility, many centers add an additional processing step in which the marrow
with either cytotoxic drugs or monoclonal antibodies that react with antigens found on the
Peripheral blood stem cell harvests have now become a routine procedure
for obtaining cells for autologous transplantation. If the harvests are performed without
prior stimulation of the patient, the circulating stem cell pool is very small and a large
number of pheresis procedures must be performed to collect a sufficient quantity.
Furthermore, these stem cells engraft slowly, resulting in a long period of aplasia. To
circumvent these problems, collections are performed after procedures designed to increase
the numbers of circulating stem cells. This occurs in patients recovering from
chemotherapy-induced aplasia, after treatment with hematopoietic growth factors, or after
using these two approaches in combination. The hematopoietic growth factors G-CSF and
GM-CSF have been shown to be highly effective in mobilization regimens.
The primary advantage of using blood-derived stem cells is that
hematological recovery following peripheral blood stem cell harvests occurs more rapidly
than that obtained with bone marrow. This significantly reduces the toxicity of high dose
chemotherapy, resulting in a reduction in the duration of hospitalization and the need for
blood products and antibiotics. In fact, the recovery after reconstitution with peripheral
stem cells is sufficiently rapid that some centers are performing transplants as
outpatients. The experience of The Institute For Transfusion
Medicine has been that neutrophil and platelet recovery using peripheral blood stem
cells harvested after cytotoxic chemotherapy and G-CSF occurs with a median time of 10 and
12 days, respectively. Recent analysis of our data further indicates that hematologic
recovery is sustained for well over two years with no signs of graft failure. The
successful use of peripheral blood stem cells for autologous transplants has recently been
extended to allogeneic transplantation with very promising early results.
Finally, there is a rapidly growing interest in the sue of
placental-umbilical cord blood as a source of stem cells. Investigators have shown that
the blood remaining in the placenta and cord after birth is a rich source of hematopoietic
progenitors. To date, more than 50 allogeneic transplants have been performed in infants
and children using cord blood. Studies suggest that cord blood may be particularly
enriched for the early, more primitive types of stem cells. This may account for the
hematologic reconstitution seen with the administration of fewer stem cells than those
obtained in marrow or peripheral blood harvests. Cord stem cell banks for both autologous
and allogeneic use have been established.