May, 1995


HEMATOPOIETIC STEM CELL TRANSPLANTS

Joseph E. Kiss, M.D., Medical Director, Hemapheresis and Blood Services

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 sibling’s 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 NMDP’s 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 donor’s 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 fatal infection.

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 restore hematopoiesis.

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 tumor cells.

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.

For questions or additional information regarding stem cell transplantation please contact Joseph E. Kiss, M.D. at the Central Blood Bank Hematopoietic Stem Cell Laboratory, (412) 209-7325.  For information on the National Marrow Donor Program, please call (412) 209-7131.

Copies of the Transfusion Medicine Update can be obtained by contacting
Deborah Small at (412) 209-7320


Copyright 1997, Institute For Transfusion Medicine