Hematopoietic cell transplantation (HCT) is the IV infusion of hematopoietic stem and progenitor cells designed to establish marrow and immune function in patients with a variety of acquired and inherited malignant and nonmalignant disorders. These include hematologic malignancies (eg, leukemia, lymphoma, and myeloma), nonmalignant acquired bone marrow disorders (aplastic anemia), and genetic diseases associated with abnormal hematopoiesis and function (thalassemia, sickle cell anemia, and severe combined immunodeficiency). HCT also is used in the support of patients undergoing high-dose chemotherapy for the treatment of certain solid tumors for whom hematologic toxicity would otherwise limit drug administration (germ-cell, soft-tissue sarcomas, and neuroblastoma).
Since the advent of HCT in the 1960s, several different methods of transplantation have evolved. At present, the hematopoietic cells used for HCT are obtained from either bone marrow or peripheral blood. The decision to use a certain type of HCT is dictated by the patient's age, disease and condition, and the availability of a donor. In some cases, more than one approach is possible. Table 1 summarizes the advantages and disadvantages of each stem-cell source.
Allogeneic BMT, match related
This method involves procurement of bone marrow from a human leukocyte antigen (HLA)-identical sibling of the patient. In some cases, a partially matched sibling or family donor (one antigen mismatch) can be used for bone marrow transplantation (BMT).
Allogeneic BMT, match unrelated
Given that there are a limited number of alleles of the HLA system, typing of large numbers of individuals has led to the observation that full molecular matches for patients exist in the general population. Tissue typing is performed on the patient's blood, and a search of the computer files of various international registries is made to determine whether a patient has a match with an unrelated individual.
This technique usually involves the transplantation of large numbers of T-cell–depleted stem cells from a donor, usually a sibling or a parent, who is half matched to the patient. Although these are the most difficult transplantations to perform successfully, there is great interest in this approach, because most patients will have a donor in their family who is at least a 50% HLA match. Most transplants will engraft, and few patients will have significant graft-vs-host disease (GVHD). However, the relapse rate is high, and the process of immune reconstitution is slow, with patients often having troublesome infections for a long time after transplantation.
Cord blood transplantation
The blood in the umbilical cord of newborn babies contains large numbers of stem cells, which have been shown to be capable of long-term engraftment in children and some adults after transplantation. Similar to unrelated-donor registries, cord blood banks have been developed to store cord blood cells that can be used for unrelated-donor transplantation. Given the immunologic immaturity of cord blood cells, these transplants can be accomplished even when there are disparities (mismatching) in the HLA typing between the donor and recipient. Cord blood transplants are generally used in situations where the patient does not have a sibling donor and an unrelated adult donor cannot be identified through the international registries.
This form of transplantation is not utilized anymore, but entails the use of the patient's own bone marrow, which is harvested and then cryopreserved prior to administration of chemotherapy and/or high-dose radiation therapy. Following completion of therapy, the marrow cells are then thawed and reinfused into the patient to reestablish hematopoiesis.
Autologous peripheral blood stem-cell transplantation
With the recognition that the marrow stem cells circulate in the peripheral blood, methods have been devised to augment the number of these cells in the patient's circulation. The blood is then collected on a cell separator and frozen in a manner similar to that of autologous marrow, to be used after high-dose chemotherapy and/or radiation therapy. This is now the most common source of stem cells used in the autologous setting.
In this form of transplantation, marrow or peripheral blood stem cells are procured from an individual who is a genetic identical twin to the patient.
Donor leukocyte infusion
This method involves the infusion of mononuclear cells from the marrow donor into the recipient to treat relapse after transplantation. The cells can mediate an antitumor effect, known as a graft-vs-tumor effect (often in association with concomitant GVHD), and can achieve remission of the malignancy.
Nonmyeloablative or reduced-intensity transplantation
This approach uses lower doses of chemotherapy, with or without total-body irradiation (TBI) and immunosuppression, to facilitate engraftment of donor stem cells. Donor stem cells obtained from either the peripheral blood or marrow are then infused into the patient, leading to hematopoietic engraftment. The major therapeutic effect that results from this type of transplantation is a graft-vs-tumor effect, as the nonmyeloablative regimen has limited long-term antitumor efficacy. Some disorders, such as chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), low-grade lymphoma, and mantle cell lymphoma, are particularly sensitive to this approach. This type of transplant allows older patients to undergo the procedure, as transplant-related mortality is greatly reduced with this approach.
Finding a related donor
As noted previously, matched related allogeneic BMT involves a donor who is an HLA-matched sibling of the recipient. The formula for calculating the chances of a particular person having an HLA-matched sibling is 1 − (0.75)N, where N denotes the number of potential sibling donors. In general, a patient with one sibling has a 25% chance of having a match. The average American family size usually limits the success of finding a family donor to approximately 30% of patients.
HLA typing is performed on blood samples or from buccal smears obtained from the patient and potential donor. Molecular methods are now used for more refined matching of both class I and class II antigens. A match is noted when the major class I antigens (A and B loci), as well as class II antigens (DR), are the same as those of the donor. Each sibling receives one set of antigens (A, B, DR) from each parent (chromosome 6). Genotypic identity can be confirmed by testing the parents and determining the inheritance of each set of antigens.
Finding an unrelated donor
In cases in which the patient needs an allogeneic transplant and a donor cannot be found within the family, the identification of a matched unrelated donor (MUD) is accomplished by searching the computer files of the National Marrow Donor Program, as well as other international registries. As there are multiple alleles of any given HLA locus, serologic identity does not necessarily imply genotypic identity, such as is the case among sibling donor-recipient pairs. The development of oligonucleotide probes has greatly increased the precision of HLA typing and has allowed for more specific selection of bone marrow donors by matching molecular alleles of the class I and II antigens.
Advantages and disadvantages
The major advantages of an allogeneic graft include the absence of malignant cells contaminating the graft; the potential for an immunologic anticancer graft-vs-tumor effect; and the ability to treat malignant and nonmalignant disorders of the bone marrow, including genetic and immunologic diseases.
The disadvantages of an allogeneic transplant include the difficulty in finding an appropriate HLA-matched donor and the development of GVHD after HCT, which contributes to the morbidity and mortality of the procedure.
Reduced-intensity transplantation has allowed older patients up to age 75 to undergo this type of transplant to treat their disease when clinically indicated.
Advantages and disadvantages
In autologous transplantation, the reinfused stem cells come from either the patient's own bone marrow or peripheral blood. These cells do not cause GVHD, and thus, autologous transplantation is associated with less morbidity and mortality than is allogeneic BMT and increases in the number of patients who can undergo the procedure in the upper age limit.
The disadvantages of autologous BMT include the likelihood of tumor cell contamination within the graft in many diseases, which can cause relapse; the lack of a significant therapeutic graft-vs-tumor effect; and the limited ability to use autologous stem cells to treat patients not in remission or with inherited nonmalignant lymphohematopoietic diseases. Table 2 summarizes the advantages and disadvantages of these two approaches.