The use of bone marrow and peripheral blood stem cell transplantation in the treatment of cancer

Bone marrow or peripheral blood stem cell transplantation is used in the treatment of cancer for two reasons. First, transplantation permits exploitation of the steep dose-response relationship seen in some tumors by allowing administration of doses of systemic chemotherapy and radiotherapy that without transplantation would cause unacceptably severe or lethal myelosuppression. Second, transplantation of allogeneic marrow confers an antitumor effect, separate from the effects of chemoradiotherapy. The first successful bone marrow transplants in humans were performed in the late 1960s. This year, it is estimated that over 15,000 patients will undergo the procedure worldwide (Fig. 1). The first suggestion that bone marrow transplantation might be possible occurred in 1949 when Jacobson et al1 made the observation that mice could survive otherwise lethal total body irradiation if the spleen was protected by lead foil. A similar radioprotective effect was seen if bone marrow from one mouse was given intravenously to a radiated recipient of the same strain.2 By the mid-1950s, several laboratories had shown, using cytogenetic markers, that the radioprotective effect of bone marrow transplantation was due to the replacement of the damaged hematopoietic system of the host with healthy cells of donor origin.3 The potential clinical implications of these studies were noted, and in 1959, the first attempts to treat leukemia using high-dose chemoradiotherapy followed by syngeneic marrow transplantation were initiated by Dr. E. Donnell Thomas.4 Initial attempts to apply transplantation outside the setting of identical twins were unsuccessful because of lack of understanding of the human histocompatibility system. In the late 1950s and early 1960s, human leukocyte antigens (HLA) and their importance in histocompatibility were first recognized. By the mid-1960s, it was demonstrated in an outbred species (the dog) that matching at the major histocompatibility complex allowed for successful allogeneic marrow transplantation.5 The work of Dr. Thomas and fellow investigators led to the first successful allogeneic transplants for leukemia in the late 1960s6 and the gradual acceptance of this therapy during the 1970s.7 Autologous marrow transplantation was first successfully employed to cure patients with lymphoma in the late 1970s8 and became widespread in the 1980s. Today, the annual number of autologous transplants surpasses that of allogeneic transplantation. In 1990, a Nobel prize in medicine was awarded to E. Donnell Thomas for his contributions to this field (Table 1). Estimated number of allogeneic and autologous marrow transplants performed worldwide by year. Data from the Statistical Center of the International Bone Marrow Transplant Registry and the Autologous Blood and Marrow Transplant Registry. Several features of human bone marrow make the transplant procedure feasible. The first is the remarkable regenerative capacity of marrow. In mice it has been demonstrated that the transfer of a single hematopoietic stem cell can result in complete and sustained hematopoietic reconstitution of a lethally irradiated recipient.9 While human bone marrow has never been put to this test, transplantation of considerably less than 10 percent of a donor's total body marrow regularly results in complete and sustained replacement of a patient's entire hematopoietic system. After the transplant, donor marrow cells normally produce all of the patient's red cells, platelets, granulocytes, and T lymphocytes and B lymphocytes as well as the patient's pulmonary alveolar macrophages, Kupffer's cells of the liver, osteoblasts, Langerhans' cells of the skin, and microglial cells of the brain. A second feature of marrow which makes transplantation practical is that after intravenous infusion, marrow cells have the capacity to home to the marrow space. The mechanisms by which this happens are not entirely understood, but a remarkably high percentage of primitive hematopoietic cells appear to end up in the marrow, in some murine studies as many as 50 percent.10 Current studies suggest that early hematopoietic cells are retained in the marrow because marrow endothelial cells express members of a family of cell adhesion molecules termed “selectins,” which bind to carbohydrate-based ligands on early hematopoietic cells.11 An additional characteristic of marrow stem cells that has made autologous transplantation feasible is their ability to survive cryopreservation with little, if any, damage. Using relatively simple techniques of freezing and thawing, cryopreserved autologous marrow is virtually as effective as fresh marrow in providing protection after otherwise lethal total body irradiation.12 Cryopreserved autologous marrow is virtually as effective as fresh marrow in providing protection after total body irradiation. An identical twin, when available, is the best possible donor. With syngeneic marrow, there are fewer complications than with allogeneic marrow transplantation, and unlike autologous marrow, marrow from a healthy identical twin cannot be contaminated with tumor cells. Syngenicity is easily established by DNA typing using restriction fragment length polymorphisms. Allogeneic marrow transplantation can be performed using HLA-identical sibling donors, other HLA-matched or HLA-mismatched family members, or HLA-matched unrelated donors. The best results occur with sibling donors who are identical with the patient for HLA class I and class II determinants. The genes encoding HLA are located on chromosome 6 and are codominantly expressed so that the probability of HLA-identity between any two siblings is 25 percent. Given the average family size in the United States, the chance of having an HLA-matched sibling is about 35 percent. The formula for calculating the chance that a patient has an HLA-identical sibling is 1-(0.75)n where n equals the number of siblings. HLA class I antigens (usually referred to as HLA-A and HLA-B) are defined using alloantisera in microcytotoxicity assays. HLA class II antigens are encoded by genes located within the HLA-D region and are termed DP, DQ, and DR. DQ and DR antigens can be identified by alloantisera, but identification of Dp requires cellular techniques, such as mixed lymphocyte culture reactions or more current molecular techniques such as sequence-specific oligonucleotide probe hybridization. While the best results with allogeneic transplantation have been achieved using HLA-identical sibling donors, transplants using family member donors identical with the patient for one haplotype but mismatched for a single locus on the other (A, B, or D) result in nearly equal survival, albeit with a higher incidence of graft-versus-host disease (GVHD).13,14 The results of transplants using family member donors mismatched for two or more loci are considerably worse with more GVHD, more graft rejection, and decreased survival.13,14 Following initial reports that transplantation could be successfully performed using an HLA-matched unrelated donor, there has been a rapid increase in this activity.15,16 Currently, more than 1.3 million normal individuals have volunteered to serve as marrow donors in the United States alone, making the odds of finding an A, B, and D matched unrelated donor about 50 percent.17 On average, it takes about four months from the time a search is initiated to identify a donor and initiate a transplant. Analysis of the first several hundred patients transplanted from unrelated donors suggests that GVHD is more common and long-term cure rates are slightly lower than with the use of matched family members.18,19 Autologous transplantation involves removing and usually cryopreserving a patient's own marrow and reinfusing that marrow to reestablish hematopoietic function after the administration of high-dose chemotherapy or chemoradiotherapy. Deciding the type of transplantation to recommend for any individual patient is complex. Autologous transplantation has the advantage of avoiding GVHD and associated complications but has the disadvantage of potentially containing viable tumor cells and lacking a graft-versus-tumor effect. Because autologous marrow may contain viable tumor cells, numerous strategies have been developed to reduce the number of tumor cells in autologous marrow. Removal of tumor cells (negative selection) using antibodies together with complement, toxins, or immunomagnetic beads is very efficient, removing three to four logs of tumor cells from marrow.20,21 In vitro treatment of marrow with chemotherapy has been studied, as has removal of tumor cells using in vitro of marrow of normal hematopoietic stem cells to separate from tumor cells are studies have demonstrated that tumor cells in marrow can to it has not been established the techniques can this is not established these techniques normal marrow Several suggest that might be effective in leukemia and but studies have not been several it has been that hematopoietic stem cells in the peripheral albeit in very Initial studies in demonstrated that at 10 more cells were to from lethal total body irradiation if from peripheral blood as with initial attempts to use peripheral blood stem cells as a of hematopoietic were by the number of or and by it has been that administration of chemotherapy hematopoietic to a in the number of hematopoietic in the peripheral as or as cells. This has of the use of peripheral blood stem cells as a for The results have been In the autologous with one to three after treatment with or a number of cells for can usually be than 1.3 million individuals in the United States have volunteered to serve as marrow donors. after using peripheral blood stem cells is considerably than after using results have been demonstrated using cells for syngeneic transplantation, and results suggest the same can be in the allogeneic about the use of peripheral blood cells for autologous transplants the that with tumor cells is than with autologous marrow. allogeneic transplantation, there is the that the of is higher than with marrow. given the rapid that has been demonstrated and the that the a procedure for the donor, it that peripheral blood to autologous tumor cells or reduce the number of allogeneic T cells will marrow as the of stem cells for use after therapy in Following identification of the of stem cells, the in the transplant procedure is the administration of high-dose chemotherapy or radiotherapy or a of the The of the is to the and in allogeneic marrow transplantation to the patient to In transplant investigators have on the use of that have high the and have as their in the the used are and total body irradiation. The of is by the clinical the disease the and of the and the of marrow. 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use of autologous transplants for is at to suggest that with current this can lead to long-term some suggestion that autologous transplantation may the of the studies are of patients transplanted in from matched siblings for treatment of Current total body irradiation or for other after transplantation is patients transplanted in the disease of marrow transplantation in leukemia has Given the of the disease and to occur in this is not the number of patients using allogeneic transplantation, complete have been achieved in and about 50 percent albeit with a of several so The number of patients using autologous transplantation is less and their have been some of which appear to be more will be to if transplantation long-term in this with lymphoma who therapy are without transplantation. therapy followed by autologous or allogeneic marrow transplantation can cure a of such A number of studies have cure rates of to 50 percent for patients transplanted after an initial but their tumors to rates the disease to A and tumor are additional in other patients transplanted using allogeneic marrow have a lower but a higher of than patients transplanted using autologous of and the of allogeneic and autologous transplantation appear an advantage for allogeneic transplantation in patients with lymphoma has been studies have to the use of transplantation in first Several studies have been A to an for transplantation in first but suggest that patients with for with chemotherapy might from early Marrow transplantation for patients with has been of to percent with a of three to four has been for patients transplanted after late have been seen in some and the cure with this is as of autologous transplantation for lymphoma in first are The results of transplantation for disease are similar to for A of patients who have chemotherapy for disease can be with are if transplants are performed when patients have disease with and a In this cure rates of to percent have been with lower rates but higher are seen with use of allogeneic as to autologous Allogeneic marrow transplantation is used to treat patients for rates for allogeneic transplantation in patients who have therapy have 35 percent at after transplant, and there to be a in survival, that some of these patients are Autologous transplantation is is less that this can lead to long-term cure with current if used patients have autologous transplantation can result in a in tumor and in many to at complete In one in so autologous transplantation used after patients had achieved a complete led to with a with has been allogeneic marrow transplantation for patients with cell leukemia and but the number of patients in any one disease is therapy followed by autologous or allogeneic marrow transplantation can cure percent of patients with and up to percent of patients with disease transplanted in results are to be to with but to this are therapy followed by autologous marrow transplantation results in a higher of complete than seen with chemotherapy in with in a number of such patients have at two to of 10 to While these results appear to achieved with will be to if patients are and this percentage is higher than seen with on these initial high high-dose therapy followed by autologous transplantation has been in patients at high to after such as patients with 10 or more results of such an appear and have led to a In to the by the of autologous transplantation for the number of patients potentially and the relatively high of have made this the in the of who for the of patients treatment on clinical this is will have a on clinical chemotherapy for cancer is to percent of patients chemotherapy with autologous marrow has in a of about percent in patients with a that is than that achieved with of high-dose therapy with stem cell are for cell and in to the In high-dose therapy followed by autologous marrow transplantation results in a higher of complete than to the clinical of marrow and peripheral blood stem cell transplantation for the treatment of are of involves the and of stem cells used for transplantation. the use of peripheral blood stem cells has the and the of autologous transplantation and may have a similar effect for allogeneic possible of allogeneic stem cells have been with the of the Marrow and the that stem cells from blood a viable to to the of autologous marrow the of more for disease and the of to tumor cells for in vitro treatment with immunomagnetic and of hematopoietic stem cells. A is made to the of the transplant in the and treatment of a number of have had a major effect, the of to and treat are and are from GVHD after transplants is but GVHD to be a major the of mismatched and unrelated the of of T cells from donor marrow in understanding of the of T cells to their a for normal have the that by the or might be these are the of the of techniques to more the used on systemic with total body irradiation. studies have demonstrated that more the but are associated with an of investigators are antibodies or other can be used to higher doses of radiotherapy or chemotherapy to of normal Initial studies that this is possible in the treatment of leukemia and lymphoma and have clinical to the of the transplant in the are on the observation that of of leukemia and lymphoma is more after syngeneic or transplantation than it is after allogeneic transplantation, if patients some A number of relatively attempts to on this effect are the use of to to produce after autologous transplantation and the use of donor or after allogeneic transplantation. in of the effect have that it is a and that the T cells that cause GVHD are not the same for the are to and T cells with for the tumor for use after allogeneic transplantation. first successful 25 the clinical use of marrow and peripheral blood stem cell transplantation has (Fig. 1). While to a when antitumor will be less and less than transplantation, current and the for at for the marrow and peripheral blood stem cell transplantation will a in the treatment of patients with