Hematopoietic Stem Cell Transplantation

Autologous Hematopoietic Cell Transplantation

In autologous HCT, stem cells from the patient himself or herself are used; this procedure is primarily performed in the treatment of malignancy. The principle behind autologous HCT is that certain malignancies exhibit a steep dose-response curve to chemotherapy and radiation. Autologous (and allogeneic) HCT allows for administration of high-dose therapy by restoring hematopoiesis. A high-dose chemotherapy or radiation preparative, or conditioning, regimen is administered, followed by infusion of cryopreserved autologous hematopoietic stem cells to restore blood production and immunity. This approach is effective against a range of hematologic malignancies and select solid tumors. It is also a promising treatment for some autoimmune diseases, wherein high-dose therapy is administered with the goal of ablating the autoreactive immune response and reconstituting immunity from stem cells.

Allogeneic Hematopoietic Cell Transplantation

Allogeneic HCT involves transplantation of cells from a healthy related or unrelated donor. Donor and recipient are usually identical or “matched” for HLA, which is derived from the MHC. The distinctive characteristics of allogeneic HCT are that the stem cell graft (1) is free of contamination by malignant cells, and (2) contains T cells that are capable of mediating an immunologic reaction against foreign antigens, such as malignant cells in the graft-versus-tumor or graft-versus-leukemia effect. This effect can potentially eradicate disease and decrease the risk of relapse. However, when the immunologic response is directed against antigens presented on normal recipient tissues, it can lead to destruction described clinically as graft-versus-host disease (GVHD).

The graft-versus-leukemia effect was first recognized in animal models and subsequently noted among patients undergoing allogeneic HCT for acute and chronic leukemias. The clinical importance of the interactions between immunocompetent donor T cells and tumor cells in mediating a graft-versus-leukemia effect is supported by an increased rate of relapse in allogeneic stem cell grafts from which T cells have been removed (T-cell depletion), an inverse correlation between relapse and severity of GVHD, and an increased rate of relapse after syngeneic or autologous HCT. These data suggested that T cells within the allograft are involved directly in eradicating leukemia. Moreover, further evidence originates from the observation that infusion of allogeneic lymphocytes, a “donor lymphocyte infusion,” can be used to treat leukemia relapse successfully after allogeneic HCT without any additional cytotoxic therapy. Despite the fact that there is great variability in the sensitivity of different malignancies to the graft-versus-tumor effect, it is clear that the significant part of the curative potential of allogeneic HCT can be attributed to this immune-mediated effect. Compared with autologous transplants, allogeneic HCT is generally more effective in eradicating malignancies, but it has a greater risk of treatment-related mortality as a result of GVHD and infections.

The general outline for allogeneic HCT includes patient selection based on disease indications, donor selection based on HLA compatibility and other factors, stem cell collection, conditioning with the preparative regimen (myeloablative or reduced intensity) to prevent graft rejection and to eliminate malignant cells, infusion of stem cells, engraftment, and prevention of complications such as prophylaxis for GVHD and infections.

Histocompatibility and Donor Selection

The incidence and severity of graft rejection and GVHD increase with greater genetic disparity between the donor and recipient, most notably if there is mismatching for HLA. The HLA gene complex is located on the short arm of chromosome 6. The HLA region is subdivided into three regions: class I, class II, and class III. The class I region contains genes that encode the classic HLA antigens, HLA-A, HLA-B, and HLA-C, which are expressed on almost all nucleated cells of the body. The class II region contains genes that encode the HLA class II molecules HLA-DR, HLA-DQ, and HLA-DP. Class II genes are expressed constitutively in only a very restricted number of cell types that are specialized in antigen presentation, such as dendritic cells and B cells, but they can be induced on several other cell types. The class III region has no known HLA class I– and class II–like genes but includes a number of genes related to the immune response. A single set of MHC alleles, described as a haplotype, is inherited from each parent, resulting in HLA pairs. In general, the best results of allogeneic HCT have occurred with an HLA-identical sibling, with the lowest risk of graft rejection and GVHD. The probability of having an HLA-matched sibling can be estimated by the formula 1 − (0.75) ⁿ , where n is the number of siblings.

Because of advances in HLA typing through molecular techniques and improved supportive care, current results of matched unrelated donor transplants are not significantly different from results of matched sibling donor transplants. Donors are ideally matched for HLA-A, HLA-B, HLA-C, and HLA-DRB1 (or 8/8 match ); data have shown that high-resolution matching at these loci maximizes posttransplantation survival in unrelated donor transplants. Although HLA matching is the most important factor in donor selection, other factors that can contribute to donor selection include age, gender, parity, cytomegalovirus (CMV) serostatus, and ABO blood type. An international network of registries to provide an HLA-matched unrelated donor has been established; this network includes the National Marrow Donor Program in the United States, and more than 18 million potential donors can be accessed worldwide. Depending on the ethnicity of the patient and donor, the probability of identifying an HLA-matched unrelated donor is 16% to 75%. Because of the tremendous polymorphism of the HLA gene complex, patients are most likely to match an individual from the same ethnic background, and persons with rare alleles or linkages and those from minority or mixed ethnicities are unlikely to have a matched unrelated donor available. Another limitation with transplantation from an unrelated donor is the time necessary to conduct the unrelated donor search and organize collection of the tissue from the donor. If a matched unrelated donor cannot be identified or the urgency of the transplant does not allow for a search, alternative donors such as umbilical cord or haploidentical transplantations are viable options.

Umbilical cord blood is an alternative source of hematopoietic stem cells for transplantation. Cord blood units are obtained by collecting blood remaining in the umbilical cord and placenta after the delivery of an infant. Umbilical cord blood T cells are less likely to produce GVHD than are stem cell grafts from adult donors, and therefore successful transplants can be performed with unrelated units matched for just four or five of the six HLA-A, HLA-B, and HLA-DR antigens. Another advantage is that umbilical cord grafts can be obtained in less than 4 weeks. An international network of cord blood banks has been established, with collection of umbilical cord blood from volunteer unrelated donors after delivery of a newborn. Approximately 500,000 umbilical cord blood units are available worldwide. Some disadvantages are related to the relatively low stem cell dose in these grafts, especially for adult patients, which results in a slower pace of hematopoietic and immune recovery and higher risk of graft failure and infection.

Haploidentical relatives are another alternative donor source that has broadened the applicability of allogeneic HCT. With recent advances including the use of posttransplantation cyclophosphamide as GVHD prophylaxis, the use of haploidentical transplants has been increasing. Parents, children, and siblings can serve as haploidentical donors and are readily available for most patients. Recently, cyclophosphamide with tacrolimus and mycophenolate has been used after haploidentical transplant to improve outcomes, with low rates of acute and chronic GVHD and treatment-related mortality. In nonrandomized parallel studies of umbilical cord and haploidentical transplantation, outcomes were similar and comparable to those reported with matched unrelated donors. A randomized trial between these two transplant strategies is ongoing; the results will help in comparing many outcomes and optimizing donor selection. As of now, the availability of matched related, matched unrelated, and alternative donors provides an opportunity for treatment of most patients with a clinical indication for HCT. A comparison of different sources of hematopoietic stem cells is presented in Table 28.1 .

Hematopoietic Stem Cell Sources

Hematopoietic stem cells and progenitor cells are contained in the CD34+ fraction of bone marrow cells and may be obtained from the bone marrow, peripheral blood, and umbilical cord blood. Stem cells from the bone marrow are used in both autologous and allogeneic HCT, although less frequently than in the past. Peripheral blood stem cells are now used in most autologous and allogeneic transplants. The greater use of peripheral blood stem cells is likely related to the relative ease of attainment and better rate of hematopoietic recovery after infusion. The concentration of hematopoietic stem cells in the peripheral blood is low in the normal setting; mobilization techniques are used to increase the number of circulating stem cells before collection by apheresis. Mobilization strategies include administration of myeloid hematopoietic growth factors, or the use of both chemotherapy and growth factors (autologous HCT only). Methods for collecting or “harvesting” hematopoietic stem cells from the bone marrow are modifications of the technique initially reported by Thomas and Storb. The harvest is performed with the patient under general anesthesia and involves repeated aspirations from the posterior iliac crest; the procedure is usually well tolerated. Hematopoietic stem cells from umbilical cord blood are collected immediately after delivery of an infant.

A large, randomized controlled trial evaluating bone marrow with peripheral blood stem cells in matched unrelated donor allogeneic HCT showed that there was no difference in survival between the two stem cell sources. There was also no difference in the incidence of acute GVHD, relapse, or death from infection. Significant differences included higher incidence of chronic GVHD with peripheral blood stem cells and higher incidence of graft failure and delayed hematopoietic recovery with bone marrow stem cells. Long-term follow-up from this trial showed that bone marrow stem cell recipients had better psychologic well-being and less burdensome chronic GVHD symptoms and were more likely to return to work. Other studies have also confirmed a more rapid time to engraftment and higher risk of chronic GVHD with peripheral blood stem cells. Although randomized studies comparing umbilical cord stem cells with either bone marrow or peripheral blood have not been performed, advantages and disadvantages of use of umbilical cord blood cells are discussed earlier in this chapter.

Conditioning or Preparative Regimens

Once an allogeneic stem cell source has been identified, patients are put on regimens with the intent of conditioning or preparing them for the infusion of stem cells. These regimens use a combination of radiation and chemotherapy or chemotherapy alone and may also include immunosuppressive agents (e.g., antithymocyte globulin, alemtuzumab). Regimens have varying intensities of myelosuppression for eradication of disease, and immunosuppression for prevention of graft rejection. Myeloablative conditioning regimens have sufficient components of both, and without infusion of stem cells would lead to irreversible myelosuppression. Reduced-intensity conditioning regimens were developed to allow for wider applicability of HCT in older patients, in whom myeloablative regimens are associated with increased toxicity and treatment-related mortality. The demonstration of the immune-mediated graft-versus-tumor effect led to the hypothesis that myeloablative conditioning was not required for disease eradication. Reduced-intensity conditioning regimens are associated with decreased morbidity and mortality but are reserved for patients who would not tolerate myeloablative conditioning or patients with nonmalignant diseases.

Disease Indications for Hematopoietic Cell Transplantation

Clinical evidence exists that autologous HCT and allogeneic HCT provide benefit in terms of response, freedom of progression, or overall survival (OS) for patients with many hematologic malignancies and select solid tumors. However, the beneficial effects vary greatly with each type of malignancy. Several factors are considered when making a decision to perform HCT, including those related to the disease, patient, and donor. A careful evaluation of available nontransplant treatment options is necessary. Patients should be educated about their disease, and the risks and potential benefits of HCT, as well as alternative forms of therapy. Once the decision is made to proceed with a transplant, a thorough assessment of factors such as the patient's age, performance status, disease status, comorbidities, and financial and psychosocial support is necessary. The Hematopoietic Cell Transplantation Comorbidity Index is a risk assessment tool that has been shown to be associated with treatment-related mortality and OS in patients undergoing HCT and is a useful instrument for evaluation of patients' fitness before HCT.

The indications for HCT vary by disease type. In general, malignancies that exhibit a marked dose response to myelosuppressive therapy or are sensitive to the graft-versus-tumor effect are best treated with HCT. Results are better in patients who have chemosensitive disease or are in remission. Outcomes of HCT are not favorable in patients with poor performance status and who have refractory or progressive disease. Evidence-based reviews regarding the role of HCT in the treatment of selected diseases have been published by the American Society for Blood and Marrow Transplantation and the European Society for Blood and Marrow Transplantation. As new therapeutic options continue to evolve, so does the role of HCT. The numbers of patients receiving autologous and allogeneic transplantation for each major indication are shown in Fig. 28.1 .