Hematopoietic Cell Transplantation

Allogeneic Hematopoietic Cell Transplantation

The distinctive characteristics of allogeneic hematopoietic cell transplantation are that the stem cell graft allows for the establishment of a new immune system in addition to reconstitution of white blood cells, red blood cells, and platelets. The new immune system can be a major advantage if the immunologic response is directed against malignant cells, referred to as the graft-versus-leukemia or graft-versus-tumor effect, which potentially can eradicate disease and reduce the chance of disease relapse. However, if the immunologic response is directed against antigens present on normal tissues, the graft-versus-host response can result in the destruction of normal organs and is clinically described as graft-versus-host disease (GVHD). The risk for both graft rejection (host-versus-graft reaction) and GVHD rises with the degree of human leukocyte antigen (HLA) disparity between the donor and the recipient as well as the degree of immune suppression.

The clinical importance of the role that immunocompetent donor T cells play in mediating a graft-versus-tumor effect is exemplified by the increased rates of relapse in patients who receive allogeneic bone marrow grafts from which T cells had been removed (T-cell depletion), an inverse correlation between relapse and severity of GVHD, and increased rates of relapse after syngeneic or autologous hematopoietic cell transplantation in patients who have received similar conditioning regimens. However, the most compelling evidence for the importance of T cells mediating the graft-versus-tumor effect is the clinical observation that infusion of allogeneic T cells alone, termed a donor lymphocyte infusion , at a time remote from the transplant conditioning regimen can successfully eradicate leukemia that has persisted or recurred after allogeneic hematopoietic cell transplantation. Nevertheless, the clinical effectiveness of graft-versus-tumor can vary widely among different malignancies.

Because of the immunologic barriers that can result in graft rejection and GVHD, allogeneic hematopoietic cell transplantation requires that the donor and the recipient share as many key genes as possible. The most important of these are HLAs ( Chapter 38 ), which are derived from the MHC located on chromosome 6. The HLA loci include HLA-A, HLA-B, HLA-C, DR, DP, and DQ. A single set of major histocompatibility complex (MHC) alleles, described as a haplotype, is inherited from each parent, thereby resulting in HLA pairs. A clinical “match” means that HLAs in the donor match the HLAs in the patient.

The choice of donor for an allogeneic hematopoietic cell transplantation takes into account several factors, including the patient’s specific disease and disease state (i.e., remission vs. relapse) and the time that is required for obtaining hematopoietic stem/progenitor cells from a donor. A fully HLA-matched sibling is the preferred donor source because the risks for graft rejection and GVHD are lowest. The probability of having an HLA match with a single sibling is 25% and increases with the number of siblings within a specific family. This probability can be estimated using the following formula: chance of having an HLA-matched sibling = 1 − (0.75) ⁿ , where n is the number of potential sibling donors. There is approximately a 1% chance of a crossover event (i.e., genetic material switched between chromosomes during meiosis), primarily between the HLA-A and the HLA-B loci. The clinical outcomes for allogeneic hematopoietic cell transplantation using a sibling with a single HLA mismatch are similar to those with a fully HLA-matched sibling.

For patients who lack an HLA-identical sibling donor, the alternative sources for allogeneic hematopoietic stem/progenitor cells include a fully HLA-matched volunteer unrelated donor, a fully or partially HLA-matched cord blood unit, or a partially HLA-matched first-degree family member. HLA genes are highly polymorphic, so the odds that any two unrelated individuals are HLA identical for main loci are less than 1 in 10,000. However, tens of millions of people worldwide are currently listed as potential volunteer donors, so a donor can be found for about 50% of all patients for whom a search is initiated. The probability of identifying a suitable volunteer donor is highly dependent on race because of varying degrees of HLA diversity. For example, for persons of northern European extraction, the probability of a match can be as high as 90%. In contrast, minority populations may have less than a 20% probability of a match because of fewer volunteer donors and a higher degree of genetic variation.

It usually takes about 2 to 4 months to locate and fully evaluate an unrelated donor, which may be too long for some patients with rapidly progressive malignancies. When a suitable volunteer is not available or a donor is needed more urgently, alternative sources can be considered, including partially HLA-matched (“haploidentical”) relatives or umbilical cord blood. Haploidentical hematopoietic stem/progenitor cells are readily available but have increased risks for graft rejection and GVHD. These risks can be reduced by either ex vivo or in vivo T-cell depletion methods, but T-cell depletion may lead to delayed immune reconstitution and competency after transplantation, thereby increasing the risks for infection and recurrent disease. However, post-transplantation cyclophosphamide for GVHD prophylaxis has markedly increased the clinical use of haploidentical donors.

Umbilical cord blood hematopoietic stem/progenitor cells, which are taken at the time of delivery and stored in cord blood banks, are readily available within 2 to 4 weeks when needed. Because of the unique immature biology of lymphocytes in umbilical cord blood, these transplants are associated with less GVHD; consequently, the HLA-matching requirements are less strict, and two or three HLA mismatches may be acceptable. However, the small volume (50 to 150 mL) of cord blood that can be collected limits the number of hematopoietic stem/progenitor cells and often prohibits their use in adults because successful engraftment correlates with the number of cells per patient body weight. The limitation of cell dose can be overcome by the use of more than one cord blood unit and the ability to expand cord blood cells ex vivo, thereby resulting in engraftment rates similar to other cell sources. One significant disadvantage is that the use of a cord blood unit eliminates the probability of obtaining additional cells if the graft fails or if a donor lymphocyte infusion is required.

After a source of allogeneic stem cells has been identified, patients then receive a pretransplant regimen with the intent of “conditioning” or “preparing” them for the infusion ( Fig. 163-1 ). These conditioning regimens are designed to be adequately immunosuppressive to overcome the host-versus-graft reaction and permit engraftment. They also are designed to eradicate the primary tumor in patients with an underlying malignancy. Most conditioning regimens use chemotherapy alone or a combination of total body irradiation or total nodal irradiation with chemotherapy. The doses of total body and total lymphoid irradiation vary between 200 and 1440 cGy. The most commonly used chemotherapy for conditioning regimens is an alkylating agent (e.g., cyclophosphamide, busulfan, thiotepa) combined with immunosuppressive drugs such as fludarabine. Conditioning regimens also may contain monoclonal antibodies that target T cells (e.g., antithymocyte globulin, alemtuzumab).

The choice of a specific conditioning regimen depends on the disease being treated, and the doses of chemotherapy and radiation are highly variable. When the doses result in a degree of myelosuppression and immunosuppression that is nearly universally fatal without the infusion of hematopoietic stem/progenitor cells as a rescue product, they are referred to as myeloablative.

Allogeneic hematopoietic cell transplantation with myeloablative conditioning regimens has been performed successfully in patients older than age 60 years, but survival after transplantations declines with increasing age, thereby limiting the application of allogeneic transplantation to a minority of patients who potentially could benefit from this procedure. However, the demonstration that an immune-mediated graft-versus-tumor effect plays a central role in the therapeutic efficacy of allogeneic hematopoietic cell transplantation led to the development of less intensive conditioning regimens that are adequately immunosuppressive to permit the engraftment of donor cells but associated with decreased toxicities compared with myeloablative regimens. Another advantage of less intensive conditioning is that it can be delivered outside of the hospital setting, so that patients receive their care in the outpatient setting and are able to stay in a local apartment or their actual home if they live close to the center. Although the reduced doses of radiation and chemotherapy result in decreased antitumor activity and are associated with higher rates of recurrent disease after transplantation, these “nonmyeloablative” and “reduced-intensity” conditioning regimens have markedly increased the potential option of allogeneic hematopoietic cell transplantation for older patients and patients with preexisting comorbidities.

Syngeneic Hematopoietic Cell Transplantation

The major advantage of a syngeneic hematopoietic cell transplantation from an identical twin is that it is not associated with GVHD or graft rejection, thereby resulting in a relatively low risk for treatment-related morbidity and mortality. Syngeneic hematopoietic cell transplantation, as with allogeneic transplantation, also avoids potential contamination with malignant cells. The major disadvantage of syngeneic transplantation is that it does not provide the graft-versus-leukemia effect associated with allogeneic transplantation. However, since far less than 1% of patients have an identical twin, syngeneic transplantation is rarely an option.

Autologous Hematopoietic Cell Transplantation

The major rationale for autologous hematopoietic cell transplantation with the patient’s own cells is that certain malignancies, such as leukemias and lymphomas, have a steep dose-response curve to chemotherapy and, to a relative degree, radiation. However, the associated limitation of higher doses of chemotherapy or radiation attenuates myelosuppressive effect. The infusion of autologous hematopoietic stem/progenitor cells (and for that matter, allogeneic and syngeneic cells) can restore hematopoiesis after the prior administration of high-dose chemotherapy, with or without radiation. The major advantages of autologous as compared with allogeneic transplantation are that the patient can serve as his or her own donor and that it may be performed in older patients with significantly lower morbidity and mortality because of the absence of GVHD. Although patients undergoing autologous hematopoietic cell transplantation have higher relapse rates than patients undergoing allogeneic transplantation, the lower rates of other complications seem to translate into similar long-term outcomes. Nevertheless, the higher conditioning doses of chemotherapy before autologous hematopoietic cell transplantation can be associated with more morbidity than conventional doses of chemotherapy.

Indications for Transplantation

An estimated 90,000 hematopoietic cell transplantations are performed annually worldwide, primarily for the treatment of hematologic malignancies, bone marrow failure states, and immune and enzyme deficiencies ( Fig. 163-2 ).