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All forms of HSCT require some conditioning of the recipient with myelotoxic therapies. Conditioning is required to kill or mobilize sufficient numbers of host HSCs to open up the stem cell niche in the marrow (Chapter 2), creating space for the HSCs in the graft. Conditioning also may serve to eradicate a host immune system that has run amok (eg, aplastic anemia, Chapter 4) or to destroy tumor cells that may be resistant to standard doses of chemotherapy and radiation (eg, the transformed HSCs that cause chronic myelogenous leukemia, Chapter 20). The precise conditioning regimen used is tailored to the disorder being treated. For nonneoplastic disorders, common regimens consist of chemotherapy with or without anti-thymocyte globulin, an antibody that recognizes and leads to the killing of T cells. For neoplastic disorders, conditioning is usually done with high-dose chemotherapy regimens, sometimes in combination with total body irradiation.
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Several days after conditioning, donor HSCs are transfused into the peripheral blood of the recipient. If all goes well, the marrow and the peripheral blood are reconstituted by donor-derived hematopoietic cells and their progeny (Fig. 26-2). The earliest formed elements that appear in the recipient are derived from late myeloid progenitors, followed by a second cohort of cells derived from early myeloid progenitors. However, sustained reconstitution requires engraftment of HSCs, the only marrow cells that possess the key properties of multipotency and self-renewing capacity.
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On average, it takes about 3 weeks for the marrow to engraft and begin to produce mature myeloid cells (platelets, red cells, and neutrophils). However, the pace and timing of reconstitution in the recipient varies depending on several factors including the source of the HSCs. In general, unfractionated bone marrow has greater numbers of early progenitors and HSCs than does cord blood, and, as a result, patients receiving unfractionated bone marrow tend to engraft more rapidly. During the critical pre-engraftment period, these patients are profoundly immunosuppressed and are completely dependent on transfusion of red cells to maintain oxygen delivery to tissues and transfusion of platelets to prevent bleeding. Because of agranulocytosis there is a very high risk of severe and potentially fatal bacterial and fungal infections during the first 2 or 3 weeks, prior to the production of adequate numbers of neutrophils from the allograft. Measures aimed at reducing the morbidity and mortality associated with infections in the immediate posttransplant period include housing of patients in special positive-pressure rooms supplied with filtered air to limit exposure to pathogens and aggressive treatment with broad-spectrum antibiotics at the earliest sign of infection.
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Other complications in the early posttransplant period are directly related to cellular injuries induced by conditioning. Nearly all patients have mucositis, particularly of the soft palate and esophagus, causing swallowing to be painful and difficult. These mucosal lesions are potential sites of entry of pathogenic bacteria. An even more serious complication is veno-occlusive disease, which appears to be caused by damage to endothelial cells lining the venous sinusoids of the liver. Although the precise pathogenesis is unknown, the injury induces fibrin deposition and obstruction of hepatic sinusoids (leading some to suggest that this entity would be better entitled sinusoidal obstruction syndrome). The blockage of blood flow causes liver engorgement and tender hepatomegaly and can lead to hypoxic centrilobular hepatic necrosis and liver failure in severe cases.
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Graft failure and graft rejection are other serious early complications of HSCT. The incidence of graft rejection is proportional to the degree of immunologic dissimilarity between the donor and the recipient and thus is relatively high in unrelated allogeneic HSCTs. Graft rejection also is increased by prior immunization of the recipient by transfusions of red cells or platelets. Graft failure may stem from an insufficiency of HSCs in the stem cell preparation, damage to the marrow microenvironment caused by the conditioning regimen, or infection. Patients who fail to engraft must undergo another transplant, typically with HSCs from an unrelated donor, if they are to recover. Understandably, second transplants are associated with a high rate of graft failure and morbidity and mortality related to a second round of conditioning.
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Once neutrophils appear, the recipient's risk of bacterial and fungal infections declines dramatically. However, as described in the following section, in allogeneic transplant recipients reconstitution of the lymphoid arm of the immune system is a much more complicated process, one involving a delicate balance between immunosuppression and GVHD, an assault on the host mediated by lymphocytes derived from the graft. Under the best of circumstances, recovery of adaptive immunity in allogeneic HSCT recipients requires many months, and, as a result, these patients are at high risk for viral infections and Epstein-Barr virus (EBV)–driven B-cell tumors for an extended period of time after transplantation.