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Kufe DW, Pollock RE, Weichselbaum RR, et al., editors. Holland-Frei Cancer Medicine. 6th edition. Hamilton (ON): BC Decker; 2003.

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Holland-Frei Cancer Medicine. 6th edition.

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Engraftment of Allogeneic Hematopoietic Transplants

, MD.

An intensive pretransplant immunosuppressive treatment, termed the “preparative regimen,” or “conditioning,” is necessary to prevent rejection of an allogeneic hematopoietic transplant. More intensive pretransplant immunosuppression is required for hematopoietic transplantation than is necessary to prevent rejection of solid organ allografts such as kidney, liver, or heart. The immunosuppressive preparative treatment administered prior to transplantation must markedly suppress the recipient's T lymphocyte and natural killer (NK) cell function. In addition, engraftment is enhanced by myelosuppressive preparative therapy, which possibly provides “space” in the bone marrow microenvironment to allow engraftment of hematopoietic stem cells or facilitates successful competition of donor-derived cells with repopulating endogenous autologous recipient-derived stem cells. The intensity of immunosuppressive therapy required for engraftment varies depending on the immunocompetence of the recipient and the composition of the transplanted cells. High doses of donor stem cells and T cells present in the allograft also enhance engraftment by an alloreactive graft-versus-host hematopoietic effect.42,43

For the treatment of malignancies, the preparative regimen is also directed to eradicating the malignancy or the defective hematopoietic tissue. The preparative regimen generally involves chemotherapy drugs alone or combined with total body irradiation (TBI). The classical “myeloablative” regimens used in the treatment of leukemia are designed to ablate both hematopoiesis and immunity in the recipient and typically involves the combination of high-dose cyclophosphamide with either TBI44,45 or high-dose busulfan.46,47 These regimens are sufficient to produce engraftment of > 98% of allogeneic transplants from HLA-identical siblings. More intensive immunosuppression is necessary for transplants from HLA-nonidentical siblings or if T cells are depleted from the allograft in order to prevent GVHD; addition of other myelosuppressive or immunosuppressive drugs have been employed to enhance engraftment in these settings.

The toxicity of high-dose myeloablative therapy limits the use of this modality to relatively young patients in good medical condition. The discovery of the curative potential of the immune mediated graft-versus-malignancy effect has led to a novel approach using lower-dose, nonablative preparative regimens as a means to reduce the toxicity of allogeneic hematopoietic transplantation. These nonmyeloablative conditioning regimens have been designed not to eradicate the malignancy, but rather to provide sufficient immunosuppression to achieve engraftment and to allow induction of graft-versus-malignancy (Figure 69-2).48–50 These regimens can be tolerated by older patients and those with comorbidities who were not eligible to receive an ablative preparative regimen. Nonablative regimens are now being investigated as an alternative strategy to reduce transplant-related morbidity in a variety of settings. Most nonablative regimens include a purine analog, such as fludarabine, combined with an alkylating agent (cyclophosphamide, melphalan, or busulfan) or low-dose total body irradiation. Engraftment has been achieved in most patients, and this approach is effective against a range of hematologic malignancies.

Figure 69-2. Scheme of nonablative allogeneic hematopoietic transplantation.

Figure 69-2

Scheme of nonablative allogeneic hematopoietic transplantation. D = donor hematopoietic cells; DLI = donor lymphocyte infusion; HSCT = hematopoietic stem cell transplant; R = recipient's normal bone marrow cells; Rl = recipient's leukemia cells in bone (more...)

After the conditioning therapy is completed, the hematopoietic cells are infused intravenously. The cells circulate transiently and sufficient numbers of stem cells home to the bone marrow to restore hematopoiesis. Peripheral blood counts are profoundly suppressed following high-dose chemotherapy, but generally recover within 3 to 4 weeks following bone marrow transplantation. The date of engraftment is generally defined as the first of three consecutive days with an absolute neutrophil count > 0.5 × 109/L. Hematopoietic growth factors granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) accelerate recovery of granulocyte counts, but have no effect on erythrocytes or platelets. Transplantation of peripheral blood progenitor cells (PBPC) generally produce more rapid hematopoietic recovery than bone marrow, and they accelerate recovery of platelets as well as granulocytes.

Allogeneic engraftment of donor cells can be documented by acquisition of donor-type cell surface antigens, isoenzymes, chromosome markers, or DNA-restriction fragment length polymorphisms. Following successful transplantation, cells of the hematologic and immunologic systems are primarily derived from the donor, although in some cases mixed chimerism occurs in which both donor and recipient derived cells are present. Mixed chimerism has been more frequent after T-cell depletion of the donor graft and after nonmyeloablative conditioning.51

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Copyright © 2003, BC Decker Inc.
Bookshelf ID: NBK13011


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