Chapter 108. Hematopoietic Cell Transplantation (Part 2)

With current techniques, the risk of graft rejection is 1–3%, and the risk of severe, life-threatening acute GVHD is ~15% following transplantation between HLA-identical siblings. The incidence of graft rejection and GVHD increases progressively with the use of family member donors mismatched for one, two, or three antigens. While survival following a one-antigen mismatched transplant is not markedly altered, survival following two- or three-antigen mismatched transplants is significantly reduced, and such transplants should be performed only as part of clinical trials.Since the formation of the National Marrow Donor Program, it has become possible to identify HLA-matched unrelated donors for...
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Chapter 108. Hematopoietic Cell Transplantation (Part 2) Chapter 108. Hematopoietic Cell Transplantation (Part 2) With current techniques, the risk of graft rejection is 1–3%, and the risk ofsevere, life-threatening acute GVHD is ~15% following transplantation betweenHLA-identical siblings. The incidence of graft rejection and GVHD increasesprogressively with the use of family member donors mismatched for one, two, orthree antigens. While survival following a one-antigen mismatched transplant isnot markedly altered, survival following two- or three-antigen mismatchedtransplants is significantly reduced, and such transplants should be performed onlyas part of clinical trials. Since the formation of the National Marrow Donor Program, it has becomepossible to identify HLA-matched unrelated donors for many patients. The genesencoding HLA antigens are highly polymorphic, and thus the odds of any twounrelated individuals being HLA-identical are extremely low, somewhat less than1 in 10,000. However, by identifying and typing >7 million volunteer donors,HLA-matched donors can now be found for ~50% of patients for whom a search isinitiated. It takes, on average, 3–4 months to complete a search and schedule andinitiate an unrelated donor transplant. Results so far suggest that GVHD issomewhat increased and survival somewhat poorer with such donors than withHLA-matched siblings. Autologous transplantation involves the removal and storage of thepatients own stem cells with subsequent reinfusion after the patient receives high-dose myeloablative therapy. Unlike allogeneic transplantation, there is no risk ofGVHD or graft rejection with autologous transplantation. On the other hand,autologous transplantation lacks a graft-versus-tumor (GVT) effect, and theautologous stem cell product can be contaminated with tumor cells that could leadto relapse. A variety of techniques have been developed to purge autologousproducts of tumor cells. Some use antibodies directed at tumor-associated antigensplus complement, antibodies linked to toxins, or antibodies conjugated toimmunomagnetic beads. In vitro incubation with certain chemotherapeutic agentssuch as 4-hydroperoxycyclophosphamide and long-term culture of bone marrowhave also been shown to diminish tumor cell numbers in stem cell products.Another technique is positive selection of stem cells using antibodies to CD34,with subsequent column adherence or flow techniques to select normal stem cellswhile leaving tumor cells behind. All these approaches can reduce the number oftumor cells from 1000- to 10,000-fold and are clinically feasible; however, noprospective randomized trials have yet shown that any of these approaches resultsin a decrease in relapse rates or improvements in disease-free or overall survival. Bone marrow aspirated from the posterior and anterior iliac crests hastraditionally been the source of hematopoietic stem cells for transplantation.Typically, anywhere from 1.5 to 5 x 108 nucleated marrow cells per kilogram arecollected for allogeneic transplantation. Several studies have found improvedsurvival in the settings of both matched sibling and unrelated transplantation bytransplanting higher numbers of bone marrow cells. Hematopoietic stem cells circulate in the peripheral blood but in very lowconcentrations. Following the administration of certain hematopoietic growthfactors, including granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF), and during recovery fromintensive chemotherapy, the concentration of hematopoietic progenitor cells inblood, as measured either by colony-forming units or expression of the CD34antigen, increases markedly. This has made it possible to harvest adequatenumbers of stem cells from the peripheral blood for transplantation. Donors aretypically treated with 4 or 5 days of hematopoietic growth factor, following whichstem cells are collected in one or two 4-h pheresis sessions. In the autologoussetting, transplantation of >2.5 x 106 CD34 cells per kilogram, a number easilycollected in most circumstances, leads to rapid and sustained engraftment invirtually all cases. Compared to the use of autologous marrow, use of peripheralblood stem cells results in more rapid hematopoietic recovery, with granulocytesrecovering to 500/µL by day 12 and platelets recovering to 20,000/µL by day 14.While this more rapid recovery diminishes the morbidity of transplantation, nostudies show improved survival. Hesitation in studying the use of peripheral blood stem cells for allogeneictransplantation was because peripheral blood stem cell products contain as muchas one log more T cells than are contained in the typical marrow har ...