Hematopoietic CellTransplantation¶
Chapter 119 | Harrison's 22e · Part 4 – Oncology: Hematologic Malignancies
Detailed clinical reference synthesised from Harrison's Principles of Internal Medicine, 22nd Edition
🔑 Key Clinical Points¶
- See source text for full details
📑 Table of Contents¶
📋 Figures in This Chapter¶
| # | Type | Description |
|---|---|---|
| 1 | 🖼 Figure | Major syndromes complicating marrow transplantation |
RAW CONTENT¶
[PAGE 914] 914 PART 4 Oncology and Hematology cells transplanted with the stem cells or developing from them can 119 Hematopoietic Cell react against the patient, causing GVHD. Alternatively, if the immuno- suppressive preparative regimen used to treat the patient before trans- Transplantation plant is inadequate, immunocompetent cells of the patient can cause graft rejection. The risks of these complications are influenced by the Frederick R. Appelbaum degree of matching between donor and recipient for human leukocyte antigen (HLA) molecules encoded by genes of the major histocompat- ibility complex. Bone marrow transplantation was the original term used to describe HLA molecules are responsible for binding antigenic proteins and the collection and transplantation of hematopoietic stem cells, but with presenting them to T cells. The antigens presented by HLA molecules the demonstration that peripheral blood and umbilical cord blood are may derive from exogenous sources (e.g., during active infections) or also useful sources of stem cells, hematopoietic cell transplantation has may be endogenous proteins. If individuals are not HLA-matched, T become the preferred generic term for this process. Hematopoietic cells from one individual will react strongly to the mismatched HLA, cell transplantation is used to treat patients with an abnormal but or “major antigens,” of the second. Even if the individuals are HLA- nonmalignant lymphohematopoietic system by replacing it with one matched, the T cells of the donor may react to differing endogenous or from a normal donor. Hematopoietic cell transplantation is also used “minor antigens” presented by the HLA of the recipient. Reactions to to treat malignancy by allowing the administration of higher doses of minor antigens tend to be less vigorous. The genes of major relevance myelosuppressive therapy than would otherwise be possible and, in the to transplantation include HLA-A, -B, -C, and -D; they are closely setting of allogeneic hematopoietic cell transplantation, by conferring linked and therefore tend to be inherited as haplotypes, with only rare an immunologic graft-versus-tumor effect. The use of hematopoietic crossovers between them. Thus, the odds that any one full sibling will cell transplantation is increasing, as it becomes safer and applicable to match a patient are one in four, and the probability that the patient has more diseases and as donor availability expands. an HLA-identical sibling is 1 − (0.75)n, where n equals the number of The Worldwide Network for Blood and Marrow Transplantation siblings. (http://www.wbmt.org) estimates that worldwide more than 100,000 With conventional techniques, the risk of graft rejection is 1–3%, transplants were performed in 2022. The frequency of transplanta- and the risk of severe, life-threatening acute GVHD is ~15% following tion varied widely from country to country, with a close association of transplantation between HLA-identical siblings. The incidence of graft transplant rates with gross national income (GNI) per capita. However, rejection and GVHD increases progressively with the use of family even among countries with similar GNIs per capita, there are substan- member donors mismatched for one, two, or three antigens. Newer tial differences between countries and regions regarding the frequency approaches to GVHD prophylaxis, including the use of posttransplant of transplantation, disease indications, and choice of donor type. high-dose cyclophosphamide, have diminished the impact of HLA mismatching, making transplantation between donor/recipient pairs who share only one HLA haplotype possible. Since the formation of the THE HEMATOPOIETIC STEM CELL National Marrow Donor Program and other registries, HLA-matched Several features of the hematopoietic stem cell (HSC) make trans- unrelated donors can be identified for many patients. The genes plantation clinically feasible, including its remarkable regenerative encoding HLA antigens are highly polymorphic, and thus the odds of capacity, its ability to home to the marrow space following intravenous any two unrelated individuals being HLA identical are extremely low, injection, and the ability of the stem cell to be cryopreserved (Chap. 101). somewhat less than 1 in 10,000. However, by recruiting >40 million Transplantation of a single stem cell can replace the entire lympho- volunteer donors, HLA-matched donors can be found for ~60% of hematopoietic system of an adult mouse. In humans, transplantation patients for whom a search is initiated, with higher rates among whites of a small percentage of a donor’s bone marrow volume regularly and lower rates among minorities and patients of mixed race. It takes, results in complete and sustained replacement of the recipient’s entire on average, 3–4 months to complete a search and schedule and initiate lymphohematopoietic system, including all red cells, granulocytes, B an unrelated donor transplant. With improvements in HLA typing and and T lymphocytes, and platelets, as well as cells comprising the fixed supportive care measures, survival following matched unrelated donor macrophage population, including Kupffer cells of the liver, pulmonary transplantation is essentially the same as that seen with HLA-matched alveolar macrophages, osteoclasts, and Langerhans cells of the skin. siblings. Homing of HSCs to their marrow niche initially involves interactions Allogeneic hematopoietic cell transplantation can be carried out between P- and E-selectins on marrow sinusoidal endothelium with across ABO blood barriers by removing isoagglutinins and/or incom- integrins including VLA-4 on HSCs. Once tethered to the vascular patible red blood cells from the donor graft. However, depending on endothelium, changes in integrin conformation result in tight adhesion the direction of the mismatch, hemolysis of donor cells by persistent following which stem cells migrate through the endothelium and extra- isoagglutinins in the host, or hemolysis of recipient red cells by isoag- cellular matrix eventually reaching the stem cell niche. This last step is glutinins in the graft or developing from it may occur despite appropri- facilitated by CXCL12 produced by the niche stroma interacting with ate manipulation of the donor cell product. the chemokine CXCR4 on HSCs. Human hematopoietic stem cells can Autologous transplantation involves the removal and storage of the survive freezing and thawing with little, if any, damage, making it pos- patient’s own stem cells with subsequent reinfusion after the patient sible to remove and store a portion of the patient’s own bone marrow receives high dose myeloablative therapy. Unlike allogeneic transplan- for later reinfusion following treatment of the patient with high dose tation, there is no risk of GVHD or graft rejection with autologous myelotoxic therapy. transplantation. On the other hand, autologous transplantation lacks a graft-versus-tumor (GVT) effect, and the autologous stem cell product CATEGORIES OF HEMATOPOIETIC CELL can be contaminated with tumor cells, which could lead to relapse. A TRANSPLANTATION variety of techniques have been developed to “purge” autologous prod- Hematopoietic cell transplantation can be described according to the ucts of tumor cells, but no prospective randomized trials have shown relationship between the patient and the donor and by the anatomic that any approach decreases relapse rates or improves disease-free or source of stem cells. In ~1% of cases, patients have identical twins who overall survival. can serve as donors. With the use of syngeneic donors, there is no risk of Bone marrow aspirated from the posterior and anterior iliac crests graft-versus-host disease (GVHD), and unlike the use of autologous mar- initially was the source of hematopoietic stem cells for transplantation. row, there is no risk that the stem cells are contaminated with tumor cells. Typically, anywhere from 1.5 to 5 × 108 nucleat
Figures & Illustrations¶
Reproduced from Harrison's 22nd Edition.
Figure 1¶
Caption: FIGURE 119-1 Major syndromes complicating marrow transplantation. CMV, cytomegalovirus; GVHD, graft-versus-host disease; HSV, herpes simplex virus; SOS, sinusoidal obstructive syndrome (formerly venoocclusive disease); VZV, varicella- zoster virus. The size of the shaded area roughly reflects the period of risk of the complication.
Generated from Harrison's Principles of Internal Medicine, 22nd Edition.