Page 1789 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 103 Overview and Choice of Donor of Hematopoietic Stem Cell Transplantation 1593

and immune effector cells posttransplant to reduce the risk of and tested for infectious agents in accordance with standards devel-
relapse. oped by governmental and specialty oversight organizations. This
Both American Society for Blood and Marrow Transplantation and worldwide network for UCB cell procurement, typing, and storage
National Comprehensive Cancer Network guidelines recommend has collected a large inventory of cords and has facilitated more than
autologous transplantation in patients with relapsed or refractory 20,000 unrelated donor UCB transplants. A major advantage of cord
diffuse large B-cell lymphoma as well as selected patients with follicu- transplant is the immediate availability of cryopreserved units. Cord
lar lymphoma. Several large studies have also showed benefit from transplants have slower engraftment, but they also may also induce
consolidating with an autograft after initial therapy in patients with less GVHD because of the relative naivety of cord T cells. One limita-
mantle-cell lymphoma. A number of different myeloablative condi- tion is the cell count, which can be limiting for individuals weighing
tioning regimens are used in patients with non-Hodgkin lymphoma more than 50 kg. However, several studies show that double cord
with the most common being BCNU, etoposide, cytosine arabinoside, blood transplant, with each unit sharing at least 4/6 HLA antigens
and melphalan (BEAM), often in combination with rituximab. with the recipient, can overcome this problem and extend the use of
cord transplant to larger adult recipients (see Chapter 107).

SOURCE OF HEMATOPOIETIC STEM CELLS
CONDITIONING REGIMENS
The major sources of stem cells for transplant are BM, mobilized PB,
and cord blood. The conditioning regimen has different roles in autologous and
allogeneic transplant. In autologous transplant, the aim of the con-
ditioning regimen is to intensify doses of chemotherapy agents that
Autologous Donors would be limited by hematopoietic toxicity. In allogeneic transplant,
the goal of conditioning is to achieve immunosuppression of the
In autologous transplantation, the source of HSCs is mobilized PB recipient sufficient to prevent rejection of the donor BM cells and to
in almost all adults and more than 90% of pediatric patients. destroy residual malignant cells (see Chapter 104). Historically,
Cytokine-mobilized PB stem cells (PBSCs) can be harvested either patients transplanted for malignancy have received intensive fully
after treatment with recombinant human granulocyte colony- ablative regimens in which hematopoietic reconstitution would not
stimulating factor (G-CSF) alone or with G-CSF given after chemo- occur without HSC support. Conditioning regimens are discussed in
therapy. In patients who are heavily pretreated and difficult to more detail in Chapter 104, but the most commonly used allogeneic
mobilize, plerixifor, an antagonist of CXCR4 that interferes with regimens use total-body irradiation and cyclophosphamide or che-
adhesion of hematopoietic progenitors in the microenvironment motherapy alone with combinations such as busulfan and cyclophos-
thereby promoting their circulation in the PB, can be used to increase phamide. Biologic agents, such as antithymocyte globulin and
+
the mobilization of CD34 stem cells when given in combination monoclonal antibodies, may also be included in some regimens to
with standard G-CSF therapy. increase immunosuppression. Reduced-intensity conditioning regi-
The success of HSC mobilization is related to the amount of mens were developed in the late 1990s and are primarily immunosup-
previous chemotherapy with some drugs such as alkylating agents pressive, relying on graft-versus-leukemia mechanisms to eradicate
having a particularly adverse effect on the success of HSC mobiliza- malignancy. Reduced-intensity conditioning is often used in older
tion. The International Myeloma Working Group has therefore rec- patients or patients with comorbidities in whom the toxicity associ-
ommended early mobilization of stem cells, preferably within the first ated with ablative conditioning would be unacceptable. A variety of
four cycles of initial therapy. 17 regimens based on low-dose total-body irradiation or fludarabine
have been used.
Allogeneic Donors
COMPLICATIONS AFTER STEM CELL TRANSPLANTATION
BM was the historic source of HSCs for transplant and remains the
most widely used source in children. Marrow can be harvested from Patients who receive transplants are at risk of a number of short- and
the posterior iliac crests of allogeneic donors in amounts up to long-term complications and require long-term follow up. Guidelines
10–20 mL per kilogram of recipient weight to obtain sufficient HSCs for screening and monitoring long-term survivors have been pub-
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for engraftment. Cytokine-mobilized allogeneic PBSC harvest has lished, and there is increasing interest in research to define the
become an alternative to marrow as a source of HSCs and is now the quality of life in long-term transplant survivors. Recipients of both
most widely used source in adults receiving allogeneic transplants. In allogeneic and autologous transplant have risks of infection during
both single-center randomized studies and CIBMTR registry studies, the period of hematopoietic and immune reconstitution and short-
use of this source of stem cells from matched sibling donors resulted and long-term complications from toxicities from the conditioning
in more rapid engraftment with no increase in acute GVHD. regimen. Allograft recipients are also at risk of graft failure and
However, there was a higher incidence of chronic GVHD associated GVHD because of the genetic disparity between donor and
with a lower risk of relapse, which translated to improved DFS in recipient.
patients transplanted for advanced hematologic malignancies.
However, this survival benefit was not seen in patients with early stage
disease. A large, prospective, randomized trial in recipients of unre- Acute Graft-Versus-Host Disease
lated HSCs who were randomized to receive BM-versus-PB grafts for
hematologic malignancies shows no difference in overall survival at GVHD is the most important cause of mortality, morbidity, and
2 years but a higher incidence of chronic GVHD in the recipients diminished quality of life after allogeneic HCT and results from
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who received PB. Longer follow up is needed to determine if this alloreactivity between donor and recipient. The process is initiated
more frequent development of chronic GVHD will be associated by donor T lymphocytes that recognize antigenic disparities between
with higher late mortality. donor and recipient. In the initial phase, chemotherapy or radiation
given as part of the conditioning regimen results in production of
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inflammatory cytokines secreted by damaged host cells. The release
Umbilical Cord Blood of microbial products that are produced by intestinal flora, as well as
the release of cytokines by damaged host tissues, lead to the activation
Another alternative source of stem cells is cord blood. There are of innate immune cells by pathogen recognition receptors such as
several large cord banks where cord blood is collected, cryopreserved, Toll-like receptors. After infusion of the HSC product, donor T cells