Histocompatibility

Histocompatibility differences between the donor and the recipient necessitate immunosuppression after an allogeneic HSCT because considerable morbidity and mortality are associated with graft failure and GVHD. Rejection is least likely to occur with a syngeneic donor, meaning that the recipient and host are identical (monozygotic) twins. In patients without a syngeneic donor, initial HLA typing is conducted on family members because the likelihood of complete histocompatibility between unrelated individuals is remote. Siblings are the most likely individuals to be histocom-patible within a family. The chance for complete histocompatibility occurring in an individual with only one sibling is 25%. Approximately 40% of patients with more than one sibling will have an HLA-identical match. Having a matched-sibling donor is no longer a requirement for allogeneic HSCT because improved immunosuppressive regimens and the National Marrow Donor Program have allowed an increase in the use of unrelated or related matched or mismatched HSCTs. The use of alternative sources of allogeneic hematopoietic cells, such as related donors mismatched at one or more HLA loci or phenotypically (i.e., serologically) matched unrelated donors, has been evaluated.5 Establishment of the National Marrow Donor Program has helped to increase the pool of potential donors for allogeneic HSCT. Through this program, an HLA-matched unrelated volunteer donor might be identified. Recipients of an unrelated graft are more likely to experience graft failure and acute GVHD relative to recipients of a matched-sibling donor. Determination of histocompatibility between potential donors and the patient is completed before allogeneic HSCT. Initially, HLA typing is performed using blood samples and compatibility for class I MHC antigens (i.e., HLA-A, HLA-B, and HLA-C) is determined through serologic and DNA-based testing methods. In vitro reactivity between donor and recipient also can be assessed in mixed-lymphocyte culture, a test used to measure compatibility of the MHC class II antigens (i.e., HLA-DR, HLA-DP, and HLA-DQ). Currently, most clinical and research laboratories are also performing molecular DNA typing using polymerase chain reaction methodology to determine the HLA allele sequence.6

The preparative regimen or GVHD prophylaxis may be altered based on the mismatch between the donor and the recipient. The risk of graft failure decreases with better matches such that those with a class I (i.e., HLA-A, -B, or -C) antigen mismatch have the highest risk of rejection; those with just one class I allele mismatch have a minimal risk. Graft failure does not appear to be associated with mismatch at a single class II antigen or allele.6 GVHD and survival have been associated with disparity for

class I and II antigens and alleles. Stem Cell Sources

Autologous hematopoietic stem cells are obtained from bone marrow or peripheral blood. The technique for harvesting autologous hematopoietic cells depends on the anatomic source (i.e., bone marrow or peripheral blood). A surgical procedure is necessary for obtaining bone marrow. Multiple aspirations of marrow are obtained from the anterior and posterior iliac crests until a volume with a sufficient number of hema-topoietic stem cells is collected (i.e., 600-1,200 mL of bone marrow). The bone marrow then is processed to remove fat or marrow emboli and usually is infused IV into the patient like a blood transfusion.

The shift to the use of PBPCs over bone marrow for autologous HSCT is primarily because of the more rapid engraftment and decreased health care resource use. Because the harvest occurs before administering the preparative regimen, autologous hematopoietic cells must be cryopreserved and stored for future use.

Transplantation with PBPCs essentially has replaced bone marrow transplantation (BMT) as autologous rescue after myeloablative preparative regimens. Autologous PBPCs are obtained by administering a mobilizing agent(s) followed by apheresis, which is an outpatient procedure similar to hemodialysis. Hematopoietic growth factors (HGFs) alone or in combination with myelosuppressive chemotherapy are used for mobilization of autologous PBPCs with similar results. The HGFs granulocyte-macrophage colony-stimulating factor (sargramostim, Leukine) and granulocyte colony-stimulating factor (filgrastim, Neupogen) are used as mobilizing agents. The use of pegylated granulocyte colony-stimulating factor (pegfilgrastim, Neulasta) for mobilization of PBPCs appears more convenient and is promising as a mobilization agent; however, further data are needed regarding graft composition, HSCT outcomes, and donor safety in allogeneic donations before widespread use of this agent can be recommended.

The combination of chemotherapy with an HGF enhances PBPC mobilization relative to HGF alone.1 In addition to treating the underlying malignancy, this approach lowers the risk of tumor cell contamination and the number of apheresis collections required, but there is a greater risk of neutropenia and thrombocytopenia. The HGF

is initiated after completion of chemotherapy and is continued until apheresis is complete. Many centers monitor the number of cells that express the CD34 antigen (i.e., CD34+ cells) to determine when to start apheresis. The CD34 antigen is expressed on almost all unipotent and multipotent colony-forming cells and on precursors of colony-forming cells, but not on mature peripheral blood cells. Apheresis is continued daily until the target number of PBPCs per kilogram of the recipient's weight is obtained. For adult recipients, the number of CD34+ cells correlates with time to engraftment. Lower yield of CD34+ cells is associated with administration of stem cell toxic drugs (e.g., carmustine and melphalan) and intensive prior chemotherapy or radiotherapy.

If patients are unable to obtain an adequate yield of CD34+ cells per kilogram after mobilization attempts fail, then allogeneic transplant may be considered as an alternative. In 2008, plerixafor (Mobozil) was FDA approved for use in combination with granulocyte colony-stimulating factor to mobilize PBPCs for collection and subsequent autologous transplantation in patients with NHL and MM. Plerixafor is an inhibitor of the CXCR4 chemokine receptor which results in more circulating PBPCs in the peripheral blood due to the inability of CXCR4 to assist in anchoring hematopoietic stem cells to the bone marrow matrix. Since administration of plerixafor with granulocyte colony-stimulating factor results in increased yield of CD34+ cells per kilogram compared to granulocyte colony-stimulating factor alone, this combination may serve as an alternative mobilization strategy in patients deemed to be at risk for mobilization failure with conventional methods.

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