yet been universally adopted because there are no convincing data in Phase 2 trials that patients receiving purged marrow fare better than those receiving unpurged cells. A retrospective analysis of the European Blood and Marrow Transplant Lymphoma Registry compared the outcome of 270 patients whose BM had been purged and with the outcome of 270 case-matched control patients.80 A variety of purging methodologies was used. Patients with low-grade lymphoma did not have a significantly improved progression-free survival if the BM was purged (P = 0.18), but they did have a significantly improved overall survival (P = 0.0018). In multiple myeloma, a Phase III randomized trial using purged versus unpurged autologous PBSC was performed using CD34 selection.81 After CD34 selection, tumor burden was reduced by a median of 3.1 log, with 54% of CD34-selected products having no detectable tumor. There was no improvement in disease-free or overall survival.

Data indicate, however, that contamination of the stem cell inoculum with tumor cells contributes to posttransplant relapse. In studies at the Dana-Farber Cancer Institute, polymerase chain reaction (PCR) amplification of the t(14;18) was used to detect residual lymphoma cells in the BM before and after purging to assess whether efficient purging had any impact on disease-free survival.82 In this study, patients with B-cell non-Hodgkin lymphoma and the bcl-2 translocation were studied. Residual lymphoma cells were detected in all patients in the harvested autologous BM. Following three cycles of immunologic purging using the anti-B-cell mAbs and complement-mediated lysis, PCR amplification detected residual lymphoma cells in 50% of patients. Patients who were infused with a source of hematopoietic cells that was free of detectable lymphoma cells had improved outcome compared to those who had residual detectable lymphoma (see Figure 6.2). This finding was independent of degree of BM infiltration at the time of BM harvest or remission status at the time of autologous BMT. Further evidence supporting the contribution of contaminating tumor cells to posttransplant relapse comes from gene marking studies in AML and neuroblastoma.83-85

Allogeneic Donors

When allogeneic transplantation is contemplated, an HLA-identical or closely matched donor must be found. The major HLA loci are located on chromosome 6 and are closely linked.86 Because every individual inherits one chromosome 6 from their mother and one from their father, the chance of any one sibling being a match is one in four. A complete match between donor and recipient was considered identity of both alleles at HLA-A, HLA-B, and HLA-DR loci. Other major loci, such as HLA-C and HLA-DQ, can influence outcome and must be checked when performing a search for an unrelated donor. Indeed, HLA-C identity is now considered as important as a match at HLA-A, -B, and -DR.87-90 Accurate HLA typing is essential. Serologic methods are no longer adequate. It is imperative that molecular techniques using site-specific oligonucleotide probes and direct sequencing be employed. The formation of the National Marrow Donor Registry (NMDR) has made possible thousands of unrelated transplants in the United States. More than 4 million people are registered as potential donors with the NMDP. The likelihood of finding an HLA-A, -B, and -DR

match is 65% to 70%, although finding a donor is more difficult in minority populations. It can take weeks to many months between the time a search is initiated and a donor is identified, medically cleared, and ultimately donates.

Even when a "complete" match is found, complications such as GVHD can still be substantial. The reason for this is that minor HLA antigens, which can influence graft rejection or GVHD, cannot be easily typed.91-93 Moreover, these minor antigens likely are not found on chromosome 6; therefore, a complete match of HLA major loci does not necessarily translate into a complete match of minor loci. Results of allogeneic transplantation using unrelated donors have been slightly worse than those of matched related transplants, but with improvements in typing, the gap has narrowed.94

Sometimes it is possible to identify more than one potential donor either within a family or through the NMDP. The most important characteristic in choosing a donor is HLA identity. The greater the HLA disparity, the greater the risk of GVHD, graft failure, and adverse outcome. Other factors that may increase GVHD include the use of female multi-parous donors for male recipients (a minor HLA antigen located on the Y chromosome has recently been identified), older donor age, and prior cytomegalovirus (CMV) exposure.95,96 ABO compatibility is desirable but is not a prerequisite for transplantation. ABO incompatibility may lead to hemolysis and delayed red cell engraftment.97

Transplantation of hematopoietic stem cells from haploidentical family members has been associated with increased risks of GVHD and graft failure.98,99 Historically, outcome has been poor. Recent studies of infusion of large numbers of haploidentical peripheral blood stem cells exhaustively depleted of T cells through positive selection of CD34+ stem cells has been reported to result in high rates of engraft-ment and low rates of GVHD.100 Despite T-cell depletion, relapse rates have been low, particularly in patients with AML. It now appears that mismatching of KIR receptor on donor NK cells and KIR ligand on recipient cells may actually promote cell-mediated destruction of AML cells and recipient antigen-presenting cells, leading to lower relapse rates without GVHD.101,102

Recent studies have demonstrated that umbilical cord blood (UCB) is very rich in stem cells but low in alloreactive T cells. As a consequence, it was hypothesized that these cells might support engraftment with less GVHD. A series of studies have confirmed that engraftment can be obtained with unrelated UCB with a reduced risk of GVHD, even when partially HLA-mismatched unrelated transplants donor cells used.103-107 However, because the number of stem cells per kilogram recipient weight is relatively low in cord blood products, engraftment is slow. The number of cells available for transplantation from cord blood may make it difficult to utilize these products with large adult recipients. Strategies currently under investigation to address low cord blood cel-lularity include the use of multiple disparate products and expansion of stem cells ex vivo before infusion.108 UCB transplantation should be considered for patients for whom traditional related or unrelated products are not available.

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