The goal of this project is to increase access to hematopoietic stem cell transplants (HSCT) from normal volunteer or partially matched family member donors for patients lacking an HLA identical sibling, and to improve the safety and efficacy of these alternative donor transplants for patients with hematological malignancy. HSCT from alternative donors are associated with greater risk of severe graft-versus-host disease (GVHD), morbidity, and non-relapse mortality than HSCT from HLA identical siblings. In the past, these differences have been partly due to inadequate methods for detecting HLA sequence polymorphisms capable of inducing allograft reactions causing graft failure and GVHD. Advances in DNA-based typing technology have provided powerful tools for detecting genetic differences between patients and donors, but the greater sensitivity achieved has created ambiguities in the definition of an acceptable match. Previous studies have demonstrated the advantages of better matching; however, the limits of safe mismatching are poorly defined. The studies proposed here will continue to examine this question and aim to determine the degree of mismatching for HLAA, B, C, DR and DQ that can be tolerated without significantly increasing the risk of severe GVHD or transplant-related mortality. Other genes encoding immune regulator molecules may also affect transplant outcome by modifying the severity of GVHD and regimen-related toxicity (RRT). Investigations will be undertaken to determine if genetic variation in these genes may explain the different degrees of toxicity seen in individual patients. The problems of RRT and transplant-related mortality (TRM) will be addressed through two approaches, modifying the conditioning regimen and minimizing the severe neutropenia usually associated with myeloablative regimens. One phase I/II trial will evaluate the safety and efficacy of substituting fludarabine for cyclophosphamide in a regimen containing busulfan. A second phase I/II trial will evaluate the ability of growth factor mobilized peripheral blood stem cells (PBSC) to mitigate RRT and TRM by improving the speed and quality of donor cell engraftment. Clinical trials will also be undertaken to determine if modifications to the pretransplant conditioning regimen can mitigate the risk of graft failure associated with donor HLA incompatibility, and future trials will evaluate new approaches for controlling GVHD in the presence of recipient HLA disparity.
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