Bone marrow transplantation (BMT) from HLA-mismatched donors is limited by the frequent occurrence of severe graft-versus-host disease (GVHD), graft rejection and prolonged immunoincompetence. For patients with refractory hematologic malignancies, BMT, particularly from HLA-mismatched donors, has rarely been successful. In a murine MHC-mismatched BMT model, mixed lymphohematopoietic chimerism is reliably achieved following a non-myeloablative conditioning regimen. These mixed chimeras are resistant to GVHD even when delayed donor leukocyte infusion-induced lymphohematopoietic GVH reactions convert the mixed chimeras to full donor chimeras. Based on the murine model, we have begun a clinical trial with a preparative regimen consisting of cyclophosphamide, peritransplant anti-thymocyte globulin and thymic irradiation, followed by HLA matched or mismatched related donor BMT. Of 21 evaluable patients with refractory hematologic malignancies, seven have achieved complete and six have achieved partial remissions following BMT. Sustained chimerism was achieved in 18 of 22 evaluable patients, including seven of eight HLA-mismatched transplant recipients. The HLA-mismatched transplant recipient followed the longest has showed stable mixed chimerism for at least 18 months. DLI has thus far been given at 5 weeks only to recipients of HLA-identical donor transplants who lack GVHD. Conversion to full donor chimerism without significant GVHD was induced in three patients who r3eceived one or two DLI at weeks 5 +/-8-9. However, two others developed GVHD after repeated DLI at weeks 5 and 8. Relapses have occurred. in only one of these five patients who received early DLI and converted to full donor chimerism. In this clinical investigation, we will define the optimal treatment schema for induction of mixed chimerism and for administration of DLI. We will evaluate multi-lineage lymphohematopoietic chimerism and recovery of lymphocytes subsets including naive T cells, and will determine the effects of DLI on these subsets. Using in vitro studies, we will evaluate the hypothesis that stronger GVH responses occur, but with less clinical GVHD, in mixed chimeras who received non-myeloablative conditioning than in full chimeras who received myeloablative conditioning. In patients with CLL, we will address the hypothesis that these stronger alloresponses reflect the presence of non-malignant host antigen-presenting cells in mixed chimeras, and that they lead to stronger anti-leukemic cytolytic responses. It is anticipated that these studies will advance a new approach to separating GVHD from graft-versus-leukemia effects of alloreactive donor T cells.
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