ALLOGENEIC BONE MARROW TRANSPLANTATION FOR CML

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Chronic myelogenous leukemia is a potentially curable disease when treated with allogeneic bone marrow transplantation. The major failures of treatment for patients with chronic phase disease are graft-versus-host disease and CMV infection. The major reasons for failure for patients with advanced disease are graft-versus-host disease, CMV infection, and relapse. Moreover, once relapse has occurred after transplantation, options are limited. In this project, we will investigate three innovative approaches to allogeneic marrow transplantation for patients with CML; CD8-depletion for prevention of graft-versus-host disease for patients with HLA-identical donors, subtotal T-cell depletion and intensive posttransplant immunosuppression for GVHD prophylaxis for patients with mismatched or unrelated donors for transplantation for early or advanced disease, and a combination of thiotepa, busulfan, and cyclophosphamide for patients with advanced CML who have HLA-identical donors. Cytogenetics, fluorescence in situ hybridization for the Philadelphia chromosome, western blot assay for the P210, flow cytometry for rare immunophenotypes, 3SR assay for bcr-abl and polymerase chain reaction for bcr-abl will be done at 3-6 month intervals to determine which test is best predictive of relapse after transplantation. BrdU/in situ hybridization specifically will be used to investigate whether residual Ph positive cells are proliferating. Polymerase chain reaction for fragment length polymorphisms will be used to assess residual host cells in various lineages to determine the relationship of mixed chimerism with relapse, infection, rejection, or GVHD. Patients will also be studied serially for reconstitution of the immune system by measurement of lymphocyte subsets by flow cytometry, nonspecific test of immune responsiveness in vitro, in vitro tests of activity against CML cells and the P210 protein, and for development of specific responses against CMV. For patients who relapse after transplantation, the combination of interferon-alpha, interleukin-2 and infusion of CD8-depleted donor lymphocytes will be evaluated to determine its efficacy and tolerability. The results of the clinical investigations will determine whether or not these innovative approaches are effective treatments for patients with chronic myelogenous leukemia, and the laboratory studies will provide further insight into the biology of the process so that future treatment strategies may be developed.