) Current allogeneic hematopoietic stem cell transplant preparative regimens used in the treatment of with hematologic malignancies consist of three components. These include high-dose myeloablative conditioning programs to eradicate the underlying disease and suppress host-versus-graft (HVG) reactions; the stem cell graft to both rescue the patient from profound marrow toxicity and eradicate residual disease through a graft-versus-host (GVH) effect; and post grafting immunosuppression to control GVH disease. In order to reduce the risk of relapse after transplant, conditioning programs have been intensified to a point where they cause significant morbidity and mortality, in particular in older patients. Based on canine preclinical studies presented in Project 1, we propose a radically different approach to stem cell transplantation. This new approach is aimed at making allografts safer such that they can be carried out in the outpatient setting and can be extended to include older patients who are currently not transplant candidates. Two groups of patients will be studied: those with CML in cronic and accelerated phases , aged 66 to 74 years, and those with B-Cell malignancies, aged 50 to 65 years. Two hypotheses will be tested. The first hypothesis (Specific aim 1) is that stable mixed donor-host hematopoietic chimerism can be established using nonmyeloablative transplant regimen that is predominantly aimed at the control of HVG and GVH reactions through short course of immunosuppression. The regimen consists of a small (200 cGy) dose of total body irradiation before a novel immunosuppressive combination of mycophenolate mofetil and cyclosporine for no more than 35 days after HLA-identical peripheral blood stem cell transplantation. Preliminary data in five patients have indicated that allogeneic engraftation can be achieved efficiently and safely using this approach. Once established, mixed chimerism will provide the immunological ~platform~ to test the second hypothesis (Specific Aim 2) that donor lymphocytes can be infused at 2 months after stem cell grafting as adoptive immunotherapy without the risk of rejection or marrow aplasia, resulting in the conversion of mixed chimerism to full-donor chimerism along with the eradication of the underlying malignancy.
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