Chronic myelogenous leukemia can be cured by bone marrow transplantation if it is delivered early in the chronic phase of this disease. Unfortunately, only a small percentage of patients are eligible for this therapy. The research programs outlined in this application are designed to take advantage of several advances which permit the regrowth of normal cells and reduce or remove the Philadelphia chromosome positive cells systemically and in vitro: a interferon, combined biological therapy and chemotherapy, in vitro removal of Philadelphia chromosome positive cells in Dexter long-term marrow culture, and bone marrow transplantation. The following specific questions will be addressed: 1) How can biological therapy, chemotherapy, in vitro bone marrow culture and bone marrow transplantation be combined to promote Philadelphia chromosome negative hematopoiesis in CML; 2) Are the diploid cells selected from Philadelphia chromosome positive marrow normal or leukemic; 3) How can we identify patients whose Philadelphia chromosome positive cells are sensitive or resistant to biological therapy; and 4) What are the mechanisms through which Philadelphia chromosome positive hematopoiesis is suppressed by biological therapy and how does resistant evolve. New cellular and molecular means of detection of minimal residual disease will be used to evaluate the response to these therapeutic programs. Studies of the molecular basis of response and resistance to biological therapy as well as the patterns of clinical responses to the therapeutic programs proposed will be evaluated in order to extend curative therapy to greater numbers of CML patients.
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