DEVELOPMENT OF AUTOLOGOUS BMT PROGRAMS IN CML

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The use of intensive systemic preparative therapy followed by transplantation of autologous cells in CML patients who were unresponsive to interferon or ineligible for allogeneic bone marrow transplantation has generated survivals in the short term which are equivalent to those seen in allogeneic bone marrow transplantation when delivered in the chronic phases of the disease (70% survival at two years of follow-up), but is associated with lower levels of survival when that autologous transplant is conducted in the accelerated and blast crisis phases of disease (35%. Since the major determinant of success appeared to be the availability of diploid autologous cells at the time of transplant, we have added the following procedures for reduction of the ratio of leukemic to normal cells in the preparations used for transplant: initial conventional dose chemotherapy, collection of predominantly peripheral blood diploid populations of hematopoietic progenitor cells early in the recovery phase from in vivo chemotherapy from ex vivo methods for positive selection of the early normal myeloid progenitor cells by CD34 column fractionation (CellPro), and monoclonal antibody negative selection techniques for the selective removal of CML cells from autologous marrow or peripheral blood preparations to be used for autologous transplantation. We are also proposing the implementation of a clinical marrow retroviral marking program, which is designed to help us evaluate the efficiency of the above methods to selectively isolate early hematopoietic normal progenitor cells free from Ph+ cells, from autologous marrow and peripheral blood. The marking program will help us independently evaluate the efficacy of preparative therapy in eradicating systemic disease and the efficiency of procedures used to remove CML cells from autologous cells used for autologous transplant after intensive therapy. In this way, we can determine if relapse arises from CML cells left in the systemic circulation versus CML cells left in the autologous marrow used for transplant following purging. We also are proposing to launch a double marking program which is designed to compare the reconstitutive capacity of peripheral blood versus marrow cells to reconstitute normal marrow function after intensive preparative therapy. This program will also allow us to compare the level of Ph+ cells in peripheral blood versus marrow which can contribute to relapse. We will study the utility of methods for ex vivo expansion of normal hematopoietic progenitor cells prior to transplant. We will evaluate genetic methods for promoting the regrowth of diploid cells in CML patients, and to suppress leukemic cells. These studies will be directed to the development of more effective programs for inducing durable cytogenetic remissions using autologous bone marrow transplantation for CML patients not eligible for biological therapy or allogenic bone marrow transplantation.