The incidence of both mixed chimerism and relapse following allogeneic bone marrow transplantation (BMT) is greater in patients with chronic myelogenous leukemia (CML who receive a T-cell depleted donor marrow. The results of these clinical transplantation studies together with the recent introduction of donor leukocyte infusion therapy for the treatment of relapse post-BMT indicate that a graft-versus-leukemia (GVL effect mediated by donor lymphoid cells is important for achieving cure in this disease. The polymerase chain reaction (PCR has revolutionized our ability to detect both mixed chimerism and minimal residual disease. The very sensitivity of PCR has however led to problems with interpretation of positive PCR assays. In particular, the clinical relevance of these studies is currently unclear. We have developed quantitative PCR for detection of BCR-ABL mRNA to assess minimal residual disease and lineage specific PCR to assess chimerism post-BMT. It is well documented that PCR for BCR-ABL mRNA is frequently positive following BMT for CML. However the factors that ultimately lead to continued clinical remission or relapse which perhaps reflects the presence or absence of in vivo GVL activity are poorly characterized. By carefully studying chimerism and minimal residual disease post-BMT together with evaluation of the donors' lymphocyte function we hope to better define the criteria which predict for relapse free survival. We propose to use these PCR assays to address a number of questions which are currently unanswered in patients receiving a BMT for treatment of CMT. Specifically, by using quantitative PCR for detection of residual disease, we will determine if the absolute amount of BCR-ABL mRNA detected post-BMT predicts relapse, if marrow testing is superior to peripheral blood testing, and if PCR positivity is due to molecular relapse of leukemic myeloid cells or is secondary to persistence of Philadelphia positive lymphoid elements. Our lineage specific PCR for chimerism should allow us to assess the incidence over time of mixed chimerism following T-cell depleted BMT. We will also be able to determine whether mixed chimerism is lineage restricted and whether mixed T-cell chimerism is associated with persistence of residual leukemia post BMT. Both the PCR methodologies will be used to assess the response to, and the morbidity of, the recently described donor leukocyte infusion therapy for the treatment of relapse post-BMT. Lastly by determining both the NK and T-cell function of the donor prior to the transplant we will assess whether these tests are predictive of chimeric status and leukemia free survival post-BMT. It is our hope that the data obtained from these studies will allow us to develop new transplantation strategies for the treatment of patients with CML.
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