Whereas it might seem obvious that if cancer cells are detected in the body then additional therapy will be necessary for cure, this has not been definitively established for the minimal numbers of cancer cells that can now be detected using sensitive techniques such as polymerase chain reaction (PCR) amplification. PCR of tumor specific chromosomal translocations or gene rearrangements is capable of detecting one tumor cell in up to 106 normal cells and presents a considerable advance over previous techniques to detect minimal residual disease (MRD). The central thesis of this proposal is that eradication of residual cancer cells is necessary for cure. With the increasing use and success of dose intensified treatment strategies for the treatment of the hematologic malignancies, two critical questions have to be addressed. First, how is the outcome of treatment assessed and second, are the attendant toxicities tolerable and if not, are they preventable or reversible? Previous studies have demonstrated that eradication of PCR detectable lymphoma cells is associated with greatly improved outcome after high dose therapy for advanced stage lymphoma. However, this improved outcome resulting from elimination of lymphoma is not without cost as we and others have observed a greatly increased incidence in myelodysplasia after ABMT. The ability to predict outcome based on the detection of MRD would allow one to tailor treatment ot patients who require additional therapy and, just as importantly, to avoid potentially toxic therapy in patients who have no detectable MRD. Therefore the primary goal of this project is to determine the contribution of the eradication of minimal residual disease to cure and in addition, to determine how therapy to achieve this aim induces stem cell damage that will affect outcome following treatment of hematologic malignancies. To this end we propose Three specific aims. First, to develop and extend PCR based assays to detect, quantitate and determine the clinical significance of MRD in patients with lymphoma and myeloma and leukemia who receive conventional, high dose ablative and novel immunologic strategies Second, to assess the clinical significance of karyotypic abnormalities and clonal hematopoiesis in patients receiving conventional and high dose ablative therapy. Based on the premise that stem cell damage is therapy induced we plan Thirdly, to attempt to isolate stem cells from patients early in the course of their disease before significant stem cell damage has occurred. Since this will likely mean that the bone marrow or peripheral blood from these patients contains significant tumor involvement we aim to attempt to improve purging strategies to deplete this increased tumor burden and to assess the efficacy of these purging strategies using PCR. The success of this project is highly interdependent upon the identification of novel tumor specific translocations, the availability of tumor specimens from patients undergoing high dose ablative therapy and bone marrow samples before during and after novel treatment approaches.
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