DETECTION AND TREATMENT OF MINIMAL RESIDUAL DISEASE

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Relapse after bone marrow transplantation (BMT) remains a substantial obstacle to cure. An approach to decrease relapse is to identify patients at high risk for disease recurrence and target this group for early therapeutic intervention after BMT. Our research goal is to detect and study the clinical significance of minimal residual disease (MRD) after BMT, in order to ultimately identify patients who could be offered early therapeutic intervention at the first sign of "molecular relapse." We plan to build upon our recently published studies using the polymerase chain reaction(PCR) to detect the leukemia-specific molecular "fingerprints" of the bcr-abl chimeric mRNA in chronic myeloid leukemia (CML) and immunoglobulin heavy chain V-D-J (IgH VDJ) rearrangements in acute lymphocyic leukemia (ALL) after BMT. In Specific Aim 1, we will use a quantitative PCR (Q-PCR) to determine if the risk of relapse following marrow and peripheral blood stem cell transplants for CML is determined by the burden of bcr-abl ells, or, alternatively, by the cell lineage of bcr-abl expressing cells. Moreover, we will test if intervention with alpha-interferon (IFN) will prevent the evolution of PCR-positive "molecular relapses" post-BMT to cytogenetic or hematologic relapses. In Specific Aim 2, we will study Ph+ ALL patients to determine if the expression of p190 or p210 bcr-abl transcripts at remission predict a different relapse risk after conventional chemotherapy and BMT. In addition, we will continue our studies examining the use of IgH VDJ rearrangements to detect MRD in Ph-ALL patients posttransplant. Lastly, in Specific 3, we will study AML patients and test if the detection of MRD post-BMT by multidimensional flow cytometry, PCR, or FISH predicts relapse. These studies will define the clinical utility of MRD detection in CML, ALL, an dAML posttransplant, and may provide a paradigm for the clinical use of molecular diagnostics in other hematologic and solid malignancies.