DETECTION AND THERAPY OF RESIDUAL LEUKEMIA IN CHILDREN

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DESCRIPTION: (Applicant's Abstract) Despite advancing cure rates in childhood acute lymphoblastic leukemia (ALL), 25-30% of all patients eventually succumb to their disease. The long-term objective of the proposed research is to improve clinical outcome in this subset of patients. By early identification of patients who are likely to relapse, it should be possible to instigate potentially curative therapy in a more timely manner, thus boosting the proportion of long term survivors. This goal will be pursued through three interrelated projects. In the first, overexpression of WT1 and BCL-2 genes will be assessed as markers of minimal residual disease (MRD) in childhood ALL patients. The underlying hypothesis is that these two indicators are more widely associated with leukemia than current markers, and will significantly expand capabilities for prospective identification of high risk patients. Specific Aim 2 seeks to expand results obtained during the previous period of support, suggesting that immunologic monitoring of MRD has clinical utility in the assessment of childhood ALL patients. Immunologic findings in sequential bone marrow samples from patients with B- and T-lineage ALL will be compared with event free survival, as well as presenting clinical and biologic risk features, to establish the independent predictive strength of this assay. The data will also provide opportunities for cross comparisons with results of WT1 and BCL-2 screening in Specific Aim 1. Based on encouraging preliminary results, studies in Specific Aim 3 seek to assess the clinical utility of MRD investigations using peripheral blood instead of bone marrow. Success in this endeavor will radically improve remission studies in patients with ALL, by overcoming the practical and ethical constraints posed by sequential bone marrow aspirations in children. The clinical significance of MRD has been in doubt because of the lack of prospective studies in a large group of uniformly treated patients. The studies proposed in this application should meet that need and demonstrate the feasibility of clinical management decisions based on MRD detection in children with ALL.