Acute lymphoblastic leukemia (ALL) and advanced-stage lymphoblastic lymphoma (LL) respond well to remission induction therapy, but about 40% of children and 90% of adults eventually relapse and die of the diseases. The major reason for treatment failure is resistance of leukemic cells to cytotoxic drugs. The likelihood of development of resistance increases with the mass of the leukemia. Therefore, it is plausible that the smaller the burden of leukemic cells, the more likely that any given combination of drugs will successfully control the disease. Since therapy is toxic, it should be given only to those who will benefit from it. These considerations lead to the conclusion that a sensitive assay for minimal residual disease is an important requirement for improving therapy in these lymphoblastic neoplasms. In the proposed study, sensitive assays for minimal residual lymphoblastic disease will be developed. These assays are based upon the expression of terminal deoxynucleotidyl transferase (TdT) by more than 90% of these neoplasms, while less than 10% of normal marrow and less than 0.1% of normal blood cells contain the enzyme. Fluorchrome-conjugated monoclonal antibodies to TdT will be used to identify this population of cells, which will then be analyzed for a variety of markers designed to distinguish leukemic from normal TdT+ subsets in blood and marrow samples from patients who are receiving continuation therapy. The DNA content and state of activation of the TdT+ subset will also be analyzed. The frequencies of appropriate TdT+ subsets will be correlated with clinical events including relapse. The sensitivity and specificity of elevations in certain TdT+ subsets for the prediction of relapse will be calculated. If prediciton of relapse is sufficiently powerful, future trials will be designed to test whether therapeutic intervention based on specific assay results can change the outcome for patients with lymphoblastic neoplasms.
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