MINIMAL RESIDUAL DISEASE EVALUATION TO GUIDE THERAPY

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DESCRIPTION: (Applicant's Abstract) Response rates for treatment of pediatric T cell acute lymphoblastic leukemia (T-ALL) with chemotherapy protocols approach 95%. Unfortunately half of the patients induced into remission will relapse. This indicates that even in clinical remission these patients harbor minimal residual disease (MRD). The long term goal of this project is to identify patients at risk of relapse as candidates for more aggressive or novel therapeutic approaches. The specific aims of this project are to: 1) develop and validate an internal calibration standard (ICS)-based PCR technology for quantification of tumor burden using chromosomal rearrangements associated with T-ALL; 2) to compare ICS-PCR sensitivity with immunohistochemistry and flow cytometry; 3) to investigate the predictive value of ICS-PCR using a SCID mouse/T-ALL xenograft model; 4) to begin the measurement of MRD in T-ALL patients during therapy and remission to determine prognostic significance. This project combines three unique aspects for MRD analysis that have not been described previously. First, a rigorous PCR approach for the accurate quantification of MRD will be developed for use in clinical laboratories, as opposed to the "semi-quantitative" research-level approaches that have been described previously. Second, an animal model will be used to demonstrate proof-of-principle. Third, a large number a T-ALL patients will be followed with sequential sampling during therapy as part of a treatment trial to provide for meaningful analysis of potentially predictive parameters associated with MRD detection and quantification. This type of study will help determine if advanced diagnostics can be used to guide therapy and thus have an significant impact on patient outcome.