) The DFCI-based ALL Consortium is a 9-institution childhood ALL clinical trials group that has been conducting multi-institutional studies since 1981. The group has a common treatment philosophy featuring intensive early therapy, and a research focus on doxorubicin, L-asparaginase, corticosteroids and central nervous system treatment. We have demonstrated differences in L-asparaginase dose responses in vivo and in vitro, as well as L-asparaginase species differences in cytotoxicity, pharmacogenetics and pharmacodynamics. Each of those studies was performed on previously untreated leukemia cells. We have also compared the toxicity of native E. coli asparaginase to polyethylene glycolated (PEG) asparaginase, as well as the Erwinia species. In addition, we have augmented our randomized studies of doxorubicin treatment efficacy by the investigation of continuous infusions, cardioprotection, and the predictive value of troponin-T. We have also interacted to complete neuropsychological toxicity studies of alternative central nervous system treatments, dose cytotoxicity studies of corticosteroids, and quantitative measures of quality of life outcomes. In addition to clinical trials in newly diagnosed patients (ages contributing to the knowledge of the pathogenesis of ALL (Projects 5-7), quantitative measures of residual disease (Project 9), as well as genomic markers of disease variability and potential targets for future therapy (Project 8). The group provides over 100 patients per year and enables the clinical and laboratory studies described in the application to be completed.
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