While remarkable therapeutic advances have been made in the treatment of pediatric acute lymphoblastic leukemia (ALL) in the past 15 years, nearly 30 percent of children still relapse with resistant disease. The use of pre-clinical and laboratory data have significantly improved their ability to stratify children to different risk-adapted regimens, yet none of these parameters allow them to precisely predict those children who will ultimately relapse and die of disease. Preliminary studies in pediatric ALL have indicated that the level of minimal residual disease (MRD) determined early in the treatment course may identify those children who are at increased risk for relapse. In the past year, she has developed two novel automated fluorescence-based molecular genetic methodologies with remarkable sensitivity and specificity that allow for precise quantitation of MRD. The ABI 310 Genetic Analyzer will be used to rapidly quantitate and size clonotypic T cell receptor (TCR) and immunoglobulin heavy chain (IgH) rearrangements while the ABI 7700 Genetic Sequence Detector """"""""TaqMan"""""""" technology will be used for quantitative """"""""real-time"""""""" RT--PCR monitoring of MRD in patients with specific ALL-associated translocations. In this application, and the accompanying R01 application in this IRPG Group (Residual Disease Detection in ALL Using Flow Cytometry; PI: Michael Borowitz), she propose to evaluate the biologic significance, prognostic utility, and optimal methodology for prospective quantitative MRD monitoring in nearly 3000 children with newly diagnosed ALL registered to the AlinC17 set of risk-adapted phase III treatment trials conducted by the Pediatric Oncology Group (POG). These trials provide a landmark opportunity to prospectively address the biological and clinical significant of MRD, to determine thresholds significant for predicting relapse, and to determine the effects of intensification on MRD levels.
The specific aims of this application are to: 1) use molecular genetic data for stratification of ALL patients to AlinC17 risk-adapted clinical trials; 2) use novel automated molecular genetic technologies for quantitative assessment of MRD at end of induction and consolidation; 3) determine the effect of early treatment intensification on quantitative MRD levels; 4) correlate the presence of MRD with outcome and with other pre-clinical and laboratory parameters, particularly cytogenetics and molecular genetics; and 5) determine the optimal methodology for MRD assessment as part of the IRPG group interaction.
| Bowman, W Paul; Larsen, Eric L; Devidas, Meenakshi et al. (2011) Augmented therapy improves outcome for pediatric high risk acute lymphocytic leukemia: results of Children's Oncology Group trial P9906. Pediatr Blood Cancer 57:569-77 |
