There is a significant need for advances in the understanding of the biology of the leukemic CLL B cell clones in this currently incurable disease. To address this, we have designed a combination chemotherapy trial utilizing two monoclonal antibodies known to have important tissue site specific impact. Rituximab and Campath, appear to synergize with chemotherapy, recognize different surface molecules on CLL B cells, and effect removal of the CLL leukemic burden from separate organ compartments. We expect this chemoimmunotherapy (CIT) approach to generate complete (CR) nodular PR or partial responses (PR) in a significant percentage, albeit not all, of relapsed patients. In this proposal, we wish to perform correlative laboratory studies on the CLL patients entering this trial. We will generate valuable, relevant information about the leukemic B cell clones in B-CLL with a variety of laboratory approaches. Our approach will allow us to a) monitor the minimal residual level of leukemic CLL B cell burden for clinical responders and their T cell repertoire status and b) study the association of biologic features, which permit elaboration of risk stratification parameters and begin to develop a prognostic model that predict response. Thus for patients who experience a CR, we will monitor for minimal residual disease (MRD) detection using detection methods that include both flow cytometry and a quantitative polymerase chain reaction assay. This will be done to ascertain if a clinical CR with or without MRD detection confers clinical advantage to the CLL patients. Because the CIT approach is likely to confer immune deficiency to these already compromised patients, we intend to monitor the extent of this by assessing blood T cell status using both flow and CDR3 spectratype analysis. The correlative laboratory tests we will determine for novel risk stratification parameters include;FISH detectable defects, immunoglobulin variable heavy region mutational status, ZAP-70 and VEGF-based autocrine pathways related to apoptosis resistance of CLL B cells and the angiogenesis status of marrow tissue in these patients. With this information we will also develop a prognostic model that can be used for more accurate counsel and stratification. Finally we intend to study microRNA expression on the CLL B cell clones. This newly defined set of genes promises to uncover genes that relate to both disease progression and use in definition of more high risk disease. This gene set will be explored for use in the developed prognostic model for CLL patients. We hypothesize that this trial will generate significant responses in more aggressive CLL, that we will be able to extend the utility of selected risk stratification parameters for CLL patients and generate further insight into the biology of CLL B cells.
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