B-CLL Biology: Impact of Combination Therapy

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B-chronic lymphocytic leukemia (B-CLL) is the most common leukemia in North America. Since the cumulative incidence continues to rise there is a significant need for advances in the understanding and treatment of this currently incurable disease. To accomplish this goal we wish to generate additional valuable, relevant information about the leukemic B cell clones in B-CLL with a variety of laboratory approaches. It is important to obtain this information on clones from B-CLL patients who represent the differing types of clinical responses typically seen in progressive B-CLL. To accomplish that goal we will study in a sequential fashion B-CLL patients with progressive disease using a unique combination of chemotherapy and monoclonal antibodies. Specifically, we will treat B-CLL patients with pentostatin/cyclophosphamide and Rituxan for up to 6 cycles of therapy. Because we believe that this trial will generate significant numbers of responding patients we will likely have at least three important cohorts of B-CLL patients to study critical biologic features of the leukemic B cell clones. Because preliminary studies using this combination approach have demonstrated high rates of overall clinical response (94 percent) and complete response (60 percent), this treatment strategy presents us with the unique opportunity to identify biological features that underlie responsive disease, primary refractory disease, and responsive but persistent disease patient subsets. The biologic parameters to be studied include the level of B-CLL apoptosis and/or drug resistance and the level of angiogenesis observed since all three of these factors have the potential to significantly alter either initial patient response to therapy or disease relapse. To complement these focused studies, we will also employ gene expression profiling of the leukemic B cells. This approach will allow us to study the expression levels of a much larger number of genes that could impact on apoptosis, drug resistance and angiogenesis. In addition, this broad approach will facilitate the identification of unanticipated or novel genes that may explain disease heterogeneity and response to this specific therapy. To do the gene profiling it is intended to use the lymphochip which has shown provocative results for subdividing B-CLL clones. However in this study we will expand the scope of our expression profiling by using the Lymphochip platform in concert with the much broader Affymetrix platform. Finally we intend to relate the collection of biologic data described above to the mutational status (i.e. germline versus somatic mutation type clone) since we and others have data that germline type B cell clones have significant resistance to chemotherapy and early relapse even within responding B-CLL patients. The complete elucidation of the relevant biologic features of the leukemic cell in B-CLL is certain to be helpful for devising strategies that will target the residual leukemic B cells, thereby ultimately achieving cures for this disease.