Detailed analysis of cellular response mechanisms after chemotherapy and antibody treatment in biological CLL subgroups
Stephan Stilgenbauer, M.D.
University of Ulm
Abstract:
CLL is the most common leukemia in the western world. It is a disease with a highly variable clinical course, some patients die from the disease, whereas others live for many years without problems. CLL is characterized by an increased white blood cell count with the expansion of lymphocytes in the peripheral blood, bone marrow and lymphoid organs. Genomic aberrations (chromosome abnormalities) are found in the CLL cells in almost all cases and define clinical subgroups. The response and survival time after chemotherapy and the antibody rituximab are poor in some of the patients with CLL, while the antibody alemtuzumab is effective in these cases. The differential mechanisms of the response to the diverse agents are not well understood but there is an association with specific genetic defects of the CLL cells (17p deletion, p53 mutation). To gain better insight into the different mechanisms of cellular response to therapy, CLL cells were collected and individually treated with chemotherapeutic agents or the antibody alemtuzumab. The treatment with chemotherapy led to induction of cell death, with significantly lower rates of dead cells in some of the cases with specific genomic aberrations. Treatment with the antibody alemtuzumab induced cell death in all CLL cases independently of the genomic aberrations. We plan to extend these preliminary analyses to approximately 50 cases to gain more reliable results. The samples will be studied for different prognostic markers (genomic aberrations, VH mutations status, ZAP-70 expression) and these will be related to the results after different treatments. Particularly, the response to treatment and mechanisms of induction of cell death will be examined in the different risk-groups. Protein expression levels of candidate genes involved in cell growth and cell death (apoptosis) control will be studied to identify different pathways leading to cellular response or resistance after treatment with chemotherapeutic agents or antibody therapy. In addition it is intended to analyze blood samples of CLL patients during therapy to compare the cell culture results with in-patient responses and to gain detailed information on the mechanism of cell death in different biological CLL risk groups. Overall, the results of this study should allow a detailed insight into the mechanisms of action of different therapeutic agents and form the basis for the development of novel treatment strategies in CLL.