Novel therapies, mRNA expression profiling and immune failure in chronic lymphocytic leukaemia (CLL); applications for in vitro research and clinical management.

Abstract

CLL is the most frequently diagnosed leukaemia in adults. For many patients CLL is a relatively indolent disease, but for those with symptomatic disease treatment may be indicated. In Australia, current front-line therapy most commonly remains chemoimmunotherapy (CIT). However, CLL therapy is in an era of unprecedented change with the development of the targeted therapies such as those discussed in this thesis. Microenvironmental niches have been shown to play a significant role in promoting CLL cell survival and proliferation. Several intracellular signaling pathways are now known to mediate the interaction between CLL cells and other cells. These pathways are key mediators of CLL cell survival and proliferation in vivo. A better understanding of the importance of the BCR signaling pathway in the pathogenesis of CLL has provided the rationale for trials of a range of novel, more targeted therapeutic agents. The marked genetic heterogeneity among CLL patients has a significant effect on response and survival rates following treatment with CIT and the novel agents. There are a number of well-established genetic lesions in CLL such as those affecting the TP53 and ATM genes and deletion of 13q14. However, none of these lesions are present in all cases and therefore it is believed there is no common pathogenic lesion in CLL. The marked improvement in survival of CLL patients in the CIT era and more recently with the novel therapies, has meant immune dysfunction, is becoming an increasingly common problem in CLL. Immune dysfunction in CLL is characterised by hypogammaglobulinaemia, increased risk of infection, autoimmune conditions and an increased risk of secondary malignancies. This thesis focuses on three important aspects of the management of CLL: novel therapeutic strategies, the effect of the tumour microenvironment on mRNA expression in CLL cells, and immune failure in CLL