Mechanisms of Resistance to Targeted Therapies in Chronic Lymphocytic Leukemia

Even if treatment options for Chronic Lymphocytic Leukemia (CLL) patients have changed dramatically in the past few years, with the approval of targeted therapeutic agents, the disease remains incurable. Beside intrinsic genetic features characterizing the leukemic cell, signals coming from the microenvironment have a key role in promoting cell survival and in protecting CLL cells from the action of drugs. Consequently, the identification of previously unrecognized genetic lesions is important in risk-stratification of CLL patients and is progressively becoming a critical tool for choosing the best therapeutic strategy. Significant efforts have also been dedicated to define microenvironment-dependent mechanisms that sustain leukemic cells favoring survival, proliferation, and accumulation of additional genetic lesions. Furthermore, understanding the molecular and biological mechanisms, potentially driving disease progression and chemoresistance, is the first step to design therapies that could be effective in high-risk patients. Significant progress has been made in the identification of the different mechanisms through which patients relapse after "new" and "old" therapies. These studies have led to the development of targeted strategies to overcome, or even prevent, resistance through the design of novel agents or their combination.In this chapter we will give an overview of the main therapeutic options for CLL patients and review the mechanisms of resistance responsible for treatment failure. Potential strategies to overcome or prevent resistance will be also discussed.