Resistance Mechanisms to Targeted Agents in Chronic Lymphocytic Leukemia

Abstract Agents that specifically target pathologic mechanisms of survival have now been approved for the treatment of chronic lymphocytic leukemia in both the treatment-naive and relapsed/refractory settings. These 4 agents include the Bruton tyrosine kinase inhibitor ibrutinib, the B-cell leukemia/lymphoma-2 inhibitor venetoclax, and the phosphatidylinositol-3 kinase inhibitors idelalisib and duvelisib. Although clinical outcomes are improved with all of these inhibitors, acquired resistance does occur and leads to progression of disease. Resistance to targeted therapy can occur through direct mutations of the target or through the overexpression of alternative cell survival pathways not affected by the specific inhibitor. Determining which patients will develop resistance, why resistance occurs, how to overcome resistance, and when to test for resistance are all subjects of ongoing research. In this review, we describe the current data relative to the development of resistance to targeted therapies in CLL.