Resistance-Associated Mutations in Chronic Lymphocytic Leukemia Patients Treated With Novel Agents

Inhibitors of B-cell receptor signalling, ibrutinib and idelalisib, and BCL-2 antagonist, venetoclax, have become the mainstay of treatment for chronic lymphocytic leukaemia (CLL). Despite significant efficacy in most CLL patients, some patients develop resistance to these agents and progress on these drugs. We provide state-of-the-art overview of the acquired resistance to novel agents. In 80% of patients with ibrutinib failure, acquired mutations in BTK and PLCG2 genes were detected. No resistance-associated mutations or deregulated signalling pathways have been reported in idelalisib failure. Acquired mutations in the BCL2 gene were detected in patients who had failed on venetoclax. In most cases, patients who have progressed on ibrutinib and venetoclax experience resistance-associated mutations, often present at low allelic frequencies. Resistance-associated mutations tend to occur between the second and fourth years of treatment and may already be detected several months before clinical relapse. We also discuss the development of next-generation agents for CLL patients who have acquired resistant mutations to current inhibitors.