Challenges with Approved Targeted Therapies against Recurrent Mutations in CLL: A Place for New Actionable Targets

SIMPLE SUMMARY: Chronic lymphocytic leukemia harbors a high degree of genetic variability and interpatient heterogeneity. Some of the genetic alterations have an impact on the disease’s prognosis and evolution, but few data exist about the response to new approved targeted therapies in patients carrying recurrent mutations other than TP53. In this review, we present the knowledge about the impact of these new genetic alterations in the treatment response together with the possibility to use new actionable targets. ABSTRACT: Chronic lymphocytic leukemia (CLL) is characterized by a high degree of genetic variability and interpatient heterogeneity. In the last decade, novel alterations have been described. Some of them impact on the prognosis and evolution of patients. The approval of BTK inhibitors, PI3K inhibitors and Bcl-2 inhibitors has drastically changed the treatment of patients with CLL. The effect of these new targeted therapies has been widely analyzed in TP53-mutated cases, but few data exist about the response of patients carrying other recurrent mutations. In this review, we describe the biological pathways recurrently altered in CLL that might have an impact on the response to these new therapies together with the possibility to use new actionable targets to optimize treatment responses.