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Summary  The treatment landscape of chronic lymphocytic leukemia (CLL) has shifted from chemotherapy-based approaches to targeted agents in the last decade. However, evolving drug resistance and accumulating toxicity remain challenges that still limit patients’ clinical outcomes. Furthermore, currently licensed targeted agents such as inhibitors of Bruton’s tyrosine kinase (BTK) and anti-apoptotic protein B‑cell lymphoma 2 (BCL2) do not adequately compensate for the poor clinical outcomes associated with high-risk genetics such as TP53 alterations. New insights into disease biology facilitated design and investigation of several new targeted agents with encouraging results in early clinical trials. This short review focuses on novel actionable targets and investigational drugs aimed at circumventing acquired resistance and avoiding accumulating toxicity.

New actionable targets and investigational drugs in chronic lymphocytic leukemia