Emerging bruton tyrosine kinase inhibitors for chronic lymphocytic leukaemia: one step ahead ibrutinib.

: In the last few years, the expansion of therapy with pathway inhibitors has revolutionized the treatment landscape of chronic lymphocytic leukemia (CLL). As a matter of fact, ibrutinib, the first-in-class Bruton tyrosine kinase (BTK) inhibitor, became a milestone in the treatment of both naïve or relapsed/refractory CLL patients. Most patients treated with such an agent achieve durable clinical response; however, a deeper response is rarely reached and continuous treatment is required. Since ibrutinib-resistant CLL clones can develop in about 20% of patients and toxicities, leading to drug discontinuation, occur in about 30% of patients treated with ibrutinib, several new BTK inhibitors have been developed in order to lower off-target effects and overcome ibrutinib resistance.: In this review, we summarize the main English publications exploring efficacy and side effects of first and next-generation BTK inhibitors. Results of clinical trials evaluating these novel agents are presented and critically discussed.: Efforts in the development of highly specific second-generation BTK inhibitors and combination strategies provide challenging options to overcome limitations of therapy with ibrutinib. It is also crucial to identify additional risk factors and to understand disease biology underlying clonal evolution of CLL in the context of novel agents.