BTK Inhibitors: Focus on Ibrutinib and Similar Agents
Since Bruton tyrosine kinase (BTK) is a critical effector molecule for B cell development and lymphomagenesis, BTK inhibitors have been investigated in B cell malignancies during the last decade. Ibrutinib, a first-in-class, potent, orally administered covalently-binding inhibitor of BTK was recently approved for the treatment of chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), Waldenström’s macroglobulinemia (WM) and marginal-zone lymphoma (MZL). Its use led to impressive responses in CLL, MCL, WM and MZL with a favorable safety profile. Mechanisms of resistance to ibrutinib are different according to disease biology and still need to be fully elucidated. In CLL and WM patients progressing on ibrutinib, BTK and downstream kinase Phospholipase Cγ2 (PLCγ2) mutations have been identified leading to resistance. BTK and PLCγ2 mutations are almost always absent at the beginning of treatment and they are detected at a later timepoint, suggesting the evolution of clonal dynamics under treatment pressure. Primary and secondary resistances in MCL are driven by mutations promoting the activation of the alternative NFκB-pathway and PI3K-AKT pathway. Further work needs to be done to elucidate the mechanisms behind primary refractory patients, to define the risk for clonal evolution/new mutations over time on treatment, and to identify prognostic/predictive markers for patients on BTK inhibitors.
KeywordsBTK inhibitors Ibrutinib B cell malignancies Acalabrutinib ONO/GS4059 BGB-3111 CC-292
The Authors would like to thank Dr. Panagiotis Baliakas for his critical review of the manuscript and his helpful suggestions.
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