Bruton Tyrosine Kinase Inhibitors in B-Cell Malignancies: Their Use and Differential Features

Starting with the first-in-class agent ibrutinib, the development of Bruton tyrosine kinase (BTK) inhibitors has led to dramatic improvements in the management of B-cell malignancies. Subsequently, more-highly selective second-generation BTK inhibitors (including acalabrutinib, zanubrutinib, tirabrutinib and orelabrutinib) have been developed, primarily with an aim to reduce off-target toxicities. More recently, third-generation agents including the non-covalent BTK inhibitors pirtobrutinib and nemtabrutinib have entered later-stage clinical development. BTK inhibitors have shown strong activity in a range of B-cell malignancies, including chronic lymphocytic leukaemia/small lymphocytic lymphoma, mantle cell lymphoma, Waldenström's macroglobulinaemia and marginal zone lymphoma. The agents have acceptable tolerability, with adverse events generally being manageable with dosage modification. This review article summarises the evidence supporting the role of BTK inhibitors in the management of B-cell malignancies, including highlighting some differential features between agents.Bruton tyrosine kinase (BTK) is a key signalling molecule in the B-cell receptor pathway which is important for B-cell proliferation and survival. The development of drugs which inhibit BTK has led to dramatic improvements in the management of B-cell malignancies, difficult-to-treat diseases that primarily affect older populations. Following ibrutinib (the first-in-class BTK inhibitor), second-generation agents (including acalabrutinib, zanubrutinib, tirabrutinib and orelabrutinib) have been developed, primarily with an aim to improve drug tolerability. More recently, third-generation agents (including pirtobrutinib and nemtabrutinib) have entered later-stage clinical development, aiming to provide further treatment options. BTK inhibitors have shown strong activity in a range of B-cell malignancies. The agents have acceptable tolerability, with adverse events generally being manageable with dosage modification. This review article summarises the evidence supporting the role of BTK inhibitors in the management of B-cell malignancies, a rapidly developing field.