The covalent Bruton's tyrosine kinase inhibitors (BTKis) are highly effective for the treatment of chronic lymphocytic leukemia (CLL). The dominant resistance mechanism observed with the BTKi ibrutinib is the development of BTK Cys481 codon mutations. Whether a similar resistance mutation profile exists for the newer-generation, more selective BTKi zanubrutinib is unknown. In samples referred for diagnostic next-generation sequencing in patients with progressive CLL, we observed an enrichment in the kinase-dead BTK Leu528Trp mutation in patients treated with zanubrutinib compared with ibrutinib (54%; 7 of 13 vs 4%; 1 of 24, P = .001). We describe 2 patients with BTK Leu528Trp mutations who showed clinical cross-resistance and progressive enrichment of the BTK Leu528Trp mutation over time when treated with the noncovalent BTKi pirtobrutinib. Both patients subsequently responded to venetoclax-based treatment. In summary, we have identified an enrichment of the BTK Leu528Trp mutation arising in patients treated with zanubrutinib that may impart cross-resistance to the noncovalent inhibitor pirtobrutinib and therefore may have implications for sequencing of these treatments in CLL.
Leukemia, Lymphocytic, Chronic, B-Cell , Agammaglobulinaemia Tyrosine Kinase , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Mutation , Piperidines , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Pyrazoles , Pyrimidines
Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/etiology , Cardiovascular System/drug effects , Protein Kinase Inhibitors/adverse effects , Animals , Cardiovascular Diseases/therapy , Clinical Decision-Making , Diagnosis, Differential , Disease Management , Disease Susceptibility , Humans , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/therapeutic use , Risk Factors
The development of bruton tyrosine kinase inhibitors (BTKi) has been a significant advancement in the treatment of chronic lymphocytic leukemia and related B-cell malignancies. As experience in using ibrutinib increased, the first drug to be licensed in its class, atrial fibrillation (AF) emerged as an important side effect. The intersection between BTKi therapy for B-cell malignancies and AF represents a complex area of management with scant evidence for guidance. Consideration needs to be taken regarding the interplay of increased bleeding risk versus thromboembolic complications of AF, drug interactions between ibrutinib and anticoagulants and antiarrhythmic agents, and the potential for other, as yet seldom reported cardiac side effects. This review describes the current knowledge regarding BTKi and potential pathophysiologic mechanisms of AF and discusses the management of BTKi-associated AF. Finally, a review of the second generation BTKi is provided and gaps in knowledge in this evolving field are highlighted.
Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Antineoplastic Agents/adverse effects , Cardiotoxicity/etiology , Protein Kinase Inhibitors/adverse effects , Adenine/analogs & derivatives , Agammaglobulinaemia Tyrosine Kinase/metabolism , Anticoagulants/therapeutic use , Antineoplastic Agents/therapeutic use , Atrial Fibrillation/diagnosis , Atrial Fibrillation/etiology , Atrial Fibrillation/physiopathology , Atrial Fibrillation/therapy , Cardiotoxicity/diagnosis , Cardiotoxicity/metabolism , Cardiotoxicity/therapy , Clinical Trials as Topic , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/complications , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Piperidines , Protein Kinase Inhibitors/therapeutic use , Pyrazoles/adverse effects , Pyrazoles/therapeutic use , Pyrimidines/adverse effects , Pyrimidines/therapeutic use , Signal Transduction , Treatment Outcome
