A 72-year-old man has been on ibrutinib for CLL for 14 months. He now develops a new atrial fibrillation, hypertension, and grade 3 bleeding. The mechanism of ibrutinib causing these adverse effects is:

• A Off-target inhibition of EGFR leading to vasoconstriction and atrial re-entry
• B On-target BTK inhibition in cardiac myocytes causing QT prolongation
• C Irreversible VEGFR inhibition causing capillary leak and platelet activation
• D Off-target inhibition of TEC and EGFR kinases, with TEC inhibition impairing atrial myocyte gap junction communication and platelet collagen signalling ✓

Explanation

Ibrutinib is an irreversible BTK inhibitor but also inhibits related TEC kinase family members (TEC, TXK) and EGFR. TEC kinase is expressed in cardiomyocytes and its inhibition impairs PI3K-AKT survival signalling, promoting atrial fibrillation (AF occurs in ~10–15% of patients). TEC and EGFR kinase inhibition also impairs platelet GP VI/collagen and thrombin signalling, causing a vonWillebrand-like platelet aggregation defect leading to bleeding. Second-generation BTK inhibitors (acalabrutinib, zanubrutinib) are more selective for BTK and have lower rates of AF and bleeding.

Reference: Harrison's Principles of Internal Medicine, 21st ed.

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