How does Ibrutinib (Ibrutinib, generic name) cause myocarditis?

From the Guidelines

Ibrutinib can cause myocarditis through its inhibition of Bruton's tyrosine kinase (BTK), which affects both cancer cells and normal cardiac function, as supported by the most recent study 1. The drug works by blocking BTK signaling pathways that are important for B-cell malignancies, but these same pathways play roles in cardiac tissue maintenance and immune regulation. Myocarditis from ibrutinib typically develops through several mechanisms:

• direct cardiotoxicity where the drug damages heart muscle cells
• dysregulation of immune responses leading to inflammation of the heart muscle
• disruption of cardiac electrical signaling pathways, as seen in the development of atrial fibrillation in patients treated with ibrutinib 1. Additionally, ibrutinib affects platelet function and can cause hypertension, which may contribute to cardiac stress. Patients taking ibrutinib should be monitored for symptoms like chest pain, shortness of breath, fatigue, palpitations, or irregular heartbeat. The risk appears dose-dependent and may be higher in patients with pre-existing cardiovascular conditions. If myocarditis is suspected, prompt medical evaluation with cardiac biomarkers, ECG, and imaging is essential, as early detection and management (which may include ibrutinib dose reduction or discontinuation) can prevent progression to severe heart failure, as recommended by recent guidelines 1. It is also important to note that the management of ibrutinib-induced myocarditis may involve the use of high-dose corticosteroids and the withholding of further therapy with ICIs, as suggested by recent studies 1. Overall, the risk of myocarditis associated with ibrutinib use highlights the need for careful monitoring and management of patients receiving this medication, particularly those with pre-existing cardiovascular conditions.

From the Research

Ibrutinib and Myocarditis

• There is limited direct evidence on how ibrutinib causes myocarditis, as the provided studies focus on the association between ibrutinib and various cardiovascular toxicities, including atrial fibrillation, bleeding, and hypertension 2, 3, 4, 5.
• However, one study suggests that ibrutinib may cause atrial fibrillation through the inhibition of C-terminal Src kinase (CSK) 6.
• Another study reports a high prevalence of atrial and ventricular arrhythmias in patients treated with ibrutinib, which may be related to the drug's cardiotoxic effects 4.
• The exact mechanisms underlying ibrutinib-induced cardiotoxicity, including myocarditis, remain unclear and require further research 2, 5.

Cardiovascular Toxicities Associated with Ibrutinib

• Ibrutinib has been associated with an increased risk of various cardiovascular toxicities, including:
  • Supraventricular arrhythmias (SVAs) 3
  • Central nervous system (CNS) hemorrhagic events 3
  • Heart failure 3
  • Ventricular arrhythmias 3, 4
  • Conduction disorders 3
  • CNS ischemic events 3
  • Hypertension 3
• These cardiovascular toxicities can occur early after ibrutinib administration and may be associated with fatalities 3.

Management and Future Research

• The management of ibrutinib-related cardiovascular toxicities requires careful consideration and monitoring 2, 5.
• Further research is needed to optimize strategies for diagnosing, monitoring, and managing ibrutinib-related arrhythmias and other cardiovascular complications 4, 5.
• The development of more selective BTK inhibitors, such as acalabrutinib, may help reduce the risk of cardiovascular toxicities associated with ibrutinib 5, 6.