Pulmonary complications of Bcr-Abl tyrosine kinase inhibitors

Area of Science:

• Oncology
• Pharmacology
• Pulmonology

Background:

• Tyrosine kinase inhibitors (TKIs) targeting the Bcr-Abl oncoprotein have transformed chronic myelogenous leukaemia (CML) treatment.
• Second- and third-generation TKIs offer varied inhibition profiles and off-target effects, leading to diverse toxicities.
• Pulmonary complications represent a significant, though often under-recognized, class of TKI-related adverse events.

Purpose of the Study:

• To review the spectrum of pulmonary complications associated with Bcr-Abl TKIs used in CML treatment.
• To highlight the specific pulmonary toxicities linked to different TKIs, focusing on incidence and clinical presentation.
• To discuss the known and unknown mechanisms underlying TKI-induced lung injury and emphasize diagnostic and management considerations.

Main Methods:

• Literature review of published studies on Bcr-Abl TKIs and their associated pulmonary toxicities.
• Analysis of reported cases and clinical trial data concerning pleural effusions, pulmonary arterial hypertension, and interstitial lung disease.
• Examination of mechanistic studies investigating dasatinib's effect on pulmonary endothelium.

Main Results:

• Pleural effusions are the most common pulmonary complication, frequently linked to dasatinib and bosutinib.
• Pulmonary arterial hypertension, though rare, is a serious complication associated with dasatinib, bosutinib, and ponatinib, but not imatinib.
• Interstitial lung disease is a rare complication, predominantly reported with imatinib.

Conclusions:

• Pulmonary complications, particularly pleural effusions and pulmonary arterial hypertension, are significant adverse events of Bcr-Abl TKIs.
• Dasatinib exhibits a distinct mechanism involving pulmonary endothelial damage via oxidative stress and apoptosis.
• Vigilance for early diagnosis and management of these potentially reversible pulmonary toxicities is essential for CML patients undergoing TKI therapy.