Abstract
Tyrosine kinase inhibitors (TKIs) targeting the Bcr-Abl oncoprotein revolutionised the treatment of chronic myelogenous leukemia. Following the success of imatinib, second and third generation molecules were developed. Different profiles of kinase inhibition and off-target effects vary between TKIs, which leads to a broad spectrum of potential toxicities.
Pulmonary complications are most frequently observed with dasatinib but all other Bcr-Abl TKIs have been implicated. Pleural effusions are the most frequent pulmonary complication of TKIs, usually associated with dasatinib and bosutinib. Pulmonary arterial hypertension is an uncommon but serious complication of dasatinib, which is often reversible upon discontinuation. Bosutinib and ponatinib have also been associated with pulmonary arterial hypertension, while imatinib has not. Rarely, interstitial lung disease has been associated with TKIs, predominantly with imatinib.
Mechanistically, dasatinib affects maintenance of normal pulmonary endothelial integrity by generating mitochondrial oxidative stress, inducing endothelial apoptosis and impairing vascular permeability in a dose-dependent manner. The mechanisms underlying other TKI-related complications are largely unknown. Awareness and early diagnosis of the pulmonary complications of Bcr-Abl TKIs is essential given their seriousness, potential reversibility, and impact on future treatment options for the underlying chronic myelogenous leukemia.
Footnotes
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Conflict of interest: Dr. Weatherald reports grants, personal fees and non-financial support from Janssen Inc., grants, personal fees and non-financial support from Actelion, personal fees and non-financial support from Bayer, personal fees from Novartis, grants from Alberta Lung Association, grants from Canadian Vascular Network, grants from European Respiratory Society, grants from Canadian Thoracic Society, outside the submitted work.
Conflict of interest: Dr. Chaumais reports personal fees from Actelion, non-financial support from Bayer, non-financial support from Boehringer Ingelheim, outside the submitted work.
Conflict of interest: Dr. Guignabert has nothing to disclose.
Conflict of interest: Dr. Savale reports personal fees from Actelion, grants and personal fees from Bayer, grants and personal fees from GSK, outside the submitted work.
Conflict of interest: Dr. Jaïs reports grants and personal fees from Actelion, grants and personal fees from MSD, grants from Bayer, outside the submitted work.
Conflict of interest: Dr. Sitbon reports grants, personal fees and non-financial support from Actelion Pharmaceuticals, personal fees and non-financial support from Acceleron Pharmaceuticals, grants, personal fees and non-financial support from Bayer HealthCare, personal fees from Ferrer, grants from GlaxoSmithKline, personal fees from Gossamer Bio, grants, personal fees and non-financial support from MSD, personal fees from United Therapeutics, outside the submitted work.
Conflict of interest: Dr. ROUSSELOT reports grants and personal fees from Pfizer, grants and personal fees from Incyte, grants from Britol Myers Squibb, outside the submitted work.
Conflict of interest: Dr. Humbert reports personal fees from Acceleron, grants and personal fees from Actelion, grants and personal fees from Bayer, grants and personal fees from GSK, personal fees from Merck, personal fees from Morphogen IX, personal fees from United Therapeutics, outside the submitted work.
Conflict of interest: Dr. Bergeron reports grants from SOS oxygene, personal fees from Shire, personal fees from Pfizer, personal fees from MSD, personal fees from Gilead, outside the submitted work.
Conflict of interest: Dr. MONTANI reports grants and personal fees from Actelion, grants and personal fees from Bayer, personal fees from GSK, personal fees from Pfizer, personal fees from MSD, personal fees from Chiesi, outside the submitted work
Conflict of interest: Dr. Bondeelle has nothing to disclose.
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- Received February 9, 2020.
- Accepted June 2, 2020.
- Copyright ©ERS 2020
