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Review
. 2020 Oct 29;56(4):2000279.
doi: 10.1183/13993003.00279-2020. Print 2020 Oct.

Pulmonary complications of Bcr-Abl tyrosine kinase inhibitors

Jason Weatherald  1   2 , Louise Bondeelle  3   2 , Marie-Camille Chaumais  4   5   6 , Christophe Guignabert  6   7 , Laurent Savale  6   7   8 , Xavier Jaïs  6   7   8 , Olivier Sitbon  6   7   8 , Philippe Rousselot  9 , Marc Humbert  6   7   8 , Anne Bergeron  3 , David Montani  6   7   8
Affiliations
Free article
Review

Pulmonary complications of Bcr-Abl tyrosine kinase inhibitors

Jason Weatherald et al. Eur Respir J. .
Free article

Abstract

Tyrosine kinase inhibitors (TKIs) targeting the Bcr-Abl oncoprotein revolutionised the treatment of chronic myelogenous leukaemia. 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 leukaemia.

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Conflict of interest statement

Conflict of interest: J. Weatherald reports grants, personal fees and non-financial support from Janssen Inc. and Actelion, personal fees and non-financial support from Bayer, personal fees from Novartis, grants from Alberta Lung Association, Canadian Vascular Network, European Respiratory Society and Canadian Thoracic Society, outside the submitted work. Conflict of interest: L. Bondeelle has nothing to disclose. Conflict of interest: M-C. Chaumais reports personal fees from Actelion, non-financial support from Bayer and Boehringer Ingelheim, outside the submitted work. Conflict of interest: C. Guignabert has nothing to disclose. Conflict of interest: L. Savale reports personal fees from Actelion, grants and personal fees from Bayer and GSK, outside the submitted work. Conflict of interest: X. Jaïs reports grants and personal fees from Actelion and MSD, grants from Bayer, outside the submitted work. Conflict of interest: O. Sitbon reports grants, personal fees and non-financial support from Actelion Pharmaceuticals, Bayer HealthCare and MSD, personal fees and non-financial support from Acceleron Pharmaceuticals, personal fees from Ferrer, Gossamer Bio and United Therapeutics, grants from GlaxoSmithKline, outside the submitted work. Conflict of interest: P. Rousselot reports grants and personal fees from Pfizer and Incyte, grants from Britol Myers Squibb, outside the submitted work. Conflict of interest: M. Humbert reports personal fees from Acceleron, Merck, Morphogen IX and United Therapeutics, grants and personal fees from Actelion, Bayer and GSK, outside the submitted work. Conflict of interest: A. Bergeron reports grants from SOS oxygene, personal fees from Shire, Pfizer, MSD and Gilead, outside the submitted work. Conflict of interest: D. Montani reports grants and personal fees from Actelion and Bayer, personal fees from GSK, Pfizer, MSD and Chiesi, outside the submitted work.

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