High sensitivity c-reactive protein and circulating biomarkers of endothelial dysfunction in patients with chronic myeloid leukemia receiving tyrosine kinase inhibitors

Abstract

Tyrosine kinase inhibitors (TKIs) have revolutionized the management of patients with chronic myelogenous leukemia (CML); however, they may cause cardiovascular (CV) toxicities. In this cross-sectional study, we explored whether high-sensitivity C-reactive protein (hsCRP) and novel markers of vascular dysfunction were associated with exposure to specific TKIs, in 262 CML patients. Hs-CRP level was not associated with CML disease activity or treatment with a specific TKI. Body mass index (OR: 1.15, 95% CI: 1.108–1.246; p < 0.001) and CML duration (OR: 1.004, 95% CI: 1.001–1.008; p = 0.024) were independently associated with higher hs-CRP. In exploratory analyses, novel endothelial-centric markers (e.g. ET-1 and VCAM-1) were differential across the various TKIs, particularly amongst nilotinib- and ponatinib-treated patients. While Levels of hs-CRP do not appear to be correlated with specific TKIs, circulating markers of vascular dysfunction were altered in patients treated with specific TKIs and should be explored as potential markers of TKI-associated CV risk.

Keywords:

• Chronic myelogenous leukemia
• inflammation
• endothelium
• hsCRP
• tyrosine kinase inhibitors
• cardiovascular risk

Acknowledgements

We would like to gratefully acknowledge the participants who graciously contributed to the study, teams of research coordinators, as well as the clinicians, nurses, and biobank members who assisted with the collection of samples that were utilized in this study. In addition, we would like to acknowledge that these studies used resources from the Toronto General Hospital Research Institute, University Health Network, Toronto, Canada and the Princess Margaret Cancer Center, University Health Network, Toronto, Canada.

Author contributions

N.A., D.G., D.D., J.E.F., and J.L contributed to the study design. N.A., D.G., and E.A. contributed to patient recruitment, data collection, and analysis of clinical data. D.G. contributed to wet-lab data generation and subsequent analysis. N.A., D.G., J.E.F., and J.L. wrote and revised the manuscript. All authors discussed and commented on the manuscript. J.E.F. and J.L. provided funding to support this study.

Disclosure statement

The authors declare no competing financial interests.

Data availability statement

The authors declare that all supporting data are available within the article. Further information and requests for resources, reagents, or patient-level datasets from qualified researchers trained in human subject confidentiality protocols may be sent to the lead contact, Dr. Jeffrey Lipton ([email protected]).

Additional information

Funding

Work for this project is supported by our patients through the Friends for Life Fund, Princess Margaret Hospital Foundation. Cardio-oncology research in the laboratory of J.E.F is supported by a Project Grant from the Canadian Institutes of Health Research (Grant: PJT-175301) and infrastructure funding from the Canada Foundation for Innovation, the John R. Evans Leaders Fund, and the Ontario Research Fund. J.E.F. is supported by a Tier 2 Canada Research Chair in Vascular Cell and Molecular Biology from the Canadian Institutes of Health. D.G. received salary support from the Frederick Banting and Charles Best Canada Graduate Scholarship Doctoral Award from the Canadian Institutes of Health Research, education funding from the Ted Rogers Center for Heart Research, and an Ontario Graduate Scholarship.