clinical topic updates

Cardiovascular Side Effects of Available Tyrosine Kinase Inhibitors

by Mark J. Levis, MD, PhD

Overview

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML) to such an extent that this once-lethal disease has become a manageable chronic condition for most patients. Cardiovascular comorbidity is one of several patient-level factors that are considered, along with TKI toxicity profiles, when selecting and adjusting therapy.

Expert Commentary

Mark J. Levis, MD, PhD

Director, Adult Leukemia Service
Co-Division Director, Hematologic Malignancies
Professor of Oncology
The Sidney Kimmel Comprehensive Cancer Center
Johns Hopkins University
Baltimore, MD

We give quite a bit of consideration to cardiovascular side effects, particularly as we change medications and try to balance the impacts of TKIs on the CML and on comorbid cardiovascular disease.”

Mark J. Levis, MD, PhD

We have decades of data suggesting that imatinib is a reasonably safe option. In a younger patient (eg, aged 30 years) with low-risk CML, one would generally begin with imatinib. If imatinib is poorly tolerated, there are a number of options for your next choice of TKI. In contrast, some older patients who have significant cardiovascular comorbidity (eg, congestive heart failure and atrial fibrillation) may present with high-risk CML, and decisions may be more complicated in these cases. As such, we give quite a bit of consideration to cardiovascular side effects, particularly as we change medications and try to balance the impacts of TKIs on the CML and on comorbid cardiovascular diseaseThis includes the consideration of potential interactions with cardiovascular medications that the patients may already be taking. TKIs are extensively metabolized by cytochrome P450 enzymes, which can show substantial interindividual variability. Beta blockers can have drug interactions with TKIs that may increase the exposure to the TKI, the beta blocker, or both. Interactions have also been reported with calcium channel blockers and statins.

The mechanisms behind cardiovascular adverse events associated with specific TKIs are not completely understood. TKIs for CML are designed to have activity against BCR-ABL1, but there may be off-target toxicities, and the extent to which they have activity against other relevant kinases, such as VEGFR, for instance, could be important. VEGFR inhibition and resulting hypertension might be implicated in some of these toxicity profiles. However, when these events have occurred, it has often been challenging to understand the independent contribution of the TKI, in part because of uncertainty about the baseline cardiovascular risk profile of patients with CML (ie, irrespective of therapy or as they commence therapy). A current ongoing prospective study (NCT03045120) is assessing the baseline cardiovascular risk factors and the follow-up cardiovascular risks of a real-world population of patients with CML on chronic TKI therapy.

References

Casavecchia G, Galderisi M, Novo G, et al. Early diagnosis, clinical management, and follow-up of cardiovascular events with ponatinib. Heart Fail Rev. 2020;25(3):447-456. doi:10.1007/s10741-020-09926-y

ClinicalTrials.gov. Determining change in cardiovascular and metabolic risks in patients with chronic phase chronic myeloid leukemia receiving BCR-ABL tyrosine kinase inhibitor first-line therapy in the United States. Accessed May 14, 2021. https://clinicaltrials.gov/ct2/show/NCT03045120

Haguet H, Douxfils J, Mullier F, Chatelain C, Graux C, Dogné J-M. Risk of arterial and venous occlusive events in chronic myeloid leukemia patients treated with new generation BCR-ABL tyrosine kinase inhibitors: a systematic review and meta-analysis. Expert Opin Drug Saf. 2017;16(1):5-12. doi:10.1080/14740338.2017.1261824

Hamed NAM. Preventing and managing cardiovascular toxicities of tyrosine kinase inhibitors in chronic myeloid leukemia. Canc Ther Oncol Int J. 2018;10(1):555779. doi:10.19080/CTOIJ.2018.10.555779

Haouala A, Widmer N, Duchosal MA, et al. Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib. Blood. 2011;117(8):e75-e87. doi:10.1182/blood-2010-07-294330

Jain P, Kantarjian H, Boddu PC, et al. Analysis of cardiovascular and arteriothrombotic adverse events in chronic-phase CML patients after frontline TKIs. Blood Adv. 2019;3(6):851-861. doi:10.1182/bloodadvances.2018025874

Lenihan DJ, Kowey PR. Overview and management of cardiac adverse events associated with tyrosine kinase inhibitors. Oncologist. 2013;18(8):900-908. doi:10.1634/theoncologist.2012-0466

Manouchehri A, Kanu E, Mauro MJ, Aday AW, Lindner JR, Moslehi J. Tyrosine kinase inhibitors in leukemia and cardiovascular events: from mechanism to patient care. Arterioscler Thromb Vasc Biol. 2020;40(2):301-308. doi:10.1161/ATVBAHA.119.313353

Moslehi JJ, Deininger M. Tyrosine kinase inhibitor-associated cardiovascular toxicity in chronic myeloid leukemia. J Clin Oncol. 2015;33(35):4210-4218. doi:10.1200/JCO.2015.62.4718

Mughal TI, Gotlib J, Mesa R, et al. Recent advances in the genomics and therapy of BCR/ABL1-positive and -negative chronic myeloproliferative neoplasms. Leuk Res. 2018;67:67-74. doi:10.1016/j.leukres.2018.02.008

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