Elsevier

International Journal of Cardiology

Volume 288, 1 August 2019, Pages 124-127
International Journal of Cardiology

Short communication
Recurrent arterial occlusive events in patients with chronic myeloid leukemia treated with second- and third-generation tyrosine kinase inhibitors and role of secondary prevention

https://doi.org/10.1016/j.ijcard.2019.04.051Get rights and content

Highlights

  • Risk of death is particularly high in patients with a previous history of arterial occlusive events (AOEs) and the probability for a recurrent event is around 20%.

  • Recurrent AOE in patients with Chronic Myeloid Leukemia (CML) treated with second- and third-generation tyrosine kinase inhibitors (2ndG/3rdG TKIs), represent a clinical challenge.

  • CML patients with a previous history of AOE treated with 2ndG/3rdG TKI represent a particular patient population with a higher probability of experiencing a recurrent AOE;

  • Individualized treatment is needed to optimize secondary prevention.

Abstract

Background

Risk of death is particularly high in patients with a previous history of arterial occlusive events (AOEs) and the probability for a recurrent event is around 20%. Little is known about recurrent AOE and the role of secondary prevention in patients with Chronic Myeloid Leukemia (CML) with previous AOE, treated with second- and third-generation tyrosine kinase inhibitors (2ndG/3rdG TKIs), nilotinib, dasatinib, bosutinib and ponatinib.

Methods

We identified a real-life cohort of 57 consecutive adult CML patients treated with 2ndG/3rdG TKI. All patients had a previous history of AOE. Ongoing use of secondary prevention of AOE (including antiplatelet agents, anticoagulant therapy, and statins) before starting a 2ndG/3rdG TKI was recorded, as well as CV risk factors.

Results

The 60-month cumulative incidence rate of recurrent AOEs was 47.8 ± 10.9%. Despite a history of AOE, 10 patients (16%) were not receiving secondary preventative measures. Patients treated with nilotinib and ponatinib showed a higher incidence of recurrent AOEs (76.7 ± 14.3% and 64 ± 20.1%, respectively) than those treated with dasatinib and bosutinib (44 ± 24.2% and 30.5 ± 15.5%, respectively) (p = 0.01). Only treatment with a 2ndG/3rdG TKI given as second or subsequent line therapy showed a significant association with an increased incidence of recurrent AOE (p = 0.039). Overall, 17 recurrent AOEs were observed; 3 CV-related deaths were reported.

Conclusion

CML patients with a previous history of AOE treated with 2ndG/3rdG TKI represent a particular patient population with a higher probability of experiencing a recurrent AOE; individualized treatment is needed to optimize secondary prevention.

Introduction

Cardiovascular disease (CVD) remains the most important cause of death worldwide, and is responsible for a third of all deaths before the age of 65 [1]. Risk of death is particularly high in patients with a previous history of CVD. Data from a large cohort of such patients showed that the mean estimated risk rate for a recurrent vascular event was 20%, which increased with age (from 10% for patients aged <50 years to 32% for those >70 years) [2]. Nilotinib, dasatinib, bosutinib and ponatinib are second- and third-generation tyrosine kinase inhibitors (2ndG/3rdG TKIs) effective in the treatment of chronic myeloid leukemia (CML), but are potentially associated with cardiovascular (CV) complications; their use in patients with pre-existing CVD requires caution [[3], [4], [5], [6]]. CML patients with a history of CVD represent a challenge for clinicians and thus far, limited information is available regarding the incidence of recurrent arterial occlusive events (AOEs) in patients treated with 2ndG/3rdG TKIs, associated risk factors, and the role of secondary prevention.

We therefore reported a real-life cohort of Italian CML patients treated with 2ndG/3rdG TKIs outside clinical trials, with a previous history of CVD. The primary endpoint was to establish the incidence of recurrent arterial occlusive events (AOE)s and the association with risk factors. Secondary endpoints were to evaluate the role of secondary prophylaxis in preventing AOEs and to report the management of AOEs complications in the clinical practice.

Section snippets

Methods

We identified 57 consecutive adult patients with CML who were initiated on a 2ndG/3rdG TKI between 2012 and 2017 in 17 Italian centers. All patients had a previous history of AOE, including myocardial infarction, angina, stroke, peripheral artery disease, and ischemic cerebrovascular events. Ongoing use of therapeutic measures for secondary prevention of AOE (including antiplatelet agents, anticoagulant therapy, and statins) before starting a 2ndG/3rdG TKI was recorded. Tobacco use, systolic

Results

The CV patients' characteristics are summarized in Table 1. The median age at initiation of 2ndG/3rdG TKI treatment was 52 years (range, 45–87). All patients were evaluated according to the Sokal score, a prognostic model that evaluates the risk of leukemia progression, on the basis of age, spleen size, platelet and blast cell count at baseline [7].

The Sokal score was intermediate to high in 43.9% of patients. The majority of patients reported a history of myocardial infarction/angina (63%),

Discussion

AOEs represent off-target relevant complications of 2ndG/3rdG TKIs [9]. Given the long-term (often lifelong) TKI treatment required by the majority of CML patients, who today can expect survival similar to that of the general population [10], an individualized treatment approach based also on CV safety and quality of life is needed [11]. This is crucial for CML patients with a previous history of AOE. Indeed, this study showed a higher incidence of recurrent AOEs in patients treated with a 2ndG

Ethics approval and consent to participate

Data on patients were retrospectively collected in accordance with the 1975 guidelines of the Declaration of Helsinki.

Competing interests

The other authors have no conflicts of interest to disclose.

Funding

None.

Acknowledgments

We are deeply grateful to the patients who participated in this study.

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1

This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

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