The use of tyrosine kinase inhibitors (TKIs) has dramatically changed how chronic myeloid leukemia (CML) is managed and improved survival rates. That’s especially true for second- and third-generation TKIs. However, that improvement comes with another type of cost: a heavier toxicity profile, including adverse cardiovascular events (CVAEs).

In this report, a team of researchers in Italy reviewed CVAE risks associated with the use of TKIs in patients with CML. Their report, published in Frontiers in Physiology, discussed the cardiac and vascular toxicity of 5 ABL-inhibiting TKIs.

Imatinib This first-generation TKI is the most convenient with regard to cardiovascular and metabolic toxicity. It appears to have potential benefit with insulin resistance, hyperglycemia, and pulmonary hypertension.

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Nilotinib This second-generation TKI is associated with better molecular responses but possibly a worse safety profile. Thrombosis mediators are increased, triggering a prothrombotic state.

Dasatinib This second-generation TKI associated with pulmonary arterial hypertension. Although not a cardiac or vascular toxicity, pleural effusion is part of the differential diagnosis in assessing cardiac impairment.

Bosutinib The researchers report potentially no cardiovascular-associated toxicities. However, most of both the clinical trials and real life data on this second-generation TKI are from patients receiving second- and third-line treatment.

Ponatinib This third-generation TKI is the most potent of the drugs reviewed, and the PACE trial initially reported high rate of CVAE; however, analysis revealed this was due to patients having a high CV risk prior to treatment. But those with traditional CV risk factors are high risk for arterial thrombotic events.

A correct patient evaluation and risk classification are essential first steps in developing an effective cardiovascular event prevention strategy; however, an appropriate cardiovascular risk score for baseline evaluation is an “unmet need” at present, the researchers noted. Ideally, a score would provide an estimate for the 10-year probability of conditions such as myocardial ischemia, peripheral artery obstructive disease, and other fatal and nonfatal cardiovascular events. Referral to the cardio-oncology unit at the time of diagnosis also is recommended.

“Optimizing modifiable CV risk factors through lifestyle modifications and eventual prescription of primary prophylactic drugs is the preferred strategy to be applied upon CML diagnosis despite the TKI chosen,” the researchers concluded, adding that low-dose aspirin therapy may also be used in some patients to reduce their pre-TKI CV risk.


Santoro M, Mancuso S, Accurso V, Di Lisi D, Novo G, Siragusa S. Cardiovascular issues in tyrosine kinase inhibitors treatments for chronic myeloid leukemia: a review. Front Physiol. Published online July 5, 2021. doi:10.3389/fphys.2021.675811