Targeted Chronic Myeloid Leukemia Drugs Show Divergent Cardiovascular Risk Profiles, JACC Cardio-Oncology State-of-the-Art Review Reports

A recent state-of-the-art review highlights that Cardiovascular disease (CVD) and CV risk factors are frequent in patients with Chronic Myeloid Leukemia (CML). Therefore, it is crucial to evaluate the CV safety profile of various BCR::ABL1 (Breakpoint cluster region gene::Abelson murine leukemia gene 1) tyrosine kinase inhibitors (TKIs) before starting the treatment and aggressively manage CV risk factors during treatment to mitigate the risk.

The state-of the-art review is published in October 2025 issue of the Journal of the American College of Cardiology (JACC) CardioOncology.

The review emphasizes that given the low incidence of CML, the most robust data regarding the CV toxicity of medications can be derived from clinical trials involving new pharmacological agents.

Chronic Myeloid Leukemia (CML), a myeloproliferative neoplasm characterized by the BCR::ABL1 fusion oncogene, has transitioned from a near-universally fatal disease to one where patient survival closely approaches that of age-matched controls. This remarkable achievement is attributed to the introduction of targeted therapies, specifically tyrosine kinase inhibitors (TKIs), which block the proliferation of malignant cells.

However, this therapeutic success introduces a new clinical imperative: managing the cardiovascular (CV) side effects of these life-saving drugs. CV disease and its risk factors are notably prevalent among CML patients. Approximately 18% of patients with CML have established CV disease (such as coronary artery disease (CAD) or peripheral arterial disease (PAD) at the time of diagnosis. With increased life expectancy due to TKI treatment, patients face heightened risk for future CV disease due to pre-existing risk factors and potential off-target effects of BCR::ABL1 TKIs.

Varied Tyrosine Kinase Inhibitors’ (TKI)-Specific CV Risks: Clinical Evidence Review

TKIs differ significantly in their potency and inhibition of kinases that regulate the CV system, leading to diverse toxicity profiles. Understanding these differences is crucial for individualized patient care:

• Imatinib (First-Generation TKI): This agent possesses a favorable CV safety profile. After a long-term median follow-up of 10.9 years in the IRIS trial*, only 7.1% of patients experienced CV events. Imatinib has minimal clinical impact on cardiac function and may even exert beneficial effects on metabolism and the CV system.

• Nilotinib (Second-Generation TKI): In contrast to imatinib, nilotinib significantly increases the risk of CV events, including acute coronary syndrome, stroke, and PAD. The ENESTnd* 10-year analysis showed CV event rates as high as 23.5% in the higher-dose nilotinib group, compared to 3.6% with imatinib. Nilotinib is also known to cause diabetes and dyslipidemia.

• Ponatinib (Third-Generation TKI): Patients treated with ponatinib are at high risk for developing CV events, including acute coronary syndrome, stroke, and PAD. This toxicity is dose-dependent. Findings suggest the incidence of CV events with ponatinib is similar to rates seen in CV clinical trials involving high-risk individuals.

• Dasatinib (Second-Generation TKI): The most distinct and serious CV complication is Pulmonary Arterial Hypertension (PAH), which is uncommon but significant. PAH occurs in at least 0.45% of chronically exposed individuals. Dasatinib may also cause pleural effusion, though this is considered an off-target, non-CV effect.

• Asciminib (STAMP Inhibitor): Preliminary data from the ASC4FIRST trial suggest a promising CV risk profile (1% CV events). However, longer-term follow-up is necessary for a comprehensive comparison.

Clinical Insights: Aggressive CV Risk Assessment & Mitigation Strategies

The high incidence of CV risk factors in patients eligible for TKI treatment mandates a comprehensive baseline assessment before therapy initiation. The specific CV safety profile of the chosen TKI should guide treatment selection.

For patients receiving nilotinib or ponatinib, they should be considered at increased risk for future CV events regardless of traditional risk calculators. Aggressive modification of risk factors is advised, including primary prevention with statins to maintain LDL levels below 70 mg/dL. Patients starting nilotinib require follow-up lipid profiles and HbA1c checks within three to four months due to the potential for new-onset diabetes and hyperlipidemia.

If a CV event occurs in a patient on nilotinib or ponatinib, it may be considered to discontinue the TKI and transition to a lower CV-risk alternative. If PAH is confirmed in a patient receiving dasatinib, it must be discontinued.

Furthermore, clinicians must be vigilant for potential drug-drug interactions between TKIs and CV medications (e.g., diltiazem, verapamil, simvastatin, atorvastatin) that are metabolized by the CYP3A4 enzyme, as TKIs could elevate the plasma concentrations of these drugs.

Abbreviations: *IRIS Trial: (International Randomized Study of Interferon and STI571, ENESTnd trial: Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients

Reference: Aghel, N, Lipton, J. Cardiovascular Disease in Patients With Chronic Myeloid Leukemia: JACC: CardioOncology State-of-the-Art Review. J Am Coll Cardiol CardioOnc. 2025 Oct, 7 (6) 668–682.

https://doi.org/10.1016/j.jaccao.2025.06.007

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