Mechanisms,Clinical Phenotype and Potential Risk Prediction for Cardiovascular Toxicity Induced by Tyrosine Kinase Inhibitors In Chronic Myeloid Leukemia

Abstract

Tyrosine kinase inhibitors (TKIs) form the cornerstone of targeted therapy for chronic myeloid leukemia (CML), significantly improving patient prognosis. However, long-term use of TKIs, particularly second-generation (e.g., nilotinib) and third-generation (e.g., ponatinib) drugs, has led to adverse cardiovascular events (CV-AEs). CV-AEs pose a critical challenge to patients’ long-term quality of life and treatment adherence. This narrative review systematically elucidates the complex mechanisms underlying TKI-induced cardiovascular toxicity and proposes the “Metabolism-Endothelium-Thrombosis Axis” as a unifying conceptual framework, integrating endothelial dysfunction, metabolic impairment, oxidative stress, inflammatory responses, and abnormal platelet activation into a coherent pathophysiological cascade. These mechanisms collectively contribute to a spectrum of clinical phenotypes. At the clinical management level, identifying individuals at high risk is crucial. Multiple risk prediction models demonstrate predictive value for CV-AEs, particularly arterial occlusive events (AOEs). Future research should focus on elucidating TKI-specific toxicity pathways, validating and optimizing risk prediction models, and exploring effective cardioprotective strategies. Ultimately, this work will maximize cardiovascular risk reduction while preserving antileukemic efficacy.

Keywords

tyrosine kinase inhibitors chronic myeloid leukemia cardiovascular adverse events mechanisms risk prediction tools

1. Introduction

Chronic myeloid leukemia (CML) is a malignant clonal disease of hematopoietic stem cells. It is driven by the Philadelphia chromosome-positive BCR-ABL1 fusion gene.¹ Tyrosine kinase inhibitors (TKIs) selectively target and prevent the abnormal kinase activity of the BCR-ABL1 fusion protein, which is the foundation of current targeted therapy for CML. Imatinib, as a first-generation TKI, received approval from the U.S. Food and Drug Administration (FDA) in 2001 for the treatment of BCR-ABL-positive CML and remains one of the preferred therapeutic options to date.² Owing to the emergence of imatinib resistance and intolerance in some patients, second- and third-generation TKIs have been developed. Current first-line treatments for CML include imatinib, dasatinib, nilotinib, and bosutinib. Ponatinib serves as a second-line option for patients with the T315I mutation and/or those unsuitable for other TKIs.¹ China’s second-generation TKI, flumatinib, is a structural analog of imatinib with enhanced binding affinity to the BCR/ABL1 protein.³ Olverembatinib (HQP1351) is a third-generation TKI that is indicated for the treatment of adult patients with T315I-mutated TKI-resistant chronic-phase CML (CML-CP) or accelerated-phase CML (CML-AP).⁴

Although TKIs form the core of targeted therapy for CML, data have increasingly suggested that they may induce adverse events across multiple systems, particularly cardiovascular adverse events (CV-AEs).^5-8 Major CV-AEs include ischemic heart disease (IHD) or peripheral arterial occlusive disease (PAOD), pulmonary hypertension, pericardial effusion, hypertension, and QT interval prolongation.^9-11 The occurrence of CV-AEs during TKI therapy poses significant challenges for patients, often leading to interruption or discontinuation of TKI treatment.

However, differences exist among TKIs in terms of target selection, efficacy, and safety profiles, and the underlying mechanisms contributing to TKI-induced cardiovascular toxicity are complex. Furthermore, at the clinical level, we still lack prospectively validated risk prediction models for identifying individuals at high risk. These issues have hindered the development of effective prevention and treatment strategies.

This narrative review aims to address the above challenges. First, we systematically elucidate the mechanisms underlying TKI-induced cardiovascular toxicity. Second, based on the latest evidence, we summarize clinical phenotypes and risk prediction tools. To accomplish these objectives, we conducted a literature search in PubMed, focusing mainly on publications from January 2015 to April 2026. The search terms included “tyrosine kinase inhibitors”, “cardiovascular toxicity”, “chronic myeloid leukemia”, and their synonyms. Studies were included if they were original research, reviews, or clinical guidelines focusing on TKI-induced cardiovascular adverse events in patients with CML. Data on mechanisms, clinical phenotypes, and risk assessment tools were extracted and synthesized narratively. The goal of this review is to provide insights for future research directions to alleviate the cardiovascular burden in CML survivors and optimize their long-term prognosis.

2. Mechanisms of TKI-Induced Cardiovascular Adverse Events

The complete molecular mechanism underlying TKI-induced CV-AEs is unclear. TKIs tend to bind and inhibit multiple signaling pathways simultaneously, and these off-target effects may contribute to adverse reactions.¹² Furthermore, vascular toxicity may be associated with off-target effects rather than on-target effects.¹³ Current scientific consensus identifies five interrelated factors as key contributors to the development of CV-AEs: endothelial dysfunction, metabolic impairment, oxidative stress, inflammatory responses, and abnormal platelet activation. Based on available evidence, the ‘Metabolism-Endothelium-Thrombosis Axis’ has been proposed as a unifying conceptual framework. Endothelial dysfunction and metabolic dysregulation together increase susceptibility to vascular endothelial injury. Oxidative stress and inflammatory responses are active throughout thrombogenesis, reinforcing each other in a cascade. Within this prothrombotic environment, aberrant platelet activation ultimately leads to clinical thrombotic events. The following sections delineate the specific impact of individual TKIs on each component of this axis and examine their interrelated mechanistic interactions.

2.1. Endothelial Dysfunction

Extensive research has indicated that TKIs have multiple adverse effects on vascular endothelial function. Dasatinib exhibits particularly unique endothelial toxicity. It severely disrupts angiogenesis by inducing endothelial cell contraction, disrupting intercellular junctions, inhibiting migration, and impairing barrier integrity, which is considered one of its key mechanisms for inducing PH.¹⁴ Concurrently, ponatinib and nilotinib also exhibit significant vascular toxicity. Both markedly reduce the viability of human vascular endothelial cells (HUVECs). Dasatinib and ponatinib strongly inhibit HUVEC tube formation, directly impeding neovascularization, whereas bosutinib has no adverse effects on either cell viability or tube formation.^15,16 Ponatinib also synergistically blocks downstream Akt/eNOS and MAPK (ERK/p38) signaling pathways, ultimately comprehensively suppressing endothelial cell proliferation, migration, and tubulogenesis.¹⁶

Previous studies¹⁷ have indicated that nilotinib and ponatinib significantly alter the levels of a series of key factors, such as Ang-2, ET-1, and Tie-2, thereby disrupting angiogenesis and vascular tension. Ponatinib-mediated inhibition of the VEGFR2-Akt/eNOS axis reduces the phosphorylation and activation of eNOS, thereby decreasing the production of NO, a key mediator of vascular homeostasis, which ultimately leads to vasodilatory dysfunction.¹⁶ At the molecular level, ponatinib directly inhibits the phosphorylation of VEGFR2 in a dose-dependent manner.¹⁶ It contributes to hypertension through mechanisms such as increased vasoactive substances and reduced capillary density.¹⁸ In clinical practice, it should be noted that VEGF inhibitor–associated hypertension is generally manageable with standard antihypertensive agents. However, verapamil and diltiazem should be avoided, as they may inhibit cytochrome P450 3A4 (CYP3A4) and thereby increase plasma concentrations of VEGF inhibitors, potentially exacerbating toxicity.¹⁹

Both nilotinib and ponatinib consistently upregulate key immune activation markers (including E-selectin, VCAM-1, ICAM-1, and TREM-1) in endothelial cells,¹⁷ particularly in the microvascular endothelium.²⁰ Leukocytes initially roll on the surface of activated endothelial cells via interactions with selectins, followed by firm adhesion and transendothelial migration mediated by ICAM-1 and VCAM-1, thereby facilitating their recruitment to sites of vascular injury. Agents with endothelial-protective properties warrant prospective evaluation in patients receiving ponatinib—for example, statins, which possess pleiotropic anti-inflammatory and endothelium-stabilizing effects. Notably, when co-administered with TKIs, pravastatin or rosuvastatin are preferred over atorvastatin or simvastatin due to their lower potential for drug–drug interactions.²¹

In summary, TKIs contribute to cardiovascular toxicity through two interrelated endothelial mechanisms. On the one hand, they inhibit angiogenesis and impair vasodilation, leading to adverse events such as hypertension and pulmonary hypertension. On the other hand, they markedly enhance endothelial cell activation and promote leukocyte adhesion, thereby creating a prothrombotic microenvironment conducive to thrombus formation. Collectively, these endothelial perturbations constitute a central component of the “Metabolism-Endothelium-Thrombosis Axis.” (Figure 1①)

Figure 1.

The mechanisms underlying TKI-induced cardiovascular toxicity. The mechanisms include endothelial dysfunction, metabolic impairment, oxidative stress, inflammatory responses, and abnormal platelet activation.(This figure was created in BioRender. Zheng, H. (2026) https://BioRender.com/xouoaax.)

2.2. Metabolic Impairment

Different TKIs exhibit significant variations in their effects on glucose and lipid metabolism, demonstrating distinct metabolic profiles. Imatinib has consistently been shown to lower blood glucose and lipid levels in patients with CML.^22,23 Dasatinib has also been shown to increase insulin sensitivity in patients with CML.^24,25 In stark contrast, nilotinib is associated with the most significant risk of new-onset diabetes and hyperlipidemia following TKI therapy.²⁶ Nilotinib perturbs systemic glucose metabolism by reducing peripheral insulin sensitivity, which subsequently triggers compensatory hyperinsulinemia and leads to a decrease in endogenous insulin secretion.^27-30 The underlying mechanism of this insulin resistance involves the downregulation of IRS1 expression and the inhibition of adiponectin secretion. Conversely, imatinib increases plasma adiponectin levels.^30-32 Concurrently, it reduces lipid storage within adipocytes, promoting ectopic lipid deposition in the liver and skeletal muscle,^30,32 which may involve nilotinib downregulating the expression of LDLR and VLDLR.³¹ Simultaneously, nilotinib also mildly downregulates Glut4 expression, potentially reducing glucose uptake by adipocytes and contributing to the clinically observed insulin resistance.³² Chronic hyperglycemia and insulin resistance increase oxidative stress and reduce nitric oxide (NO) bioavailability. This results in impaired vasodilation, vascular stiffening, and enhanced platelet adhesion to dysfunctional endothelium,³³ thereby exacerbating vascular injury, particularly in the microvasculature. Metformin is a widely available antidiabetic agent. It inhibits mTORC1 and PI3K/Akt pathways, suppresses glycolysis, and enhances TKI-induced apoptosis even in resistant CML cells.³⁴ In patients with nilotinib-associated insulin resistance or hyperglycemia, metformin may improve glycemic control while potentially augmenting antileukemic efficacy.

A comparative study of imatinib, nilotinib, and dasatinib revealed distinct effects on lipid profiles among the three agents.³⁵ This study revealed that patients in the dasatinib and nilotinib groups had significantly higher levels of total cholesterol (TC) and LDL-C than did those in the imatinib group. However, no significant difference in these two parameters was observed between the dasatinib and nilotinib groups. HDL-C levels were significantly higher in the nilotinib group than in the dasatinib and imatinib groups, whereas no significant difference in HDL-C levels was detected between the latter two groups. This finding may be related to the action of the three TKIs on PDGFR, which induces the phosphorylation of LDL receptor-associated proteins. Another study³⁶ confirmed the significant impact of nilotinib on lipids, demonstrating a marked increase in TC within three months of treatment initiation, characterized by elevations in both LDL-C and HDL-C components. In clinical practice, statins remain the cornerstone of lipid-lowering therapy. Their anti-inflammatory and endothelium-protective effects may also counteract TKI-induced vascular toxicity.

In summary, metabolic dysregulation is not only an independent risk factor for TKI-associated cardiovascular toxicity but also further activates other components of the “Metabolism-Endothelium-Thrombosis Axis” by promoting oxidative stress and inflammatory responses (Figure 1②).

2.3. Oxidative Stress

TKIs can induce cardiovascular toxicity through multiple mechanisms by triggering redox imbalance. At the vascular level, nilotinib and imatinib promote the conversion of NO, which has vasoprotective effects, to proinflammatory hydrogen peroxide (H₂O₂).³⁷ In the short term, H₂O₂ acts as a compensatory mediator to maintain baseline blood flow. However, long-term accumulation drives further increases in reactive oxygen species (ROS) levels and triggers lipid peroxidation, inflammatory responses, and pathological vascular remodeling, thereby leading to proatherosclerotic effects. Furthermore, all TKIs (including imatinib and dasatinib) can trigger endoplasmic reticulum stress by inhibiting the expression of ABL kinase, leading to a significant increase in ROS levels.^38-41 This cascade depletes mitochondrial and intracellular glutathione (GSH) reserves, exacerbating mitochondrial superoxide production, lipid peroxidation, and protein carbonylation. Ultimately, mitochondrial dysfunction, impaired ATP synthesis, and collapse of the membrane potential lead to cell death. Concurrently, ferroptosis has been implicated in TKI-associated cardiovascular injury.^42,43 This novel iron-dependent form of cell death is closely associated with the dysregulation of GSH metabolism, iron metabolism, and lipid metabolism. Specifically, imatinib (IMA) significantly downregulates the expression of the key antioxidant protein GPX4 and inhibits GSH activity; it simultaneously elevates the levels of intracellular iron, malondialdehyde (MDA) (a lipid peroxidation end product), and ROS. Imatinib subsequently induces ferroptosis by activating ROS and inhibiting the Nrf2 signaling pathway.^42,44 Strategies that target oxidative stress show potential for clinical translation. For example, edaravone is an antioxidant that has shown therapeutic efficacy in ischemic stroke models. It works by scavenging free radicals, protecting vascular endothelial cells, and inhibiting platelet thrombus formation.⁴⁵ These findings suggest that adding antioxidants for TKI-treated patients may help reduce vascular injury caused by oxidative stress.

A previous study³⁹ suggested that imatinib activates Caspase-3/7 and induces apoptosis. Notably, a study in human endogenous cardiac progenitor cells (hCPCs) revealed that, although imatinib caused a significant decrease in cell viability, no activation of Caspase-3/7 was detected, ruling out a dominant role for the classical apoptotic pathway.⁴⁶ Its core mechanism lies in the induction of mitochondrial dysfunction and impaired autophagic flux, which subsequently activates the RIP1/RIP3/MLKL signaling axis and triggers necroptosis. Importantly, inhibition of the key upstream protein RIP1 has been shown to effectively rescue cell viability, revealing that targeting the programmed necrosis pathway is a highly promising new strategy for mitigating imatinib-induced cardiotoxicity.

In summary, oxidative stress is a common driver of the “Metabolism-Endothelium-Thrombosis Axis,” directly damaging endothelial cells and linking metabolic dysregulation to thrombogenesis through lipid peroxidation and inflammatory amplification (Figure 1③).

2.4. Inflammatory Responses

Both nilotinib and ponatinib consistently upregulate key immune activation markers (including E-selectin, VCAM-1, ICAM-1, and TREM-1) in endothelial cells, indicating that these compounds strongly promote endothelial immune activation and leukocyte recruitment, thereby driving chronic inflammatory processes.¹⁷ Substantial evidence further demonstrates that nilotinib upregulates the expression of a series of cytokines and chemokines, including CCL2, IL-6, CXCL8, CXCL2, CXCL20, TYROBP, and CSF1R.^31,47 This process leads to markedly elevated levels of soluble P-selectin, E-selectin, ICAM-1, and VCAM-1 and promotes thrombin generation. Collectively, these effects accelerate the formation and destabilization of atherosclerotic plaques. Notably, under insulin-resistant conditions, high concentrations of free fatty acids can similarly activate M1 macrophages and promote the secretion of chemokines, including CCL2, TNF-α, CXCL8, CXCL2, and IL-6. Similarly, ponatinib has been demonstrated to increase the levels of key proinflammatory markers (TNF-α, IFN-γ, and IL-6) and sP-selectin.⁴⁸ Furthermore, studies indicate that, compared with imatinib or asciminib, ponatinib upregulates TNFR1 and TNFR2 and increases the infiltration of T cells, macrophages, and monocytes within atherosclerotic plaques. This promotes the formation of rupture-prone inflammatory plaques, which is a key mechanism underlying its cardiovascular toxicity. Accordingly, TNFR inhibition can block ponatinib-induced endothelial adhesion molecule expression and leukocyte recruitment, and abrogate ponatinib-elicited plaque inflammation; however, it does not reduce ponatinib-induced platelet or leukocyte activation, and its potent immunosuppressive effects are clinically unacceptable in patients with CML.⁴⁹ Inflammatory responses operate throughout the entirety of the “Metabolism-Endothelium-Thrombosis Axis,” serving as both a consequence of metabolic dysregulation and endothelial injury, and as a direct trigger for platelet activation and thrombogenesis (Figure 1①).

2.5. Abnormal Platelet Activation

Different TKIs exhibit significant variations in their effects on platelet function and thrombogenesis and present distinct risk profiles. Nilotinib exhibits potent prothrombotic properties in vitro, ex vivo, and in vivo.⁴⁷ It can activate endothelial cells and platelets, upregulate soluble adhesion molecules such as sP-selectin and sE-selectin, and intensify leukocyte recruitment and platelet adhesion. Similarly, as a third-generation TKI, ponatinib induces platelet hyperresponsiveness by mediating the binding of the von Willebrand factor (VWF) A1 domain to platelet GPIbα, which significantly increases the risk of arterial thrombosis, leading to prothrombotic vascular lesions characterized by platelet adhesion.^50,51 In addition to its direct effects on platelets, ponatinib also indirectly activates platelets through endothelial injury and inflammatory responses. Targeting these mechanisms, clinically available antiplatelet agents have demonstrated potential for intervention. In a zebrafish ischemic stroke model, both aspirin (a thromboxane A2 inhibitor) and clopidogrel (an ADP receptor antagonist) effectively reduced ponatinib-induced cerebral thrombus formation.⁴⁵ In terms of platelet aggregation, nilotinib and bosutinib significantly promote both collagen- and arachidonic acid-induced aggregation, whereas imatinib specifically enhances collagen-induced platelet aggregation.⁵² Beyond promoting aggregation, bosutinib may also increase procoagulant activity via the MAPK pathway, potentially increasing thrombotic risk.⁵³ Collectively, these studies indicate that TKIs exert drug-specific and individual-variant effects on platelet function, necessitating clinical selection that balances thrombotic and hemorrhagic risks. For patients receiving TKIs associated with a high thrombotic risk, such as ponatinib or nilotinib, especially those with additional cardiovascular risk factors, adjunctive antiplatelet therapy (such as aspirin or clopidogrel) may be considered for primary or secondary prevention, following a thorough assessment of bleeding risk.⁵⁴ In summary, abnormal platelet activation constitutes the final step of the “Metabolism-Endothelium- Thrombosis Axis.” This activation is regulated by upstream metabolic dysregulation, endothelial injury, and inflammatory responses, and directly mediates the occurrence of clinical arterial thrombotic events (Figure 1④).

3. Clinical Phenotypes of TKI-Induced Cardiovascular Adverse Events

Some studies have suggested that imatinib may have a cardioprotective effect.^9,55 Flumatinib has a favorable and manageable safety profile with relatively low rates of adverse cardiovascular events.^56,57 Some second- and third-generation TKIs carry a risk of CV-AEs (Table 1).

Table 1.

Comparative Cardiovascular Toxicity Profiles and Underlying Mechanisms of Different Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia: This Table Summarizes the Unique Cardiovascular Adverse Event Patterns Reported in the Reviewed Literature

TKI	Primary targets	Main cardiovascular toxicity	Key mechanistic features
Imatinib	BCR-ABL, c-KIT, PDGFR⁵⁸	Heart failure, pulmonary hypertension (possible), new-onset hypertension,	Lowers blood glucose and lipids; Induces ER stress, ROS, and ferroptosis via ABL inhibition
Nilotinib	BCR-ABL, c-KIT, PDGFRα/β, DDR⁵⁸	Peripheral arterial disease, myocardial infarction, cerebrovascular events, QT prolongation	Promotes insulin resistance and dyslipidemia; Upregulates pro-inflammatory cytokines and platelet activation.
Ponatinib	BCR-ABL (including T315I), VEGFR, SRC, FGFR, TNFR, PDGFR⁵⁹	Arterial thrombotic events, severe hypertension, heart failure, myocardial infarction, cerebrovascular events	Pan-VEGFR inhibition leads to endothelial apoptosis and a procoagulant state; heart failure risk correlates positively with dose intensity.
Dasatinib	BCR-ABL, SRC, c-KIT, PDGFR, DDR⁵⁸	Pulmonary hypertension, pleural effusion, pericardial effusion, QT prolongation, arrhythmia	Disrupts endothelial junctions and tube formation; increases insulin sensitivity; associated with PDGFR-β/Src inhibition in PH.
Bosutinib	BCR-ABL, SRC⁶⁰	Generally low cardiotoxicity; occasional pulmonary hypertension	Fewer off-target vascular effects, but may increase procoagulant activity via the MAPK pathway.
Flumatinib	BCR-ABL, PDGFR, KIT⁶¹	Arrhythmia (predominantly sinus bradycardia), QT prolongation (mostly mild)	low incidence of cardiovascular adverse events; further mechanistic studies are needed.
Olverembatinib	BCR-ABL (including T315I), KIT, FLT3, FGFR1, PDGFRα⁶²	Arterial occlusive events, hypertension, pericardial effusion, arrhythmia (premature ventricular beats, atrial fibrillation)	Multitarget inhibition and limited mechanistic understanding.

Abbreviations: DDR, discoidin domain receptor; ER, endoplasmic reticulum; FGFR, fibroblast growth factor receptor; FLT3, Fms-like tyrosine kinase 3; MAPK, mitogen-activated protein kinase; PDGFR, platelet-derived growth factor receptor; PH, pulmonary hypertension; ROS, reactive oxygen species; SRC, proto-oncogene tyrosine-protein kinase Src; TKI, tyrosine kinase inhibitor; TNFR, tumor necrosis factor receptor; VEGFR, vascular endothelial growth factor receptor.

3.1. Arterial Occlusion Events (AOE)

The risk of AOE varies significantly among different TKIs. The risk of AOE associated with ponatinib is particularly pronounced. A real-world study⁶³ revealed an exposure-adjusted incidence of 4.5 cases per 100 patient-years among chronic-phase CML patients; cerebral infarction (1.10%) and myocardial infarction (0.69%) constituted the primary types of major AOE. In a comparative study against imatinib,⁶⁴ the AOE incidence rate in the ponatinib group (7%) was significantly higher than that in the imatinib group (2%). Notably, one patient treated with ponatinib experienced a severe venous thromboembolic event, whereas none occurred in the imatinib group. The risk of AOE with nilotinib also warrants attention. A study that evaluated cardiotoxicity during treatment with imatinib and nilotinib revealed a high incidence of cardiovascular events (14%) in the nilotinib group, with none reported in the imatinib group.⁶⁵ Peripheral arterial disease was the most common (10%, mostly new-onset cases), while non-ST-segment elevation myocardial infarction (NSTEMI) and cerebrovascular events were also observed. Furthermore, olverembatinib also induces AOE signals. A multicenter RCT of olverembatinib⁶⁶ reported that nine patients (11%, 9/80) experienced arterial occlusion events during treatment, with two patients (3%) experiencing treatment-related arterial occlusion events. All arterial occlusion events were Grade 1 or 2. However, a prospective clinical trial⁶⁷ indicated that three patients (3/80, 3.75%) treated with olverembatinib experienced arterial occlusion events, including a case of myocardial infarction involving a 39-year-old male subject without typical cardiovascular risk factors. Notably, in another clinical trial,⁶² one patient discontinued treatment due to acute myocardial infarction, suggesting a persistent risk of fatal outcomes. In contrast, arterial ischemic events are uncommon during dasatinib therapy,⁶⁸ and imatinib is associated with a relatively low risk of AOE. For patients with chronic myeloid leukemia receiving ponatinib, nilotinib, or olverembatinib, strict and proactive monitoring and management of arterial occlusive events (AOE), particularly involving the cardiovascular and cerebrovascular systems, must be implemented both before and during treatment. The possibility of severe AOE cannot be excluded, even in patients lacking typical cardiovascular risk factors.

3.2. Pulmonary Hypertension

Clinical studies have indicated that dasatinib-induced pleural effusion and pulmonary hypertension warrant close attention. In a study⁶⁹ of consecutive CML-CP patients treated with dasatinib, a cross-sectional analysis revealed that more than one-quarter (28.4%) of patients developed imaging-confirmed pleural effusions. A longitudinal follow-up cohort revealed that pericardial effusion and pleural effusion were more frequently observed during the first year of treatment. The 3-year cumulative incidence of pulmonary hypertension reached 22.1%, indicating a time-dependent increase. Pulmonary hypertension often co-occurs with pleural effusion, suggesting a potential shared pathophysiological basis (e.g., PDGFR-β/Src pathway inhibition). Notably, case reports⁷⁰ indicate that the risk of pulmonary hypertension persists even after switching to ponatinib, although discontinuation and targeted therapy can lead to reversal. Furthermore, case reports have linked bosutinib to pulmonary arterial hypertension (PAH), suggesting that Src tyrosine kinase inhibition may represent a shared pathway underlying both bosutinib- and dasatinib-induced PAH. Unlike dasatinib and Bosutinib, imatinib inhibits signaling pathways such as PDGFR and c-KIT, thereby slowing the proliferation of vascular smooth muscle cells. This effect contributes to reversing pulmonary vascular remodeling and ultimately improving cardiac hemodynamics.⁷¹ For patients with chronic myeloid leukemia receiving dasatinib, proactive, long-term, and multi-modal cardiopulmonary monitoring must be implemented, with a focus on the early identification and management of pleural effusion and pulmonary hypertension (PH). Even after the early phase of treatment, annual echocardiography screening should be continued, with attention to parameters of right heart function.

3.3. Heart Failure and Ventricular Dysfunction

Conclusions regarding the cardiac safety of TKIs vary across studies. A study⁷² comparing treatment-naive and imatinib-experienced CML patients revealed no significant increase in the incidence of pulmonary hypertension or left ventricular systolic or diastolic dysfunction with imatinib. A study⁷³ comparing the cardiovascular safety of TKIs revealed that the risk of heart failure or left ventricular dysfunction (LVEF < 50%) was significantly greater in the imatinib group than in the dasatinib group, suggesting that dasatinib may offer greater safety advantages for patients at high risk of heart failure. Notably, a case report⁷⁴ described an 86-year-old female CML patient who developed severe drug-related left ventricular dysfunction (LVEF decreased from 54% to 42%, with markedly elevated BNP) and pleural effusion after 6 months of low-dose dasatinib (20 mg/day), indicating that dasatinib also has potential cardiotoxic effects. Furthermore, a pooled analysis of three trials⁷⁵ confirmed that ponatinib dose intensity is a significant predictor of heart failure risk. Multivariate analysis revealed that heart failure was most strongly associated with dose intensity (odds ratio = 2.3), which indicates that each 15 mg/day increase in dose intensity elevates the risk of heart failure by 2.3-fold. This highlights the crucial role of dose management in reducing the risk of heart failure. In patients with CML receiving ponatinib, dose intensity should be proactively managed as an independent predictor of heart failure. Any dose adjustment should be accompanied by more frequent cardiac function assessments.

3.4. Hypertension

TKI therapy can lead to significant increases in both systolic and diastolic blood pressure in patients.⁷⁶ The overall incidence and the incidence of grade 3 or higher hypertension were highest in the ponatinib and imatinib 400 mg groups, whereas the incidence was lowest in the dasatinib group. Compared with 400 mg of imatinib, ponatinib was independently associated with a significantly increased risk of hypertension. Olverembatinib also increased the risk of hypertension. A dose-related study⁷⁷ indicated that the incidence rates of hypertension were 29% (18/62) for the 30 mg dose and 30% (55/184) for the 40 mg dose. Another interventional clinical trial⁶² of olverembatinib reported hypertension as the most common cardiovascular event, occurring in 13.3% (22/165) of patients. Furthermore, a nationwide retrospective cohort study²⁶ revealed that, among patients without baseline hypertension, the incidence rates of new-onset hypertension were 13.21/1000 person-years for imatinib, 6.14/1000 person-years for nilotinib, and 9.05/1000 person-years for dasatinib. Although nilotinib itself is not a significant risk factor for hypertension (its risk is lower than age ≥55 years or prior diabetes), new-onset hypertension during TKI therapy increases the subsequent risk of cardiovascular disease by 7.68-fold, suggesting that it may serve as a “sentinel” event for cardiovascular events. One study⁷⁸ conducted an in-depth analysis of blood pressure control and TKI-related factors. Among 57 patients, the majority (69.2%) developed hypertension after TKI therapy. The incidence in the nilotinib group (84.62%) was greater than that in the imatinib and dasatinib groups (53.85%). Although the difference between groups did not reach statistical significance, a clear trend was evident. In summary, continuous blood pressure monitoring and proactive management are critical for patients receiving TKI therapy.

3.5. Arrhythmia and Prolonged QT Interval

Multiple studies have collectively revealed the risk profiles of different TKIs on the QT interval. A cross-sectional study⁷⁹ confirmed no significant difference in the QTc interval between standard-dose imatinib-treated patients and untreated patients or healthy controls, suggesting its first-line safety. In a phase III clinical trial (HS-10096-301), flumatinib demonstrated cardiac toxicity primarily manifested as arrhythmias, with sinus bradycardia being the most common occurrence (4.1%). Although most QT prolongations were mild and manageable without treatment discontinuation,⁸⁰ one study⁸¹ reported a patient on flumatinib who experienced grade 3 QT prolongation and ventricular premature beats, leading to discontinuation of the drug. Olverembatinib resulted in a diverse spectrum of arrhythmia,⁶² including ventricular premature beats (4.2%) and atrial fibrillation (3.0%). Notably, the QTcF values did not exceed the clinically significant threshold of 500 ms in any patient, suggesting a lower risk of severe QT prolongation. Second-generation TKIs, such as nilotinib, carry a significant risk. An analysis based on the FAERS database⁷ revealed that, among the TKIs used for CML treatment, nilotinib exhibited the strongest association with arrhythmias and torsades de pointes/QT prolongation, with both signal strength (aROR) and reported case numbers far exceeding those of other TKIs. Another cross-sectional study⁸² further confirmed the extremely high association strength between nilotinib and QT interval prolongation. Second-generation TKIs (dasatinib and nilotinib) carry a significantly higher risk of QTc prolongation than do first-generation agents (imatinib). Dasatinib exhibited the highest incidence (41.7%), and nilotinib led all drugs in causing QTc ≥500 ms (31%) or ≥60 ms progression from baseline (58.6%).⁸³ This risk is markedly time- and dose dependent. The vast majority of events (67.7%) occurred within 1 to 6 months after treatment initiation and predominantly at high doses.^7,83 Although QT interval prolongation itself rarely causes direct fatalities, it may progress to serious complications such as torsades de pointes, ventricular tachycardia, or even sudden cardiac death.⁸² Therefore, intensive ECG monitoring is essential during the initial phase of treatment with nilotinib and dasatinib (particularly during the first month), with vigilance maintained throughout the entire course of therapy. For patients with CML initiating nilotinib or dasatinib, mandatory, high-frequency ECG monitoring must be implemented during the early phase of treatment (particularly the first 1–6 months) to proactively screen for QTc interval prolongation and prevent its progression to torsade de pointes or sudden cardiac death.

3.6. Pleural and Pericardial Effusion

Different TKIs exhibit distinct patterns and risks of causing pleural effusion. Dasatinib is the TKI most frequently associated with pleural effusion, particularly in elderly patients. However, this risk is generally manageable through dose adjustments or drug interventions.^68,84,85 A study⁸⁶ of 7 chronic-phase CML patients revealed that 57% (4/7) of dasatinib-associated pleural effusion cases were concurrently complicated by pericardial effusion, which is also supported by a case report.⁸⁷ Pleural effusion is not unique to dasatinib. While imatinib has been suggested to have potential cardioprotective effects, it can induce pleural effusion through fluid retention.⁸⁸ A case report revealed the potential of nilotinib to cause severe drug-related pleural effusion.⁸⁹ There is even a report of concurrent pleural and pericardial effusions occurring during nilotinib therapy.⁹⁰ Furthermore, a study⁶² revealed that the incidence of pericardial effusion with olverembatinib was 8.5%. Most patients recovered or improved after the drug was discontinued, but one patient died due to pericardial effusion. For patients with CML receiving dasatinib or olverembatinib, while monitoring for pleural effusion, active imaging screening for pericardial effusion must be implemented concurrently, as the two often occur together and pericardial effusion can lead to fatal outcomes.

In summary, first, surveillance strategies must be tailored to the drug-specific toxicity profile rather than adhering to a one-size-fits-all approach. Second, all monitoring must be sustained across the treatment continuum, with distinct emphases on the on the early and long-term phases, reflecting a dynamic management paradigm that accounts for time-dependent risks. Third, reliance on a single metric is often insufficient for risk prediction; a comprehensive assessment combining imaging, electrophysiology, and biomarkers is essential. Notably, dose intensity, as a modifiable variable, occupies a central role in mitigating the risks of both ponatinib-associated heart failure and nilotinib-associated QT prolongation, underscoring that precise dose titration is a critical nexus for balancing efficacy and safety. Collectively, these principles converge on a core clinical strategy: shifting the paradigm of cardiovascular risk management from “reactive management of complications” to “proactive, mechanism-based, whole-course prevention and control.”

4. Risk Assessment for TKI-Induced Cardiovascular Adverse Events

4.1. Risk Assessment Model

TKI-induced cardiovascular toxicity not only directly threatens patients’ long-term survival but also frequently leads to treatment discontinuation or dose reduction, compromising treatment adherence. Given that TKI therapy often requires lifelong continuation, effective toxicity prediction models have become the cornerstone for optimizing patient management, and their necessity is self-evident.

In a multicenter real-world study,⁵⁴ researchers evaluated the predictive 0065fficacy of the SCORE risk chart in 85 Italian adult patients with CML who received ponatinib treatment. This risk chart incorporates elements such as sex, age, smoking status, systolic blood pressure, and total cholesterol level. An analysis confirmed that the SCORE is an independent predictor of CV-AEs. Patients in the high-to very-high-risk groups exhibited significantly higher event rates.

In a comparative study of CV-AE risk prediction models,¹⁰ both the Framingham risk score and the Hisayama score model demonstrated superior performance to the SCORE chart in identifying high-risk patients. Specifically, the Framingham score and Hisayama model classified 55% and 42% of patients as high-risk for VAE, respectively, whereas the SCORE chart revealed that only 16% of patients were at high risk. With respect to model composition, the FRS calculates risk percentages by integrating multiple risk factors through a sex-specific algorithm. The core variables included age, sex, total cholesterol level, HDL cholesterol level, systolic blood pressure, use of antihypertensive medication, smoking status, and, in some versions, diabetes status. The Hisayama score model aims to assess 10-year atherosclerotic cardiovascular disease risk, primarily based on eight core variables: sex, systolic blood pressure, diabetes (or impaired glucose tolerance), serum HDL-C, serum LDL-C, proteinuria, smoking habits, and exercise habits. Note that this model is not applicable to individuals under 40 years of age.

To establish a universal cardiovascular risk management strategy, a risk stratification algorithm for CML patients has been developed, which is applicable across all ages and cardiovascular disease histories.⁹¹ This algorithm performs initial risk classification based on age, prior cardiovascular disease history, and Framingham risk score. It innovatively introduces the coronary artery calcium score (CACS) for precise restratification among Framingham intermediate-risk patients. The feasibility of this approach was demonstrated in a single-center retrospective study involving 88 patients treated with TKIs. The results indicated that CACS provides critical restratification criteria for intermediate-risk patients, effectively identifying those with moderate leukemia risk but extremely low cardiovascular risk, which offers objective evidence for safely selecting second-generation TKIs and optimizing treatment decisions for such patients.

In 2021, the ESC updated the SCORE chart.⁹² Unlike SCORE, which primarily predicts fatal CV-AE events, SCORE2 introduces a composite endpoint that also incorporates the risk of a first nonfatal CV-AE event within 10 years, aligning more closely with the overall goal of clinical prevention. This assessment is primarily based on age, sex, smoking status, systolic blood pressure, and non-HDL cholesterol. Research⁹³ has indicated that the SCORE2 risk chart effectively predicts AOE risk in patients receiving nilotinib and ponatinib therapy, with significantly higher incidence rates observed among those with high risk scores.

The Heart Failure Association (HFA) of the European Society of Cardiology (ESC) Cardio-Oncology Research Group, in collaboration with the International Cardio-Oncology Society (ICOS), has proposed a baseline cardiovascular risk stratification proforma.⁹⁴ This comprehensive tool incorporates multiple variables, including medical history, demographic risk factors, and lifestyle, to stratify patients before they receive anticancer therapies with known cardiovascular toxicity.⁹⁵ Compared with SCORE, the HFA/ICOS tool demonstrated greater sensitivity and effectively predicted overall risk. It also has significant advantages in predicting specific events, such as myocardial ischemia and peripheral arterial disease.

5. Limitations and Future Directions

Firstly, as a narrative review, our literature search may not be as thorough as that of a systematic review or meta-analysis. Although we searched PubMed with a set timeframe, some relevant studies, may have been missed, introducing potential selection bias, especially those in non-indexed journals or non-English languages.

Second, while we summarized the molecular mechanisms of TKI-induced cardiotoxicity, much of the evidence comes from preclinical models. These models may not capture the complexity of human physiology, including comorbidities and medications in CML patients. Thus, these mechanisms need further validation in rigorous clinical studies.

Third, although we attempted to provide monitoring recommendations for each clinical phenotype, the level of evidence supporting these suggestions varies. Many recommendations are extrapolated from expert consensus or general cardiology guidelines rather than from large-scale, TKI-specific prospective trials. As a result, the optimal screening strategies and management algorithms for TKI-treated CML patients remain to be established.

Fourth, despite recent advances in the understanding of TKI-associated cardiovascular toxicity in recent years, several critical questions remain: (1) The molecular mechanisms underlying the markedly higher vascular risk associated with ponatinib compared with other TKIs remain incompletely understood, particularly whether unique off-target effects beyond VEGFR/FGFR/PDGFR inhibition are involved. (2) Validated predictive biomarkers for the early detection and risk stratification of TKI-induced cardiovascular toxicity are lacking; existing candidate biomarkers have not undergone standardized detection methods or prospective validation. (3) Current cardiovascular risk prediction tools have not been adequately validated externally in real-world CML populations, and their generalizability across different TKI regimens and patient subgroups remains uncertain. (4) The extent and time course of reversibility of TKI-induced cardiovascular toxicity following drug discontinuation remain undefined. Although isolated case reports suggest that certain manifestations (such as dasatinib-associated pulmonary hypertension) may reverse upon cessation, the recovery dynamics within the “Metabolism-Endothelium-Thrombosis Axis” framework have not been systematically characterized, nor has the optimal duration of post-discontinuation surveillance been established. (5) The influence of genetic predisposition on individual risk for TKI-induced cardiovascular toxicity is unknown. The occurrence of severe arterial occlusive events in young patients lacking conventional cardiovascular risk factors⁶⁷ strongly implies the existence of unrecognized genetic or epigenetic modifiers, yet current risk stratification models do not incorporate such variables. (6) The risk associated with sequential TKI therapy has not been quantified. Evidence that the risk of pulmonary hypertension may persist after switching from dasatinib to ponatinib⁷⁰ suggests that vascular injury initiated by one agent may not fully resolve and could potentially be exacerbated by subsequent therapy. The net cardiovascular risk trajectory during TKI switching has not been studied.

6. Conclusion

This narrative review systematically elucidates the complex mechanisms underlying TKI-induced CV-AEs. These mechanisms involve multiple interrelated pathophysiological processes, including endothelial dysfunction, metabolic disorders, oxidative stress, inflammatory responses, and abnormal platelet activation. Collectively, these processes are integrated within the “Metabolism-Endothelium-Thrombosis Axis” framework. At the clinical management level, identifying high-risk patients is crucial. Future risk management strategies should establish an individualized management framework that integrates baseline risk assessment, dynamic monitoring during treatment, and multidisciplinary collaboration. Future research in this field should prioritize addressing the clearly defined knowledge gaps identified in this review, such as elucidating the molecular basis of ponatinib’s unique vascular risk, validating predictive biomarkers, and prospectively evaluating existing risk prediction models in real-world chronic myeloid leukemia (CML) cohorts. In addition to these priorities, prospective studies are required to determine the reversibility of tyrosine kinase inhibitor (TKI)-induced vascular injury, investigate the influence of genetic susceptibility, and delineate the cardiovascular risk trajectory during sequential TKI therapy. Systematic investigation of these unresolved questions will facilitate a transition from reactive monitoring to a proactive, mechanism-based, and individualized approach to cardiovascular risk mitigation, thereby preserving both the antileukemic efficacy of TKI therapy and the long-term health of CML survivors.

Footnotes

Acknowledgments

The author(s) gratefully acknowledge the financial supports for this article: This work was supported by Zhejiang Provincial Natural Science Foundation Project, LKLY25H160010. The figure in this review was created by biorender. This review was edited for proper English language, grammar, punctuation, spelling, and overall styleby one or more of the highly qualified English speaking editors at AJE.

ORCID iD

Gongqiang Wu

Ethical Considerations

This study was approved by our institutional review board.

Consent to Participate

There are no human subjects in this article, and informed consent is not applicable.

Author Contributions

Hui Zheng contributed to the design and conceived of the program and wrote and edited the manuscript. Chentong Huang, Zhanna Zhang, Manqi Su and Panruo Jiang assessed the studies and edited and critically revised the manuscript. Gongqiang Wu conceived of the program and critically revised the manuscript. All authors read and approved the final manuscript and accept accountabilities for all aspects of this work.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Zhejiang Provincial Natural Science Foundation Project, LKLY25H160010.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Statement of Human and Animal Rights

This article does not contain any studies with human or animal subjects.

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