Cardiovascular Challenges in Chronic Lymphocytic Leukemia (CLL) Patients Undergoing Bruton Tyrosine Kinase (BTK) Inhibitor Therapy.

1
Introduction
Bruton tyrosine kinase inhibitors (BTKis) have revolutionized the treatment landscape of chronic lymphocytic leukemia (CLL), establishing themselves as a cornerstone of therapy [1]. Ibrutinib, the pioneering first‐in‐class BTKi, has demonstrated remarkable efficacy, becoming widely adopted across the world. Its success has spurred nearly 300 ongoing clinical trials investigating its potential in CLL and other hematological malignancies [1].
Despite its groundbreaking impact, ibrutinib has been associated with a more than fourfold increased risk of cardiovascular (CV) adverse events (AEs), including atrial fibrillation (AF), ventricular arrhythmias (VA), heart failure, and hypertension, compared to untreated CLL patients [2]. This elevated risk poses a significant challenge in balancing the continuation of a potentially life‐saving treatment with the need to manage its cardiotoxic effects, which often lead to discontinuation [3].
In response to these concerns, next‐generation BTKis, such as acalabrutinib and zanubrutinib, have been developed, to improve target specificity while potentially mitigating CV toxicity [4, 5]. These agents have been approved for CLL treatment, and demonstrate an efficacy which is comparable to ibrutinib, as evidenced by key clinical trials [4, 5]. However, emerging data from cardiac‐focused studies suggest that even next‐generation BTKis may carry a residual risk of cardiovascular complications. This underscores the importance of evaluating current evidence and practical strategies for managing cardiovascular risks in this growing patient population [6].
Several studies have explored the CV effects of BTKis, offering practical guidance for clinicians managing patients receiving these therapies [6, 7, 8]. However, the evolving therapeutic landscape—shaped by long‐term outcomes from BTKi trials and the increasing adoption of fixed‐duration combination regimens involving venetoclax and BTKis—necessitates a comprehensive reassessment of this issue.
This expert opinion paper provides an updated analysis of the most common CV toxicities associated with BTKis, incorporating insights from recent clinical studies and cardiac‐focused trials. It also offers evidence‐based strategies to optimize patient management, aiming to support the development of personalized therapeutic approaches. This is particularly relevant for patients with pre‐existing CV comorbidities, who face a heightened risk of complications and treatment discontinuation.
Ultimately, this review seeks to support clinicians and researchers in effectively balancing the therapeutic advantages of BTKis with the management of associated cardiovascular risks, thereby aiming to optimize clinical outcomes in patients with CLL.

2
Materials and Methods
A hematologist (S.M.) with expertise in the treatment of CLL and a cardio‐oncologist specialized in managing CV toxicities (S.O.) associated with BTKis collaborated to assess the clinical relevance of CV side effects of first‐ and second‐generation BTKis. Their goal was to provide practical recommendations for optimizing treatment selection and mitigating CV toxicities in clinical practice.
To capture the breadth of clinically relevant publications on CLL and cardio‐oncology, a comprehensive literature search was conducted using PubMed. Additionally, abstracts from major hematology conferences, including the American Society of Hematology (ASH) and the European Hematology Association (EHA), were manually reviewed to identify key studies published from database inception through December 2024. The analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines to ensure methodological rigor and transparency (see Figure 1).
Through a series of virtual and in‐person sessions, the experts analyzed and discussed findings from the literature. Drawing on their respective expertise, they developed, refined, and validated strategies for managing CV toxicities linked to BTKis.
This collaborative process culminated in evidence‐based recommendations aimed at guiding clinical decision‐making. The recommendations focus on optimizing BTKi treatment selection and proactively as well as reactively managing cardiovascular toxicities, ultimately enhancing overall care for patients with CLL.

3
The Pathways Behind BTKi Cardiovascular Adverse Effects
AF stands out as the hallmark CV complication most strongly associated with BTKi treatment [6, 8, 9]. The arrhythmogenic effects of BTKis are linked to their off‐target inhibition of Tec protein tyrosine kinase (TEC) [10] and downstream phosphoinositide 3‐kinase (Akt) signaling. By inhibiting Akt, these agents increase late sodium currents, which prolong the cardiac action potential and elevate the risk of early and delayed after depolarizations [11, 12]. Moreover, ibrutinib interacts with human epidermal growth factor receptor 2 (HER2)—a key protein also targeted by anti‐HER2 monoclonal antibody trastuzumab—that supports cardiomyocyte homeostasis, stress tolerance, and efficient contractility [13, 14]. Together, these mechanisms contribute to both acute and chronic cardiomyocyte dysfunction, potentially culminating in heart failure [12, 15, 16].
The mechanisms underlying the development of hypertension (HTN) with the use of BTKis remain incompletely defined. Possible pathways include inhibition of nitric oxide, vasoconstriction, and fibrosis [2, 12].
BTK inhibitors also disrupt critical pathways involved in platelet functions. These include Tec protein signaling, activation triggered by damaged collagen, pseudopod formation, and granule release [17]. As a result, the risk of significant bleeding is heightened, particularly in patients on concurrent antithrombotic therapies [17]. However, these risks have not been entirely eliminated. Additionally, balancing the risks of bleeding and thrombosis remains a significant challenge in the management of patients receiving BTK‐targeted therapies [4, 5, 18].
CV events associated with BTKis typically occur soon after treatment initiation, though they may also emerge during longer follow‐up periods.

4
Influence of Age and Other Comorbidities on CV Complications in CLL
CLL is categorized as a mature B‐cell neoplasm with an annual incidence of approximately 4.92 cases per 100 000 individuals in Europe (Metta la referenza progressiva Alaggio 2022). The disease predominantly affects individuals older than 70 years, many of whom present with age‐related comorbidities that significantly contribute to therapy discontinuation and adverse clinical outcomes. To optimize treatment strategies, clinical assessment tools such as the Cumulative Illness Rating Scale (CIRS) and the CLL comorbidity index (CLL‐CI) provide valuable insights in predicting overall survival (OS) and event‐free survival (EFS) [19, 20, 21, 22]. However, their effectiveness in forecasting specific treatment‐related toxicities remains an area of active research [23].
In this context, a pragmatic approach should prioritize the assessment of individual comorbidities that are strongly linked to therapy discontinuation and adverse outcomes, with a particular focus on pre‐existing CV diseases [23].
Age‐related changes in cardiac structure and function, along with the influence of metabolic comorbidities, can exacerbate the hemodynamic stress induced by BTKis [19]. Furthermore, polypharmacy, which is prevalent among elderly patients, increases the likelihood of drug interactions that may heighten cardiovascular risk [24]. To mitigate these risks and optimize patient outcomes, the integration of CV risk stratification and the adoption of a multidisciplinary care approach are essential, particularly in this vulnerable patient population [3, 25].
Ultimately, while comorbidities constitute a “nonmodifiable” aspect of the treatment decision‐making process, the “modifiable” component can be effectively addressed through the selection of a BTKi agent with a more favorable safety profile. Emerging evidence suggests that second‐generation BTKis, such as acalabrutinib and zanubrutinib, which have a more favorable CV profile, should be prioritized for elderly patients with comorbid CLL [26, 27].

5
CV Risk Factors in CLL
Assessing the risk of developing CV complications relies on traditional scores generated for the general population. These include the Framingham Risk Score (FRS), Atherosclerotic Cardiovascular Disease (ASCVD) Risk Score, and Cardiovascular Risk Score (QRISK2/3). Notably, the CHADS2 and CHA2DS2–VASc scores, which were specifically designed to evaluate stroke risk in patients with AF, are particularly relevant in this context [28, 29, 30, 31].
FRS: Framingham Risk Score, ASCVD: Atherosclerotic Cardiovascular Disease, AHA/ACC: American Heart Association/American College of Cardiology, QRISK2/QRISK3: UK Cardiovascular Risk Prediction Algorithms (versions 2 and 3), CHADS2: congestive heart failure, hypertension, age ≥ 75 years, diabetes, stroke (doubled), CHA2DS2‐VASc: congestive heart failure, hypertension, age ≥ 75 years (doubled), diabetes, stroke (doubled), vascular disease, age 65–74 years, sex category (female), AF: atrial fibrillation, CHF: congestive heart failure, HTN: hypertension, TIA: transient ischemic attack, BP: blood pressure, CKD: chronic kidney disease, RA: rheumatoid arthritis, SLE: systemic lupus erythematosus, BMI: body mass index.
While these models demonstrate efficacy for the general population, their applicability to CLL patients may be limited, as they were not specifically validated within this cohort. Moreover, they fail to consider leukemia‐specific risks, which may have relevance in this context. A population‐based study comparing untreated CLL patients to healthy controls revealed significant disparities in the levels of 8 out of 11 biomarkers associated with cardiovascular disease and inflammation. Notably, this study identified novel findings, including elevated expression of growth differentiation factor 15 (GDF15), a member of the transforming growth factor β (TGFβ) cytokine superfamily and myostatin [32]. Future prospective studies in patients with neoplastic diseases should aim to establish a more precise association between these biomarkers and the development of CV diseases. In the context of CLL, the interplay between BTKi use, pre‐existing CV disease, and CLL‐related factors such as anemia may further amplify CV risk [6].
Shanafelt et al. [33] utilized the Mayo Clinic database to assess the prevalence and risk factors associated with AF in the context of CLL. Among 2444 newly diagnosed patients, 6.1% (148 patients) had a history of AF at diagnosis, while an additional 6.1% (139 out of 2292) developed AF during follow‐up, corresponding to an annual incidence of 1%. Older age (p < 0.0001), male sex (p = 0.01), valvular heart disease (p = 0.001), and hypertension (p = 0.04) were identified as significant risk factors for AF. A risk stratification model incorporating these variables categorized patients into groups with 10‐year AF risks ranging from 4% to 33% (p < 0.0001), offering valuable insights into AF risk in CLL patients receiving BTKi‐based therapies.
Recent studies have shown that an artificial intelligence electrocardiography (AI‐ECG) algorithm provides a more sensitive tool for assessing the risk of AF in patients with CLL. In a cohort of 754 newly diagnosed CLL patients, the 10‐year cumulative risk of AF was estimated at 26.1%. Patients with an AI‐ECG score of ≥ 0.1 had a significantly higher risk of developing AF, even after adjusting for factors included in the Shanafelt et al. [33] risk score such as heart failure, chronic kidney disease, and CLL treatment. In a second group of 220 CLL patients undergoing BTKi therapy, a pretreatment AI‐ECG score ≥ 0.1 was associated with a nonsignificant increase in AF risk [34].
Future research should better assess the potential of machine learning and artificial intelligence (AI) to define the risk of AF in patients undergoing BTKi therapy; however, models informed by these innovative tools, should complement, rather than replace, clinical expertise, and sound medical judgment [34].

6
Prevalence of Cardiovascular Events With Covalent BTKis
Current estimates suggest that more than 200 000 patients are being treated with ibrutinib, a first‐generation BTKi, while the use of second‐generation agents, such as acalabrutinib and zanubrutinib, is steadily rising [35]. However, with growing evidence of CV toxicities associated with these agents, a detailed understanding of their prevalence and type of CV events related to BTKis is essential for optimizing treatment strategies.
6.1
AF
A large pharmacovigilance study, utilizing data from the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), assessed CV AEs in a cohort of 86 370 patients treated with BTKis. The study included patients with CLL and various non‐Hodgkin lymphoma (NHL) subtypes, including relapsed/refractory mantle cell lymphoma (MCL), activated B‐cell (ABC) diffuse large B‐cell lymphoma, and lymphoplasmacytic lymphoma [36]. CV complications were categorized into three main groups: (1) cardiac arrhythmias, (2) major adverse cardiovascular events (MACE)—defined as death from CV causes, nonfatal stroke, or nonfatal myocardial infarction—and (3) pericardial complications, such as effusion or hemorrhage.
The cohort was stratified by treatment, with 79 278 patients receiving ibrutinib, 5200 on acalabrutinib, and 1354 treated with zanubrutinib. Among all BTKi‐treated patients, 8500 CV events were reported, with incidence rates as follows: ibrutinib 10.15%, acalabrutinib 5.73%, and zanubrutinib 4.72%.
Cardiac arrhythmias were the most commonly reported complication, with AF being the predominant subtype. The incidence of arrhythmias was significantly higher in the ibrutinib cohort (6.6%) compared with acalabrutinib (3.1%) and zanubrutinib (2.3%). Specifically, AF occurred in 5.1% of ibrutinib‐treated patients, 2.1% of acalabrutinib‐treated patients, and 1.8% of zanubrutinib‐treated patients.
The incidence of MACE was slightly elevated in the ibrutinib group (2.79%) compared to acalabrutinib (2.4%) and zanubrutinib (2.0%). Similarly, pericardial complications were more frequent in ibrutinib‐treated patients (0.72%) than in those receiving acalabrutinib (0.21%) or zanubrutinib (0.44%). All differences in cardiovascular AE rates between the groups were statistically significant (p = 0.011).
Complementary insights were drawn from a US‐based study that exclusively examined CLL patients treated with second‐generation BTKis over a 2‐year period [37]. The cohort included 1476 patients receiving first‐line therapy with either acalabrutinib (n = 1039) or zanubrutinib (n = 437). In the cohort, 13.7% of patients treated with acalabrutinib and 13.0% of those treated with zanubrutinib had a documented history of cardiac events in the year prior to initiating treatment.
The study also tracked treatment‐emergent AF over time, providing a temporal perspective on cardiovascular risks. Among acalabrutinib‐treated patients, the incidence of AF was reported as 3.1% at 9 months, 4.2% at 12 months, and 4.0% at 15 months. In zanubrutinib‐treated patients, AF rates were 2.7% at 9 months, 4.2% at 12 months, and 6.1% at 15 months.
These data suggest that while the overall incidence of AF was comparable between the two agents, zanubrutinib with respect to acalabrutinib may exhibit an increase in late‐onset AF at longer follow‐up intervals [37].
To further contextualize the CV safety of second‐generation BTKis, a matching‐adjusted indirect comparison (MAIC) evaluated acalabrutinib (both as monotherapy and in combination with obinutuzumab) versus zanubrutinib in treatment‐naïve CLL patients. The analysis revealed no significant difference in the odds of AF or flutter between the two therapies. The odds ratio (OR) for any‐grade AF/flutter was 0.66 (95% CI, 0.25–1.73), while the OR for grade ≥ 3 events was 0.30 (95% CI, 0.03–2.95) [38].
Despite information available in current literature, the burden, severity, and implications of BTKi‐related AF remain complex and understudied. A recent analysis of 98 patients with CLL utilized extended ambulatory rhythm monitoring to quantify AF burden, defined as the percentage of time patients spent in AF during a 24‐h monitoring period. Patients with an AF burden of ≥ 10% were classified as having a high AF burden. Most patients in the study were treated with ibrutinib (62.2%), while 38.8% received next‐generation BTKis. Over a combined monitoring time of 28 224 h—averaging 12 days per patient—the results revealed a high prevalence of arrhythmias. Overall, 72.4% of patients developed rhythm disturbances, including 16.3% with incident AF, 31.6% with sustained supraventricular tachycardias (SVTs), and 14.3% with ventricular tachycardia (VT). Among these, 14.3% of patients demonstrated high AF burden, with similar rates observed between ibrutinib and next‐generation BTKis. Crucially, high AF burden emerged as a strong prognostic marker for long‐term outcomes. Patients with high burden experienced a markedly higher risk of MACE (HR, 3.12; p = 0.005) and mortality (HR, 2.97; p = 0.007) [39]. These findings highlight AF burden not merely as a side effect of BTKi therapy, but as a critical prognostic marker for future cardiovascular risks.
Although the incidence of AF has risen in CLL patients due to the increasing use of BTK inhibitors, the associated risk of thromboembolic events remains incompetently understood. An analysis of data from the National Inpatient Sample (NIS) database (2016–2018), which included 1 165 283 patients without CLL and 6361 patients with CLL who were hospitalized for AF (excluding patients on anticoagulation), suggests that CLL patients have a lower risk of ischemic stroke compared to those without CLL. CLL patients were predominantly male (62.5% vs. 37.5%, p < 0.001), older (74.6 vs. 78.8 years, p < 0.001), but had lower rates of diabetes, hypertension, coronary artery disease, and hyperlipidemia. However, the study, which was reported in abstract form, did not specify the proportion of patients receiving BTKi therapy. This omission limits the ability to draw definitive conclusions regarding the association between BTK inhibitor therapy and the risk of atrial fibrillation‐related stroke [40].

6.2
Ventricular Fibrillation
In addition to AF, more severe CV events, including sudden death, have been reported in patients treated with ibrutinib [2]. A retrospective analysis of ibrutinib‐treated patients revealed a rate of 0.788 sudden deaths per 100 patient‐years, a figure that raised significant concerns within the medical community [41]. Further investigation into the FLAIR trial, which examined the combination of ibrutinib and rituximab in previously untreated CLL patients, revealed a similar trend, with a sudden or cardiac death rate of 0.5 per 100 patient‐years [42].
This trend was not confined to a single study. A meta‐analysis of Phase 3 trials, including the GENUINE and HELIOS trials, reinforced these findings, with rates of sudden cardiac death of 0.49 per 100 patient‐years [42].
Although follow‐up periods for second‐generation BTKis are relatively shorter, preliminary data suggest a lower prevalence of VAs with these agents. A comprehensive analysis of five acalabrutinib clinical trials, involving 1299 patients reported that 16 patients (1.2%) experienced sudden death (SD) or VAs, with an event rate of 0.350 per 100 patient‐years. Nonfatal VAs were observed in 11 patients (0.8%), the majority of whom experienced premature ventricular contractions (PVCs). Fatal SDs and VAs occurred in five patients (0.4%), corresponding to an event rate of 0.109 per 100 patient‐years. The median time to event was 46.2 months. Overall, SDs and VAs were rare, and no evidence was found to suggest an increased risk with acalabrutinib [43].
In conclusion, the analysis of acalabrutinib clinical trials indicates that SDs and VAs occur at relatively low rates with insufficient evidence to support an increased risk of SD or VA in patients receiving this second‐generation BTKis. Moreover, it is crucial that high‐risk patients be closely monitored. Further safety data will be gathered through ongoing clinical trials and postmarketing surveillance.

6.3
Hypertension
Ibrutinib has been associated with the development or exacerbation of hypertension in a significant proportion of patients undergoing treatment [2]. In a study involving 562 patients treated between 2009 and 2016, 78.3% experienced new or worsened hypertension over a median follow‐up period of 30 months. Of these, 17.7% developed high‐grade hypertension, defined as blood pressure exceeding 160/100 mmHg [2]. Another analysis of 247 patients revealed that 34.8% developed hypertension after initiating ibrutinib, while nearly half (49.5%) of those with pre‐existing hypertension experienced severe systolic hypertension (grade ≥ 3). Furthermore, approximately one in five patients with pre‐existing hypertension (20.6%) required changes to their cardiovascular medication regimen within the first year of treatment. The median time to peak blood pressure was found to be 6 months, emphasizing the necessity for continuous blood pressure monitoring during and after treatment initiation [44].
A meta‐analysis by Caldeira et al. [45] provides strong evidence that ibrutinib is associated with a significantly increased risk of hypertension. With a risk ratio of 2.82 and a highly significant p‐value (p < 0.001), the findings suggest that patients receiving ibrutinib are nearly three times more likely to develop hypertension compared to those in control groups. The inclusion of major randomized controlled trials like RESONATE and RESONATE‐2 further reinforces the robustness of these conclusions.
Three Phase 3 clinical trials compared ibrutinib with second‐generation inhibitors BTKis, namely acalabrutinib and zanubrutinib [4, 5, 46]. In these studies, acalabrutinib exhibited notably lower rates of hypertension compared to ibrutinib (9% vs. 23%) [47]. Hypertension rates were similar between patients in the ALPINE trial (24% with zanubrutinib vs. 23% with ibrutinib) [4, 5].
Safety data on new or worsening hypertension were also analyzed from 11 clinical trials of acalabrutinib monotherapy, including ELEVATE‐RR, ELEVATE‐TN (NCT02475681), and ASCEND (NCT02970318). Hypertension data for ibrutinib were sourced from the ELEVATE‐RR study, while data for other comparators came from ELEVATE‐TN and ASCEND. This analysis found that the prevalence of hypertension in CLL patients treated with acalabrutinib was comparable to that observed in untreated CLL patients [48].
Furthermore, real‐world data from the Integra Connect Precision Q deidentified database revealed that the rate of treatment‐emergent hypertension in patients with at least 9, 12, or 15 months of follow‐up was lower in patients receiving acalabrutinib (5.2%, 5.7%, and 6.9%, respectively) compared to zanubrutinib (8.1%, 9.7%, and 9.1%, respectively) [37].
These findings underscore the critical need for frequent blood pressure monitoring, particularly within the first 6 months of treatment when the risk for significant increases is highest. Physicians must remain vigilant, especially in patients with pre‐existing hypertension, and should be prepared to adjust cardiovascular medications accordingly to manage this side effect effectively. Regular monitoring and timely intervention are essential for ensuring patient safety and optimizing treatment outcomes.

6.4
Heart Failure
While initial clinical trials did not show a significant risk of heart failure with ibrutinib, recent long‐term data from pooled Phase 3 trials suggest a potential increase in risk [49]. Up to 5% of patients developed heart failure, often years after treatment began. In a retrospective study of 860 CLL patients, the risk of heart failure was 7.7% with ibrutinib, compared to 3.6% with chemotherapy [50]. Additionally, a pharmacovigilance database study found a threefold higher likelihood of heart failure with ibrutinib [49].
Patients with pre‐existing AF and those with myocardial fibrosis, detected by cardiac MRI, are at increased risk for heart failure on ibrutinib. However, the predictive value of these findings for future heart failure remains unclear [1].
Currently, there is limited long‐term data on the risk of heart failure associated with newer BTK inhibitor therapies. Among them, acalabrutinib has the most extensive evidence base. A pooled analysis involving 760 patients using acalabrutinib showed that fewer than 1% developed any grade of symptomatic congestive heart failure [51]. Data regarding heart failure in other next‐generation BTK inhibitors, including reversible inhibitors, remains scarce, as this outcome was often not included in the studies.

7
Cardiovascular Events With Noncovalent BTKis
Pirtobrutinib is a novel, noncovalent BTKi specifically designed to overcome resistance mutations associated with covalent BTK inhibitors [52, 53]. In 2023, it received accelerated approval from the US FDA for the treatment of relapsed or refractory MCL in patients who had undergone at least two prior lines of therapy, including a BTK inhibitor. Early safety data from the Phase 1–2 BRUIN study demonstrated promising outcomes, with low rates of hypertension (14.2%), AF (3.8%), and major hemorrhage (2.2%). These findings suggest a favorable safety profile compared to existing BTKi therapies [54]. Currently, a Phase 3 clinical trial (BRUIN‐CLL‐314) is underway, directly comparing pirtobrutinib with ibrutinib in patients with CLL or small lymphocytic lymphoma (SLL), with results anticipated in 2028 (NCT05254743) [55].
In a study involving 127 patients intolerant to prior BTK inhibitors without evidence of progressive disease, pirtobrutinib demonstrated significant safety and efficacy. The most frequently reported AEs leading to discontinuation of prior BTKi therapies included cardiac disorders (31.5%) and, particularly, AF (23.6%). Remarkably, 75% of patients who had discontinued previous BTKi therapy due to cardiac‐related AEs experienced no recurrence of these events with pirtobrutinib. Furthermore, no patient discontinued pirtobrutinib due to the same AE that necessitated cessation of their prior therapy [52].
The BRUIN CLL‐321 is the first randomized, Phase III clinical trial conducted in patients with CLL/SLL after treatment with a cBTKi to determine whether pirtobrutinib improved PFS compared with either idelalisib with rituximab (IdelaR) or bendamustine with rituximab (BR).
Pirtobrutinib demonstrated a more favorable safety profile compared with IdelaR/BR, and this advantage became even clearer when adjusted for treatment duration. Discontinuations related to pirtobrutinib were uncommon (5.2%). Additionally, AEs typically linked to the cBTKi class—such as atrial fibrillation, hypertension, and major bleeding—were rarely observed with pirtobrutinib [56].
These findings highlight the potential of pirtobrutinib as a safe, tolerable, and effective therapeutic option for patients with prior BTKi intolerance. Its ability to address safety concerns, particularly in those with cardiac comorbidities, positions pirtobrutinib as a critical advancement in the treatment of relapsed/refractory hematologic malignancies.

8
Cardiovascular Events With Fixed‐Duration BTKi–Venetoclax Combinations
The ibrutinib–venetoclax combination, licensed as a fixed‐duration treatment in Europe but not in the United States, offers patients with CLL the benefit of treatment‐free intervals. This approach reduces the likelihood of long‐term AEs and drug resistance [57]. CV events observed in fixed‐duration ibrutinib–venetoclax trials occurred at varying rates. The most common Grade 3–4 AEs were AF (0.8%–16%) and hypertension (6%–16%). The GLOW trial, which specifically enrolled elderly and medically unfit patients, reported a discontinuation rate of 10.4% for the ibrutinib–venetoclax combination. Two patients (1.9%) discontinued ibrutinib due to AF but continued treatment with venetoclax [58]. Among 15 reported deaths, 4 were attributed to cardiac events. In the fixed‐duration CAPTIVATE trial, targeting patients younger than 70 years, one sudden death occurred during the ibrutinib lead‐in phase. The rates of hypertension and AF were 16% and 4%, respectively, with Grade 3–4 events reported at 6% and 1% [59, 60].
In the ibrutinib–venetoclax arm of the FLAIR trial, three cases of sudden unexplained or cardiac deaths were reported. Two of these deaths occurred after the end of treatment (35 and 411 days later) and were deemed by local investigators to be unrelated to treatment. Additionally, 80 AEs involving hypertension were observed in 34 patients (13.5%), while a total of 62 AEs involving AF or arrhythmia occurred in the same 34 patients (13.5%) in the ibrutinib–venetoclax group [61]. These findings underscore that cardiotoxicity remains a major concern with venetoclax–ibrutinib fixed‐duration therapies.
The AMPLIFY trial, compared the upfront combination of acalabrutinib and venetoclax (AV) with or without obinutuzumab to physician's choice chemoimmunotherapy consisting of fludarabine–cyclophosphamide–rituximab (FCR) or bendamustine–rituximab (BR). In the AV combination arm, AEs of any grades leading to treatment discontinuation occurred in 7.9% of patients (2.1% due to COVID‐19 pneumonia and 0.3% due to COVID‐19). Of note, cardiac events of any grade were observed in 9.3% of patients, with Grade ≥ 3 events occurring in 1.7%. AF was experienced by 0.7% of patients (none at Grade ≥ 3), while hypertension was reported in 4.1% of patients (Grade ≥ 3 in 2.7%) [62].
We anticipate that the favorable safety outcomes observed with the fixed‐duration AV combination, primarily in a younger cohort of CLL patients, will similarly extend to older or medically unfit populations and will represent a new opportunity to minimize the onset of such cardiac events observed with a combination of venetoclax and first‐generation BTKi [63].

9
Beyond BTKi: Cardiovascular Toxicity and Venetoclax
Preclinical studies suggest that venetoclax‐induced cardiotoxicity may result from oxidative stress, which triggers cardiac inflammation and apoptosis through the NF‐κB and BCL‐2 pathways [64]. However, cardiac complications are relatively uncommon in CLL patients receiving venetoclax therapy.
In the CLL14 trial, which compared the venetoclax–obinutuzumab (VO) combination to chlorambucil–obinutuzumab in treatment‐naïve, older, and medically unfit patients, the rate of Grade 3–4 cardiac events was 4.7% [65]. In the CLL13 trial, enrolling fit or younger CLL patients, no cases of AF were reported among patients treated with the VO combination, although 9.3% of patients developed any grade of hypertension [66].
It is worth noting that in the context of venetoclax use in acute myeloid leukemia (AML), a single‐center study reported a 20% incidence of CV events when venetoclax was used in combination with hypomethylating agents (HMAs). Although the study may be subject to selection bias due to an over‐representation of patients with pre‐existing CV comorbidities, prospective real‐world studies are necessary to confirm these findings and optimize strategies for cardiovascular risk management.
From a practical standpoint, patients with pre‐existing cardiac comorbidities, regardless of the targeted therapy employed—whether BTKi or venetoclax—should undergo vigilant monitoring for CV AEs.

10
Stratification of Patients According to the Burden of CV Comorbidities
As previously discussed, validated scores predicting CV risk for CLL patients, which could guide the selection of therapy with BTKi, are not currently available. The European guidelines on Cardio‐Oncology, developed by the European Society of Cardiology (ESC) in collaboration with the EHA, do not consider the use of a cardio‐oncological risk score for CLL patients requiring BTKi therapy [67].
Due to the lack of strong evidence for specific risk stratification, the ESC guidelines suggest using other well‐established risk scores, such as SCORE2 and SCORE2‐OP. These scores have been validated in the European population, but they may not precisely identify the individual risk of patients [67].
We anticipate that new predictive models, potentially derived from AI algorithms, could enhance risk stratification for patients eligible for BTKi therapy in CLL.

11
Choice of Therapy Based on the Risk of Developing CV Toxicity
Clinical trial data suggests that patients without significant baseline CV risk factors, particularly those under the age of 70, can generally be treated with either ibrutinib or a second‐generation BTKi. This is due to the relatively lower incidence of AEs observed in these patients, making both ibrutinib and second‐generation BTK inhibitors viable options for managing [6].
However, when it comes to patients with pre‐existing CV risk factors, the choice of treatment requires a more careful consideration of safety profiles. In these patients who may have well‐controlled AF, hypertension (HTN), or valvular heart disease, second‐generation BTK inhibitors, such as acalabrutinib or zanubrutinib, are particularly helpful [26, 27].
The safety profile of these second‐generation BTK inhibitors, which includes fewer CV‐related complications, provides reassurance for both clinicians and patients. Additionally, these newer agents maintain similar efficacy to ibrutinib in treating conditions like CLL or MCL, allowing for effective management without exacerbating existing heart conditions [4, 5, 46].

12
Work Up at the Time of BTKi Initiation
Before initiating BTKi therapy, a cardiac assessment tailored to the patient's CV history is essential. Regardless of CV risk, obtaining a detailed CV history, measuring blood pressure, and performing a 12‐lead ECG are mandatory.
For patients with multiple CV disease risk factors—such as age over 65, or a history of arrhythmias, hypertension, or heart failure—a baseline echocardiogram is recommended to provide a more comprehensive evaluation of cardiac function [9, 68].
When the decision is made to initiate BTKi therapy a structured plan for close CV monitoring should be implemented. In this context, secondary prevention of AF becomes a key objective. Given the high prevalence of hypertension among patients with AF, strict management of pre‐existing hypertension is essential to reduce the risk of cardiovascular complications.
It is also important to recognize that BTKi therapies are associated with an increased risk of bleeding, which is further exacerbated when combined with anticoagulants [52, 69].

13
Clinical‐Therapeutic Management of CV Adverse Events
For the management of cardiovascular AEs associated with BTKi therapy, the ESC guidelines should be regarded as the primary reference for evidence‐based recommendations [67].
If AF develops after the initiation of BTKi therapy, it is important to pursue a collaborative approach with cardio‐oncology specialists to manage the patient's care effectively. In this scenario, a key next step is to assess the patient's stroke risk using the CHA2DS2‐VASc score, which will help determine whether anticoagulant therapy is necessary. For patients at an elevated risk of stroke, direct oral anticoagulants (DOACs) are generally the preferred option due to their ease of use and more predictable pharmacokinetics [1]. If the risk of bleeding is high (active or recent major bleeding < 1 month before; recent/evolving intracranial lesions; platelet count < 25 000/μL) anticoagulant therapy is temporarily omitted and reconsidered when hematological changes are observed. When managing symptomatic AF in these patients, initial treatment typically involves beta‐blockers. In some cases, alternative atrioventricular nodal blockers may be considered. However, the effect of BTKis on the CYP3A4 metabolic pathway makes it challenging to predict the therapeutic levels of these medications accurately.
Finaly, while rhythm control strategies may be considered in patients with AF, the available data on their utility in the context of BTKi therapy is limited. Therefore, any decision regarding rhythm control should be carefully tailored to the individual patient, taking into account their specific medical circumstances and response to treatment [1].
ESC guidelines should be used in clinical practice also for the management of BTKi‐associated hypertension. The recommended antihypertensive medications for patients on BTKi therapy are largely the same as those used in the general population, with one key exception: nondihydropyridine calcium channel blockers (CCB) should be avoided due to the potential for hazardous drug interactions [1]. The first‐line treatment options include angiotensin‐converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB), as well as dihydropyridine CCB. Beta‐blockers, on the other hand, are considered second‐line agents. Notably, all patients with Grade 2 hypertension require treatment regardless of life expectancy, while those with low‐grade hypertension and a poor prognosis may be managed conservatively without antihypertensive therapy [67].
In case of severe hypertension, temporary interruption of BTKi therapy and dose reduction upon stabilization may be necessary. Switching from ibrutinib to alternative BTK inhibitors, such as acalabrutinib, can be considered in recurrent severe cases. If patients develop treatment‐emergent or worsening hypertension, clinicians should look for other cardiotoxicities, as uncontrolled hypertension enhances AF development [1, 24, 70].
In contrast, there are no specific guidelines for the management of VA in BTKi‐treated patients. This is largely due to the limited number of patients experiencing sudden cardiac death who have been included in clinical trials. Patients with significant arrhythmias are often at an inherently high risk of cardiotoxicity due to their pre‐existing cardiovascular disease burden [41, 42]. Current evidence suggests that the risk of VA is a common concern across all BTKi agents, irrespective of the specific drug used.
Finally, patients with decompensated heart failure are generally not initiated on BTKi therapy. For those with compensated heart failure, second‐generation BTKis are preferred to minimize additional cardiotoxic effects. Screening echocardiograms and baseline ECGs are advised before initiating therapy. During treatment, frequent monitoring of weight, blood pressure, and systolic function is essential. If symptomatic heart failure with depressed LVEF occurs, prompt discontinuation of BTKi therapy and initiation of guideline‐directed medical therapy are recommended [71]. Multidisciplinary discussion should guide subsequent treatment plans [1].

14
Conclusions
The management of CLL in elderly patients treated with BTKis requires a delicate balance between therapeutic efficacy and safety. Individualized treatment plans are paramount, as older patients often present with pre‐existing comorbidities and age‐related vulnerabilities that heighten their risk for CV complications. Tailoring therapy to the patient's specific risk profile, incorporating tools such as geriatric assessments and CV risk stratification, can optimize outcomes while minimizing harm. Promisingly, newer‐generation BTKis, such as acalabrutinib and zanubrutinib, have demonstrated reduced CV toxicity profiles, offering viable alternatives for high‐risk populations, with acalabrutinib monotherapy showing significantly lower chances of having hypertension compared to zanubrutinib [6, 38].
Looking ahead, the integration of precision medicine approaches holds significant potential for improving care in this population [72, 73]. Advances in genomic and biomarker research may enable more accurate identification of patients at heightened cardiovascular risk, facilitating proactive management strategies [72]. Additionally, collaborations between oncology and cardiology specialists will be critical to developing comprehensive, multidisciplinary care models. Notably, a collaborative approach involving both hematologists and cardio‐oncologists should be initiated at the time of diagnosis, particularly in elderly patients or those with a history of CV disease, even if they are asymptomatic [6]. Early involvement of a cardio‐oncology team allows for proactive management aimed at preventing cardiovascular comorbidities that may worsen over time. This multidisciplinary strategy ensures that cardiovascular conditions are appropriately managed prior to the initiation of BTKi therapy, thereby minimizing the risk of treatment‐related complications and enhancing overall patient outcomes. A flow chart of this approach is shown in Figure 2.
We propose a patient‐centric approach that begins at the first diagnosis of CLL and incorporates longitudinal monitoring of CV conditions that may be exacerbated by aging or treatment. As shown, a proactive strategy for managing CV conditions could help mitigate pre‐existing cardiovascular disease, ensuring it does not become a barrier to BTKi use (Figure 2).

Author Contributions
The authors designed the study, selected and evaluated studies, performed data extraction, evaluated and interpreted results, and wrote the manuscript.

Conflicts of Interest
Stefano Molica received consulting honoraria from Janssen, Abbvie, and AstraZeneca. Stefano Oliva received consulting honoraria from AstraZeneca.