Bruton tyrosine kinase inhibitor-related atrial fibrillation and its implications in the treatment of B-cell lymphoma

Adverse events of atrial fibrillation (AF) have been commonly reported in lymphoma patients in treating Bruton's tyrosine kinase inhibitors (BTKi). The incidence rate of AF can vary depending on the specific types of BTKi and the patient population. Totally 45 published studies have revealed that the overall incidence rate of AF is 5% (95% CI 4%–7%). By performing a subtype single-rate analysis, the second-generation BTKi shows a lower AF incidence rate and lower cardiovascular toxicity. In the subtype single-rate analysis, we conclude the different AF incidence rates of Ibrutinib (10%, 95% CI 7%–13%), Acalabrutinib (4%, 95% CI 1%–6%), Orelabrutinib (0%, 95% CI 0%–1%), and Zanubrutinib (0%, 95% CI 0%–1%). The comprehensive analysis of AF inspires us to better predict and manage AF and other cardiovascular events in treating lymphoma. Meticulous evaluation, collaboration between cardiologists and hematologists, and discovery of new biomarkers are essential for its management.


Introduction
The applications of BTKi in the treatment of lymphoma BTK inhibitors are a kind of small molecule targeting the critical component BTK on the signal pathway of B Cells, related to B cell proliferation and survival, making it a significant therapeutic target for B-cell lymphoma (1,2).BTK inhibitors have gained considerable attention in recent years due to their demonstrated efficacy in treating B-cell lymphoma (3) (Table 1).

Indications and adverse events of BTK inhibitors
Since the emergence of the first-generation BTKi, Ibutinib, it has become a critical targeted drug for treating lymphoma, showing a good prognosis and relatively few side effects.The BTKi have been approved for marketing in many countries, and have been listed in chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) (4), mantle cell lymphoma (MCL) (5), Waldenstrom's Macroglobulinemia (WM) (6) and marginal zone lymphoma (MZL) (7), etc.Also, the different doses of BTKi are being tested, and indications' ranges are expanding to other B cell lymphoma or immune diseases.The different combinations of BTKi and other medications are being explored, like rituximab, Obinutuzumab, and venetoclax, for better outcomes and fewer side effects.
In conclusion, we may find the importance and high risk of the incidence of AF in treating B-cell lymphoma.In contrast, the reports of AF and other cardiovascular events vary from each other.Thus, we may conclude different reports and have a more detailed description of AF in the different types of BTKi.Furthermore, we may find a better way to manage BTKi-related AF, improving the prognosis of lymphoma patients.

Methods
Due to the wide use of the BTKi in treating lymphoma and the noteworthy AEs of cardiotoxicity like AF in the clinical trial or normal therapeutic use, we collected related reports and paid special attention to AF events.Through extensive reading, different previous clinical trials and research suggest that diverse BTKi may act differently in the safety of AF.To further compare the safety of different generations of BTKi and have more reassuring guidance on clinical treatment, we systematically collected the clinical trials paper with NCT number (except Orelabrutinib) mentioned AF incidence rate.The data are collected from the most commonly used databases like Pubmed and Web of Science with keywords like BTKi and AF.All the clinical trials are collected from the published papers from 2013 to 2022, among a total of 657 papers from Web of Science and 225 papers from PubMed using the same strategy.After type filtering, eliminating duplicates, and screening contents, we finally reduced the scope to 45 papers Figure 1.

The AF incidence with BTK inhibitors
Through a comprehensive single-rate analysis encompassing data extracted from forty-two clinical trials conducted within the period spanning 2013-2022, we have concluded that the overall incidence rate of AF is relatively accurate at 5% (95% CI 4%-7% in the random effects model).It has been observed that secondgeneration BTKi exhibits fewer serious adverse events.Notably, the occurrence rate of AF displays significant variability, spanning from 0% to 35%.Having established an overall incidence rate of 5%, comparing the different BTKi therapies could provide valuable guidance for clinical treatment, particularly for patients with high cardiovascular risks.The heterogeneity observed between the four types of BTKi is evident (I 2 = 85% > 50%, p < 0.01), indicating the need for subtype analysis to uncover differences and explore the underlying causes of heterogeneity.Through subtype analysis, we found the AF incidence rates for Ibrutinib (10%, 95% CI 7%-13% in random effects model) (Table 2), Acalabrutinib (4%, 95% CI 1%-6% in random effects model) (Table 3), Orelabrutinib (0%, 95% CI 0%-1% in common effects model) (Table 4), and Zanubrutinib (0%, 95% CI 0%-1% in common effects model) (Table 5).

Discussion
Based on comprehensive analysis results, the critical result of AF incidence is 6.0%.Nevertheless, our findings regarding the incidence rate of AF align with those of other systematic reviews and adhere to similar methodological approaches employed in meta-analyses of bleeding events (53).Meanwhile, through weighted mean, we can also approximately estimate

First-generation
Second-generation Third-generation Ibrutinib Acalabrutinib Zanubrutinib Orelabrutinib Pirtobrunib incidence rates of the cardiac-related events: hypertension (14.8%) and heart failure (4.6%).The uncertainty of AEs will affect the prognosis of patients with lymphoma because of the discontinuation of treatment and the high risks for cardiovascular diseases like heart failure and stroke.Previous studies on Ibrutinib have reported common adverse events (AEs) including diarrhea (49%), upper respiratory tract infection (33%), fatigue (32%), cough (31%), and rash (27%) (4).Among these AEs, AF is a type of abnormal heart rhythm that affects the atria.When the atria are not beating coordinatedly, blood may form clots, travel to the brain vessels, and then lead to a stroke (54).Furthermore, it is imperative to underscore the strong correlation between AF and an elevated risk of heart failure, given that irregular atrial contractions can impede the heart's ability to efficiently pump blood.In summation, AF emerges as a salient and pivotal adverse event, particularly within the domain of BTKi treatment for lymphoma for its wide applications and potential risks.
The elevated risks and unique off-target toxicities associated with AF have garnered significant attention, leading to the emergence of a sub-discipline known as Cardio-oncology.This discipline emphasizes the collaboration between hematologists and cardiologists, aiming to enhance the management and prevention of adverse events associated with BTKi.The BTKi-related AF has not been fully discovered.According to certain studies, BTKi-related AF may related to relatively broad selectivity and targets, including BTK, TEC (55), EGFR, and CSK (56).In comparing Ibrutinib and other second-generation BTKi, differences in the target of CSK may lead to the difference in the incidence of AF.

The first generation BTKi: Ibrutinib
As the original and first-generation BTKi used in the treatment of lymphoma, Ibrutinib has emerged as a successful paradigm and Flow diagram of the study.The diagram of the study shows the inclusion and exclusion criteria and a specific number of studies we obtained from different sources.We set atrial fibrillation and corresponding BTK inhibitors as keywords to exclude non-clinical trial studies and reviews.Eventually, 45 studies in different BTK inhibitors were taken into further research.The lower incidence of AF with Acalabrutinib might be interpreted with caution due to the shorter follow-up.
NCT 02180711 MC, multiple-center; SA, single-arm; CLL, chronic lymphocytic leukemia; SLL, small lymphocytic lymphoma; R/R, relapsed/refractory disease; TN, treatment naive; N/A, not acquired; AF, artificial fibrillation; AEs, adverse events; BTKi, Bruton's tyrosine kinase inhibitor.a catalyst for related research.With extensive experimental support and clinical trial data, the reliability of its efficacy in terms of progression-free survival (PFS) and incidence rates of serious adverse events (AEs) has increased.However, notable heterogeneity remains within the Ibrutinib-treated group due to lymphoma types, study designs, and baseline data variations.To conduct further analysis in detail, we categorized the data into more specific subtypes.Nevertheless, the currently available clinical trials have limitations in providing a more nuanced analysis of these subtypes.The reported incidence rate of AF at 10% in Ibrutinib-treated patients can be considered relatively accurate and a reliable clinical reference.Notably, a meta-analysis focusing on AF incidence rate in CLL patients treated with Ibrutinib reported an AF incidence rate of 5% (57).This discrepancy could be attributed to the extensive application of Ibrutinib in lymphoma cases, as CLL was among the earliest approved indications for Ibrutinib, with a relatively low incidence rate of AF.Furthermore, more recent clinical trials have reported rates higher than 10% (25)(26)(27).The 10% incidence rate is understandable given the inherent heterogeneity associated with a single-rate analysis.

The second generation BTKi: zanubrutinib, orelabrutinib, and acalabrutinib
The progress in BTKi therapy has notably lessened treatment complications and bolstered treatment endurance.Zanubrutinib was brought into sharp focus due to its PFS efficiency results or relatively fewer side effects.Safety has become a key factor in the recommendation of lymphoma treatment.Also, based on the NCCN guideline (Version 1.2023) of CLL/SLL, Zanubrutinib is taken as the highest level of clinical recommendation.In contrast, Ibrutinib is taken as another recommendation for its potential cardiovascular risks.According to the result, we may observe that the AF incidence rate is approximately 0% due to the high risks of bias in certain studies.In the head-to-head trials, the AF incidence rate is 2.5% (58).The difference may originate from the limitations of different independent research reports and the methodology of single-group rate analysis.Larger studies, more compact study designs, and real-world data are necessary for further evidence to support the encouraging results of Zanubrutinib.
Orelabrutinib is still at the stage of various clinical trials.Only a few studies disclosed the results, while it is still considered a promising drug as BTKi for more effective and fewer AEs treatment.Although the current results from the single-rate analysis suggest an incidence rate of 0% for AF and no reported cases of AF, it is vital to acknowledge such analyses' limitations and potential biases.
Based on the subtype meta-analysis, the incidence rate of AF with Acalabrutinib in the random effect model is about 4%.Though the induced studies are limited, there is no significant difference between trials or other previous reports.The incidence of AF in the first randomized phase III trial of Ibrutinib (41/263, 15.6%) vs. Acalabrutinib (24/266, 9.0%) may offer us newly updated supportive data.Forest plots of the included studies of atrial fibrillation or flutter occurrence rate and sub-type analysis.Through the single-rate analysis of AF incidence, we determined the AF incidence rates for Ibrutinib (10%, 95% CI 7%-13% in random effects model), Acalabrutinib (4%, 95% CI 1%-6% in random effects model), Orelabrutinib (0%, 95% CI 0%-1% in common effects model), Zanubrutinib (0%, 95% CI 0%-1% in common effects model), and overall AF incidence rate (5%, 95% CI 4%-7% in random effects model).New generation BTKi: pirtobrunib The approval of Pirtobrutinib in January 2023 as a noncovalent BTK inhibitor for MCL patients resistant to covalent ones marks a significant advancement in the third-generation BTKi (59).Also, we may expect the emergence of more third-generation BTKi, including pirtobrutinib (60) and Fenebrutinib (61).These developments highlight the ongoing evolution of BTK inhibitor therapy and the potential for better outcomes in diverse disease contexts.The field of BTKi has evolved from the first generation of exploratory and innovative compounds.Subsequently, the focus shifted towards the second generation of inhibitors, aiming to improve efficacy while minimizing side effects.Presently, the introduction of third-generation non-covalent binding inhibitors represents a significant advancement, expanding the therapeutic indications, and narrowing adverse events.

Comparative analysis between ibrutinib and zanubrutinib
The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) warn against the utilization of Ibrutinib for its cardiovascular risks.In the age of targeted therapy, survival time of CLL/SLL patients has been largely prolonged.Thus, monitoring and  Through the comparison of Ibrutinib and Zanubrutinib, we may observe a significant difference in that Zanubrutinib performs better in the cardiac safety profiles in Figure 2. Theoretically, we may agree with the higher inhibition effects of Ibrutinib in HER2, HER4, TEC (mainly related to AF) (62) and fewer off-target effects of Zanubrutinib with lower IC50 against BTK (mainly related to the treatment of lymphoma) and higher IC50 for other kinases like EGFR(21nM), TEC(44nM), ITK (50nM) (63).More Head-to-head clinical trials or more detailed disclosure of procedures and results may help us identify their PFS and cardiotoxicity.The different baselines of cardiac risk factors, the ignorant monitoring of AEs, and the median followup time may contribute to the difference between the BTKi.
Generally, the incidence rate of AF would increase with longer follow-up time due to its stable long-term risks.However, some studies suggest that AF primarily occurs during a specific period and does not increase over time (62,64).Comparing the median age and median follow-up time between the two groups, the mean age of both groups is approximately 65.2 months.However, the mean follow-up times differ, with 31.5 months in the Ibrutinib group and 23.38 months in the Zanubrutinib group.Furthermore, future clinical designs and systematic reviews should pay attention to baseline differences and the AF occurrence time.

Guidance for the management of AF in the treatment of BTKi
The advancements in BTKi have primarily focused on three key areas: developing new generations of BTKi, exploring different dosage regimens, and expanding medication options.
However, managing AF as a confirmed AE requires careful consideration before treatment initiation.A thorough assessment of high-risk factors, such as AF history, hypertension, bleeding history, age ≥ 65y, male sex, and underlying diseases, is necessary.Based on a recent study, reported Ibrutinib, age ≥ 65y, blood culture positive, hypertension, diabetes, and sex as risk factors for developed AF in CLL patients (65).Specifically, some studies may focus on AF-risk scores used in patients with CLL, if patients with a score ≥5 should be carefully monitored or changed to secondgeneration BTKi (66)(67)(68).Commonly used clinical tools like the CHA2DS2-VASc and the HAS-BLED aid in evaluating the riskbenefit balance of AF patients in the area of BTKi treatment.For instance, if the CHA2DS2-VASc score exceeds 2, oral anticoagulants such as aspirin are recommended (69).Also, newly developed AF prediction models like HARMS2-AF risk scores can be tested in future trials (70).The personalized treatment plans should be formulated based on patient-specific factors such as scores, electrocardiogram (ECG) results, and blood pressure, including tailored doses and durations of BTKi, anticoagulants, and other supportive treatments (71) (Figure 3).
Moreover, based on clinical needs, early detection methods and specific biomarkers are essential for the management of lymphoma treatment.There are already biomarkers, including Brain Natriuretic Peptide (BNP), ST2, Galectin-3 (72), FGF-23 (73), and microRNAs (74).While we may expect further exploration of the specific biomarker for BTKi-related AF, working as a convenient and inexpensive method.In cases where medically managing BTK inhibitor-related AF proves challenging, discontinuation of BTK inhibitor treatment may be considered.However, this decision must be weighed against its potential impact on treatment efficacy.Thus, striking a balance between side effects and the continuity of treatment is imperative.

Conclusion
Through a relatively comprehensive collection, we conclude different types of AEs, mainly focusing on the incidence of AF.The incidence rate of AF varies from 0% to 35%, and through a single rate analysis, the overall AF incidence rate is considered as 5% (95% CI 4%-7%).The profiles of BTKi are tolerable and controllable, showing a great advancement in the secondgeneration BTK with less serious AEs.Also, the cardiac-related AEs indicate us to manage patients regularly and prevent the occurrence of AF during the treatment of lymphoma.In the future, we may further explore the mechanism of BTKi-related AF and find more measures to monitor cardiac-related AEs.

FIGURE 3
FIGURE 3The risk factors, adverse events, and interventions of BTKi-related atrial fibrillation in the treatment of lymphoma.BTK inhibitors are related to different cardiovascular adverse events including AF (5%), hypertension (14.8%), and heart failure (4.6%).It is related to different receptors like BTK, EGFR, and TEC expressed by myocardial cells and vascular endothelial cells.Risk factors and evaluation methods like CHA2DS2-VASc and HAS-BLED are taken to evaluate its interventions.Dosage adjustment or anticoagulants are common clinical measures, and a healthy lifestyle and continuous monitoring are advised to manage risk factors, hypertension, and diabetes.Patients with an AF history are highly risky for BTKi-related AF and require special monitoring and decisions.

TABLE 1
The overall introduction of different BTK inhibitors.

TABLE 2
Incidence of atrial fibrillation or flutter in ibrutinib.The AF patients with MYD88 L265P or CXCR4 WT are all with AF history, and their overall toxic effects are moderate.
N/AThe therapy with Ibrutinib for more than five years is similar to earlier reports.Patients with TP53 aberration also reach durable responses.cell Lymphoma; FL, follicular lymphoma; WM, Waldenstrom's macroglobulinemia; CNSL, central nervous system lymphoma; MZL, marginal zone lymphoma; R/R, Relapsed/refractory disease; TN, treatment naive; N/A, not acquired; AF, artificial fibrillation; AEs, adverse events; BTKi, Bruton's tyrosine kinase inhibitor.

TABLE 3
Incidence of atrial fibrillation or flutter in acalabrutinib.

TABLE 4
Incidence of atrial or flutter in orelabrutinib.

TABLE 5
Incidence of atrial fibrillation or flutter in zanubrutinib.