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).

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.

We may discover that the indications of BTKi are gradually expanding. Some of them have been proven while more indications are still in clinical trials. More than relatively common types of lymphoma, BTKi are in trials with central nervous system lymphoma (CNSL, NCT04438044) (8), large B cell lymphoma (DLBCL, NCT01855750) (9), and follicular lymphoma (FL, NCT02343120) (10). Furthermore, BTKi also plays a more curial role in autoimmune diseases, including multiple sclerosis (MS, NCT02975349) (11), systemic lupus erythematosus (SLE, NCT02975336) (3), and rheumatoid arthritis (RA, NCT03233230) (12).

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.

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 second-generation 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 (I²= 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).

As the original and first-generation BTKi used in the treatment of lymphoma, Ibrutinib has emerged as a successful paradigm and 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% (25–27). The 10% incidence rate is understandable given the inherent heterogeneity associated with a single-rate analysis.

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.

The approval of Pirtobrutinib in January 2023 as a non-covalent 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.

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 prevention of cardiovascular events is vital for clinical treatment choices based on comprehensive physical conditions and drug toxicity. Recently, based on a head-to-head experiment (Zanubrutinib vs. Ibrutinib), the incidence rate of AF significantly decreased (2.5% vs. 10.19%, P = 0.001). In the study of ALPINE, 6 cases of 652 patients died of cardiac events with Ibrutinib. Also, the PFS in the Zanubrutinib group was better than that in the Ibrutinib group (94.9% vs. 84.0%) (58).

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 follow-up 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.

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 second-generation BTKi (66–68). Commonly used clinical tools like the CHA2DS2-VASc and the HAS-BLED aid in evaluating the risk-benefit 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.