Discovery of novel imidazo[4,5-b]pyridine derivatives as noncovalent reversible Bruton's tyrosine kinase inhibitors.

Efficacy and safety of Bruton's tyrosine kinase inhibitors compared to Teriflunomide in relapsing multiple sclerosis: A systematic review and meta-analysis.

Immune thrombocytopenia (ITP) is a secondary autoimmune complication that can develop in patients with connective tissue diseases (CTDs). Its pathogenesis involves autoantibody-mediated platelet destruction and immune complex deposition, constituting a distinct clinical manifestation of CTD-related autoimmune abnormalities in the hematologic system. Among the subtypes of CTD-related immune thrombocytopenia (CTD-ITP), systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (pSS) are the most prevalent. CTD-ITP occurs within the unique clinical context of being a secondary condition to systemic diseases such as SLE or primary pSS, resulting in more complex clinical management and an increased risk of adverse outcomes. At present, no disease-specific treatment guidelines exist for CTD-ITP, and clinical management is largely based on therapeutic strategies established for primary ITP. However, conventional therapies, including glucocorticoids, often fail to achieve durable clinical remission, and prolonged use is associated with serious adverse effects. In recent years, the introduction of targeted agents such as thrombopoietin receptor agonists (TPO-RAs) and rituximab has markedly improved treatment response rates in CTD-ITP. Meanwhile, emerging targeted therapies, such as spleen tyrosine kinase (Syk) and Bruton's tyrosine kinase (BTK) inhibitors, as well as neonatal Fc receptor (FcRn) inhibitors, have shown considerable clinical promise. This narrative review, based on recent literature, focuses on SLE-ITP and pSS-ITP, summarizing their clinical heterogeneity, disease-specific pathophysiological mechanisms, and recent therapeutic advances. The objective is to provide evidence-based guidance for the personalized management of CTD-ITP.

Background: Acalabrutinib is a selective Bruton tyrosine kinase inhibitor widely used for chronic lymphocytic leukemia and mantle cell lymphoma. Real-world safety evidence from Latin America remains limited, which restricts local benchmarking and pharmacovigilance planning. In this study we aimed to assess exposure-adjusted adverse events in routine care in Mexico. Methods: We analyzed postmarketing surveillance datasets and spontaneous reports from March 2020 to August 2024, classifying events with MedDRA and summarizing seriousness, severity, and incidence per 100 patient-years. Results: A total of 266 patients were registered; 193 had evaluable exposure and safety data, contributing 242.73 patient-years. The overall adverse event incidence was 24.71 per 100 patient-years. Twenty-eight individual case safety reports documented 60 events. Forty-four events were serious. Among 33 events with reported severity, 14 were severe, 14 moderate, and five mild. Frequently affected system organ classes were blood and lymphatic, vascular, and infections. Seven deaths were reported; most were associated with COVID-19 complications or disease progression. Conclusions: The adverse event profile observed aligns with published trial experience and supports the tolerability of acalabrutinib in Mexican practice. These country-level, exposure-adjusted estimates provide actionable context for clinicians, institutional pharmacists and pharmacovigilance teams and point to the value of strengthening report completeness to improve signal detection in routine oncology care.

Bruton's Tyrosine Kinase (BTK) is a cytoplasmic kinase essential for B cell-mediated signalling,yet has also received recent recognition as a direct regulator of myeloid cell function. Beyond its established role in B cell malignancies, BTK influences receptor-driven activation in monocytes, macrophages, microglia, granulocytes, and other organ-specific macrophages by influencing key molecular pathways involved in phagocytosis, inflammatory-mediated signalling, and cell metabolism (e.g., NFκB, STAT3, and NLRP3). BTK inhibitors (BTKis) were initially developed and approved to treat B cell-related cancers, however, they have also demonstrated significant therapeutic/clinical efficacy in autoimmune, allergic, and immune-driven neuroinflammatory disorders, including rheumatoid arthritis, IgA nephropathy, multiple sclerosis, and chronic spontaneous urticaria. This review specifically addresses, compares, and summarises how BTK inhibition within distinct myeloid-derived cell subsets alters inflammatory-related phenotypes and functions within these cells. Together, providing cell-specific insights into BTK as a central regulator of innate immunity and myeloid cell function may help generate significant translational potential for BTKis in multiple inflammatory-mediated diseases.

Ibrutinib exposure correlates with improved efficacy of CAR T cells in patients with mantle cell lymphoma.

It is widely acknowledged that B-cell lymphoma represent a significant threat to human health, and Bruton Tyrosine Kinase inhibitors (BTKi) have been shown to exhibit superior clinical efficacy and safety in comparison to conventional chemotherapy and immunotherapy modalities. However, as patients continue to use BTKi over a time, they will inevitably encounter the drug resistance. This resistance renders the therapeutic efficacy of BTKi, thereby significantly constraining its clinical benefits. Drug resistance of tumor is a multifaceted process influenced by numerous factors, mainly including individual genetic variations, tumor stem cells, drug inactivation, reduced drug absorption, and altered metabolism of anti-tumor drugs. The tumor microenvironment (TME) has been demonstrated to exert an important influence on the process of therapy resistance. It is evident that non-cellular components (e.g. the extracellular matrix, hypoxia, an acidified microenvironment, exosome, and cytokines) modulate the drug resistance through different mechanisms. These mechanisms include physical barriers that impede drug delivery, the formation of an immunosuppressive microenvironment, metabolic reprogramming and the activation of bypass signal moueculars. Furthermore, the presence of mutations of moleculars involved in the BCR signaling pathways (e.g. BTK and PLCG2 mutations) and the aberrant activation of key pathways such as PI3K-AKT-mTOR, NF-κB, Wnt/β-catenin and MAPK/ERK signaling further weakened the efficacy of BTKi. This review focus on the mechanism of BTKi resistance, the role of the TME and its components in drug resistance. It emphasized that targeting TME remodeling and combined the inhibition of multiple pathways may provide a new strategy for overcoming drug resistance, optimizing the treatment paradigm of B-cell lymphoma.

Venetoclax represents a significant advancement in target anticancer therapy in the management of relapsed/refractory chronic lymphocytic leukemia (RR-CLL). This study aims to compare the efficacy and safety of the venetoclax + rituximab (VenR) regimen with other therapies approved in Brazil. A systematic review and network meta-analysis (NMA) was conducted to evaluate the efficacy and safety of treatments approved in Brazil for RR-CLL. Comprehensive literature searches were performed to identify randomized controlled trials. Risk of bias and certainty of evidence for each outcome were assessed across the included studies. The NMA was conducted using a frequentist framework. The primary efficacy outcomes were progression-free survival, overall survival, overall response rate, and time to next therapy. Safety was assessed on the basis of the incidence of serious adverse events. A total of 24 publications related to 12 trials were identified and included. VenR was associated with better survival outcomes when compared with standard regimens such as rituximab (HR 0.16; 95%CI 0.03-0.74) and physician choice (HR 0.17; 95%CI 0.04-0.81). In terms of progression-free survival, VenR achieved HR < 0.20, supported by narrow confidence intervals, when compared to treatments such as bendamustine plus rituximab, ofatumumab and physician choice, in addition to significantly favorable results compared to ibrutinib and acalabrutinib. Approximately half of the studies presented a low risk of bias, and the certainty of evidence assessed using the GRADE-NMA approach resulted in very low certainty of evidence, mainly due to risk of bias, intransitivity, and imprecision. This NMA provides valuable evidence to support rational therapeutic choices for RR-CLL in Brazil, highlighting VenR and Bruton tyrosine kinase inhibitors as leading treatment options across diverse clinical scenarios.

Amyotrophic lateral sclerosis(ALS) is a devastating neurodegenerative disorder with limited therapeutic interventions. Neuroinflammation represents a central pathogenic mechanism in ALS, yet the upstream molecular regulators that integrate multiple inflammatory cascades remain poorly understood. Here, we investigated whether Bruton's tyrosine kinase (BTK), which integrates DNA-sensing and Toll-like receptor signals upstream of the cGAS-STING-NF-κB cascade, serves as a key regulatory node in ALS pathogenesis. Public RNA-seq datasets of motor neurons and post-mortem tissues from ALS patients were utilized to identify BTK expression patterns. SOD1-mutant human induced pluripotent stem cells (hiPSC) were differentiated into motor neurons (hiPSC-MNs) and microglia (hiPSC-MGs). NF-κB dysregulation was profiled by scRNA-seq (hiPSC-MGs) and bulk RNA-seq (hiPSC-MNs). DNA damage (γH2AX), inflammatory signalling (western blot/ELISA) and phagocytosis (pH-rodo uptake) were quantified, and MG-conditioned medium was tested for MN toxicity. Monocultures and MN-MG co-cultures received zanubrutinib (3 µM, 12 h). SOD1-G93A mice were administered zanubrutinib (30 mg/kg, daily) from 2.5 months; motor performance, survival, spinal histology and PI3K-AKT-mTOR activity were assessed after 2 months of treatment. ALS spinal cord and cortex tissues of patients, as well as SOD1-mutant hiPSC-MGs and hiPSC-MNs, demonstrated elevated BTK phosphorylation with increased p-STING, p-TBK1, and nuclear NF-κB accumulation. ALS hiPSC-MGs exhibited inflammatory activation, NLRP3 induction, and impaired phagocytosis, while ALS hiPSC-MNs showed DNA damage and caspase-3-mediated apoptosis. Conditioned medium from inflammatory microglia amplified neuronal STING-NF-κB activity and apoptosis, demonstrating non-cell-autonomous toxicity. The STING inhibitor H-151 reduced neuronal p-STING/p-TBK1/NF-κB and apoptosis, confirming pathway causality. Pharmacological BTK inhibition reduced DNA damage in ALS hiPSC-MNs by 61.4% (p<0.05), restored phagocytosis in ALS hiPSC-MGs to 87.2% of control levels (p<0.01), and prevented neuronal apoptosis induced by microglial conditioned medium. In SOD1-G93A mice, BTK blockade extended median survival from 158 to 173 days (p<0.01, log-rank test), improved motor function, and attenuated neuroinflammation while moderately rebalancing PI3K-AKT-mTOR signaling without impairing autophagy-lysosome dynamics. We identify BTK as a critical upstream regulator of the dysregulated cGAS-STING-NF-κB signalling axis characteristic of ALS pathogenesis. BTK orchestrates both cell-autonomous dysfunction in motor neurons and non-cell-autonomous toxicity through microglial activation, representing a convergent regulatory node that integrates multiple pathogenic pathways. These mechanistic insights provide a molecular framework for understanding ALS neuroinflammation and establish a rational basis for BTK-targeted therapeutic intervention in neurodegeneration.

Remibrutinib, an oral, highly selective, Bruton's tyrosine kinase (BTK) inhibitor, has shown efficacy and favorable safety in pivotal global phase3 studies in patients with chronic spontaneous urticaria (CSU). This 52-week safety study evaluated the effect of remibrutinib in Japanese patients with CSU. BISCUIT, a phase3 (NCT05048342), open-label, single-arm study, investigated the safety and efficacy of remibrutinib 25mg twice-daily as an add-on medication in Japanese patients with CSU who remain symptomatic despite treatment with H1-antihistamines. The primary endpoint was the proportion of patients with ≥ 1 adverse events (AEs). Overall, 71 Japanese patients (mean age 43.5years) had a median remibrutinib exposure of 52.1weeks; 87.3% of patients reported ≥ 1 AE, and all events were mildor moderate in severity. COVID-19 (19.7%) and headache (12.7%) were the most common AEs. Three serious AEs, unrelated to remibrutinib, were reported. No deaths occurred during the treatment period. At week12, mean change from baseline in weekly Urticaria Activity Score (UAS7) and weekly Itch/Hives Severity Scores was - 18.1, - 8.0, and - 10.1, respectively; responses appeared to occur as early as week1 and appeared to be sustained until week52. Additionally, 53.6% of the patients had well-controlled disease (UAS7 ≤ 6) and 30.4% had completeabsence of itch and hives (UAS7 = 0) at week52. Remibrutinib showed a favorable safety profile and a meaningful improvement in CSU symptoms (itch and hives) at week12, with fast improvement as early as week1 that was sustained up to week52, supporting its potential as an effective oral BTK inhibitor for Japanese patients with CSU. Trial Registration: NCT05048342.

Rheumatoid arthritis (RA) is a severe autoimmune disease characterized by dysregulated functions of multiple immune cells such as phagocytes, lymphocytes, and dendritic cells. Bruton's tyrosine kinase (BTK) and FMS-like tyrosine kinase 3 (FLT3) play critical roles in RA pathogenesis, regulating B-cell survival, myeloid cell differentiation, and dendritic cell activation. Starting from the lead compound CC-292, a series of novel 5-fluoro-aminopyrimidine derivatives were designed and synthesized as dual BTK/FLT3 inhibitors for potential RA therapy. Our in vitro screening revealed that compounds 7a, 7b, and 7c are potent dual inhibitors, demonstrating potent activity with IC50 values in the low nanomolar range. Among them, 7b demonstrated particularly strong dual-target activity (BTK IC50 = 18nM; FLT3 IC50 = 10nM), along with high plasma stability and hepatic microsomal metabolic stability. In collagen-induced arthritis model, 7b administration produced dose-dependent reductions in joint swelling and significantly mitigated cartilage degradation and bone erosion, as confirmed by histopathological evaluation. Acute toxicity tests revealed no obvious adverse effects at a dose of 1000mg/kg, indicating a promising safety profile. This work presents not only a promising lead compound but also a strategic framework for developing next-generation RA therapies.

Abstract PLCγ2 (phospholipase C gamma 2) functions as a critical signaling molecule in immune cells, particularly B-cells, and is associated with immune dysregulation. PLCγ2 mutations drive immunodeficiency syndromes (PLCγ2-associated Antibody deficiency and Immune Dysregulation (PLAID) and Autoinflammatory PLCγ2-associated Antibody deficiency and Immune Dysregulation (APLAID)). PLCγ2 mutations are also seen in Bruton tyrosine kinase (BTK) inhibitor-resistant chronic lymphocytic leukemia (CLL). The recurrent PLCγ2 R665W is the most frequently occurring BTKi resistance mutation in 45% of cases, yet it’s in-vivo immunologic consequences remain poorly understood. To characterize PLCγ2 function in-vivo in B-cells, both in and out of a cancer context, we generated conditional B-cell specific Mb1-Cre+ PLCγ2 R665W heterozygous mice with and without crossing to the CLL mouse model Eμ-TCL1. First, C57BL/6 PLCγ2 R665W mice were generated and crossed to C57BL/6 Mb1-Cre to produce B-cell restricted Mb1-Cre+ PLCγ2 R665W heterozygous mice. R665W heterozygous mice without Cre expression were used as controls. The point mutation was confirmed using Sanger sequencing. Beginning at week 4, and at subsequent 4-week intervals, the mice were weighed, bled, and flow cytometry performed to analyze blood cell types (n≥10, 5M and 5F). These mice were followed till end-of-life and a Kaplan-Meier survival curve generated. To study B-cell development by B-cell subtyping, other cohorts of mice (n≥9) was euthanized at week 12 and 48, and blood, spleen and bone marrow analyzed. Subsequently, scRNAseq was performed on week 12 splenocytes (n=5). Mb1-Cre+ PLCγ2 R665W mice were crossed to Eμ-TCL1 to study R665W in a CLL context. B-cell–restricted PLCγ2 R665W expression did not affect overall survival or weight but caused a sustained reduction in total white blood cells and B-cells, with the most pronounced differences at week 12 and after week 32, suggesting a possible developmental or selection disruption. B-cell subtyping at week 12 and 48 showed decreased peripheral blood T2 transitional B-cells and decreased spleen follicular II B-cells in experimental vs control mice. scRNAseq on week 12 splenocytes revealed decreased B-cell receptor signaling through ERK1/2 and NFκB in almost all mutant B-cell subtype clusters. Ongoing studies following antigenic immunization suggest altered activation potential in mutant B-cells. In the CLL context, Eμ-TCL1 Mb1-Cre+ PLCγ2 R665W mice exhibited significantly reduced total B-cells and a non-significant trend toward fewer CD19+CD5+ leukemic cells, without changes in survival or body weight. Due to variability in the development of CLL, a transplant model is being generated for further studies. These results indicate that PLCγ2 R665W impairs B-cell development and attenuates BCR signaling in-vivo, reshaping immune homeostasis and modifying leukemic B-cell expansion. This model provides a versatile platform for dissecting how PLCγ2-driven immune alterations influence resistance to targeted therapy and antitumor immunity. Citation Format: Vindhya Nawaratne, Jacob Jahn, Alexandra Chirino, Wasif N. Khan, David G. Coffey, Justin Taylor. Immune dysregulation and B-cell fitness driven by PLCγ2 R665W: Insights from a novel conditional B-cell mouse model [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr A074.

Abstract Background: Bruton’s tyrosine kinase (BTK), a downstream mediator of the B-cell receptor (BCR) signaling pathway, is known to be essential in differentiation and proliferation of B-cell. Thus, BTK inhibitors are used to treat refractory mantle cell lymphoma and chronic lymphocytic leukemia. Recent discoveries have revealed the expression of BTK in myeloid-derived suppressor cells, known to worsen breast cancer (BC) outcomes. To this end, it was of interest to investigate the clinical relevance of BTK expression in BC. Methods: Total of 9297 BC patients from 23 independent cohorts with tumor transcriptome and clinical data were analyzed. Results: Based on two independent single-cell sequencing cohorts, approximately 15% of B-cells and 30% of myeloid cells within the tumor microenvironment expressed BTK, while no other cells exhibited BTK expression, suggesting that the BTK expression signal from bulk tumor samples primarily originates from these cells. Correlation with BTK expression was highest in macrophage regulation (r=0.94), and leukocyte fraction, lymphocyte infiltration, TCR Shannon and TCR Richness (all r&amp;gt;0.74), but not with BCR Shannon nor BCR Richness. Total macrophage, M1 and M2 macrophage, dendritic cells, total B-cells, memory B-cells, as well as CD8 and CD4 cells were all highly infiltrated in BTK high BCs. Moreover, BTK expression correlated with both PD1 &amp; PD-L1 in all BC subtypes. Biologically, BTK high BC expression was linked to immune-related gene sets, with gene set enrichment analysis (GSEA) showing enrichment in pathways related to immune response such as Complement, Inflammatory response, Allograft rejection, IFN-γ, IFN-α, IL2, IL6, and TNFα signaling. At the same time, BTK high BC enriched tumor-aggravating signaling pathways such as PI3k/AKT/mTOR signaling and mTORC1 signaling. The cytolytic activity score, reflecting the global immune killing, was significantly higher in the BTK high BC. Given that BC with abundant tumor infiltrating lymphocytes respond better to chemotherapy, the relationship between BTK expression and response to neoadjuvant chemotherapy was assessed. Somewhat unexpectedly, BTK expression was associated with better response in only one out of ten neoadjuvant cohorts. Further, no change in BTK expression were observed before and after neoadjuvant chemotherapy in six cohorts. While BTK expression was higher in primary sites compared to metastatic sites, it was not associated with distant recurrence. Across the TCGA, METABRIC, and SCAN-B cohorts, no significant overall survival differences were observed between the BTK high and low expression groups. All findings were consistent regardless of the BC subtypes. Conclusions: Myeloid cells and B-cells were the source of BTK expression, and it was associated with macrophage regulation and infiltration of various types of immune cells and proteins including PD1 &amp; PD-L1 and enriched immune related gene sets. However, BTK expression was not associated with response to neoadjuvant chemotherapy or Impact on survival, regardless of BC subtypes. Citation Format: T. ALRammah. Expression of Brutons tyrosine kinase (BTK) in breast cancer associates with tumor immune microenvironment but lacks predictive value for clinical outcome [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-13-11.

This review focuses on the pathophysiology, diagnostic approach, and current and emerging treatments of chronic spontaneous urticaria (CSU), with an emphasis on mast-cell mediated mechanisms and therapeutic targets. CSU is a mast-cell mediated disease involving both immunoglobulin E (IgE) and non-IgE mediated pathways, thus targeting mast cells and their downstream mediators can provide therapeutic benefit. Emerging therapies such asdupilumab, Bruton's tyrosine kinase (BTK) inhibitors, anti-KIT antibodies, Janus kinase (JAK) inhibitors, Mas-related G protein-coupled receptor X2 (MRGPRX2) inhibitors, interleukin (IL)-17 and IL-5 inhibitors, anti-thymic stromal lymphopoietin (TSLP) monoclonal antibodies, and mast cell silencers, as well as lifestyle changes such as low-histamine diets, are under investigation for antihistamine- refractory disease. While current international guidelines recommend second-generation H1-antihistamines as first-line treatments of CSU, novel treatments targeting mast-cell mediated pathways show promise for refractory disease. Recent advancements in targeted therapies and biomarkers may improve treatment personalization and response.

The clinical and biological significance of clonal hematopoiesis (CH) has not been investigated in the myeloid compartment of chronic lymphocytic leukemia (CLL). By studying 488 newly diagnosed CLL through CAPP‐seq using a 28‐gene panel on granulocyte genomic DNA (gDNA), CH occurred in 231 (47.3%) patients. Cell sorting of cases that never developed Richter transformation (RT) confirmed that CH mutations, including CH‐related TP53 mutations, were restricted to the myelomonocytic compartment and absent in CLL cells, as also documented by single‐cell DNA sequencing. CH associated with shorter overall survival (OS) (hazard ratio [HR] 1.36, 95% CI 1.04–1.77, P = 0.023); specifically, TET2 mutations independently predicted inferior OS (HR 1.62, 95% CI 1.15–2.28, P = 0.01) after adjusting for age and for CLL‐related prognostic biomarkers, namely IGHV and TP53 status. Regarding therapy‐related toxicities, CH correlated with a higher incidence of Grade ≥ 3 neutropenia (P = 0.004) after venetoclax‐based regimens. Sequential samples (n = 57) analysis showed that Bruton tyrosine kinase (BTK) and BCL2 inhibitors do not induce CH expansion, which was instead driven by chemotherapy. CH is significantly associated with a higher risk of second hematological malignancies only in chemo‐exposed patients. Single‐cell RNA sequencing of seven CH+ and six CH− CLL revealed that the T‐cell compartment of CH+ patients exhibits a less exhausted phenotype, documented by lower expression of TOX, the master regulator of T‐cell exhaustion, and a higher pro‐inflammatory profile. CH also influenced RT, since CH ASXL1 mutations independently associated with higher RT risk (HR 11.19, 95% CI 4.09–30.62, P < 0.001). Overall, CH in CLL impacts survival, therapeutic toxicity, and transformation risk while also influencing the T‐cell immune compartment.

ABSTRACT Background Assessing Bruton tyrosine kinase inhibitors (BTKis) for treating chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is crucial to understand associated real-world outcomes in diverse populations. This study evaluated real-world treatment patterns, switching, and sequencing to next line of therapy in patients initiating BTKis as first-line (1L) or second-line (2L) CLL/SLL treatment. Research design and methods The IntegraConnect PrecisionQ database was used to identify CLL/SLL patients initiating 1L or 2L zanubrutinib, acalabrutinib, or ibrutinib (1/1/2020–2/28/2023). Switching was measured as patients initiating another treatment within the same line or advancing to following line of therapy within 90 days. Sequencing to next line of therapy was calculated from time to the next treatment Kaplan–Meier curve. Results 2816 and 1253 patients initiated 1L or 2L BTKi (zanubrutinib, 157/107; acalabrutinib, 1238/672; ibrutinib, 1421/474), respectively. The 90-day switching rate was significantly lower for zanubrutinib vs acalabrutinib and ibrutinib (1L: p < 0.0001; 2L: p < 0.0001). Estimated proportion of patients receiving next line of therapy at 180 days was lower for zanubrutinib vs acalabrutinib and ibrutinib (1L p = 0.2958; 2L p < 0.0001). Conclusions Zanubrutinib was associated with lower 90-day switching rates and estimated proportion of patients receiving next line of therapy at 180 days vs acalabrutinib and ibrutinib in 1L and 2L.

ABSTRACT Background Chronic lymphocytic leukemia (CLL) commonly affects older patients, who often endure greater health disparities and treatment burdens. This study assessed treatment utilization patterns, discontinuation, and healthcare resource utilization (HCRU) of first-line (1L) use of Bruton tyrosine kinase inhibitors (BTKis) in elderly patients with CLL. Research design and methods A retrospective observational study using the Symphony Integrated Dataverse identified CLL patients aged ≥65 years initiating a 1L BTKi (zanubrutinib, acalabrutinib, ibrutinib; 01/2022–11/2024). Baseline characteristics and outcomes were reported for each BTKi. Treatment discontinuation rate was estimated at 3, 4, 5, 6, 12, 18, and 24 months, and by time to discontinuation (TTD), using Kaplan–Meier method. HCRU (outpatient, inpatient, and other services) was evaluated as per patient per year (PPPY). Results A total of 5,344 patients ≥65 years were included (acalabrutinib = 2,662; zanubrutinib = 1,577; ibrutinib = 1,105). Baseline characteristics were similar across each BTKi. Zanubrutinib had the longest median TTD overall (zanubrutinib: 22.8 months, acalabrutinib: 17.4 months, ibrutinib: 14.3 months; p < .0001). Average outpatient visits PPPY were lowest for zanubrutinib (zanubrutinib: 9.7, acalabrutinib: 10.9, ibrutinib: 11.5; p = .0018). Conclusions This real-world study demonstrated that zanubrutinib was associated with longer TTD, lower discontinuation rates, and less HCRU than acalabrutinib or ibrutinib in older CLL patients aged ≥65 years.

Background: Bruton's tyrosine kinase inhibitors, particularly ibrutinib, have improved outcomes in patients with chronic lymphocytic leukemia but are associated with an increased risk of atrial fibrillation. The early identification of patients with increased susceptibility to atrial fibrillation remains a major challenge in cardio-oncology. Methods: This prospective pilot study included 45 patients with chronic lymphocytic leukemia treated with ibrutinib. All patients underwent comprehensive transthoracic echocardiography at baseline and after 6 months. Left atrial structure and function were assessed, with particular emphasis on speckle-tracking-derived left atrial strain parameters, including peak atrial longitudinal strain and peak atrial contraction strain. Results: At follow-up, a modest but significant increase in indexed left atrial volume was observed, while left atrial functional parameters remained stable. Patients who developed atrial fibrillation showed significantly lower baseline Peak Atrial Contraction Strain values compared with those who remained in sinus rhythm, whereas no significant differences in Peak Atrial Longitudinal Strain were detected. Conclusions: Ibrutinib-related atrial fibrillation appears to be driven primarily by pre-existing atrial vulnerability rather than early drug-induced atrial dysfunction. The baseline impairment of left atrial contractile function may represent a candidate echocardiographic marker of atrial functional vulnerability and may inform cardiovascular surveillance and monitoring strategies in patients treated with ibrutinib.

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of cancer and immune disorders. However, their cardiotoxicity, particularly the risk of atrial fibrillation (AF), raises growing concerns. We aimed to comprehensively examine the associations between TKIs and AF using real-world pharmacovigilance data. We conducted a case-control study by analyzing adverse event (AE) reports from the FDA Adverse Event Reporting System between 2004 and 2023 for 56 FDA-approved TKIs. AF cases were identified using the preferred term "atrial fibrillation". Patient characteristics were compared between fatal and non-fatal cases. Disproportionality analysis, quantified using the reporting odds ratio (ROR), was employed to assess the associations between TKIs and AF. Among 561,551 TKI-related AE reports, 3794 (0.7%) involved AF. The majority of AF events (89.7%) were classified as serious, with 11.3% associated with fatal outcomes. Significant differences in gender, age, drug categories, and systems involved in the indication were observed between fatal and non-fatal outcome groups (all P < 0.05). Disproportionality analysis identified 12 TKIs significantly associated with AF. Notably, Bruton's tyrosine kinase inhibitors showed the strongest signals, with ibrutinib (ROR: 9.83; 95% CI: 9.34-10.34) leading, followed by zanubrutinib (ROR: 6.29; 95% CI: 3.70-10.69) and acalabrutinib (ROR: 5.58; 95% CI: 4.38-7.11). Additionally, nine other TKIs, including nilotinib, ponatinib, and nintedanib, among others, were associated with increased reporting frequencies. These findings suggest that certain TKIs are associated with an elevated risk of AF, underscoring the importance of vigilant cardiovascular monitoring during TKI therapy.

Btk (Bruton's tyrosine kinase), a Tec-family kinase initially recognized for its role in B-cell signaling, has emerged as a critical player in thrombosis and cardiovascular disease. Beyond the established therapeutic effects of Btk inhibitors in B-cell malignancies, its expression in platelets, macrophages, and neutrophils implicates Btk in platelet activation, atherothrombosis, and innate immunity. This state-of-the-art review synthesizes the current understanding of Btk's mechanistic contributions to thrombosis and cardiovascular disease, evaluates the evolution of Btk inhibitors (BTKi), and explores their therapeutic potential. Patients with X-linked agammaglobulinemia who lack Btk do not have a bleeding diathesis, indicating that platelet-selective Btk inhibition would be a safe antithrombotic strategy. In platelets, Btk mediates immunoreceptor tyrosine-based activation motif-dependent and -independent signaling, driving atherothrombosis, venous thrombosis, and immunothrombosis without affecting hemostatic platelet functions. In myeloid cells, Btk amplifies inflammation via NLRP3 inflammasome activation and neutrophil extracellular trap formation, linking it to thromboinflammation and atherosclerosis. First-generation BTKi such as ibrutinib demonstrate antithrombotic efficacy but are limited by off-target effects, including bleeding and atrial fibrillation. Second- and third-generation inhibitors (eg, acalabrutinib, zanubrutinib, and pirtobrutinib) show enhanced selectivity, reducing cardiovascular toxicity in patients with B-cell malignancies. Highly selective BTKi (fenebrutinib and remibrutinib) do not show bleeding in clinical trials of various autoimmune disorders, and covalent selective BTKi applied at low dosage are expected to selectively inhibit Btk in platelets without bleeding side effects. Preclinical data and early observations from compassionate use in patients with atypical autoimmune thrombosis highlight the potential of BTKi as selective antithrombotic agents beyond traditional therapies. This review conceptualizes and underscores Btk's pivotal role at immune-thrombosis interfaces in atherothrombosis, advocating for precision medicine approaches and innovative platforms to unlock its full therapeutic potential in cardiovascular disease management.