The classification of lymphomas represents a crucial element in the clinical management of these heterogeneous tumors, profoundly influencing prognosis, follow-up, and therapeutic strategies through the integration of clinical, imaging, and molecular aspects. The 5th Edition of the World Health Organization Classification of Hematolymphoid Tumors (WHO-HAEM5) of 2022 introduced significant updates, recognizing new entities based on genomic and molecular data, such as high-grade B-cell lymphomas with MYC/BCL2 rearrangements and subtypes with non-germinal center B-cell-like phenotype. Fluorodeoxyglucose positron emission tomography/computed tomography imaging remains the essential tool for staging, therapeutic response assessment, and relapse detection, with sensitivity exceeding 90% in aggressive lymphomas such as diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma, surpassing the limitations of conventional computed tomography and predicting outcomes using metrics like SUVmax and Deauville score. Molecular aspects, including MYD88/CD79B mutations in DLBCL and markers such as circulating tumor DNA, refine risk stratification, guiding targeted therapies such as Bruton's tyrosine kinase inhibitors, venetoclax, or CAR-T cells. This systematic review synthesizes recent evidence (2020-2025) from PubMed literature, highlighting how an optimal multimodal approach reduces mortality and improves progression-free survival, incorporating radiomics and artificial intelligence for more accurate predictions. Challenges persist in access to advanced technologies and prospective validation, but the integration of these developments promises personalized management, reducing overtreatment and improving quality of life.

The rapid expansion of oncologic systemic therapy has produced major advances for patients with cancer. This array of pharmacologic mechanisms also presents challenges for neurosurgeons. Many agents impair wound healing, hemostasis, and immune function, elevating perioperative risk. Yet, consolidated evidence-based guidance for neurosurgical drug management remains limited. Our goal is to provide a comprehensive, clinically actionable framework for perioperative management of targeted and biologic therapies in patients undergoing neurosurgical procedures. We conducted a systematic review of pivotal clinical trials, US Food and Drug Administration safety data, meta-analyses, and society guidelines to assess the impact of key agents on surgical outcomes. Drug classes were evaluated based on pharmacokinetics, mechanism of action, and adverse events relevant to wound healing, bleeding, and immune dysregulation. Recommendations were stratified by risk level and supported by available evidence and expert consensus. Wound healing risk was highest with anti-vascular endothelial growth factor (VEGF) monoclonal antibodies and mammalian target of rapamycin inhibitors, warranting extended preoperative holds (≥4 weeks for VEGF inhibitors, ≥1 week for mammalian target of rapamycin agents) and postoperative delays of 2 to 4 weeks (fibroblast and angiogenesis suppression). Bleeding risk was most significant with VEGF receptor-tyrosine kinase inhibitors and Bruton's tyrosine kinase inhibitors (eg, ibrutinib), independent of platelet count, necessitating short-term holds of up to 1 week with resumption after 3 to 7 days. Immunosuppression noted with CDK4/6 inhibitors, janus kinase inhibitors, and biologic immunomodulators (eg, TNF, IL-6, CD20 blockers), increasing postoperative infection risk. These agents often require brief interruption (2-7 days) with resumption 1 to 2 weeks postoperative depending on half-life and schedule. For BRAF/MEK inhibitors and immune checkpoint inhibitors, perioperative data are limited. Modern systemic therapies necessitate refinement of perioperative management in neurosurgical oncology. This review synthesizes data into a pragmatic framework for drug timing and risk mitigation. Considering interruption intervals is essential to balance surgical safety with oncologic control. Integrating these principles can reduce complications, standardize care, and improve outcomes for this complex patient population.

Treatment for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has shifted from chemoimmunotherapy (CIT) to targeted therapies, administered as continuous treatment until progression or in fixed-duration regimens. Fixed-duration regimens with targeted therapies (usually in combination regimens with venetoclax and a Bruton tyrosine kinase inhibitor [BTKi] and/or an anti-CD20 monoclonal antibody) are of increasing interest, and recent phase3 trial results support this approach. Fixed-duration treatment offers a pre-defined treatment stopping point and may provide patients with a treatment-free interval, potentially reducing the burden of long-term therapy while minimizing cumulative toxicity and costs. Here, we review the currently approved fixed-duration regimens and some investigational combinations in ongoing registrational clinical trials. The registrational fixed-duration studies CLL14 (venetoclax plus obinutuzumab), GLOW (ibrutinib plus venetoclax), CAPTIVATE (ibrutinib plus venetoclax), AMPLIFY (acalabrutinib plus venetoclax with or without obinutuzumab), and MURANO (venetoclax plus rituximab) along with the investigator-initiated CLL17 study, which may impact treatment guidelines, demonstrated extended treatment-free intervals. Generally, targeted fixed-duration regimens in patients with unmutated immunoglobulin heavy chain variable region or TP53 and/or del(17p) demonstrated greater efficacy than CIT, but outcomes were typically poorer than in patients without these high-risk features. Cardiovascular toxicity and death remain a significant concern with ibrutinib plus venetoclax, which was also associated with high rates of diarrhea and atrial fibrillation. Successful fixed-duration regimens in CLL should achieve deep remission (i.e., undetectable minimal residual disease), sustain long-term progression-free survival, decrease the burden of treatment-related adverse events, and allow for re-treatment with minimal risk of drug resistance. Although fixed-duration treatment represents a positive step forward for most patients with CLL/SLL, the currently approved regimens often fall short in patients at high risk of progression. Continued research and development of next-generation drugs is essential to enhance efficacy and safety, ultimately improving outcomes in all patients with CLL/SLL.

Updates on Kinase Inhibitors in Allergy.

Systemic Treatments for Chronic Spontaneous Urticaria: Anti-IgE and Beyond.

Chronic spontaneous urticaria (CSU) is a common dermatologic disorder marked by significant patient heterogeneity. Existing treatment strategies often fall short of adequately addressing patients' clinical needs. In the past decade, insights into the pathophysiology of CSU have catalyzed the development of novel targeted therapies, which can be categorized into three main approaches: targeting mast cells, targeting cytokines, and targeting Janus kinase (JAK) signaling. Mast cell-targeted strategies focus on surface receptors (e.g., activating receptors, the KIT receptor governing mast cell proliferation/survival, and inhibitory receptors) and intracellular pathways such as Bruton's tyrosine kinase (BTK). Cytokine-targeted therapies aim at specific mediators including IL-4, thymic stromal lymphopoietin (TSLP), IL-17, IL-23, and IL-5. Regarding JAK-targeted therapy, besides approved JAK inhibitors, several novel agents, including dual-target inhibitors, are under investigation. This review systematically delineates recent advances in targeted therapies for CSU, comparing the features and clinical potential of different agents, to inform evidence-based and personalized management of this condition.

Immune thrombocytopenia (ITP) is a chronic autoimmune disorder associated with platelet destruction and increased bleeding risk, substantial economic burden, and impairment of health-related quality of life. The pathophysiology of ITP involves increased platelet destruction and impaired platelet production due to a multifactorial breakdown of immune tolerance driven by dysregulated B and T cells. Advances in understanding ITP pathophysiology have led to the development of new immune-modulating therapies, such as Bruton tyrosine kinase (BTK) inhibitors. Rilzabrutinib (Wayrilz; Sanofi) is an oral BTK inhibitor recently approved for treatment of adult patients with persistent or chronic ITP who have had an insufficient response to a previous treatment. Rilzabrutinib targets several aspects of ITP disease pathophysiology by modulating multiple immune pathways. Approval was based on results from a phase 3 trial (LUNA 3 [NCT04562766]), in which patients with ITP who received rilzabrutinib demonstrated a rapid, durable platelet response and improvements in fatigue and bleeding with a tolerable safety profile.

Waldenström's macroglobulinaemia (WM) is a rare B-cell lymphoproliferative disorder with multiple effective front-line treatment options. However, real-world comparative data on commonly used regimens are limited. We conducted a retrospective cohort study of 348 consecutive, newly diagnosed WM patients treated between 2002 and 2024. Patients received first-line therapy with either bortezomib-dexamethasone-rituximab (BDR, n = 35), Bruton's tyrosine kinase inhibitors (BTKis, n = 57) or dexamethasone-rituximab-cyclophosphamide (DRC, n = 256). BTKi demonstrated the highest MRR (major response rate, ≥PR) (80.7%), followed by DRC (68.4%) and BDR (40.0%) (p < 0.001). The median PFS and OS did not differ significantly among regimens. TTNT seemed to be longer in the BTKi group (log-rank p = 0.025), with a 74% reduced risk of salvage therapy compared to DRC (aHR = 0.26, p = 0.016). Cumulative WM-related mortality at 5 years was lowest in BTKi-treated patients (4.1% vs. 13.0% DRC vs. 17.1% BDR), though differences were not statistically significant. In this single-centre analysis, both BTKi and DRC led to prolonged disease control in the upfront treatment of patients with WM. Extended follow-up and prospective validation are needed to reveal potential long-term survival differences.

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.

Inhibiting the platelet glycoprotein VI (GPVI) receptor is a promising strategy for reducing cerebral ischemia-reperfusion injury (CIRI) without severe compromise of hemostasis, while targeting glycoprotein IIb/IIIa (integrin αIIbβ3) causes bleeding. The underlying cellular mechanism remains unclear. This study shows that megakaryocyte-platelet-specific deficiency of the autophagic protein Rubicon (Run domain protein as Beclin-1 interacting and cysteine-rich containing) accelerates stroke development and exacerbates cerebral hemorrhage. Rubicon interacts with Bruton's tyrosine kinase (Btk) to inhibit GPVI-mediated thrombus formation, while it prevents αIIbβ3-mediated selective autophagy and degradation of Btk to stabilize platelet thrombi. The expression of Rubicon in platelets is decreased in patients with acute ischemic-reperfusion injury. A cell-permeable peptide mimicking the Rubicon-Btk interaction significantly reduces cerebral infarction volume in a mouse model. As Rubicon is dispensable for hemostasis but crucial in the reperfusion stage of CIRI, peptides mimicking its effects may offer a selective and safe therapeutic strategy.

Elevated sodium concentrations are commonly observed in tumors and sites of inflammation. Previous studies have shown that high salt levels modulate the phenotype and function of CD4+ and CD8+ T cells, regulatory T cells, and macrophages. In this study, we performed transcriptomic studies that revealed profound alterations in the neutrophil transcriptome upon high salt exposure, with changes that significantly exceeded those triggered by conventional agonists. By integrating transcriptomic data with functional assays, our findings suggest that high salt-induced neutrophil activation involves mitochondrial ROS production, which subsequently activates p38 MAPK and engages FOS-, Bruton's tyrosine kinase (BTK)-, and cyclooxygenase 2 (COX2)-dependent pathways. Remarkably, the plasticity of the neutrophil transcriptome in response to high salt was further evidenced by the upregulation of genes typically associated with other cell types, including semenogelin 1 (SEMG1), intercellular adhesion molecule-4 (ICAM4), tripartite motif69 (TRIM69), amphiregulin (AREG), oncostatin (OSM), and transducer of ERBB2-1 (TOB1), suggesting a broader role for neutrophils in different biological processes beyond their participation in innate immunity.

In 2025, several major advances have marked the field of neurology. Anti-FcRN and anti-C5 antibodies have confirmed their long-term efficacy in the treatment of myasthenia gravis. Bruton tyrosine kinase inhibitors have expanded the therapeutic arsenal for multiple sclerosis. An antibody targeting α-synuclein appears to slow motor decline in early-stage Parkinson's disease. The efficacy of late thrombolysis in strokes with radiological mismatch has been confirmed. A blood biomarker facilitates early detection of Alzheimer's disease, and Swiss guidelines specify the modality for the use of anti-amyloid therapies in this disease. Finally, in pregnant women with epilepsy, the recommended dose of folic acid has been reduced.

Combination therapies offer promise for improving cancer treatment efficacy and preventing recurrence. Preclinical screening strategies can prioritize synergistic drug combinations. However, identifying optimal combinations tailored to specific cancer subtypes and patients is challenging due to the vast number of possibilities and tumor heterogeneity. To address this gap, we developed PAIRWISE which explicitly modeled synergistic effects of drug combinations in cancer cell lines or tumor samples. PAIRWISE outperformed competing models with an AUROC of 0.847 on held-out cancer cell lines. When applied to an independent dataset with Bruton Tyrosine Kinase inhibitors in Diffuse Large B Cell Lymphoma, PAIRWISE accurately predicted synergistic combinations with an AUROC of 0.720. We validated 30 approved or investigational agents for DLBCL treatment and their synergy with BTKi in HTS. PAIRWISE showed strong concordance with in vitro screening results. These findings demonstrate the ability of PAIRWISE to nominate effective personalized drug combinations, accelerating precision oncology development.

Bruton tyrosine kinase (Btk) is essential for B cell function. Its role in myeloid cells is less understood. Greater insights into Btk significance in myeloid cells are needed to evaluate its potential as a therapeutic target during the effector phase of antibody-induced autoimmune diseases, where inhibiting autoantibody production suppresses tissue inflammation only after a delay. Such a situation can be observed, for example, in acute flares of pemphigoid diseases, a group of autoimmune blistering skin diseases. We examined the effect of neutrophil-specific Btk gene deficiency and of the Btk inhibitor ibrutinib on disease in the antibody-transfer model of bullous pemphigoid (BP)-like epidermolysis bullosa acquisita (EBA), a model that solely reflects the effector phase. We additionally investigated the effect of Btk inhibitors on responses of neutrophils relevant for autoimmune diseases in vitro. Both neutrophil-specific Btk deficiency and ibrutinib administration, systemic or topical, markedly protected against skin inflammation and disrupted established inflammation. Stimulation of murine neutrophils with immune complexes activated Btk and induced the release of leukotriene B4 (LTB4) and reactive oxygen species (ROS). Btk deficiency abolished LTB4 but not ROS release, indicating distinct signalling pathways regulating LTB4 and ROS following Fcγ receptor activation. Our findings demonstrate that EBA skin inflammation is critically controlled by a Fcγ receptor-Btk-LTB4 axis in neutrophils. This highlights Btk as promising drug target to treat EBA and potentially other antibody-induced autoimmune diseases.

BTK (Bruton's tyrosine kinase) has become a key therapeutic target across several hematologic diseases, beginning with its original use in CLL/SLL. As a central mediator of B-cell receptor signaling and microenvironment interactions, BTK supports survival, proliferation, and trafficking in multiple mature B-cell malignancies (mantle cell lymphoma, marginal zone lymphoma, Waldenström macroglobulinemia, and other indolent/aggressive lymphomas) and in selected immune-mediated conditions such as chronic graft-versus-host disease. Covalent BTK inhibitors (ibrutinib, acalabrutinib, and zanubrutinib) irreversibly bind the C481 residue and have produced high response rates and durable disease control, often replacing chemoimmunotherapy in the relapsed setting and, for some entities, even in the first line. Differences in kinase selectivity lead to different safety profiles: second-generation covalent agents generally maintain efficacy while reducing significant off-target toxicities, especially atrial fibrillation and hypertension. Resistance to covalent BTK inhibitors most commonly develops through BTK C481 substitutions and activating PLCG2 mutations, with other kinase-domain variants increasingly recognized. Non-covalent BTK inhibitors (e.g., pirtobrutinib) bind BTK independently of C481, can overcome classic C481-mediated resistance, and extend BTK pathway targeting into later lines of therapy. Overall, BTK inhibition has evolved into a versatile platform enabling long-term, often chemo-free management strategies.

Progressive multiple sclerosis: Six trials to watch.

Safety of Bruton kinase inhibitors in chronic lymphocytic leukemia: Real world clinical practice.

Bruton tyrosine kinase inhibitors (BTKis) have dramatically changed the therapeutic landscape of chronic lymphocytic leukemia (CLL), with ibrutinib, first-in-class, demonstrating durable efficacy even in high-risk patients. However, off-target adverse events (AEs) have raised concerns, prompting the development of more selective second-generation BTKi, as zanubrutinib, designed to improve tolerability while maintaining efficacy. Despite encouraging results from clinical trials, real-world data comparing zanubrutinib with ibrutinib remain limited. In this multicenter, retrospective study, we analyzed 934 CLL patients treated outside clinical trials, including 393 receiving zanubrutinib and 541 receiving ibrutinib. We evaluated time to treatment discontinuation (TTD) and time to next treatment or death (TTNTD) in both the overall cohort and a propensity score-matched population. Zanubrutinib-treated patients experienced lower 12-month discontinuation rates (overall:12.6% versus 21.4%; matched:12.4% versus 20.2%) and higher 12-month TTNTD rates (overall:91.9% versus 83.0%; matched:93.2% versus 83.4%). Multivariable analyses confirmed zanubrutinib as an independent predictor of longer TTD and TTNTD, while high-risk features, including age, relapsed/refractory disease, Binet stage C, TP53 disruption, ECOG 2-3, and congestive heart failure, were consistently associated with poorer outcomes. AEs leading to discontinuation, particularly atrial fibrillation, bleeding, and infections, were less frequent with zanubrutinib, reflecting its favorable safety profile. These findings provide real-world evidence that zanubrutinib offers more durable disease control and improved persistence compared with ibrutinib, reinforcing its clinical value as a preferred second-generation BTKi. Nevertheless, the relatively short follow-up for zanubrutinib warrants cautious interpretation of long-term outcomes and underscores the need for ongoing observation to fully characterize its durability and safety.

DNA-encoded chemical libraries (DELs) enable the highly efficient screening of billions of small molecules for binding to a target of interest and provide valuable training data for machine learning models for virtual screening. However, DEL screening data are notoriously noisy due in large part to significant variance in the synthetic yield of library members. Here, we show an analysis from a split-sample DEL screening strategy against Bruton's tyrosine kinase (BTK), which includes a panel of affinity selections against the target at varying concentrations and a probabilistic model to estimate the binding affinity and relative input concentrations of library members. We compared model predictions to SPR measurements of resynthesized DNA-conjugated compounds and found that this methodology yielded an improved ranking of library members by binding affinity compared to enrichment metrics. Additionally, the method successfully recovered a library member with a potent binding affinity that would not have been detected in our standard DEL selection.

In multiple sclerosis (MS), a variety of immunosuppressive treatments are available. While effective, these approaches often lead to sustained impairment of essential components of the immune system, posing long-term safety concerns. Consequently, there is a growing interest in alternative therapeutic approaches that selectively limit pathogenic B-cell functions while preserving their physiologic roles. In this study, we investigated the therapeutic potential of inhibiting the enzyme Bruton tyrosine kinase (BTK), a key signaling molecule in both B-cell and myeloid cell activation. The effects of the BTK inhibitor evobrutinib were evaluated in various experimental in vivo models of CNS demyelination, each representing different aspects of disease pathology as well as a naïve healthy condition. The impact on disease onset and severity was determined, and phenotypical alterations in different cell populations were assessed via flow cytometry. Furthermore, functional changes in both murine and human myeloid cells induced by BTK inhibition under specific Fc receptor-dependent stimulation were analyzed in in vitro settings using flow cytometry. In a naïve, healthy environment, evobrutinib promoted the development of regulatory B-cell properties. In various experimental models of CNS demyelination, BTK inhibition limited the differentiation of proinflammatory B cells while supporting their regulatory properties. Beyond modulating B-cell responses, BTK inhibition also attenuated the activation of myeloid cells after Fc receptor-mediated antigen uptake, a process assumed to be of importance in conditions, such as neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein-antibody associated disease. In addition, BTK inhibition was shown to suppress the secretion of proinflammatory cytokines and reduce antigen presentation, further dampening pathogenic immune responses. These findings highlight the potential of BTK inhibition as a selective and sustainable immunomodulatory strategy for both B cells and myeloid cells in the context of chronic CNS inflammation. Despite their efficacy, broad-spectrum immunosuppressive therapies often fail to provide targeted immune modulation. By contrast, BTK inhibition promotes regulatory B-cell properties while leaving other B-cell functions intact, providing the basis for its broad use-potentially in combination with established anti-inflammatory agents.