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Summary Idiopathic multicentric Castleman disease (iMCD) is a rare and heterogeneous lymphoproliferative disorder that lacks standardised treatment options for patients with refractory or relapsed (r/r) disease. Blocking Bruton's tyrosine kinase (BTK) has emerged as a promising therapeutic approach for iMCD without depleting B cells. This single‐centre, retrospective study enrolled 10 patients with r/r iMCD who were treated with orelabrutinib, a novel, next‐generation BTK inhibitor. The median age at orelabrutinib initiation was 48 (range: 31–58) years. The overall response rate was 70% (7/10 patients, 95% CI: 34.8–93.3), with 20% (n = 2) achieving complete response and 50% (n = 5) achieving partial response. The median time to response was 9.8 (range: 5.9–20.5) months. Patients in the non‐responder group also demonstrated a continuous improvement in haemoglobin (91–105 g/L) and albumin (32–38 g/L) levels at month 12 of treatment despite not fulfilling response criteria. No grade 3 or higher adverse events occurred during the median time to the next treatment of 29.0 (range: 15.0–36.2) months. No patient mortality was recorded during the median follow‐up duration of 32.8 (range: 15.0–36.9) months. In conclusion, orelabrutinib is a safe and effective regimen for r/r iMCD. [ABSTRACT FROM AUTHOR]

The New England Journal of Medicine article delves into Hairy-Cell Leukemia (HCL), a rare cancer affecting mature B cells, primarily in males. HCL is characterized by specific symptoms like cytopenias and splenomegaly, with a genetic cause linked to the BRAFV600E mutation. Treatment options include purine analogues, rituximab, and BRAF inhibitors, with newer therapies like ibrutinib showing promise. The text emphasizes the importance of genetic testing, challenges in managing infections and leukopenia, and explores potential treatments like allogeneic stem cell transplantation and immunotherapy for HCL. [Extracted from the article]

Background and Purpose Experimental Approach Key Results Conclusion and Implications Pathological retinal angiogenesis is a typical manifestation of vision‐threatening ocular diseases. Many patients exhibit poor response or resistance to anti‐vascular endothelial growth factor (VEGF) agents. Bruton's tyrosine kinase (BTK) controls the proliferation and function of immune cells. Therefore, we examined the anti‐inflammatory and anti‐angiogenic effects of BTK inhibition on retinal angiogenesis.Retinal neovascularisation and vascular leakage in oxygen‐induced retinopathy in C57/BL6J mice were assessed by whole‐mount retinal immunofluorescence. PLX5622 was used to deplete microglia and Rag1‐knockout mice were used to test the contribution of lymphocytes to the effects of BTK inhibition. The cytokines, activation markers, inflammatory and immune‐regulatory activities of retinal microglia/macrophages were detected using qRT‐PCR and immunofluorescence. NLRP3 was detected by western blotting, and the effects of BTK inhibition on the co‐culture of microglia and human retinal microvascular endothelial cells (HRMECs) were examined.BTK inhibition suppressed pathological angiogenesis and vascular leakage, and significantly reduced retinal inflammation, which involved microglia/macrophages but not lymphocytes. BTK inhibition increased anti‐inflammatory factors and reduced pro‐inflammatory cytokines that resulted from NLRP3 inflammasome activation. BTK inhibition suppressed the inflammatory activity of microglia/macrophages, and acted synergistically with anti‐VEGF without retinal toxicity. Moreover, the supernatant of microglia incubated with BTK‐inhibitor reduced the proliferation, tube formation and sprouting of HRMECs.BTK inhibition suppressed retinal neovascularisation and vascular leakage by modulating the inflammatory activity of microglia and macrophages. Our study suggests BTK inhibition as a novel and promising approach for alleviating pathological retinal angiogenesis. [ABSTRACT FROM AUTHOR]

Introduction: Blastoid variant‐mantle cell lymphoma (BV‐MCL) represents an aggressive subset of patients with no established standard of care treatment approach. Methods: We performed a retrospective analysis of the clinical characteristics and outcomes of 17 de novo BV‐MCL patients treated at our institution between May 2009 and September 2023. In addition, we reviewed the literature supporting 2nd/3rd generation Bruton's Tyrosine‐kinase (BTKi)‐based therapies for upfront management. Results: The complete response rate to frontline and salvage therapy was 66.7% and 25%, respectively. Two‐year overall survival (OS) was low at 62.5% (95% CI, 34.7%–81.1%). Variables associated with higher OS included receipt of consolidative HSCT (p = 0.017), TP53‐wild type (p = 0.031), intermediate‐ versus high‐risk Mantle Cell Lymphoma Prognostic Index score (p = 0.026), and achieving complete response with induction therapy (p = 0.027). Discussion: Treatment outcomes with chemo‐immunotherapy in BV‐MCL patients are poor, especially among TP53‐mutated patients. Recent findings describing positive outcomes with novel BTKi‐based therapies are encouraging and should be considered in this high‐risk population. [ABSTRACT FROM AUTHOR]

The article discusses the impact of ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor, on patients with chronic lymphocytic leukaemia (CLL) in two landmark trials. While ibrutinib has shown superior outcomes in terms of progression-free survival, it is associated with cardiovascular toxicities, including pericardial events. The study analyzed data from two trials, ECOG-ACRIN E1912 and Alliance A041202, and found that pericardial events occurred in 2.5% of patients on ibrutinib-based regimens compared to 0.9% on chemoimmunotherapy regimens. Further research is needed to understand the rates of pericardial toxicity with ibrutinib in different treatment combinations. [Extracted from the article]

Summary: Mantle cell lymphoma (MCL) is a rare lymphoproliferative neoplasm considered incurable, with a median survival of 3–5 years. In recent years, Bruton's tyrosine kinase inhibitors (BTKi) have been introduced, demonstrating high therapeutic activity. However, the prognosis for MCL patients failing ibrutinib therapy is particularly poor, with a survival expectation of a few months. In this phase II trial, we assessed the efficacy and safety of the carfilzomib‐lenalidomide‐dexamethasone (KRD) combination in MCL patients who were relapsed/refractory (R/R) or intolerant to BTKi and in need of treatment. The primary objective of the study was to evaluate the antitumor efficacy of the KRD combination in terms of 12‐month overall survival (12‐month OS). From September 2019 to December 2020, 16 patients were enrolled from 11 Italian centers. After a median follow‐up of 2.37 months (95% CI 0.92–6.47), the 12‐month OS was 13%. The rate of grade 3–4 adverse events (AEs) was 35%, and the overall response rate (ORR) was 19%. These results led to the premature termination of enrollment, as defined in the protocol stopping rules. The efficacy of the KRD combination in advanced‐stage MCL patients who are R/R to BTKi is unsatisfactory and too toxic. [ABSTRACT FROM AUTHOR]

Summary: Real‐world evidence comparing clinical outcomes between venetoclax and Bruton tyrosine kinase inhibitors (BTKis) in patients with frontline (1 L) chronic lymphocytic leukaemia (CLL) is lacking. We compared treatment effectiveness of 1 L venetoclax plus obinutuzumab (VenO) versus BTKi‐based regimens. This retrospective observational study using Optum Clinformatics Data Mart® included adult patients with CLL (≥2 outpatient or ≥1 inpatient claim) who received VenO or BTKi‐based regimens in 1 L (1/2019–9/2022). Baseline characteristics were balanced using stabilised inverse probability weighting. Outcomes included duration of therapy (DoT), persistence, time to next treatment or death (TTNT‐D), and time off‐treatment. Among 1506 eligible patients (VenO: 203; BTKi: 1303), the median follow‐up duration was 12.6 (VenO) and 16.2 months (BTKi). Median DoT for VenO was 12.3 months; persistence remained higher in VenO versus BTKi through expected 1 L fixed treatment duration. Median TTNT‐D was not reached for VenO; however, more VenO‐ versus BTKi‐treated patients had not switched therapies/experienced death through Month 12 (87.1% vs. 75.3%). Among patients that discontinued, median time to discontinuation was 11.7 vs. 5.9 months for VenO versus BTKi and median time off‐treatment was 11.3 vs. 4.3 months. In this real‐world study, VenO was associated with better effectiveness outcomes than BTKi‐based regimens in 1 L CLL. [ABSTRACT FROM AUTHOR]

A robust and reproducible HPLC–UV‐based bioanalytical method for acalabrutinib (ACP) was developed and validated in rat plasma using prednisone as internal standard. The samples were prepared by single‐step protein precipitation method using methanol with 1% v/v formic acid. A polar C18 stationary phase was used with a combination of 10 mM ammonium acetate (pH 3.5) and methanol (60:40 ratio), flow rate 1.1 mL/min, and 50 µL injection volume. ACP and internal standard were retained at ∼5.96 and 8.29 min, respectively. The method was validated according to the United States Food and Drug Administration and ICH M10 bioanalytical method validation guidelines. It was linear in the calibration range (0.08–5 µg/mL) with RPRESS2$R_{{\mathrm{PRESS\ }}}^2$ as 0.9989; accurate (% bias ≤ 0.50 ± 0.67), and precise (%RSD ≤ 0.986) for any quality control standard. Further, the method was applied in estimating ACP in rat plasma samples collected during in vivo pharmacokinetic study of the bulk drug as well as a nanocrystal (NC) suspension formulation. ACP‐NCs were formulated by bottom‐up solvent–antisolvent precipitation with mean particle size 266.32 ± 29.90 nm, 0.25 ± 0.05 PDI, with 92.7% ± 2.3% yield. The NC formulation improved both in vitro dissolution and in vivo absorption, supporting a further development of ACP‐loaded nanodrug delivery systems. [ABSTRACT FROM AUTHOR]

This letter to the editor discusses a phase II study on the use of the drug duvelisib in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The study aimed to determine if intermittent dosing of duvelisib would improve safety while maintaining efficacy. The results showed that intermittent dosing of duvelisib was well-tolerated and resulted in a clinical benefit for the majority of patients. However, adverse events and treatment discontinuations still occurred, and the desired progression-free survival goal was not reached. The article suggests that further dose adjustments or combination therapies may improve outcomes, but interest in duvelisib has decreased due to concerns about mortality and alternative treatments. [Extracted from the article]

This document discusses the shift in first-line therapies for United States Veterans Affairs (VA) patients with chronic lymphocytic leukemia (CLL). CLL is a manageable but incurable condition, and a watch-and-wait approach is often used for asymptomatic patients. However, for patients requiring treatment, targeted therapies have revolutionized the treatment landscape. This study analyzed data from the VA system and found that the use of targeted therapies has increased over time, surpassing traditional chemotherapy/chemoimmunotherapy. Specifically, the use of ibrutinib accounted for the greatest proportion of targeted therapy use, followed by venetoclax and acalabrutinib. The study highlights the importance of understanding treatment patterns and the impact of targeted therapies in CLL management. [Extracted from the article]

Purpose: To report two cases of ibrutinib-related uveitis and review the literature to date. Methods: We report two cases of ibrutinib-related uveitis using CARE guidelines and review the cases reported in the literature. Results: Case 1) A 55-year-old female with recurrent primary central nervous system lymphoma presented with bilateral decreased visual acuity, photophobia, and floaters that started one month after initiating oral treatment with ibrutinib. Chronic non-granulomatous bilateral anterior-intermediate uveitis with macular edema was identified. Secondary causes were ruled out, and a presumptive diagnosis of ibrutinib-related uveitis was made. Case 2) A 57-year-old female with Waldenström macroglobulinemia who was treated with ibrutinib for two years presented with bilateral blurred vision, photophobia, red eyes, and floaters. A diagnosis of non-granulomatous, noninfectious panuveitis with bilateral cystoid macular edema was made. Secondary causes were ruled out, and ibrutinib toxicity was the most likely cause. Conclusion: Ibrutinib-related uveitis is a novel and under-diagnosed clinical entity. The most frequent clinical presentation in the literature is bilateral, non-granulomatous, anterior, and intermediate uveitis. Macular edema is a frequent complication. Uveitis usually requires topical treatment and the suspension of ibrutinib. Switching to second-generation Bruton tyrosine kinase inhibitors is proposed as a potential therapeutic alternative. [ABSTRACT FROM AUTHOR]

Introduction: Multiple sclerosis (MS) is a chronic neurodegenerative disease that leads to impaired cognitive function and accumulation of disability, with significant socioeconomic burden. Serious unmet need in the context of managing MS has given rise to ongoing research efforts, leading to the launch of new drugs planned for the near future, and subsequent concerns about the sustainability of healthcare systems. This study assessed the changes in the Italian MS market and their impact on the expenditures of the Italian National Healthcare Service between 2023 and 2028. Methods: A horizon-scanning model was developed to estimate annual expenditure from 2023 to 2028. Annual expenditure for MS was calculated by combining the number of patients treated with each product (clinical inputs) and the yearly costs of therapy (economic inputs). Baseline inputs (2020–2022) were collected from IQVIA® real-world data, while input estimation for the 5-year forecast was integrated with analog analyses and the insights of clinicians and former payers. Results: The number of equivalent patients treated in 2028 in Italy was estimated at around 67,000, with an increase of 10% versus 2022. In terms of treatment pattern evolution, first-line treatments are expected to reduce their shares from 47% in 2022 to 27% in 2028, and Bruton tyrosine kinase inhibitors are expected to reach 23% of patient shares. Overall, expenditure for MS is estimated to decrease from €721 million in 2022 to €551 million in 2028, mainly due to losses of exclusivity and renegotiation of drug prices. Conclusion: Despite the increase in the number of patients treated for MS and the launch of new molecules that will reach high market penetration, the model confirmed sustainability for the Italian National Healthcare Service. [ABSTRACT FROM AUTHOR]

Objective: The objective was to evaluate the efficacy/safety of pirtobrutinib in the treatment of B-cell malignancies and distinguish it from other available Bruton's tyrosine kinase (BTK) inhibitors. Data sources: A literature search of PubMed (January 2021 through November 2023) and Clinicaltrials.gov was conducted using terms pirtobrutinib, Jaypirca, and LOXO 305. Licensing trials of available BTK inhibitors were also reviewed. Study selection and data extraction: Relevant English-language clinical trials were evaluated. Data synthesis: Pirtobrutinib was approved by the US Food and Drug Administration for the treatment of relapsed/refractory mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) based largely on a phase 1/2 study in B-cell malignancies. Pirtobrutinib demonstrated a 73% overall response rate (ORR) in the CLL population and 58% in MCL. Pirtobrutinib has activity in patients resistant to earlier-generation, covalent BTK inhibitors. In fact, the ORRs were similar in BTK-pretreated and naïve patients. Adverse effects include fatigue, diarrhea, bleeding, and infection. Atrial fibrillation, a class effect of BTK inhibitors, may be less common with pirtobrutinib. Relevance to patient care and clinical practice in comparison with existing drugs: Compared with earlier-generation BTK inhibitors, pirtobrutinib is more selective for BTK and binds noncovalently to the receptor. Ongoing studies are evaluating pirtobrutinib's use in multiple B-cell malignancies and comparing it with other BTK inhibitors. Conclusion: The characteristics of pirtobrutinib render it useful in the treatment of B-cell malignancies no longer responding to a previous BTK inhibitor, and results from ongoing clinical trials may support future expanded use. [ABSTRACT FROM AUTHOR]

Introduction: In the era of chemo-immunotherapy, high-risk factors unequivocally predicted inferior outcomes for patients with CLL. The widespread adoption of BTK inhibitors has challenged the practical implications of such testing, as many patients have improved outcomes despite the presence of high-risk features. The impact of adverse prognostic factors, such as unmutated IGHV, on survival has been ameliorated by continuous treatment with BTK inhibitors, but not by finite-duration therapy with venetoclax-based combinations. Furthermore, TP53 abnormalities continue to be associated with worse outcomes in the era of novel agents. New treatment modalities, such as pirtobrutinib, lisocabtagene maraleucel, and ongoing studies combining BTK inhibitors with venetoclax, raise new questions on the significance of prognostic factors of survival for patients with CLL. Areas covered: Herein, we summarized the available literature on patients with CLL harboring high-risk biomarkers, with a focus on data from key clinical trials. Expert opinion: Testing for prognostic biomarkers will remain relevant to identify patients who may have increased benefit from novel therapeutic strategies, such as combination therapies and novel agents. Patients with high-risk disease should be encouraged to participate in clinical trials. [ABSTRACT FROM AUTHOR]

Ibrutinib, a highly effective inhibitor of the Bruton tyrosine kinase, has significantly transformed the therapeutic approach in chronic lymphocytic leukemia (CLL). Despite these advancements, the disease continues to be characterized by immune dysfunction and increased susceptibility to infections, with mortality rates from infections showing no significant improvement over the past few decades. Therefore, timely prevention, recognition, and treatment of infections remains an important aspect of the standard management of a patient with CLL. A panel of hematologists with expertise in CLL met to discuss existing literature and clinical insights for the management of infectious in CLL undergoing ibrutinib treatment. Despite not being a fully comprehensive review on the topic, this work provides a set of practical recommendations that can serve as a guide to healthcare professionals who manage these patients in their daily clinical practice. [ABSTRACT FROM AUTHOR]

Summary Acalabrutinib is a selective, second‐generation Bruton tyrosine kinase inhibitor. In this open‐label, parallel‐group study, patients with relapsed/refractory (R/R) follicular lymphoma (FL) were randomised to either acalabrutinib monotherapy or acalabrutinib plus rituximab. An additional cohort of patients with treatment‐naive (TN) FL received only the acalabrutinib‐rituximab combination. Acalabrutinib‐rituximab was well tolerated and active in R/R and TN FL; in the TN cohort the overall response rate was 92.3% with most remissions lasting over 4 years. Acalabrutinib monotherapy was also well tolerated and active in R/R FL. These results support further study of acalabrutinib alone and in combination with rituximab in FL. [ABSTRACT FROM AUTHOR]

This document is a letter to the editor published in the journal Leukemia & Lymphoma. The letter discusses the results of a phase 1 trial that tested the combination of abexinostat and ibrutinib in patients with relapsed/refractory mantle cell lymphoma (MCL) and non-germinal center diffuse large B cell lymphoma (DLBCL). The trial aimed to determine the maximum tolerated dose of the combination therapy and assess its safety and efficacy. The results showed that the combination had favorable activity in the MCL group, with an overall response rate of 86% and complete response observed in 71%. However, there was no appreciable activity in the non-GCB DLBCL group. The authors suggest that further studies with a larger sample size are warranted to confirm these findings. The document also suggests that future studies should explore alternative dosing schedules and second-generation BTK inhibitors. [Extracted from the article]

Summary Covalent Bruton's tyrosine kinase‐inhibitors (cBTK‐i) are highly active in MYD88‐mutated (MYD88Mut) Waldenstrom's macroglobulinaemia and suppress nuclear factor kappa‐light‐chain‐enhancer of activated B cells and extracellular signal‐regulated kinases‐1/2 (ERK1/2)‐related signalling. BTKCys481 mutations are associated with cBTK‐i acquired resistance and are accompanied by reactivation of ERK1/2 that promotes inflammatory cytokine secretion and paracrine‐mediated resistance of BTK wild‐type (BTKWT) tumour cells. Pirtobrutinib is a non‐covalent BTK‐inhibitor that binds at non‐BTKCys481 sites. We show that pirtobrutinib blocked p‐ERK1/2, ERK1/2‐driven inflammatory cytokines, and overcame paracrine‐mediated resistance in MYD88Mut lymphoma cells expressing mutated BTKCys481. Our results provide important mechanistic insights for the activity of pirtobrutinib in MYD88Mut lymphomas carrying BTKCys481 mutations. [ABSTRACT FROM AUTHOR]

Background: Bruton's tyrosine kinase inhibitors (BTKi) and the B‐cell lymphoma 2 (BCL2) inhibitor venetoclax have significantly improved outcomes and achieved durable remission in patients with chronic lymphocytic leukemia (CLL). BTKi/venetoclax‐treated patients with exposure to both novel agents (regardless of the reason for discontinuation) are classified as "double‐exposed," and often have poor prognoses. This study aims to assess the efficacy and effectiveness of treatments in double‐exposed CLL patients. Methods: PubMed, Embase, and Web of Science databases were searched until December 2023. Results: We retrieved 3948 articles for screening and included 13 publications covering nine distinct studies. Three clinical trials reported a median PFS of 16.8 months with pirtobrutinib, 13 months with lisocabtagene maraleucel, and 10.1 months with nemtabrutnib. ORR ranged from 58% with nemtabrutinib and 80% with lisocabtagene maraleucel. In observational studies, PFS ranged from 3 months with chemoimmunotherapy to 12 months with BTKi, and ORR ranged from 31.8% with chemoimmunotherapy to 85.7% with chimeric antigen receptors (CAR) T‐cell therapy. Conclusion: This study highlights the limited clinical data on efficacy outcomes for double‐exposed CLL/SLL patients. Pirtobrutinib, lisocabtagene maraleucel, and a combination of ibrutinib and venetoclax have shown promising effects. However, the scarcity of treatment options and efficacy data for patients who have failed BTKi and venetoclax underscores a significant unmet medical need. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental Approach Key Results Conclusion and Implications Bifunctional small molecule degraders, which link the target protein with E3 ubiquitin ligase, could lead to the efficient degradation of the target protein. BGB‐16673 is a Bruton's tyrosine kinase (BTK) degrader. A translational PK/PD modelling approach was used to predict the human BTK degradation of BGB‐16673 from preclinical in vitro and in vivo data.A simplified mechanistic PK/PD model was used to establish the correlation between the in vitro and in vivo BTK degradation by BGB‐16673 in a mouse model. Human and mouse species differences were compared using the parameters generated from in vitro human or mouse blood, and human or mouse serum spiked TMD‐8 cells. Human PD was then predicted using the simplified mechanistic PK/PD model.BGB‐16673 showed potent BTK degradation in mouse whole blood, human whole blood, and TMD‐8 tumour cells in vitro. Furthermore, BGB‐16673 showed BTK degradation in a murine TMD‐8 xenograft model in vivo. The PK/PD model predicted human PD and the observed BTK degradation in clinical studies both showed robust BTK degradation in blood and tumour at clinical dose range.The presented simplified mechanistic model with reduced number of model parameters is practically easier to be applied to research projects compared with the full mechanistic model. It can be used as a tool to better understand the PK/PD behaviour for targeted protein degraders and increase the confidence when moving to the clinical stage. [ABSTRACT FROM AUTHOR]

Background: X-linked agammaglobulinemia (XLA), also referred to as Bruton's tyrosine kinase deficiency, is a rare genetic disorder that affects the immune system. We conducted genetic analysis on patients suffering from immunodeficiency by utilizing Next-Generation Sequencing techniques, as well as their closest relatives, to facilitate accurate diagnosis, offer genetic counseling services, and enhance our comprehension of XLA. [ABSTRACT FROM AUTHOR]

Bruton tyrosine kinase inhibitor (BTKi) combined with rituximab-based chemotherapy benefits diffuse large B-cell lymphoma (DLBCL) patients. However, drug resistance is the major cause of relapse and death of DLBCL. In this study, we conducted a comprehensive analysis BTKi-resistance related genes (BRRGs) and established a 10-gene (CARD16, TRIP13, PSRC1, CASP1, PLBD1, CARD6, CAPG, CACNA1A, CDH15, and NDUFA4) signature for early identifying high-risk DLBCL patients. The resistance scores based on the BRRGs signature were associated with prognosis. Furthermore, we developed a nomogram incorporating the BRRGs signature, which demonstrated excellent performance in predicting the prognosis of DLBCL patients. Notably, tumor immune microenvironment, biological pathways, and chemotherapy sensitivity were different between high- and low-resistance score groups. Additionally, we identified TRIP13 as a key gene in our model. TRIP13 was found to be overexpressed in DLBCL and BTKi-resistant DLBCL cell lines, knocking down TRIP13 suppresses cell proliferation, promotes cell apoptosis, and enhances the apoptosis effect of BTKi on DLBCL cells by regulating the Wnt/β-catenin pathway. In conclusion, our study presents a novel BRRGs signature that could serve as a promising prognostic marker in DLBCL, and TRIP13 might be a potential therapeutic target for resistant DLBCL. [ABSTRACT FROM AUTHOR]

This article summarizes a randomized trial that evaluated the effectiveness of a combination therapy for relapsed diffuse large B-cell lymphoma (DLBCL) prior to stem cell transplant. The trial compared the response rates and outcomes of patients who received the combination therapy with those who received chemotherapy alone. The results showed that the response rate was higher in the chemotherapy group, leading to the discontinuation of the combination therapy. The study also analyzed the genetic subtypes of DLBCL and found that certain patients responded better to the combination therapy. The article emphasizes the need for biomarker-driven trials and comprehensive studies in therapeutic trials for DLBCL. The trial was supported by funding from various organizations. [Extracted from the article]

Background: Glioblastoma is a highly malignant disease with limited treatment options. Ibrutinib, a covalent Bruton tyrosine kinase inhibitor, is an oral agent with manageable side effects used for hematological diseases including Waldenström macroglobulinemia. We present the case of a 69-year-old Caucasian male patient treated with ibrutinib for suspected Bing–Neel syndrome (BNS), which following a biopsy, was reclassified as glioblastoma. Case presentation: In December 2018, a 69-year-old Caucasian male patient was diagnosed with Waldenström macroglobulinemia. As the patient was asymptomatic, without bone marrow failure or high M-component count, watchful waiting was initiated. Due to increasing neurological symptoms, the patient, based on magnetic resonance imaging, was diagnosed with Bing–Neel syndrome in May 2019. The patient received different treatments before starting ibrutinib monotherapy in August 2019 due to disease progression, both on magnetic resonance imaging and clinically. The patient remained clinically stable for 7 months. In March 2020, the patient developed headaches, and both magnetic resonance imaging and a biopsy revealed glioblastoma IDH-wildtype. Treatment was changed in line with the new diagnosis, but the patient died at the end of 2020. Conclusion: We present a case in which a patient with glioblastoma IDH-wildtype remained clinically stable for 7 months when treated with ibrutinib monotherapy, which is similar to what would be expected for the standard treatment for glioblastoma. To our knowledge, this is the first patient receiving ibrutinib for a glioblastoma IDH-wildtype with a meaningful clinical outcome. Our case may therefore support previous nonclinical findings, indicating a therapeutic value of ibrutinib in patients with glioblastoma and support for further investigation of ibrutinib as a possible treatment for glioblastoma. [ABSTRACT FROM AUTHOR]

Introduction: Bruton's tyrosine kinase (BTK) and interleukin (IL)-2 Inducible Tcell Kinase (ITK) inhibitors have anti-inflammatory properties. We investigated the therapeutic effect of ibrutinib, an orally bioavailable BTK/ITK inhibitor, in a mouse model of Graves' orbitopathy (GO). Methods: Genetic immunization was performed through intramuscular administration of the recombinant plasmid, pCMV6-hTSHR cDNA, to 8-weekold female BALB/c mice. Serum levels of T3, T4, and thyroid-stimulating hormone receptor (TSHR) antibodies (TRAbs) were quantified using enzymelinked immunosorbent assay. Histopathological changes in orbital tissues were examined using immunohistochemistry (IHC) staining for TSHR and various inflammatory markers. Following successful genetic immunization, ibrutinib was orally administered daily for 2 weeks in the GO model mice. After treatment, the mRNA and protein expression levels of BTK, ITK, IL-1b, and IL-6 in orbital tissues were evaluated using real-time PCR and Western blotting. Results: In total, 20 mice were sacrificed to confirm successful genetic immunization. The GO mouse group exhibited significantly increased serum T3, T4, and TRAb levels. IHC revealed increased expression of TSHR, IL-1b, IL-6, transforming growth factor-b1, interferon-g, CD40, CD4, BTK, and ITK in the GO mouse model. The orbital inflammation was significantly attenuated in ibrutinibtreated mice. The mRNA and protein expression levels of BTK, ITK, IL-1b, and IL-6 in orbital tissue were lower in ibrutinib-treated GO mouse group compared to the phosphate-buffered saline-treated GO mouse group. Conclusion: The GO mouse model demonstrated enhanced BTK and ITK expression. Ibrutinib, a BTK/ITK inhibitor, suppressed the inflammatory cytokine production. These findings highlight the potential involvement of BTK/ITK in the inflammatory pathogenesis of GO, suggesting its role as a novel therapeutic target. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia among adults in Western countries. Despite the introduction of targeted therapies, including first-line Bruton's tyrosine kinase inhibitor (BTKi) treatment, CLL remains largely incurable. Frequent disease relapses occur due to remaining treatment-resistant CLL cells, calling for novel therapies to eliminate minimal residual disease (MRD). Peptide-based vaccination targeting human leucocyte antigen (HLA)-presented CLL-associated antigens represents a promising, low-side-effect therapeutic option to optimize treatment responses and eliminate residual tumor cells by inducing an anti-leukemic immune response. The iVACXS15-CLL01 trial is an open-label, first-in-human (FIH) Phase I trial, evaluating the CLL-VAC-XS15 vaccine in CLL patients undergoing BTKi-based therapy. The vaccine was developed from HLA-presented CLL-associated antigen peptides, identified through comparative mass-spectrometry-based immunopeptidome analyses of CLL versus healthy samples in a previous study. To facilitate rapid and cost-effective deployment, vaccine peptides are selected for each patient from a pre-manufactured "peptide warehouse" based on the patient's individual HLA allotype and CLL immunopeptidome. The trial enrolls 20 CLL patients, who receive up to three doses of the vaccine, adjuvanted with the toll-like-receptor (TLR) 1/2 ligand XS15 and emulsified in Montanide ISA 51 VG. The primary objective of the iVAC-XS15-CLL01 trial is to assess the safety and immunogenicity of the CLL-VAC-XS15 vaccine. Secondary objectives are to Frontiers in evaluate the vaccine impact on MRD, progression-free survival, and overall survival, as well as comprehensive immunophenotyping to characterize vaccine-induced T-cell responses. This Phase I trial aims to advance CLL treatment by enhancing immune-mediated disease clearance and guiding the design of subsequent Phase II/III trials to implement a new therapeutic strategy for CLL patients. [ABSTRACT FROM AUTHOR]

This document provides a summary of various studies and trials related to multiple sclerosis (MS). The studies investigate different aspects of MS, including the association between changes in serum glial fibrillary acidic protein (sGFAP) and neurofilament light chain (sNfL) levels with long-term progression independent of relapse activity (PIRA) risk, the relationship between depression and disease activity and disability worsening in individuals with MS, the immune response to the Epstein-Barr virus (EBV) in MS patients, and the effectiveness of simvastatin in slowing disability progression in secondary progressive MS. The document also discusses ongoing trials evaluating the efficacy and safety of tolebrutinib in participants with relapsing MS and non-relapsing secondary progressive MS. The results of these studies and trials will contribute to a better understanding of MS and potential treatment options. [Extracted from the article]

Introduction: Primary central nervous system lymphoma (PCNSL) is a rare subtype of aggressive extranodal non-Hodgkin lymphoma. Currently, there is no standard of care for the treatment of refractory or relapsed PCNSL (r/r PCNSL). We conducted a prospective single-arm phase II study to evaluate zanubrutinib plus cytarabine for r/r PCNSL. Methods: Using Simon's two-stage design, we analyzed 34 patients who received high-dose cytarabine (3.0 g/m2 once daily) for 2 days and zanubrutinib (160 mg twice daily) for 21 days each cycle for up to 6 cycles. The study was registered at www.chictr.org.cn as #ChiCTR2000039229. Results: The median follow-up was 19 months. The overall response rate was 64.7% (95% confidence interval [CI], 47.9–78.5%) with a complete remission or unconfirmed complete remission rate of 47.1% (16/34) and a partial remission rate of 17.6% (6/34). The median progression-free survival was 4.5 months (95% CI, 1.5–9.4), and the median OS was 18 months (95% CI, 9.5 to not estimable). The median duration of the response was 9 months (95% CI, 3.2 to not estimable). The most common treatment-emergent adverse events were thrombocytopenia (55.9%). No treatment-related death occurred. Conclusion: Zanubrutinib and cytarabine showed efficacy in r/r PCNSL with an acceptable safety profile. [ABSTRACT FROM AUTHOR]

Introduction: Targeting the B-cell receptor pathway via ibrutinib, a specific inhibitor of Bruton's tyrosine kinase, has shown marked clinical efficacy in treatment of patients with chronic lymphocytic leukemia (CLL), thus becoming a preferred first line option independent of risk factors. However, acquired resistance to ibrutinib poses a major clinical problem and requires the development of novel treatment combinations to increase efficacy and counteract resistance development and clinical relapse rates. Case Presentation: In this study, we performed exome and transcriptome analyses of an ibrutinib resistant CLL patient in order to investigate genes and expression patterns associated with ibrutinib resistance. Here, we provide evidence that ibrutinib resistance can be attributed to aberrant mammalian target of rapamycin (MTOR) signaling. Conclusion: Thus, our study proposes that combined use of MTOR inhibitors with ibrutinib could be a possible option to overcome therapy resistance in ibrutinib treated patients. [ABSTRACT FROM AUTHOR]

AIM: To investigate the impact of Bruton tyrosine kinase (BTK) on Alzheimer disease (AD)-like pathology through the NIMA (never in mitosis gene A)-related kinase 7 (NEK7)-nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) pathway. METHODS: 5xFAD and wild-type (WT) mice aged 2, 4 and 6 months were utilized to assess the expression of BTK, NEK7 and NLRP3 proteins in the hippocampus and cortex via Western blot and immunofluorescence. Co-immunofluorescence was conducted to identify the interaction between NEK7 and NLRP3 in the brains of 4-month-old mice. Three-month-old mice were divided into a control group and an ibrutinib treatment group, receiving intraperitoneal injections of ibrutinib (10 mg/kg) or solvent for 14 d, and were then subjected to behavioral assessments including learning and memory tests using the Morris water maze and Y-maze. Wild-type mice were induced with an AD model by intracerebroventricular injection of Aβ42. Morris water maze tests were performed after 14 d to evaluate learning and memory, followed by measurement of BTK protein levels in the brain via Western blot. BV2 microglial cells were treated with ibrutinib, followed by LPS or Aβ42 stimulation. Western blot analysis was conducted to measure the protein levels of NEK7, NLRP3, BTK and p-BTK (Y223), while immunofluorescence was used to assess the protein expression of ASC, caspase-1, NEK7 and NLRP3. RESULTS: The levels of BTK, NEK7 and NLRP3 in the brains of 5XFAD mice were significantly elevated compared to WT mice, with observed interaction between NEK7 and NLRP3 in the 5xFAD mouse brains. Ibrutinib treatment significantly improved learning and memory functions in mice compared to the AD group. In BV2 cells, pre-treatment with ibrutinib effectively suppressed the NLRP3 inflammasome pathway and NEK7 proteins in response to Aβ42 stimulation. CONCLUSION: BTK plays a regulatory role in AD-like pathology through the NEK7-NLRP3 pathway both in vivo and in vitro. [ABSTRACT FROM AUTHOR]

Obesity is associated with metabolic inflammation, which can contribute to insulin resistance, higher blood glucose, and higher insulin indicative of prediabetes progression. The nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a metabolic danger sensor implicated in metabolic inflammation. Many features of metabolic disease can activate the NLRP3 inflammasome; however, it is not yet clear which upstream triggers to target, and there are no clinically approved NLRP3 inflammasome inhibitors for metabolic disease. Bruton's tyrosine kinase (BTK) mediates activation of the NLRP3 inflammasome. Ibrutinib is the most-studied pharmacological inhibitor of BTK, and it can improve blood glucose control in obese mice. However, inhibitors of tyrosine kinases are permissive, and it is unknown if BTK inhibitors require BTK to alter endocrine control of metabolism or metabolic inflammation. We tested whether ibrutinib and acalabrutinib, a new generation BTK inhibitor with higher selectivity, require BTK to inhibit the NLRP3 inflammasome, metabolic inflammation, and blood glucose in obese mice. Chronic ibrutinib administration lowered fasting blood glucose and improved glycemia, whereas acalabrutinib increased fasting insulin levels and increased markers of insulin resistance in high-fat diet-fed CBA/J mice with intact Btk. These metabolic effects of BTK inhibitors were absent in CBA/CaHN-Btkxid/J mice with mutant Btk. However, ibrutinib and acalabrutinib reduced NF-κB activity, proinflammatory gene expression, and NLRP3 inflammasome activation in macrophages with and without functional BTK. These data highlight that the BTK inhibitors can have divergent effects on metabolism and separate effects on metabolic inflammation that can occur independently of actions on BTK. NEW & NOTEWORTHY: Bruton's tyrosine kinase (BTK) is involved in immune function. It was thought that BTK inhibitors improve characteristics of obesity-related metabolic disease by lowering metabolic inflammation. However, tyrosine kinase inhibitors are permissive, and it was not known if different BTK inhibitors alter host metabolism or immunity through actions on BTK. We found that two BTK inhibitors had divergent effects on blood glucose and insulin via BTK, but inhibition of metabolic inflammation occurred independently of BTK in obese mice. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukemia (CLL) is a B-cell-derived hematologic malignancy whose progression depends on active B-cell receptor (BCR) signaling. Despite the spectacular efficacy of Ibrutinib, an irreversible inhibitor of Bruton tyrosine kinase (BTK), resistance can develop in CLL patients, and alternative therapeutic strategies are therefore required. Cancer immunotherapy has revolutionized cancer care and may be an attractive approach in this context. We speculated that characterizing the immune responses of CLL patients may highlight putative immunotherapeutic targets. Here, we used high-dimensional spectral flow cytometry to compare the distribution and phenotype of non-B-cell immune populations in the circulating blood of CLL patients treated with Ibrutinib displaying a complete response or secondary progression. Although no drastic changes were observed in the composition of their immune subsets, the Ibrutinib-resistant group showed increased cycling of CD8+ T cells, leading to their overabundance at the expense of dendritic cells. In addition, the expression of 11 different surface checkpoints was similar regardless of response status. Together, this suggests that CLL relapse upon Ibrutinib treatment may not lead to major alterations in the peripheral immune response. [ABSTRACT FROM AUTHOR]

Chronic spontaneous urticaria (CSU) is a debilitating, inflammatory skin condition characterized by infiltrating immune cells. Available treatments are limited to improving the signs and symptoms. There is an unmet need to develop therapies that target disease‐driving pathways upstream of mast cell activation to inhibit or delay the progression of CSU and associated comorbidities. Here, we aim to define disease modification due to a treatment intervention and criteria that disease‐modifying treatments (DMTs) must meet in CSU. We have defined disease modification in CSU as a favorable treatment‐induced change in the underlying pathophysiology and, therefore, the disease course, which is clinically beneficial and enduring. A DMT must fulfil the following criteria: (1) prevents or delays the progression of CSU, (2) induces long‐term, therapy‐free clinical remission, which is the sustained absence of CSU signs and symptoms without the need for treatment, and (3) affects the underlying mechanism of CSU, as demonstrated by an effect on disease‐driving signals and/or a biomarker. DMTs in CSU should slow disease progression, achieve long‐lasting disease remission, target disease‐driving mechanisms, reduce mast cell‐activating IgE autoantibodies, target cytokine profile polarization, and normalize the gut microbiome and barrier. Treating CSU at the immune system level could provide valuable alternatives to pharmacotherapy in CSU management. Specific DMTs in CSU are yet to be developed, but some show potential benefits, such as inhibitors of Bruton's Tyrosine Kinase, IL‐4 and IL‐13. Future therapies could prevent CSU signs and symptoms, achieve long‐term clinical benefits after discontinuing treatment, and prevent associated concomitant disorders. [ABSTRACT FROM AUTHOR]

Aims: Bruton's tyrosine kinase inhibitors (BTKIs), including first‐generation ibrutinib, second‐generation acalabrutinib and zanubrutinib, may be involved in the mechanisms of action related to adverse events (AEs) of the cardiovascular system. We aimed to characterize the cardiovascular AEs of BTKIs reported in the US Food and Drug Administration (FDA) Adverse Event Reporting System, and to compare the cardiovascular risks of BTKIs. Methods: Across all indications of three FDA‐approved BTKIs, primary suspect drugs were extracted over two periods: from January 2013 to December 2022 (after the approval of the first BTKI), and from January 2020 to December 2022 (all three BTKIs on the market). Disproportionality was measured by reporting odds ratios (RORs) and information components. Additional analyses were performed without incorporating patients with underlying cardiovascular disease (CVD). Results: A total of 10 353 cases included the uses of ibrutinib, acalabrutinib and zanubrutinib. Ibrutinib was significantly associated with 47 cardiovascular AEs. Acalabrutinib was associated with new signals, including cardiac failure (ROR = 1.82 [1.13‐2.93]), pulmonary oedema (ROR = 2.15 [1.19‐3.88]), ventricular extrasystoles (ROR = 5.18 [2.15‐12.44]), heart rate irregular (ROR = 3.05 [1.53‐6.11]), angina pectoris (ROR = 3.18 [1.71‐5.91]) and cardiotoxicity (ROR = 25.22 [17.14‐37.10]). In addition, cardiovascular events had an earlier onset in acalabrutinib users. Zanubrutinib was only associated with atrial fibrillation. Acalabrutinib and zanubrutinib had lower ROR values than ibrutinib. The AE signals were generally consistent between the population receiving and not receiving CVD medications. Conclusions: Potential cardiovascular risks identified in this study were not clearly noted on the label of marketed acalabrutinib. Caution should be paid to the cardiovascular risks of BTKIs having been or being developed. [ABSTRACT FROM AUTHOR]

Our study aimed to assess the influence of incorporating new oral anticoagulant (NOAC) therapy on clinical outcomes among patients who underwent endovascular intervention for below-the-knee (BTK) occlusions necessitating reintervention. The inclusion criteria encompassed patients with chronic limb-threatening ischemia (CLTI) and had undergone a successful endovascular intervention for BTK artery occlusion, necessitating reintervention. Patients who underwent endovascular interventions for BTK reocclusion were compared to those who received dual-pathway inhibition with NOAC (rivaroxaban 2.5 mg 2 × 1) and clopidogrel (NOAC group), or dual-antiplatelet therapy with clopidogrel and aspirin (DAPT group). The primary endpoints were target vessel reocclusion and target lesion revascularization (TLR) at the 1-year follow-up, while major and minor amputations served as the secondary endpoint. Additionally, a one-year comparison was conducted between the two groups for major bleeding events. 64 patients in our clinic treated with endovascular reintervention (NOAC = 28, DAPT = 34). The TLR rate is 10.7% in NOAC group (N = 3) and 32.4% in DAPT group (N = 11, p = 0.043). The target vessel reocclusion rate is 17.8% in NOAC group (N = 5) and 41.2% in DAPT group (N = 14, p = 0.048). Minor or major amputation rate at 1-year follow-up was 3.6% in NOAC group (N = 1) and 11.7% in DAPT group (N = 4, p = 0.245). The patency rate is significantly higher, and the TLR rate is significantly lower in the NOAC group compared to the DAPT group, with no significant difference in major bleeding between the two groups. Although no statistically significant difference exists in amputation rates, a numerical distinction is evident. [ABSTRACT FROM AUTHOR]

• The update covers the approval of time-limited ibrutinib–venetoclax in first line and new data on MRD-driven treatment. • It also covers the approval of the BTKi zanubrutinib in both treatment-naive and relapsed or refractory CLL. • Additional evidence on the time-limited combination of venetoclax plus an anti-CD20 antibody in the first line are included. • Options for later-line treatments based on the type of prior lines of treatment are also included. • Recommendations are based on available scientific data and the authors' collective expert opinion. [ABSTRACT FROM AUTHOR]

Activation of Bruton's tyrosine kinase (BTK) has been shown to play a crucial role in the proinflammatory response of B cells and myeloid cells upon engagement with B cell, Fc, Toll‐like receptor, and distinct chemokine receptors. Previous reports suggest BTK actively contributes to the pathogenesis of multiple sclerosis (MS). The BTK inhibitor Evobrutinib has been shown to reduce the numbers of gadolinium‐enhancing lesions and relapses in relapsing–remitting MS patients. In vitro, BTK inhibition resulted in reduced phagocytic activity and modulated BTK‐dependent inflammatory signaling of microglia and macrophages. Here, we investigated the protein expression of BTK and CD68 as well as iron accumulation in postmortem control (n = 10) and MS (n = 23) brain tissue, focusing on microglia and macrophages. MS cases encompassed active, chronic active, and inactive lesions. BTK+ and iron+ cells positively correlated across all regions of interests and, along with CD68, revealed highest numbers in the center of active and at the rim of chronic active lesions. We then studied the effect of BTK inhibition in the human immortalized microglia‐like HMC3 cell line in vitro. In particular, we loaded HMC3 cells with iron‐dextran and subsequently administered the BTK inhibitor Evobrutinib. Iron treatment alone induced a proinflammatory phenotype and increased the expression of iron importers as well as the intracellular iron storage protein ferritin light chain (FTL). BTK inhibition of iron‐laden cells dampened the expression of microglia‐related inflammatory genes as well as iron‐importers, whereas the iron‐exporter ferroportin was upregulated. Our data suggest that BTK inhibition not only dampens the proinflammatory response but also reduces iron import and storage in activated microglia and macrophages with possible implications on microglial iron accumulation in chronic active lesions in MS. [ABSTRACT FROM AUTHOR]

Introduction: Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), characterized by its monoclonal lymphoproliferative nature, is an indolent but incurable malignancy. The treatment landscape of CLL/SLL has drastically transformed in the last decade since the introduction of targeted therapy and immune-effector T-cell therapy. The paradigm shift from chemoimmunotherapy to targeted and cellular therapies was largely driven by improved efficacy and safety. With the success of targeted therapies, novel agents and combinations are rapidly emerging on the horizon. Areas Covered: In this review, we will summarize clinical evidence supporting current and emerging therapies with emphasis on investigational therapies and novel combinations of commercial agents. Clinical trials were identified via clinicaltrials.gov, and a PubMed literature search was last performed in June 2024. Expert Opinion: With the availability of more effective and better-tolerated treatments for CLL/SLL, the role of early intervention should be further investigated due to its potential to alter disease course, delay progression, and improve overall survival rates. With many highly effective agents and combinations expected to become commercially available, attention to safety profiles and careful selection of patients for each treatment will be critical, with consideration of comorbidities, logistical issues, and financial burden of treatment. [ABSTRACT FROM AUTHOR]

Bruton's tyrosine kinase (BTK) inhibitors are important therapeutic advances with promising efficacy outcomes in the treatment of patients with chronic lymphocytic leukemia and other B‐cell lymphoma subtypes. However, the utility of BTK inhibitors can be limited by adverse events such as infections. In this systematic review and meta‐analysis, we aim to determine the risk of various infections associated with BTK inhibitor monotherapy in B‐cell lymphoma patients. A comprehensive search was conducted in MEDLINE/PubMed, Embase, and Web of Science databases from their inception until October 2023. ClinicalTrials.gov, bibliographies, and relevant conference abstracts were also searched for additional records. Randomized controlled trials that included any B‐cell lymphoma patients treated with BTK inhibitor monotherapy and reported infection were included. Meta‐analysis was performed to calculate risk ratio (RR) using a random‐effects model in R Statistical Software, version 4.3.2. Of 3292 studies retrieved, we included 12 studies in this systematic review and meta‐analysis. The median age of patients across the study arms ranged between 64 and 73 years. The overall pooled RR for any grade upper respiratory tract infections (URTI) associated with BTK inhibitor treatment was 1.55 (95% Confidence Interval (CI) 1.22–1.97). The RR of grade ≥3 URTI was reported in 14 out of 1046 patients, yielding an RR of 1.46 (95% CI 0.61–3.54), which was not statistically significant. The pooled RR of any grade pneumonia was 1.20 (95% CI 0.68–2.10) and grade ≥3 pneumonia was 1.12 (95% CI 0.67–1.85), both of which were not statistically significant. Patients with B‐cell lymphoma who are undergoing BTK inhibitor monotherapy face an elevated risk of developing URTI. Clinicians prescribing BTK inhibitors should be aware of the potential infectious events that may occur. Close monitoring and the implementation of effective prophylactic measures are essential for managing these patients. [ABSTRACT FROM AUTHOR]

The article discusses the use of ibrutinib therapy in the treatment of chronic lymphocytic leukemia (CLL). It highlights the shift from chemo-immunotherapy to targeted therapy, specifically Bruton's tyrosine kinase (BTK) inhibitors like ibrutinib. The article emphasizes the long-term outcomes and benefits of ibrutinib, particularly for patients with TP53 mutations. It also addresses concerns about the safety profile of ibrutinib, including cardiovascular events. The article presents real-world studies that demonstrate improvements in the management of adverse events and retention rates with ibrutinib. It suggests that dose reduction of ibrutinib can optimize treatment outcomes without compromising efficacy. The article concludes by emphasizing the need for a personalized and patient-centered approach to CLL treatment, integrating real-world insights, proactive management strategies, and patient-reported outcomes. [Extracted from the article]

This document provides information on the use of Bruton tyrosine kinase inhibitors (BTKi) for patients with chronic lymphocytic leukemia (CLL) and severe renal dysfunction. The study, conducted on US veterans, found that BTKi can be a viable treatment option for CLL patients with significant renal impairment, including those on hemodialysis. The study also suggests that reducing the dose of BTKi may improve tolerability without compromising effectiveness. However, it is important to exercise caution when applying these findings to newer BTK inhibitors and subsequent treatment options. Further research is needed to fully understand the effects of BTKi in patients with severe renal dysfunction. [Extracted from the article]

In recent years, as more and more lung-cancer patients have been treated with immunotherapeutic agents, their survival has been prolonged compared to before. It is well known that BTK (Bruton's tyrosine kinase) is predominantly found in cells of the hematopoietic system. However, there is a distinct lack of literature on BTK expression in lung adenocarcinoma (LUAD) patients and its effect on the immune microenvironment. Consequently, the main goal of this investigation was to analyze how BTK expression in lung adenocarcinoma affects its progression, along with its prognostic significance, through the utilization of bioinformatics online resources and publicly available databases. Data on the sequencing results and clinical records of lung adenocarcinoma patients were gathered from The Cancer Genome Atlas (TCGA) database. Based on the expression level of BKT, TCGA categorized lung adenocarcinoma patients into BTK high-expression and low-expression groups. We investigated the effects of BKT on clinicopathologic, genomic, and immunologic characteristics of lung adenocarcinoma patients. We analyzed BTK mRNA expression in tumors and normal tissues using two key resources: Tumor Immuno Estimation Resource 2.0 (TIMER 2.0) and Gene Expression Profiling Interactive Analysis 2 (GEPIA 2). We analyzed the prognosis of the patients using GEPIA2 and validated the results using univariate and multivariate analyses. In addition, we assessed BTK protein expression by Human Protein Atlas (HPA). We sought to elucidate the clinical prognostic significance of BTK in The TCGA using the online tool GEPIA 2. Furthermore, to clarify the biologic roles and pathways linked to BTK, we conducted a genomic enrichment analysis of the information. To predict the proportion of various immune cell infiltrations in the immune microenvironment of lung adenocarcinoma patients diagnosed in the TCGA database, we performed an analysis using the TIMER online tool. Using TIMER and CIBERSORT, the correlation between genes co-expressed with BTK and the corresponding tumor-infiltrating immune cells was explored; finally, the relationship between BTK expression and immune infiltration and immune checkpoints in the TMB group and the high and low groups was analyzed by R language analysis using the TCGA database. The expression of BTK provides some hints about the prognosis of the patients. The high expression of BTK is involved in immune response regulation signaling pathways, leukocyte-mediated immunity, leukocyte intercellular adhesion, graft rejection, and complement. Analysis of the GEPIA 2 database showed that BTK was co-expressed with the genes FGD2, SASH3, NCKAP1L, CD53, ARHGAP30 and LPXN. Increased expression of the above-mentioned genes resulted in increased proportions of CD8 + T cells, memory CD4 + T cells, B cells, macrophages, and dendritic cells, and decreased proportions of Treg cells and TH2 cells. In addition, our study revealed a strong positive correlation between various key immune checkpoints (e.g., PDCD1, CD274, PDCD1LG2, CTLA4, HAVCR2, LAG3, TIGIT, and SIGLEC15) and BTK expression. In conclusion, increased BTK expression in lung adenocarcinoma is closely associated with prolonged survival of lung-cancer patients. Moreover, the genes classified under the BTK high-expression group exhibit significant enrichment in immune-related pathways, suggesting a potential impact on the tumor microenvironment. We investigated the potential of BTK as a tumor suppressor gene in predicting prolonged patient survival. In addition, we further investigated the possibility that BTK further affects the immunotherapeutic response of patients by influencing the microenvironment of tumor immune infiltration, but the relevant mechanisms remain to be further studied. [ABSTRACT FROM AUTHOR]

Introduction: We describe a unique case of sclerouveitis that progressed to endogenous Fusarium endophthalmitis in a 69‐year‐old male with chronic lymphocytic leukemia (CLL). We highlight the risk of treating sclerouveitis with oral corticosteroids, which can exacerbate an infection and contribute to disease progression. Case Presentation: A 69‐year‐old male with CLL on zanubrutinib, a second‐generation Bruton's tyrosine kinase inhibitor, was admitted to the hospital for osteomyelitis of the left foot. At presentation, the patient also reported right eye pain for 1 week and vision loss over the course of 1 month. Vision in the right eye was hand motion. Slit lamp examination revealed scleral inflammation in the right eye with violaceous injection, chemosis, inflammation in the anterior chamber, and diffuse subconjunctival hemorrhage. There was significant corneal edema preventing fundus examination. B‐scan ultrasonography demonstrated a flat retina with no vitritis or scleral thickening. Forty‐eight hours after treatment with oral and topical corticosteroids, the patient's eye pain improved but his vision worsened. Repeat B‐scan showed new‐onset vitritis. Fungal culture obtained by diagnostic pars plana vitrectomy (PPV) revealed growth of Fusarium. The patient was treated with oral and intravitreal voriconazole in addition to intravenous voriconazole and amphotericin B for systemic therapy. Corticosteroids were discontinued. Despite aggressive therapy, the patient's disposition declined to the point of transitioning to comfort‐focused care, and he passed away. Conclusion: Endogenous fungal endophthalmitis is most commonly seen in immunocompromised patients, and oral corticosteroid therapy for such patients should be used with caution as it can worsen an infection. In cases of fusarial endophthalmitis, visual prognosis is poor. [ABSTRACT FROM AUTHOR]

Summary The optimal therapeutic approach for relapsed/refractory (R/R) Waldenström's Macroglobulinaemia (WM) has not been clearly defined, especially after treatment with chemoimmunotherapy (CIT) and covalent Bruton's tyrosine kinase inhibitors (cBTKi). The PembroWM trial is a multi‐centre, phase II, single‐arm study assessing the safety, tolerability and efficacy of rituximab with pembrolizumab in R/R WM patients who had received at least one prior line of treatment, with all having relapsed post‐CIT and most also exposed to cBTKi. A total of 17 patients were enrolled, with a median age of 70, and median of three prior lines of therapy with 15 either refractory or intolerant of a cBTKi. A significant proportion was identified as genomically high risk with BTKC481, CXCR4 and MYD88 L265P wild‐type aberrations. Twenty‐four‐week overall response rate was 50% (60% CI 39.3%–60.7%), and median duration of response was 11.6 months (IQR: 6.3–17). The median progression‐free survival was 13.6 months (95% CI 3–19.8), and the median overall survival (OS) was not reached. Treatment was well tolerated, with minimal numbers of immune‐mediated AEs typically seen with checkpoint inhibitors. PembroWM is the first study to evaluate the feasibility of PD‐1 axis modulation in WM and has shown that in combination with Rituximab the combination is safe and deliverable. [ABSTRACT FROM AUTHOR]

The last decade has seen remarkable progress in our understanding of disease biology of chronic lymphocytic leukaemia (CLL) and the development of novel targeted therapies. Randomised clinical trials have reported improved progression-free survival and overall survival with targeted therapies compared with chemoimmunotherapy, and thereby the role of chemoimmunotherapy in todays' era for treatment of CLL is limited. Bruton tyrosine kinase (BTK) inhibitors, BCL2 inhibitors, and CD20 monoclonal antibodies have been established as appropriate therapy options for patients with CLL, both as the first-line treatment and in the treatment of relapsed or refractory CLL. Several ongoing phase 3 trials are exploring different combinations of targeted therapies, and the results of these trials might change the treatment framework in first-line treatment of CLL. Non-covalent BTK inhibitors, chimeric antigen receptor T-cell therapy, and other therapeutic strategies are being investigated in relapsed CLL. Some of the therapies used in relapsed CLL, such as non-covalent BTK inhibitors, are now being pursued in earlier lines of therapy, including first-line treatment of CLL. [ABSTRACT FROM AUTHOR]

Multiple clinical trials have reported favorable outcomes after drug-coated balloon therapy for peripheral artery disease in above-the-knee and below-the-knee lesions and in both de novo and in-stent restenosis. However, there are still insufficient data to identify and tackle the risk factors associated with a higher risk of restenosis, which is the primary concern for patients who are treated with an endovascular approach. A modern armamentarium, which includes improved lesion preparation techniques such as plaque modification balloons, mechanical atherectomy, intravascular lithotripsy, and imaging, is crucial for obtaining better long-term clinical outcomes. Moreover, a better understanding of the molecular properties of drug-coated balloons has led to improved devices that could tackle the shortcomings of previous generations. This comprehensive review focuses on drug-coated balloon technology as a tool to treat peripheral artery disease and the effects of the molecular mechanisms involved in preventing vascular restenosis. [ABSTRACT FROM AUTHOR]

Introduction: The review article explores the evolving role of Bruton's tyrosine kinase (BTK) inhibitors in immune-mediated dermatological conditions, addressing significant gaps in current treatment approaches. Areas Covered: The review comprehensively discusses the mechanisms of action of BTK inhibitors, including irreversible and reversible inhibitors. Clinical applications of BTK inhibitors in dermatological diseases such as pemphigus, chronic spontaneous urticaria (CSU), hidradenitis suppurativa (HS), systemic lupus erythematosus (SLE), and atopic dermatitis are explored, highlighting recent advancements and ongoing clinical trials. Potential advantages of BTK inhibitors over existing therapies and challenges in translating preclinical findings to clinical outcomes are discussed. Expert Opinion/Commentary: BTK inhibitors represent a promising therapeutic avenue for immune-mediated dermatological conditions, offering oral administration, targeted pathway inhibition, and a favorable safety profile compared to biologic therapies. Ongoing research and clinical trials hold the potential to address unmet needs and reshape the therapeutic landscape in dermatology. Plain Language Summary: Our manuscript explores how a new class of medications called Bruton tyrosine kinase (BTK) inhibitors could revolutionize the treatment of skin conditions caused by the immune system. These conditions, like chronic spontaneous urticaria (CSU), pemphigus, and systemic lupus erythematosus (SLE), often lack effective treatments. BTK inhibitors work by targeting specific pathways in the immune system, offering hope for patients with these challenging conditions. We reviewed clinical trials and research studies to understand how BTK inhibitors could benefit patients. One significant advantage of BTK inhibitors is their ability to provide targeted therapy, meaning they can specifically block the faulty immune responses driving these conditions without affecting the entire immune system. This targeted approach could lead to fewer side effects compared to current treatments, such as corticosteroids or immunosuppressants, which can have widespread effects on the body. Overall, BTK inhibitors represent a promising new approach to treating immune-mediated skin conditions. With further research and development, they could offer safer and more effective alternatives to current treatments, improving the lives of patients worldwide. [ABSTRACT FROM AUTHOR]

Chronic cerebral hypoperfusion (CCH), a disease afflicting numerous individuals worldwide, is a primary cause of cognitive deficits, the pathogenesis of which remains poorly understood. Bruton's tyrosine kinase inhibition (BTKi) is considered a promising strategy to regulate inflammatory responses within the brain, a crucial process that is assumed to drive ischemic demyelination progression. However, the potential role of BTKi in CCH has not been investigated so far. In the present study, we elucidated potential therapeutic roles of BTK in both in vitro hypoxia and in vivo ischemic demyelination model. We found that cerebral hypoperfusion induced white matter injury, cognitive impairments, microglial BTK activation, along with a series of microglia responses associated with inflammation, oxidative stress, mitochondrial dysfunction, and ferroptosis. Tolebrutinib treatment suppressed both the activation of microglia and microglial BTK expression. Meanwhile, microglia-related inflammation and ferroptosis processes were attenuated evidently, contributing to lower levels of disease severity. Taken together, BTKi ameliorated white matter injury and cognitive impairments induced by CCH, possibly via skewing microglia polarization towards anti-inflammatory and homeostatic phenotypes, as well as decreasing microglial oxidative stress damage and ferroptosis, which exhibits promising therapeutic potential in chronic cerebral hypoperfusion-induced demyelination. [ABSTRACT FROM AUTHOR]

Severe alcohol-associated hepatitis (AH) is a life-threatening form of alcohol-associated liver disease. Liver neutrophil infiltration is a hallmark of AH, yet the effects of alcohol on neutrophil functions remain elusive. Identifying therapeutic targets to reduce neutrophil-mediated liver damage is essential. Bruton's tyrosine kinase (BTK) plays an important role in neutrophil development and function; however, the role of BTK in AH is unknown. Using RNA sequencing of circulating neutrophils, we found an increase in Btk expression (P = 0.05) and phosphorylated BTK (pBTK) in patients with AH compared with healthy controls. In vitro, physiologically relevant doses of alcohol resulted in a rapid, TLR4-mediated induction of pBTK in neutrophils. In a preclinical model of AH, administration of a small-molecule BTK inhibitor (evobrutinib) or myeloid-specific Btk knockout decreased proinflammatory cytokines and attenuated neutrophil-mediated liver damage. We found that pBTK was essential for alcohol-induced bone marrow granulopoiesis and liver neutrophil infiltration. In vivo, BTK inhibition or myeloid-specific Btk knockout reduced granulopoiesis, circulating neutrophils, liver neutrophil infiltration, and liver damage in a mouse model of AH. Mechanistically, using liquid chromatography–tandem mass spectrometry, we identified CD84 as a kinase target of BTK, which is involved in granulopoiesis. In vitro, CD84 promoted alcohol-induced interleukin-1β and tumor necrosis factor–α in primary human neutrophils, which was inhibited by CD84-blocking antibody treatment. Our findings define the role of BTK and CD84 in regulating neutrophil inflammation and granulopoiesis, with potential therapeutic implications in AH. Editor's summary: Alcoholic liver disease is uniquely characterized by the hepatic infiltration of neutrophils. Nagesh et al. now show that Bruton's tyrosine kinase (BTK) is involved in this altered neutrophil homeostasis. Studying mouse models of alcohol-associated hepatitis, they found that BTK directly interacted with CD84 to promote bone marrow granulopoiesis and the inflammatory neutrophil infiltration that drives subsequent liver injury, particularly after alcohol binge. Pharmacological BTK inhibition reduced proinflammatory cytokines and attenuated neutrophil-mediated liver damage in a mouse model of alcohol-associated hepatitis. BTK activation was also found to be increased in patients with alcohol-associated hepatitis, indicating translational relevance of the identified mechanism of alcohol-induced liver injury. —Catherine Charneski [ABSTRACT FROM AUTHOR]