Bruton\'s tyrosine kinase inhibitors (BTKis) have revolutionized the treatment of B-cell lymphomas. However, safety issues related to the use of BTKis may hinder treatment continuity and further affect clinical efficacy. A comprehensive and systematic expert consensus from a pharmacological perspective is lacking for safety issues associated with BTKi treatment. A multidisciplinary consensus working group was established, comprising 35 members from the fields of hematology, cardiovascular disease, cardio-oncology, clinical pharmacy, and evidence-based medicine. This evidence-based expert consensus was formulated using an evidence-based approach and the Delphi method. The Joanna Briggs Institute Critical Appraisal (JBI) tool and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach were used to rate the quality of evidence and grade the strength of recommendations, respectively. This consensus provides practical recommendations for BTKis medication based on nine aspects within three domains, including the management of common adverse drug events such as bleeding, cardiovascular events, and hematological toxicity, as well as the management of drug-drug interactions and guidance for special populations. This multidisciplinary expert consensus could contribute to promoting a multi-dimensional, comprehensive and standardized management of BTKis.

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Chronic urticaria (CU) is a common and long-lasting mast cell-mediated skin disease associated with psychiatric and autoimmune comorbidities, high economic costs, and considerable impact on quality of life. Available therapies show limited efficacy in many CU patients, which may be related to distinct underlying pathophysiology. Targeted and disease-modifying treatments with higher and broader efficacy are needed and are under development for CU. These novel drugs, small molecules, and monoclonal antibodies target mast cells and their receptors, signaling pathways, or mediators and other immune cells. In this article, the authors focus on the most promising emerging therapeutics in advanced development and discuss their potential place in future management of CU.

The recent evolution in chronic lymphocytic leukemia (CLL) targeted therapies led to a progressive change in the way clinicians manage the goals of treatment and evaluate the response to treatment in respect to the paradigm of the chemoimmunotherapy era. Continuous therapies with BTK inhibitors achieve prolonged and sustained control of the disease. On the other hand, venetoclax and anti-CD20 monoclonal antibodies or, more recently, ibrutinib plus venetoclax combinations, given for a fixed duration, achieve undetectable measurable residual disease (uMRD) in the vast majority of patients. On these grounds, a time-limited MRD-driven strategy, a previously unexplored scenario in CLL, is being attempted. On the other side of the spectrum, novel genetic and non-genetic mechanisms of resistance to targeted treatments are emerging. Here we review the response assessment criteria, the evolution and clinical application of MRD analysis and the mechanisms of resistance according to the novel treatment strategies within clinical trials. The extent to which this novel evidence will translate in the real-life management of CLL patients remains an open issue to be addressed.

Inhibitors of Bruton\'s tyrosine kinase (BTKi) and chimeric antigen receptor T-cell (CAR-T) therapy targeting CD19 are paradigm-shifting advances in treating patients with aggressive mantle cell lymphoma (MCL). However, clinical relapses following BTKi and CD19-directed CAR-T treatments are a fast-growing medical challenge. Development of novel therapies to overcome BTKi resistance (BTKi-R) and BTKi-CAR-T dual resistance (Dual-R) are urgently needed. Our single-cell RNA sequencing data revealed major transcriptomic reprogramming, with great enrichment of MYC-targets evolving as resistance to these therapies developed. Interestingly, cyclin-dependent kinase 9 (CDK9), a critical component of the positive transcription elongation factor-b complex, was among the top upregulated genes in Dual-R vs. BTKi-R samples. We therefore hypothesized that targeting CDK9 may turn off MYC-driven tumor survival and drug resistance. Enitociclib (formerly VIP152) is a selective CDK9 inhibitor whose potency against MCL has not been assessed. In this study, we found that enitociclib was highly potent in targeting lymphoma cells, with the half-maximal inhibitory concentration (IC50) ranging from 32 to 172 nM in MCL and diffuse large B-cell lymphoma cell lines. It inhibited CDK9 phosphorylation and downstream events including de novo synthesis of the short-lived proteins c-MYC, MCL-1, and cyclin D1, and induced apoptosis in a caspase-3-dependent manner. Enitociclib potently inhibited in vivo tumor growth of cell line-derived and patient-derived xenografts having therapeutic resistance. Our data demonstrate the potency of enitociclib in overcoming therapeutic resistance in MCL models and provide evidence in favor of its clinical investigation.

UNASSIGNED: Impact of B-cell depletion following treatment with Bruton tyrosine kinase-inhibitors (BTKi) on the outcome of SARS-CoV-2 infection in chronic lymphocytic leukemia (CLL) patients remain controversial. We investigated the impact of BTKi on susceptibility and the severity of COVID-19 in Chinese patients with CLL during the first wave of COVID-19 (Omicron variant).
UNASSIGNED: CLL patients (n=171) visiting the Institute of Hematology, Peoples\' Hospital, China (November 15, 2022- January 20, 2023) were included in the study. Seventeen patients receiving BTKi and venetoclax with or without obinutuzumab were excluded. Data from 117 patients receiving treatment with BTKi were collected using a standardized questionnaire through telephone interviews. Thirty-four patients without CLL-specific treatment served as controls. The data was analysed using IBM SPSS Software version 21 and a P value of <0.05 was considered statistically significant.
UNASSIGNED: The median age of patients was 67 years and majority were males (n=100). Treatment with BTKi was not associated with higher incidence of COVID-19 (74% [95% Confidence Interval (CI) 60%, 92%]) versus 74% (CI 48%, 100%) without any treatment (P=0.92). Hypoxemia was reported by 45% (32%, 61%) and 16% (4%, 41%) (P=0.01). BTKi was the only independent risk factor of hypoxemia (Hazard Ratio [HR], 4.22 [1.32, 13.50]; P = 0.02). Five (5.7%) patients with COVID-19 under BTKi required ICU admission; 4 of them died. No ICU admissions/deaths were observed in the control group.
UNASSIGNED: In Chinese patients with CLL and treated with BTKi experienced more severe lung disease and ICU admissions due to COVID-19 than patients without CLL therapy. Frequency of infections with SARS-CoV-2, however, was not different in patients with or without BTKi treatment.

Bruton\'s tyrosine kinase (BTK) has emerged as a therapeutic target for B-cell malignancies, which is substantiated by the efficacy of various irreversible or reversible BTK inhibitors. However, on-target BTK mutations facilitating evasion from BTK inhibition lead to resistance that limits the therapeutic efficacy of BTK inhibitors. In this study we employed structure-based drug design strategies based on established BTK inhibitors and yielded a series of BTK targeting compounds. Among them, compound S-016 bearing a unique tricyclic structure exhibited potent BTK kinase inhibitory activity with an IC50 value of 0.5 nM, comparable to a commercially available BTK inhibitor ibrutinib (IC50 = 0.4 nM). S-016, as a novel irreversible BTK inhibitor, displayed superior kinase selectivity compared to ibrutinib and significant therapeutic effects against B-cell lymphoma both in vitro and in vivo. Furthermore, we generated BTK inhibitor-resistant lymphoma cells harboring BTK C481F or A428D to explore strategies for overcoming resistance. Co-culture of these DLBCL cells with M0 macrophages led to the polarization of M0 macrophages toward the M2 phenotype, a process known to support tumor progression. Intriguingly, we demonstrated that SYHA1813, a compound targeting both VEGFR and CSF1R, effectively reshaped the tumor microenvironment (TME) and significantly overcame the acquired resistance to BTK inhibitors in both BTK-mutated and wild-type BTK DLBCL models by inhibiting angiogenesis and modulating macrophage polarization. Overall, this study not only promotes the development of new BTK inhibitors but also offers innovative treatment strategies for B-cell lymphomas, including those with BTK mutations.

Bruton\'s Tyrosine Kinase (BTK) inhibitors have become one of the most vital drugs in the therapy of chronic lymphocytic leukemia (CLL). Inactivation of BTK disrupts the B-cell antigen receptor (BCR) signaling pathway, which leads to the inhibition of the proliferation and survival of CLL cells. BTK inhibitors (BTKi) are established as leading drugs in the treatment of both treatment-naïve (TN) and relapsed or refractory (R/R) CLL. Furthermore, BTKi demonstrate outstanding efficacy in high-risk CLL, including patients with chromosome 17p deletion, TP53 mutations, and unmutated status of the immunoglobulin heavy-chain variable region (IGHV) gene. Ibrutinib is the first-in-class BTKi which has changed the treatment landscape of CLL. Over the last few years, novel, covalent (acalabrutinib, zanubrutinib), and non-covalent (pirtobrutinib) BTKi have been approved for the treatment of CLL. Unfortunately, continuous therapy with BTKi contributes to the acquisition of secondary resistance leading to clinical relapse. In recent years, it has been demonstrated that the predominant mechanisms of resistance to BTKi are mutations in BTK or phospholipase Cγ2 (PLCG2). Some differences in the mechanisms of resistance to covalent BTKi have been identified despite their similar mechanism of action. Moreover, novel mutations resulting in resistance to non-covalent BTKi have been recently suggested. This article summarizes the clinical efficacy and the latest data regarding resistance to all of the registered BTKi.

UNASSIGNED: This review evaluates zanubrutinib as a treatment option for adults with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Zanubrutinib, a covalent BTK (Bruton\'s tyrosine kinase) inhibitor, was recently approved by the US FDA based in part on head-to-head data demonstrating improved efficacy and safety compared to ibrutinib.
UNASSIGNED: The review discusses the efficacy, safety, and comparative advantages of zanubrutinib, highlighting its safety profile compared to other BTK inhibitors. It also addresses the unmet needs of current therapies in CLL/SLL and provides an overview of competitor compounds and ongoing research in BTK inhibition.
UNASSIGNED: Zanubrutinib, the first BTK inhibitor to demonstrate superior efficacy and safety compared to another BTK inhibitor in CLL, is likely to be widely adopted due to its high-quality data and ease of use. Looking ahead, pirtobrutinib, a novel non-covalent BTK inhibitor, has shown promise in heavily pretreated CLL patients, including those unresponsive to covalent inhibitors, with ongoing phase 3 trials comparing it against ibrutinib. The field is also exploring time-limited therapies like the combination of ibrutinib and venetoclax, with ongoing trials evaluating different combinations to optimize efficacy and minimize toxicity, indicating a promising future for combination therapies in CLL treatment.

This study presents two cases of type II mixed cryoglobulinemia. One case is essential, while the other is presumably associated with hepatitis B virus (HBV) infection. Both patients tested positive for monoclonal IgMκ, but negative for MyD88 mutation. They showed resistance to rituximab combined with a glucosteroid regimen, but responded positively to BTK inhibitors. These cases highlight the remarkable effectiveness of BTK inhibitors in treating refractory type II cryoglobulinemia without MyD88 mutation. The first patient achieved rapid complete remission of nephrotic syndrome within one month of starting ibrutinib, along with a significant reduction in cryoglobulin levels and abnormal clonal cells. The second patient had a rapid disappearance of rash within three days and accelerated wound healing within one week of initiating orelabrutinib, accompanied by a reduction in C-reactive protein. However, there was no reduction in cryoglobulin levels during the 12-month follow-up. These findings suggest varied mechanisms of action of BTK inhibitors in type II cryoglobulinemia through different mechanisms.