Ibrutinib

Post-transplant lymphoproliferative disorder (PTLD) is a rare complication of solid organ transplantation, and cytotoxic chemotherapy is associated with treatment-related morbidity and mortality. Current treatment takes a sequential, risk-stratified approach, patients with low-risk disease following initial immunotherapy can avoid escalation to immunochemotherapy. TIDaL is a prospective, single-arm phase 2 trial investigating the activity and tolerability of ibrutinib combined with risk-stratified therapy for first-line treatment of PTLD...

Cofactor mimicry represents an attractive strategy for the development of enzyme inhibitors but can lead to off-target effects due to the evolutionary conservation of binding sites across the proteome. Here, we uncover the ADP-ribose (ADPr) hydrolase NUDT5 as an unexpected, noncovalent, off-target of clinical BTK inhibitors. Using a combination of biochemical, biophysical, and intact cell NanoBRET assays as well as X-ray crystallography, we confirm catalytic inhibition and cellular target engagement of NUDT5 and reveal an unusual binding mode that is independent of the reactive acrylamide warhead...

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This analysis investigated the incidence of sudden deaths (SDs) and non-fatal and fatal ventricular arrhythmias (VAs) in five acalabrutinib clinical trials. In total, 1299 patients received acalabrutinib (exposure, 4568.4 patient-years). Sixteen (1.2%) patients experienced SD or VA (event rate, 0.350/100 patient-years). Non-fatal VAs occurred in 11 (0.8%) patients, nine (0.7%) of whom had premature ventricular contractions only. SD and fatal VAs occurred in five (0.4%) patients (event rate, 0.109/100 patient-years; median time to event: 46...

Pharmacotherapy options for chronic lymphocytic leukaemia (CLL) have expanded significantly in recent years. These options include chemotherapy, chemoimmunotherapy and signalling pathway inhibitors. A notable shift in the treatment landscape began with the widespread adoption of ibrutinib in 2016. This analysis of claims data focuses on understanding how the use of novel therapies has evolved in clinical practice over the past decade in Germany. Anonymized claims data (2010-2022) from German statutory health insurance was used, covering patient demographics, treatments, and prescriptions...

Systemic antifungal therapy is critical for reducing the mortality from many invasive and chronic fungal infections. Triazole antifungals are the most frequently prescribed antifungals but require attention to dosing and drug interactions. Nearly 600 severe drug-drug interactions and over 1100 moderate interactions requiring dose modifications are described or anticipated with systemic antifungal agents (see https://www.aspergillus.org.uk/antifungal-drug-interactions/). In this article, we address the common and less common, but serious, drug interactions observed in clinical practice with triazole antifungals, including a group of drugs that cannot be prescribed with all or most triazole antifungals (ivabradine, ranolazine, eplerenone, fentanyl, apomorphine, quetiapine, bedaquiline, rifampicin, rifabutin, sirolimus, phenytoin and carbamazepine)...

Bruton tyrosine kinases (BTKs) play critical roles in various diseases, including chronic lymphatic leukemia (CLL), Waldenström Macroglobulinemia, Marginal Zone Lymphoma, Mantle Cell Lymphoma (MCL), and Graft Versus Host diseases. BTKs are a family of tyrosine kinases involved in B lymphocyte signal transduction, development, and maturation. Their overexpression can lead to cancer as they are essential for the activation of the B Cell Receptor (BCR) signaling pathway. Blocking the activation of BTKs presents a promising approach for treating CLL...

Objective: To conduct a nationwide physician survey to better understand clinicians' disease awareness, treatment patterns, and experience of Waldenström macroglobulinemia (WM) in China. Methods: This cross-sectional study was conducted from February 2022 to July 2022 by recruiting clinicians with WM treatment experience from hematology, hematology-oncology, and oncology departments throughout China. Quantitative surveys were designed based on the qualitative interviews. Results: The study included 415 clinicians from 219 hospitals spread across thirty-three cities and twenty-two provinces...

The Inflation Reduction Act of 2022 (IRA) allows the Medicare program to negotiate drug prices beginning in 2024. Based on the guidance in the statute, CMS has selected specific data items to use to adjust initial price offers for 10 drugs in the decision-making process. Although much of the data are publicly available, some of these data items will need to be collected directly from drug companies. A 2019 US House of Representatives Committee on Oversight and Accountability investigative report collected a wide range of data from manufacturers of 12 high-revenue drugs that show what is available from the drug companies, including development costs, marketing, pricing, competition, and patent status...

The t(1;19) translocation, which codes for the oncogenic fusion protein E2A (TCF3)-PBX1, is involved in acute lymphoblastic leukemia (ALL) and associated with a pre-B cell receptor (preBCR+) phenotype. Relapse in E2A-PBX1+ ALL patients frequently occurs in the central nervous system (CNS). Therefore, there is a medical need for the identification of CNS active regimens for the treatment of E2A-PBX1+/preBCR+ ALL. Using unbiased shRNA library screening approaches, we identified Bruton's tyrosine kinase (BTK) as a key gene involved in both proliferation and dasatinib sensitivity of E2A-PBX1+/preBCR+ ALL...

Posttransplant lymphoproliferative disease (PTLD) is a major therapeutic challenge that has been difficult to study using human cells because of a lack of suitable models for mechanistic characterization. Here, we show that ex vivo-differentiated B cells isolated from a subset of healthy donors can elicit pathologies similar to PTLD when transferred into immunodeficient mice. The primary driver of PTLD-like pathologies were IgM-producing plasmablasts with Epstein-Barr virus (EBV) genomes that expressed genes commonly associated with EBV latency...

Parsaclisib, a potent and highly selective phosphoinositide 3-kinase δ inhibitor, has shown clinical activity in relapsed/refractory (R/R) B-cell lymphoma. The phase 1 CITADEL-112 (NCT03424122) study assessed safety and efficacy of parsaclisib in combination with investigator choice standard of care (SOC; rituximab [Treatment A], rituximab plus bendamustine [Treatment B], or ibrutinib [Treatment C]) in 50 patients with R/R B-cell lymphoma. The most common treatment-emergent adverse events included neutropenia (62...

Ibrutinib is a first-in-class Bruton kinase inhibitor against B-cell neoplasms including Waldenström macroglobulinemia (WM). This study evaluated the efficacy and safety of ibrutinib-rituximab in Japanese patients with WM. Patients received ibrutinib 420 mg orally once daily plus weekly rituximab 375 mg/m2 IV (8 infusions total). The primary end point was major response rate (MRR; PR or better) by Independent Review Committee assessment. Secondary endpoints were progression-free survival (PFS), safety, pharmacokinetics, and biomarkers...

The incidence of primary central nervous system lymphoma (PCNSL) has steadily increased, particularly in elderly patients. Although highly responsive to first-line chemotherapy and radiotherapy, approximately 50% of patients relapse or become refractory within 1 year. Prognosis following relapse is dismal and no standard salvage therapy exists. Bruton's tyrosine kinase (BTK), a key regulator of the B-cell receptor (BCR) pathway, has emerged as a promising therapeutic target. The first BTK inhibitor ibrutinib has been evaluated in the relapsed/refractory PCNSL setting, with overall response rates of 51...

In malignant glioma, cytotoxic drugs are often inhibited from accessing the tumor site due to the blood-tumor barrier (BTB). Ibrutinib, FDA-approved lymphoma agent, inhibits Bruton tyrosine kinase (BTK) and has previously been shown to independently impair aortic endothelial adhesion and increase rodent glioma model survival in combination with cytotoxic therapy. Yet additional research is required to understand ibrutinib's effect on BTB function. In this study, we detail baseline BTK expression in glioma cells and its surrounding vasculature, then measure endothelial junctional expression/function changes with varied ibrutinib doses in vitro...

Bruton's Tyrosine kinase (BTK) plays a pivotal role as the key mediator in B cell signaling. Recent research has revealed that it is also expressed in cells critical to asthma development, such as T cells, and eosinophils. This study aims to investigate the potential of BTK inhibitor in eosinophilic asthma mouse model. BALB/c mice were sensitized with ovalbumin (OVA) via intraperitoneal injections and followed by OVA nebulizations. The mice were treated with 250 µg/ml or 500 µg/ml of ibrutinib before the second intraperitoneal injection and the first nebulization...

Bruton's tyrosine kinase (BTK) is central to the survival of malignant and normal B-lymphocytes and has been a crucial therapeutic target of several generations of kinase inhibitors and newly developed degraders. These new means for targeting BTK have added additional agents to the armamentarium for battling cancers dependent on B-cell receptor (BCR) signaling, including chronic lymphocytic leukemia and other non-Hodgkin lymphomas. However, the development of acquired resistance mutations to each of these classes of BTK inhibitors has led to new challenges in targeting BTK as well as novel insights into BCR signaling...

The NFKBIE gene, which encodes the NF-κB inhibitor IκBε, is mutated in 3-7% of patients with chronic lymphocytic leukemia (CLL). The most recurrent alteration is a 4-bp frameshift deletion associated with NF-κB activation in leukemic B cells and poor clinical outcome. To study the functional consequences of NFKBIE gene inactivation, both in vitro and in vivo, we engineered CLL B cells and CLL-prone mice to stably down-regulate NFKBIE expression and investigated its role in controlling NF-κB activity and disease expansion...

The blood-brain barrier (BBB)/blood-tumor barrier (BTB) impedes brain entry of most brain-targeted drugs, whether they are water-soluble or hydrophobic. Endothelial WNT signaling and neoplastic pericytes maintain BTB low permeability by regulating tight junctions. Here, we proposed nitazoxanide (NTZ) and ibrutinib (IBR) co-loaded ICAM-1-targeting nanoparticles (NI@I-NPs) to disrupt the BTB in a time-dependent, reversible, and size-selective manner by targeting specific ICAM-1, inactivating WNT signaling and depleting pericytes in tumor-associated blood vessels in breast cancer brain metastases...

BACKGROUND: This study analyzed the bleeding adverse events (AEs) resulting from the treatment of B-cell lymphoma with Bruton tyrosine kinase (BTK) inhibitors, according to reports in the US Food and Drug Administration's Adverse Event Reporting System (FAERS). METHODS: Bleeding AEs associated with BTK inhibitors (including ibrutinib, zanubrutinib, and acalabrutinib) from the first quarter of 2013 to the third quarter of 2023 were extracted. Reporting odds ratio (ROR) and proportional reporting ratio (PRR) were reported...