Risk of hepatic decompensation from hepatitis B virus reactivation in hematological malignancy treatments.

In this editorial, we discussed the apparent discrepancy between the findings described by Colapietro et al, in their case report and data found in the literature. Colapietro et al reported a case of hepatitis B virus (HBV)-related hepatic decompensation in a patient with chronic myeloid leukemia and a previously resolved HBV infection who was receiving Bruton's tyrosine kinase (BTK) inhibitor therapy. First of all, we recapitulated the main aspects of the immune system involved in the response to HBV infection in order to underline the role of the innate and adaptive response, focusing our attention on the protective role of anti-HBs. We then carefully analyzed literature data on the risk of HBV reactivation (HBVr) in patients with previous HBV infection who were treated with either tyrosine kinase inhibitors or BTK inhibitors for their hematologic malignancies. Based on literature data, we suggested that several factors may contribute to the different risks of HBVr: The type of hematologic malignancy; the type of therapy (BTK inhibitors, especially second-generation, seem to be at a higher risk of HBVr than those with tyrosine kinase inhibitors); previous exposure to an anti-CD20 as first-line therapy; and ethnicity and HBV genotype. Therefore, the warning regarding HBVr in the specific setting of patients with hematologic malignancies requires further investigation.

Impact of therapeutic inhibition of oncogenic cell signaling tyrosine kinase on cell metabolism: in vivo-detectable metabolic biomarkers of inhibition.

BACKGROUND: Inhibition of kinases is the ever-expanding therapeutic approach to various types of cancer. Typically, assessment of the treatment response is accomplished by standard, volumetric imaging procedures, performed weeks to months after the onset of treatment, given the predominantly cytostatic nature of the kinase inhibitors, at least when used as single agents. Therefore, there is a great clinical need to develop new monitoring approaches to detect the response to kinase inhibition much more promptly. Noninvasive 1H magnetic resonance spectroscopy (MRS) can measure in vitro and in vivo concentration of key metabolites which may potentially serve as biomarkers of response to kinase inhibition. METHODS: We employed mantle cell lymphoma (MCL) cell lines demonstrating markedly diverse sensitivity of inhibition of Bruton's tyrosine kinase (BTK) regarding their growth and studied in-depth effects of the inhibition on various aspects of cell metabolism including metabolite synthesis using metabolomics, glucose and oxidative metabolism by Seahorse XF technology, and concentration of index metabolites lactate, alanine, total choline and taurine by 1H MRS. RESULTS: Effective BTK inhibition profoundly suppressed key cell metabolic pathways, foremost pyrimidine and purine synthesis, the citrate (TCA) cycle, glycolysis, and pyruvate and glutamine/alanine metabolism. It also inhibited glycolysis and amino acid-related oxidative metabolism. Finally, it profoundly and quickly decreased concentration of lactate (a product of mainly glycolysis) and alanine (an indicator of amino acid metabolism) and, less universally total choline both in vitro and in vivo, in the MCL xenotransplant model. The decrease correlated directly with the degree of inhibition of lymphoma cell expansion and tumor growth. CONCLUSIONS: Our results indicate that BTK inhibition exerts a broad and profound suppressive effect on cell metabolism and that the affected index metabolites such as lactate, alanine may serve as early, sensitive, and reliable biomarkers of inhibition in lymphoma patients detectable by noninvasive MRS-based imaging method. This kind of imaging-based detection may also be applicable to other kinase inhibitors, as well as diverse lymphoid and non-lymphoid malignancies.

Ibrutinib, a Bruton's tyrosine kinase inhibitor, regulates ventricular electromechanical activities and enhances arrhythmogenesis.

BACKGROUND: Ibrutinib, a Bruton's tyrosine kinase inhibitor used in cancer therapy, exerts ventricular proarrhythmic effects; however, the underlying mechanisms remain unclear. Excitation-contraction coupling (E-C) disorders are pivotal for the genesis of ventricular arrhythmias (VAs), which arise mainly from the right ventricular outflow tract (RVOT). In this study, we aimed to comprehensively investigate whether ibrutinib regulates the electromechanical activities of the RVOT, leading to enhanced arrhythmogenesis, and explore the underlying mechanisms. METHODS: We utilized conventional microelectrodes to synchronously record electrical and mechanical responses in rabbit RVOT tissue preparations before and after treatment with ibrutinib (10, 50, and 100 nM) and investigated their electromechanical interactions and arrhythmogenesis during programmed electrical stimulation. The fluorometric ratio technique was used to measure intracellular calcium concentration in isolated RVOT myocytes. RESULTS: Ibrutinib (10-100 nM) shortened the action potential duration. Ibrutinib at 100 nM significantly increased pacing-induced ventricular tachycardia (VT) (from 0% to 62.5%, n = 8, p = 0.025). Comparisons between pacing-induced VT and non-VT episodes demonstrated that VT episodes had a greater increase in contractility than that of non-VT episodes (402.1 ± 41.4% vs. 232.4 ± 29.2%, p = 0.003). The pretreatment of ranolazine (10 µM, a late sodium current blocker) prevented the occurrence of ibrutinib-induced VAs. Ibrutinib (100 nM) increased late sodium current, reduced intracellular calcium transients, and enhanced calcium leakage in RVOT myocytes. CONCLUSION: Ibrutinib increased the risk of VAs in the RVOT due to dysregulated electromechanical responses, which can be attenuated by ranolazine or apamin.

Navigating the complex terrain of hepatitis B virus reactivation in the era of Bruton tyrosine kinase inhibitors.

In this editorial, we offer a summary of the risk associated with hepatitis B reactivation (HBVr) in the setting of both solid and hematologic malignancies treated with Bruton tyrosine kinase (BTK) inhibitors, with insights derived from current studies. Furthermore, we emphasize the critical need for a framework regarding robust risk evaluation in patients undergoing such treatments. This framework is essential for identifying those at increased risk of HBVr, enabling healthcare providers to implement proactive measures to prevent reactivation and ensure the safe administration of BTK inhibitor therapy.

Strategies for overcoming resistance to Bruton's tyrosine kinase inhibitor zanubrutinib.

Bruton's tyrosine kinase (BTK) inhibitors have revolutionized the treatment of B-cell malignancies. They target BTK, a key effector in the B-cell receptor (BCR) signaling pathway, crucial for B-cell survival and proliferation. The first-in-class irreversible BTK inhibitor, ibrutinib, was approved for various B-cell malignancies but has limitations due to off-target effects. Second-generation inhibitors, such as acalabrutinib and zanubrutinib, offer improved selectivity and reduced side effects. However, resistance to BTK inhibitors, driven by BTK mutations, remains a challenge. Combinatorial therapies with PI3K inhibitors, immune checkpoint inhibitors, BH3 mimetics, and anti-CD20 antibodies show promise in overcoming resistance. Noncovalent BTK inhibitors and proteolysis-targeting chimeras (PROTACs) are emerging strategies with potential to combat resistance. Overall, advancements in BTK-targeted therapies provide hope for improved outcomes in patients with B-cell malignancies and a promising avenue to address drug resistance. Further research is needed to optimize combination therapies and identify optimal treatment regimens.

Bruton's tyrosine kinase inhibitor-related cardiotoxicity: The quest for predictive biomarkers and improved risk stratification.

Ibrutinib was the first Bruton's tyrosine kinase (BTK) inhibitor approved for the treatment of patients with chronic lymphocytic leukemia (CLL). While producing durable responses and prolonging survival, roughly 20-25% of patients experience dose limiting side effects, mostly consisting of cardiovascular toxicities like severe hypertension and atrial fibrillation. While clinical predictors of BTK inhibitor-related cardiotoxicity have been proposed and may aid in risk stratification, there is no routine risk model used in clinical practice today to identify patients at highest risk. A recent study investigating genetic predictors of ibrutinib-related cardiotoxicity found that single nucleotide polymorphisms in KCNQ1 and GATA4 were significantly associated with cardiotoxic events. If replicated in larger studies, these biomarkers may improve risk stratification in combination with clinical factors. A clinicogenomic risk model may aid in identifying patients at highest risk of developing BTK inhibitor-related cardiotoxicity in which further risk mitigation strategies may be explored.

Arrhythmogenic Ventricular Remodeling by Next-Generation Bruton's Tyrosine Kinase Inhibitor Acalabrutinib.

Cardiac arrhythmias remain a significant concern with Ibrutinib (IBR), a first-generation Bruton's tyrosine kinase inhibitor (BTKi). Acalabrutinib (ABR), a next-generation BTKi, is associated with reduced atrial arrhythmia events. However, the role of ABR in ventricular arrhythmia (VA) has not been adequately evaluated. Our study aimed to investigate VA vulnerability and ventricular electrophysiology following chronic ABR therapy in male Sprague-Dawley rats utilizing epicardial optical mapping for ventricular voltage and Ca2+ dynamics and VA induction by electrical stimulation in ex-vivo perfused hearts. Ventricular tissues were snap-frozen for protein analysis for sarcoplasmic Ca2+ and metabolic regulatory proteins. The results show that both ABR and IBR treatments increased VA vulnerability, with ABR showing higher VA regularity index (RI). IBR, but not ABR, is associated with the abbreviation of action potential duration (APD) and APD alternans. Both IBR and ABR increased diastolic Ca2+ leak and Ca2+ alternans, reduced conduction velocity (CV), and increased CV dispersion. Decreased SERCA2a expression and AMPK phosphorylation were observed with both treatments. Our results suggest that ABR treatment also increases the risk of VA by inducing proarrhythmic changes in Ca2+ signaling and membrane electrophysiology, as seen with IBR. However, the different impacts of these two BTKi on ventricular electrophysiology may contribute to differences in VA vulnerability and distinct VA characteristics.

Case report: BTK inhibitors is effective in type II mixed cryoglobulinemia with wild-type MyD88.

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.

BTK inhibitor-induced defects in human neutrophil effector activity against Aspergillus fumigatus are restored by TNF-α.

Inhibition of Bruton's tyrosine kinase (BTK) through covalent modifications of its active site (e.g., ibrutinib [IBT]) is a preferred treatment for multiple B cell malignancies. However, IBT-treated patients are more susceptible to invasive fungal infections, although the mechanism is poorly understood. Neutrophils are the primary line of defense against these infections; therefore, we examined the effect of IBT on primary human neutrophil effector activity against Aspergillus fumigatus. IBT significantly impaired the ability of neutrophils to kill A. fumigatus and potently inhibited reactive oxygen species (ROS) production, chemotaxis, and phagocytosis. Importantly, exogenous TNF-α fully compensated for defects imposed by IBT and newer-generation BTK inhibitors and restored the ability of neutrophils to contain A. fumigatus hyphal growth. Blocking TNF-α did not affect ROS production in healthy neutrophils but prevented exogenous TNF-α from rescuing the phenotype of IBT-treated neutrophils. The restorative capacity of TNF-α was independent of transcription. Moreover, the addition of TNF-α immediately rescued ROS production in IBT-treated neutrophils, indicating that TNF-α worked through a BTK-independent signaling pathway. Finally, TNF-α restored effector activity of primary neutrophils from patients on IBT therapy. Altogether, our data indicate that TNF-α rescued the antifungal immunity block imposed by inhibition of BTK in primary human neutrophils.

Optimizing BTK Inhibition in Waldenström Macroglobulinemia.

Bruton tyrosine kinase (BTK) inhibitors have become a standard of care in the treatment of patients with Waldenström macroglobulinemia (WM) and are the only medications approved by the FDA to treat these patients. As more patients with WM are treated with BTK inhibitors in the United States and worldwide, it is essential to optimize this therapy by selecting the patients who are more likely to benefit from it, and by managing the unique adverse effects associated with these agents. Herein, we propose a genomic-driven approach to selecting patients with WM who are more likely to experience fast, deep, and durable responses to BTK inhibitors, and provide practical strategies for managing adverse effects, including BTK inhibitor dose reductions, switching to other BTK inhibitors, and abandoning BTK inhibitor therapy. Ongoing clinical trials are evaluating covalent and noncovalent BTK inhibitors alone and in combination, as well as BTK degraders, with exciting results, making the horizon for BTK-targeting therapies in WM bright and hopeful.

Targeting the B cell receptor signaling pathway in chronic lymphocytic leukemia.

Aberrant signal transduction through the B cell receptor (BCR) plays a critical role in the pathogenesis of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). BCR-dependent signaling is necessary for the growth and survival of neoplastic cells, making inhibition of down-stream pathways a logical therapeutic strategy. Indeed, selective inhibitors against Bruton's tyrosine kinase (BTK) and phosphoinositide 3-kinase (PI3K) have been shown to induce high rates of response in CLL and other B cell lymphomas. In particular, the development of BTK inhibitors revolutionized the treatment approach to CLL, demonstrating long-term efficacy. While BTK inhibitors are widely used for multiple lines of treatment, PI3K inhibitors are much less commonly utilized, mainly due to toxicities. CLL remains an incurable disease and effective treatment options after relapse or development of TKI resistance are greatly needed. This review provides an overview of BCR signaling, a summary of the current therapeutic landscape, and a discussion of the ongoing trials targeting BCR-associated kinases.

Evaluating zanubrutinib for the treatment of adults with chronic lymphocytic leukemia or small lymphocytic lymphoma.

INTRODUCTION: 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. AREAS COVERED: 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. EXPERT OPINION: 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.

A Review of Resistance Mechanisms to Bruton's Kinase Inhibitors in Chronic Lymphocytic Leukemia.

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.

Discovery and Preclinical Characterization of BIIB129, a Covalent, Selective, and Brain-Penetrant BTK Inhibitor for the Treatment of Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic disease with an underlying pathology characterized by inflammation-driven neuronal loss, axonal injury, and demyelination. Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase and member of the TEC family of kinases, is involved in the regulation, migration, and functional activation of B cells and myeloid cells in the periphery and the central nervous system (CNS), cell types which are deemed central to the pathology contributing to disease progression in MS patients. Herein, we describe the discovery of BIIB129 (25), a structurally distinct and brain-penetrant targeted covalent inhibitor (TCI) of BTK with an unprecedented binding mode responsible for its high kinome selectivity. BIIB129 (25) demonstrated efficacy in disease-relevant preclinical in vivo models of B cell proliferation in the CNS, exhibits a favorable safety profile suitable for clinical development as an immunomodulating therapy for MS, and has a low projected total human daily dose.

[Research Progress of Targeted Therapy for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma --Review].

Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) is a relatively inert B lymphocyte proliferative disease. In recent years with the launch of new drugs, chemotherapy has been gradually replaced by targeted therapy, which significantly prolongs the survival of patients and reduces the side effects of treatment. At present, BTK inhibitors, PI3K inhibitors, spleen tyrosine kinase (SYK) inhibitors and BCL-2 inhibitors are the most studied targeted therapeutic drugs for CLL/SLL. This article reviews the research progress of different types of targeted therapeutic drugs in the treatment of CLL/SLL.