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Bruton's tyrosine kinase inhibitors (BTKis) are targeted treatments for B-cell tumors but have significant side effects. This study assesses and contrasts the side effects of BTKis alone and its four combination therapies. The reporting odds ratio (ROR) was used to analyze the data on three BTKis monotherapies and combinations of ibrutinib with rituximab, obinutuzumab, venetoclax, and lenalidomide in the FDA Adverse Event Reporting System (FAERS) database up to December 2022. We analyzed the top 20 PTs for each treatment regimen. In monotherapies, atrial fibrillation (ROR (95% CI): 9.88 (9.47–10.32)) in zanubrutinib and rash (6.97 (5.42–8.98)) in acalabrutinib had higher associations. In combinations, infection (6.86 (6.11–7.70)), atrial fibrillation (27.96 (22.61–34.58)) and myelosuppression (10.09 (8.89–11.46)) were vital signals when ibrutinib was combined with obinutuzumab, and pyrexia (4.22 (2.57–6.93)) had a high signal value when combined with lenalidomide. Hemorrhage had a lower signal value when combined with venetoclax compared to ibrutinib alone (2.50 (2.18–2.87) vs 3.60 (3.52–3.68)). The ibrutinib-obinutuzumab combo has the highest risk of infection, atrial fibrillation, and myelosuppression, and the ibrutinib-lenalidomide combo has the highest risk of pyrexia. However, the ibrutinib-venetoclax combo has a lower risk of hemorrhage than monotherapy. [ABSTRACT FROM AUTHOR]

Bruton's tyrosine kinase (BTK) inhibitors represent a class of drugs that have demonstrated their efficacy and safety in patients with chronic lymphocytic leukemia and non-Hodgkin's lymphomas who were considered refractory to any previously used type of therapy. BTK plays a key role in all stages of B lymphocyte development, but in recent years, there have been data indicating that BTK is also involved in the activation of myeloid cells.The aim of this study is to analyze and systematize all published materials on the immunomodulatory effects of BTK inhibitors (ibrutinib, acalabrutinib, etc.).A systematic review of the scientific literature was performed using a step-by-step search process in electronic databases (PubMed, Web of Science, ScienceDirect, and Scopus). The following keywords were used in the database search: “CLL”, “BTK”, “ibrutinib”, “COVID-19”, “allergy”, “inflammation.” The search for studies was conducted from the time of the first BTK inhibitor drug (ibrutinib) appearance in 2009 until December 2022.The results of the study on the influence of BTK inhibitors on the functional state of B and T lymphocytes, neutrophils, and monocytes/macrophages are presented. The immunomodulatory effects of ibrutinib on adaptive and innate immune system cells, including CD4+ and CD8+T lymphocytes and NK cells, are described. Since BTK inhibitors alter the functional activity of phagocytic cells and the ratio of T cell populations, there is a suggestion about the possibility of using these drugs for the treatment of other nosological forms, not only B cell malignancies, which is currently being studied in clinical trials. Data on the use of BTK inhibitors to combat hyperacute inflammation and to suppress allergic reactions, including anaphylaxis, are summarized. In addition, the expediency of short-term use of BTK inhibitors to reduce the risk of side effects during oral immunotherapy and for desensitization to drugs is discussed.The presented data indicate that BTK inhibitors are promising drugs with immunomodulatory effects. However, BTK inhibitors need to increase selectivity to reduce off-target effects on other kinases.

Primary central nervous system lymphoma (PCNSL) is a highly aggressive brain tumor with poor prognosis if no treatment. The activation of the NF-kB (nuclear factor kappa-B) is the oncogenic hallmark of PCNSL, and it was driven by B cell receptor (BCR) and Toll-like receptor (TLR) signaling pathways. The emergence of Bruton's tyrosine kinase inhibitors (BTKis) has brought the dawn of life to patients with PCNSL. This review summarizes the management of PCNSL with BTKis and potential molecular mechanisms of BTKi in the treatment of PCNSL. And the review will focus on the clinical applications of BTKi in the treatment of PCNSL including the efficacy and adverse events, the clinical trials currently being carried out, the underlying mechanisms of resistance to BTKi and possible solutions to drug resistance. [ABSTRACT FROM AUTHOR]

Recently, the use of novel targeted drugs has changed the treatment paradigms in chronic lymphocytic leukemia (CLL). Among the several drugs used for the management of relapsed/refractory (R/R) CLL, Bruton tyrosine kinase inhibitors (ibrutinib and acalabrutinib), phosphatidylinositol 3-kinase inhibitors (idelalisib and duvelisib), B-cell lymphoma 2 inhibitor (venetoclax), and novel CD20 monoclonal antibodies have demonstrated the greatest improvements in survival among R/R CLL patients. However, patients with relapsed but asymptomatic CLL do not need immediate alternative treatment and should be observed until evident sign of progression. Among available approved treatments, venetoclax + rituximab for 24 months or ibrutinib as continuous therapy is recommended. Another, less recommended, option is idelalisib in combination with rituximab. The correct treatment selection depends on the type of prior therapy, response to previous treatment and side effects, presence of comorbidities, and the risk of drug toxicity. Allogeneic hematopoietic stem cell transplantation and investigational therapies such as chimeric antigen receptor-T-cell therapy are promising treatment options for high-risk patients, including those progressing after 1 or more targeted therapies. The present review discusses current treatment strategies for patients with R/R CLL. [ABSTRACT FROM AUTHOR]

Waldenström macroglobulinemia (WM) is a rare lymphoplasmacytic lymphoma. The primary goal of therapy is to reduce symptoms related to direct infiltration of the bone marrow and decrease monoclonal IgM-associated complications. Active agents in the management of WM can be broadly classified as rituximab-alkylator combination therapy, proteasome inhibitor-based therapy, and Bruton's tyrosine kinase inhibitor-based therapy. MYD88L265P and CXCR4 genetic status are pivotal for tailoring treatment options. Ibrutinib is a suitable treatment option for both treatment-naïve and relapsing WM patients. Recent advances in the intracellular B cell and cytokine signaling pathways have contributed to the development of novel therapeutic strategies. Current clinical trials are promising and may further advance WM-directed therapy. [ABSTRACT FROM AUTHOR]

The adverse effects (AEs) of chemotherapy for chronic lymphocytic leukemia (CLL) can currently be avoided using Bruton's tyrosine kinase inhibitors (BTKis) and/or B-cell leukemia/lymphoma 2 (BCL2) inhibitors, which have increased the efficacy of therapy and improved the prognosis of patients. The progression-free survival and overall response rate of patients are significantly longer with the use of BTKis compared with the use of combination therapy. They are standard of care for use as frontline therapy and for the treatment of refractory or relapsed CLL. The use of BTKis is also indicated for patients with active disease and del17p, TP53 mutation, or unmutated immunoglobulin heavy chain genes, for their greater efficacy compared to chemotherapy + anti-CD20 monoclonal antibodies or BCL2 inhibitors. Ibrutinib inhibits various specific immune receptors, exerts immunomodulatory effects, and some immune manifestations respond to ibrutinib. The main limitations associated with the use of BTKis are the following: The emergence of drug resistance, low complete remission rates, the need for an indefinite treatment duration and possible AEs. The use of ibrutinib is not recommended for patients with ventricular arrhythmias, and the use of any BTKi is not recommended for those with a history of heart failure. Patients who are intolerant to ibrutinib can receive a more selective BTKi. Patients who develop resistance to covalent BTKis can be treated with a non-covalent BTKi or with a BCL2 inhibitor. BTKis can be administered in combination with an anti-CD20 monoclonal antibody and/or a BCL2 inhibitor to reduce the proliferation of resistant clones, and sometimes to allow the shortening of the treatment duration. Further developments include Bruton's tyrosine kinase degraders, the combination of BTKis with immune checkpoint inhibitors or chimeric antigen receptor T-cells, or drugs that target 6,7-dimethoxy-N-(pyridin-3-yl)quinazolin-4-amine or actin cytoskeleton organization. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma is an aggressive Non-Hodgkin's lymphoma that is considered incurable with standard therapies. Most patients treated with frontline immunochemotherapy relapse within a few years and do not usually respond to salvage chemotherapy. Persistent activation of the B-cell receptor pathway is critical to the pathogenesis of mantle cell lymphoma. Inhibition of Bruton's tyrosine kinase, an essential B-cell receptor pathway component with ibrutinib has shown clinical activity and has changed how MCL is treated in the relapsed/refractory setting. However, resistance to ibrutinib is common and response is limited. Novel agents targeting the B-cell receptor pathway along with therapies outside of the pathway will be reviewed in this article. Ongoing and future studies will better define how these agents should be utilized in the ever-changing treatment landscape of mantle cell lymphoma. [ABSTRACT FROM AUTHOR]

Background: Although ibrutinib is highly effective in patients with relapsed/refractory mantle cell lymphoma (MCL), a substantial proportion of patients have resistant disease. The subsequent outcomes of such patients are unknown. Patients and methods: We carried out a retrospective review of all patients with MCL treated with ibrutinib at MD Anderson Cancer Center between January 2011 and January 2014 using pharmacy and clinical databases. Patients who had discontinued ibrutinib for any reason were included in the study. Results: We identified 42 patients with MCL who discontinued therapy due to disease progression on treatment (n = 28), toxicity (n = 6), elective stem-cell transplant in remission (n = 4) or withdrawn consent (n = 4). The median age was 69 years, 35 (83%) were male; the median number of prior treatments was 2 (range 1-8) and the median time from initial diagnosis of MCL to commencing ibrutinib was 3.0 (range 0.5-15.5) years. Patients had received a median of 6.5 (range 1-43) cycles of ibrutinib. Among 31 patients who experienced disease progression following ibrutinib and underwent salvage therapy, the overall and complete response rates were 32% and 19%, respectively. After a median follow-up of 10.7 (range 2.4-38.9) months from discontinuation of ibrutinib, the median overall survival (OS) among patients with disease progression was 8.4 months. By univariate analysis, elevated serum lactate dehydrogenase at progression was associated with inferior OS. Conclusion: The outcome of patients with MCL who experience disease progression following ibrutinib therapy is poor, with both low response rates to salvage therapy and short duration of responses. Further studies to better understand and overcome ibrutinib resistance are urgently needed. [ABSTRACT FROM AUTHOR]