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.

Bruton\'s tyrosine kinase (BTK) inhibitors are an emerging class of therapeutics in multiple sclerosis (MS). BTK is expressed in B-cells and myeloid cells, key progenitors of which include dendritic cells, microglia and macrophages, integral effectors of MS pathogenesis, along with mast cells, establishing the relevance of BTK inhibitors to diverse autoimmune conditions. First-generation BTK inhibitors are currently utilized in the treatment of B-cell malignancies and show efficacy in B-cell modulation. B-cell depleting therapies have shown success as disease-modifying treatments (DMTs) in MS, highlighting the potential of BTK inhibitors for this indication; however, first-generation BTK inhibitors exhibit a challenging safety profile that is unsuitable for chronic use, as required for MS DMTs. A second generation of highly selective BTK inhibitors has shown efficacy in modulating MS-relevant mechanisms of pathogenesis in preclinical as well as clinical studies. Six of these BTK inhibitors are undergoing clinical development for MS, three of which are also under investigation for chronic spontaneous urticaria (CSU), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Phase II trials of selected BTK inhibitors for MS showed reductions in new gadolinium-enhancing lesions on magnetic resonance imaging scans; however, the safety profile is yet to be ascertained in chronic use. Understanding of the safety profile is developing by combining safety insights from the ongoing phase II and III trials of second-generation BTK inhibitors for MS, CSU, RA and SLE. This narrative review investigates the potential of BTK inhibitors as an MS DMT, the improved selectivity of second-generation inhibitors, comparative safety insights established thus far through clinical development programmes and proposed implications in female reproductive health and in long-term administration.
A review of Bruton’s tyrosine kinase inhibitors in multiple sclerosis Why was this study done? This study was done to find out about current knowledge on a type of drug, called Bruton’s tyrosine kinase inhibitors, or BTK inhibitors. There are currently six BTK inhibitors being studied as a possible new drug for treating multiple sclerosis (MS). Some of these six drugs are also being studied as a possible new drug for chronic spontaneous urticaria, rheumatoid arthritis and systemic lupus erythematosus. These are all autoimmune conditions, where the immune system mistakenly attacks parts of the body. Clinician scientists wanted to understand what is currently known about BTK inhibitors, how they work in the laboratory and how safe they could be for treating autoimmune conditions. This could help us understand more about BTK inhibitors in MS.What did the scientists do? The scientists assessed existing research on these six BTK inhibitors, through a process known as a literature review. These were results from ongoing clinical trials, and information collected through studying BTK inhibitors in laboratories. The researchers pieced together all these findings, to produce this paper that summarizes the results.What did the scientists find? The scientists found that most studies of BTK inhibitors for MS are still ongoing. So far, BTK inhibitors seem to show reasonable safety in most studies, but it is too early to know. The researchers also found out about how BTK inhibitors work in the lab, about what could happen if the drugs are taken for a long time and how they could impact female reproductive health.What do these findings mean? These findings will help other scientists learn more about BTK inhibitors in MS. Trials with BTK inhibitors for MS are still ongoing, but piecing together all the current findings gives a picture of what we know and what still needs to be done.

BACKGROUND: Vitreoretinal lymphoma (VRL) is usually treated with a combination of intraocular methotrexate (ioMTX), high-dose intravenous methotrexate (HD-MTX), or local radiotherapy (RT) as the first options. The effectiveness and safety of monotherapy like bruton\'s tyrosine kinase inhibitors (BTKi) for PVRL remain uncertain.
METHODS: A systematic review and meta-analysis of clinical trial data and conference abstracts in VRL patients treated with first-line combination therapy or monotherapy were conducted through a search of PubMed, Embase, and Scopus databases until December 2022. A total of 24 studies comprising 517 patients were included, and survival data were extracted from 279 patients due to inconsistent units across studies.
RESULTS: The combined treatment group used ioMTX + chemotherapy (in 4 studies), RT + chemotherapy (in 2 studies), ioMTX/HD-MTX based regimen (in 2 studies), ioMTX + RT + chemotherapy (in 2 studies), ioMTX + lenalidomide/BTKi (in 2 studies) and combination of multiple therapies (in 7 studies). The monotherapy group was mainly treated with oral monotherapies such as BTKi. The combination therapy had a higher overall response rate (ORR) and complete response rate (CRR) than monotherapy (ORR: 96% vs. 72%, CRR: 92% vs. 63%). Combination therapy also resulted in a longer median progression-free survival (28.8 months vs. 13 months, p = 0.012). However, the combination therapy group had more severe side effects (grade 3/4 toxicity) than the monotherapy group (45% vs. 8%).
CONCLUSIONS: The study showed combination therapy had better OR and CR rates, longer survival, and more toxicity than monotherapy. While BTK inhibitors were well-tolerated, long-term effectiveness needs confirmation from prospective studies. In addition, given the small number of studies of monotherapy for VRL, more studies are needed to validate its effects.
BACKGROUND: CRD42023400305.

Waldenström macroglobulinemia (WM) is a chronic B-cell lymphoproliferative disorder characterized by lymphoplasmacytic cell overgrowth in the bone marrow and increased secretion of IgM immunoglobulins into the serum. Patients with WM have a variety of clinical outcomes, including long-term survival but inevitable recurrence. Recent advances in disease knowledge, including molecular and genetic principles with the discovery of MYD88 and CXCR4 mutations, have rapidly increased patient-tolerable treatment options. WM patients may benefit from chemotherapy regimens that include rituximab-based regimens, alkylating drugs, proteasome inhibitors, monoclonal antibodies, and drugs targeting Bruton tyrosine kinase inhibitors. In light of these advancements, patients can now receive treatment customized to their specific clinical characteristics, focusing on enhancing the depth and durability of their response while limiting the adverse effects. Despite the rapidly developing therapeutic armament against WM, a lack of high-quality evidence from extensive phase 3 trials remains a significant challenge in the research. We believe clinical outcomes will keep improving when new medicines are introduced while preserving efficacy and minimizing toxicity.

BACKGROUND: Mantle cell lymphoma (MCL) is a rare type of mature B-cell lymphoid malignancy with the pathologic hallmark of translocation t(11;14) (q13, q32), which leads to an overexpression of Cyclin D1 (CCND1). The disease is also characterized by the presence of a high number of recurrent genetic alterations, which include aberrations in several cellular pathways. MCL is a heterogeneous disease with a wide range of clinical presentations and a majority presenting with aggressive disease in advanced stages.
RESULTS: Management of MCL is bereft with challenges due to its resistant and relapsing pattern. Despite improvements in remission durations, the disease is currently incurable with standard therapy and has a median survival of about 3-5 years. The use of small molecules like the bruton tyrosine kinase (BTK) and BCL2 inhibitors, for treating relapsed MCL has been established leading to a diminishing role for conventional chemotherapy. Combinations of small molecule inhibitors with or without chemoimmunotherapy, are showing promising results. Cellular therapy in the form of CAR-T cell therapy, has been approved recently.
CONCLUSIONS: Personalized cancer treatment and chemo-free regimens are showing promise and results from well-planned long-term studies are evolving. In India, there is a paucity of epidemiological, clinical, and research data in this field.

Recently, the treatment landscape for chronic lymphocytic leukemia (CLL) has changed dramatically due to the development of drugs targeting proteins in the B cell antigen receptor (BCR) pathway. Acalabrutinib, a second-generation Bruton\'s tyrosine kinase (BTK) inhibitor, was recently FDA approved for treatment of treatment naïve and relapsed refractory CLL. Acalabrutinib was designed as a more selective BTK inhibitor as compared to ibrutinib in an attempt to mitigate some of the treatment limiting toxicities seen with ibrutinib such as atrial fibrillation and bleeding. In preclinical studies, acalabrutinib was demonstrated to have efficacy in CLL in both patient blood samples and murine models. A multinational phase 1/2 study demonstrated the efficacy and safety of acalabrutinib monotherapy in treatment naïve, relapsed refractory and ibrutinib-intolerant CLL patients. Subsequent phase 3 studies, ASCEND and ELEVATE-TN, compared acalabrutinib monotherapy or combination acalabrutinib and obinutuzumab to standard of care treatments and demonstrated acalabrutinib\'s improved efficacy and tolerability. Currently, a phase 3 study is ongoing to compare acalabrutinib to ibrutinib monotherapy (NCT02477696). In the setting of recent FDA approval, real-world evidence will help to elucidate the optimal use of acalabrutinib in the treatment of CLL.

Bruton\'s tyrosine kinase (BTK) plays a critical role in the regulation of survival, proliferation, activation and differentiation of B-lineage cells. It participates by regulating multiple cellular signaling pathways, including B cell receptor and FcR signaling cascades. BTK is abundantly expressed and constitutively active in the pathogenesis of B cell hematological malignancies, as well as several autoimmune diseases. Therefore, BTK is considered as an attractive target for treatment of B-lineage lymphomas, leukemias, and some autoimmune diseases. Many industry and academia efforts have been made to explore small molecular BTK inhibitors.
This review aims to provide an overview of the patented BTK inhibitors for the treatment of cancer from 2010 to 2018.
BTK inhibitors attract much interest for their therapeutic potential in the treatment of cancers and autoimmune diseases, especially for B cell hematological malignancies. In 2013, ibrutinib was approved by the FDA as the first-in-class BTK inhibitors for the treatment of mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL), and now it is also undergoing clinical evaluation for other indications in either single or combined therapy. It is clear that BTK inhibitors can provide a promising clinical benefit in treating B-lineage lymphomas and leukemias.

Multiple myeloma (MM) is a disease that affects plasma cells and can lead to devastating clinical features such as anemia, lytic bone lesions, hypercalcemia, and renal disease. An enhanced understanding of MM disease mechanisms has led to new more targeted treatments. There is now a plethora of treatments available for MM. In this review article, our aim is to discuss many of the novel agents that are being studied or have recently been approved for the treatment of MM. These agents include the following: immunomodulators (pomalidomide), proteasome inhibitors (carfilzomib, marizomib, ixazomib, oprozomib), alkylating agents (bendamustine), AKT inhibitors (afuresertib), BTK inhibitors (ibrutinib), CDK inhibitors (dinaciclib), histone deacetylase inhibitors (panobinostat, rocilinostat, vorinostat), IL-6 inhibitors (siltuximab), kinesin spindle protein inhibitors (filanesib), monoclonal antibodies (daratumumab, elotuzumab, indatuximab, SAR650984), and phosphoinositide 3-kinase (PI3K) inhibitors.