BTK inhibitors in the treatment of hematological malignancies and inflammatory diseases: mechanisms and clinical studies

Journal of Hematology & Oncology, Journal Year: 2022, Volume and Issue: 15(1)

Published: Oct. 1, 2022

Bruton's tyrosine kinase (BTK) is an essential component of multiple signaling pathways that regulate B cell and myeloid proliferation, survival, functions, making it a promising therapeutic target for various malignancies inflammatory diseases. Five small molecule inhibitors have shown remarkable efficacy been approved to treat different types hematological cancers, including ibrutinib, acalabrutinib, zanubrutinib, tirabrutinib, orelabrutinib. The first-in-class agent, has created new era chemotherapy-free treatment malignancies. Ibrutinib so popular became the fourth top-selling cancer drug worldwide in 2021. To reduce off-target effects overcome acquired resistance significant efforts made developing highly selective second- third-generation BTK combination approaches. Over past few years, also repurposed Promising data obtained from preclinical early-phase clinical studies. In this review, we summarized current progress applying disorders, highlighting available results

Language: Английский

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Bruton’s Tyrosine Kinase Inhibitors (BTKIs): Review of Preclinical Studies and Evaluation of Clinical Trials

Molecules, Journal Year: 2023, Volume and Issue: 28(5), P. 2400 - 2400

Published: March 6, 2023

In the last few decades, there has been a growing interest in Bruton’s tyrosine kinase (BTK) and compounds that target it. BTK is downstream mediator of B-cell receptor (BCR) signaling pathway affects proliferation differentiation. Evidence demonstrating expression on majority hematological cells led to hypothesis inhibitors (BTKIs) such as ibrutinib can be an effective treatment for leukemias lymphomas. However, body experimental clinical data demonstrated significance BTK, not just malignancies, but also solid tumors, breast, ovarian, colorectal, prostate cancers. addition, enhanced activity correlated with autoimmune disease. This gave rise beneficial therapy rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), Sjögren’s syndrome (SS), allergies, asthma. this review article, we summarize most recent findings regarding well advanced have developed date their applications mainly cancer chronic inflammatory disease patients.

Language: Английский

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Bruton’s Kinase Inhibitors for the Treatment of Immunological Diseases: Current Status and Perspectives

Journal of Clinical Medicine, Journal Year: 2022, Volume and Issue: 11(10), P. 2807 - 2807

Published: May 16, 2022

The use of Bruton’s tyrosine kinase (BTK) inhibitors has changed the management patients with B-cell lymphoid malignancies. BTK is an important molecule that interconnects antigen receptor (BCR) signaling. (BTKis) are classified into three categories, namely covalent irreversible inhibitors, reversible and non-covalent inhibitors. Ibrutinib first covalent, inhibitor approved in 2013 as a breakthrough therapy for chronic lymphocytic leukemia patients. Subsequently, two other irreversible, second-generation BTKis, acalabrutinib zanubrutinib, have been developed malignancies to reduce ibrutinib-mediated adverse effects. More recently, BTKis under development immune-mediated diseases, including autoimmune hemolytic anemia, immune thrombocytopenia, multiple sclerosis, pemphigus vulgaris, atopic dermatitis, rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s disease, spontaneous urticaria, among others. This review article summarizes preclinical clinical evidence supporting role various autoimmune, allergic, inflammatory conditions.

Language: Английский

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Treatment of Double-Refractory Chronic Lymphocytic Leukemia—An Unmet Clinical Need

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(3), P. 1589 - 1589

Published: Jan. 27, 2024

Recent years have seen significant improvement in chronic lymphocytic leukemia (CLL) management. Targeting B-cell lymphoma (BCL-2) and Bruton’s kinase (BTK) become the main strategies to restrain CLL activity. These agents are generally well tolerated, but discontinuation of these therapies happens due resistance, adverse effects, Richter’s transformation. A growing population patients who previously used both BTK inhibitors BCL2 suffer from constriction following regimens. This review explores resistance mechanisms for ibrutinib venetoclax. Moreover, we present innovative approaches evaluated treating double-refractory CLL.

Language: Английский

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PI3K Inhibitors for the Treatment of Chronic Lymphocytic Leukemia: Current Status and Future Perspectives

Cancers, Journal Year: 2022, Volume and Issue: 14(6), P. 1571 - 1571

Published: March 18, 2022

Phosphoinositide 3-kinases (PI3Ks) signaling regulates key cellular processes, such as growth, survival and apoptosis. Among the three classes of PI3K, class I is most important for development, differentiation activation B T cells. Four isoforms are distinguished within (PI3Kα, PI3Kβ, PI3Kδ PI3Kγ). expression limited mainly to cells their precursors, blocking PI3K has been found promote apoptosis chronic lymphocytic leukemia (CLL) Idelalisib, a selective inhibitor, was first-in-class PI3Ki introduced into CLL treatment. It showed efficacy in patients with del(17p)/

Language: Английский

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The Evolution of Therapies Targeting Bruton Tyrosine Kinase for the Treatment of Chronic Lymphocytic Leukaemia: Future Perspectives

Cancers, Journal Year: 2023, Volume and Issue: 15(9), P. 2596 - 2596

Published: May 3, 2023

The development of inhibitors Bruton tyrosine kinase (BTK) and B-cell lymphoma 2 (BCL2) has resulted in a paradigm shift the treatment chronic lymphocytic leukaemia (CLL) over last decade. Observations regarding importance receptor signalling for survival proliferation CLL cells led to first-in-class BTK inhibitor (BTKi), ibrutinib, CLL. Despite being better tolerated than chemoimmunotherapy, ibrutinib does have side effects, some which are due off-target inhibition kinases other BTK. As result, more specific were developed, such as acalabrutinib zanubrutinib, demonstrated equivalent/enhanced efficacy improved tolerability large randomized clinical trials. increased specificity BTK, effects resistance remain therapeutic challenges. these drugs all bind covalently an alternative approach was develop noncovalent including pirtobrutinib nemtabrutinib. mechanisms BTK-binding agents potential overcome mutations, something that been borne out early trial data. A further step introduction degraders, remove by ubiquitination proteasomal degradation, marked contrast inhibition. This article will review evolution offer future perspectives on sequencing increasing number different agents, how this may be impacted mutations itself kinases.

Language: Английский

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Acquired BTK mutations associated with resistance to noncovalent BTK inhibitors

Blood Advances, Journal Year: 2023, Volume and Issue: 7(19), P. 5698 - 5702

Published: Jan. 20, 2023

Language: Английский

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Extramedullary and extranodal manifestations in chronic lymphocytic leukemia – an update

Annals of Hematology, Journal Year: 2024, Volume and Issue: 103(9), P. 3369 - 3383

Published: July 25, 2024

Chronic lymphocytic leukemia/small lymphoma (CLL/SLL) is a common leukemia characterized by clonal expansion of mature CD5+/CD23 + B cells in the blood, bone marrow (BM) and lymphoid tissues. CLL can undergo extramedullary extranodal infiltration, with one study noting an incidence only 0.3 per 100,000 people, 17.6% patients another report. The most sites leukemic involvement are skin central nervous system; however, other organs, including liver, lungs, kidney, gastrointestinal tract, bone, prostate heart, occasionally involved. prognostic significance extra-medullary still under debate, but prognosis such seems to be better era novel targeted drugs. Following diagnosis CLL, survival appears depend on site infiltration. This review presents overview lesions, focusing its epidemiology, pathogenesis, prognosis, clinical characteristics treatment results.

Language: Английский

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Zanubrutinib for the treatment of lymphoid malignancies: Current status and future directions

Frontiers in Oncology, Journal Year: 2023, Volume and Issue: 13

Published: March 23, 2023

Zanubrutinib (BGB-3111, Brukinsa

Language: Английский

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Leukemia Cutis—The Current View on Pathogenesis, Diagnosis, and Treatment

Cancers, Journal Year: 2023, Volume and Issue: 15(22), P. 5393 - 5393

Published: Nov. 13, 2023

Leukemia cutis (LC) is defined as the leukemic infiltration of epidermis, dermis, and subcutaneous tissue. may follow or occur simultaneously with diagnosis systemic leukemia. However, cutaneous lesions are occasionally diagnosed primary manifestation Leukemic skin infiltrations demonstrate considerable variation regarding a number changes, distribution, morphology. The highest incidence LC observed in chronic lymphocytic leukemia, monocytic myelomonocytic acute myeloid T-cell lineage Although pathogenic mechanism invasion cells into not well understood, chemokine receptors adhesion molecules genetic characteristics leukemia thought to play role. be localized disseminated alone combination on any site skin, most frequently trunk extremities. common clinical presentations papules, nodules, macules, plaques, ulcers. In patients, complete partial resolution occurs hematologic remission. patients resistant disease recurrent infiltration, local radiotherapy can used. This review presents recent data pathogenesis, diagnosis, treatment involvement different types

Language: Английский

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