Targeting Bruton's tyrosine kinase with ibrutinib in B‐cell malignancies

Abstract

The B-cell receptor signaling pathway, which is critical to the development and maturation of normal B-cells, is emerging as an attractive therapeutic target in B-cell malignancies. Ibrutinib is a potent irreversible inhibitor of Bruton's tyrosine kinase (Btk), a key kinase important for signal transduction in the B-cell receptor (BCR) pathway. In preclinical studies, ibrutinib potently bound to Btk, inhibited BCR signaling, and decreased tumor cell proliferation and survival in many B-cell malignancy models. Excellent safety and efficacy data in clinical trials have led to US Food and Drug Administration (FDA) approval of ibrutinib for previously treated mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL), as well as CLL with 17p deletion. Ongoing clinical studies have also demonstrated great potency of ibrutinib in treating other types of non-Hodgkin's lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and Waldenström's macroglobulinemia (WM). Combination of ibrutinib with chemoimmunotherapy and other promising novel agents in B-cell malignancy therapy has also been under clinical investigation.

A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies

“…Grade 3 and 4 hematologic toxicity was also seen, with neutropenia, thrombocytopenia, and anemia reported. 16,17,30 Bleeding events of CTCAE grade 3 or higher, including central nervous system hemorrhage, have been reported in 3.4% (17 of 506 CLL patients). 17 Here, we report initial clinical data from a phase 1 dose-escalation study of a selective BTK inhibitor, ONO/GS-4059, in 90 patients with relapsed and refractory B-cell malignancies.…”

Ibrutinib downregulates a subset of miRNA leading to upregulation of tumor suppressors and inhibition of cell proliferation in chronic lymphocytic leukemia

“…Ibrutinib is a selective BTK inhibitor 37 Table 11). Taken together, these results suggest that the changes in miRNA expression and target mRNA transcripts levels observed with ibrutinib treatment are likely specific to the mechanism of action of ibrutinib, and are not seen in the context of general antitumor effects with fludarabine.…”

Treatment strategies for diffusive large B-cell lymphoma

“…Inhibitors of Bruton Tyrosine Kinase (BTK), such as Ibrutinib, are researched in many B cell malignancy, included in DLBCL [46]. BTK plays an important role in intracellular signaling pathway of B-cell receptor (BCR), very important in lymphoma genesis.…”