Efficacy and Safety of Bruton Tyrosine Kinase Inhibitors in B-Cell Malignancies

Published: Sunday, Sep 30, 2018
B-cell malignancies are a heterogeneous subset of non-Hodgkin lymphomas in which treatment has remained essentially unchanged for the past 3 decades.1 However, greater understanding of the key pathways that drive proliferation, survival, and resistance patterns to commonly used therapeutics has led to the identification of novel therapeutic targets, thereby offering to significantly change the prognosis for patients affected by B-cell malignancies.1

Of these, the B-cell receptor (BCR) signaling pathway has been recognized to play a central role in the proliferation and trafficking of malignant B cells, in addition to playing a role in regulating stroma-mediated extrinsic lymphoma cell survival and interactions with the microenvironment.1,2

Ligation of BCR in healthy B cells, recruits the kinase SYK, which is phosphorylated by the SRC-family kinases. This interaction subsequently catalyzes and phosphorylates several other signaling molecules, including the lipase PLCγ2 (a lipase), B-cell linker protein, and Bruton tyrosine kinase (BTK).1,3,4 BTK is ultimately responsible for activation of cell survival mechanisms and is fundamental for B-cell migration, adhesion, selftolerance, immune activation, and cytokine secretion.1,3 However, BTK deficiency is associated with reduced numbers of mature B cells.1

Malignant B-cells take advantage of the BCR pathway as a survival and proliferation mechanism by 1 or more mechanisms: activating mutations in BCR signaling domains, antigen-dependent BCR activation, and/or ligand-independent, and autonomous BCR pathway activation.2 In vivo and ex vivo studies confirm that BCR and BTK have a prominent role in malignant B-cell homing, survival, and microenvironment- mediated drug resistance.1 Furthermore, the exact mechanism by which malignant B cells use this pathway likely varies by the subtype of B-cell malignancy and may influence how profoundly BTK is involved in cell proliferation.2 Thus, BTK does not appear to have a direct role in tumor development,5 but it is nonetheless consequential for promoting malignant cell survival and proliferation.5 Correspondingly, targeted inhibition of the BTK pathway has been shown to interfere with migration and adhesion of malignant cells in vivo and in animal models of different B-cell malignancies.2,3

In human patients, the novel BTK inhibitor, ibrutinib, has been shown to affect normalization of lymphocyte counts and remissions in patients with chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), Waldenström macroglobulinemia, and other B-cell malignancies.2 Additionally, BTK is suspected to play a role in the development or pathogenesis of other malignancies, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, multiple myeloma, and marginal zone lymphoma.3 The discovery of off-target activity associated with BTK inhibition, has prompted investigation into the potential role for these agents in solid tumors, such as ovarian, prostate, colorectal, and brain cancer.3,4

This article provides a brief overview of the role of the BCR signaling pathway in B-cell malignancies, focusing on MCL and CLL. It also reviews the available preclinical and clinical trial data with 2 novel BTK inhibitors, ibrutinib and acalabrutinib in MCL and CLL.

 

BTK in B-Cell Malignancies: CLL and MCL

Despite associations with considerable genetic heterogeneity, CLL is noted to have a complex pathogenesis that is heavily influenced by genetic factors.6 The genetic heterogeneity of CLL suggests a potential need for multiple drugs or multitargeted agents to effectively address the variety of manifestations. However, as BCR signaling has been implicated to play a central role in CLL pathogenesis and cell proliferation, inhibition of this pathway yields compartment shift of malignant B cells from the tissues into the blood, resulting in transient lymphocytosis and eventual lymph node shrinkage.7 A consequence of interfering in BCR signaling in malignant B cells in this manner permits normalization of peripheral lymphocyte counts, leading to disease remission in an appreciable number of treated patients.2,7

Given the central role of BTK in normal B-cell survival, B cells develop a survival advantage.1-3 Correspondingly, BTK has been found to be consistently amplified in CLL cells.6 The notion that the BCR pathway plays an important role in CLL development is supported by additional lines of evidence. CLL prognosis is known to differ according to IGHV mutation status. Somatic mutations in IGHV occur as a part of the natural process of affinity maturation of antibodies, in which B cells in germinal centers located in the lymph nodes experience hypermutation during an immune response. This differentiation process leads to maturation, permitting normal physiologic functions associated with healthy B-cell activity.8


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