Abstract
Tyrosine kinase inhibitors (TKIs) targeting signaling molecules downstream B cell receptor (BCR) are powerfully spreading in the therapeutic landscape of B cell lymphoproliferative disease, due to a manageable toxicity profile and encouraging clinical effectiveness. In particular, ibrutinib, previously called PCI-32765, is a potent inhibitor of Bruton tyrosine kinase (Btk), recently approved for the treatment of relapsed mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). Moreover, idelalisib (formerly GS-1101 and CAL-101) is a selective reversible inhibitor of the p110δ isoform of phosphoinositol 3 kinase (PI3K) approved for the treatment of patients with relapsed follicular lymphoma (FL) and CLL. These agents directly affect the neoplastic clone, disrupting the supportive platform provided by BCR signaling cascade and by other microenvironmental mutualistic interactions, and also interfering with chemokine gradients and adhesive properties of neoplastic B cells. In the present review, we describe the clinical efficacy of ibrutinib and idelalisib in CLL and B cell non-Hodgkin lymphoma (B-NHL), then focusing on the mode of action (MOA) of these TKIs towards the neoplastic B cell compartment. At last, the review would further expand the view on potential additional targets of ibrutinib and idelalisib belonging to other microenvironmental cellular elements.
Highlights
Signaling from the B cell receptor (BCR) is essential for normal B cell development and controls several cellular functions such as proliferation, apoptosis, differentiation, and cell migration [1]
Constitutive activation of BCR is a common hallmark of B cell malignancies, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and diffuse large B cell lymphoma (DLBCL), observation that has led the design of a novel panel of inhibitors targeting kinases responsible for BCR signal transduction
We focused on ibrutinib, approved by the Food and Drug Administration (FDA) in November 2013 for the treatment of relapsed MCL and in February 2014 as a second-line treatment for CLL and idelalisib, which was approved by FDA in July 2014 for the treatment of patients with relapsed FL or relapsed small lymphocytic lymphoma (SLL) and CLL, pointing the attention to the clinical efficacy in CLL and B cell non-Hodgkin lymphomas (NHL), the antitumor mode of action (MOA) and the possible effects of these drugs on non-malignant cells in tumor microenvironment
Summary
Signaling from the B cell receptor (BCR) is essential for normal B cell development and controls several cellular functions such as proliferation, apoptosis, differentiation, and cell migration [1]. Constitutive activation of BCR is a common hallmark of B cell malignancies, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and diffuse large B cell lymphoma (DLBCL), observation that has led the design of a novel panel of inhibitors targeting kinases responsible for BCR signal transduction. We focused on ibrutinib, approved by the Food and Drug Administration (FDA) in November 2013 for the treatment of relapsed MCL and in February 2014 as a second-line treatment for CLL and idelalisib, which was approved by FDA in July 2014 for the treatment of patients with relapsed FL or relapsed small lymphocytic lymphoma (SLL) and CLL, pointing the attention to the clinical efficacy in CLL and B cell non-Hodgkin lymphomas (NHL), the antitumor mode of action (MOA) and the possible effects of these drugs on non-malignant cells in tumor microenvironment
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