BCR pathway inhibition as therapy for chronic lymphocytic leukemia and lymphoplasmacytic lymphoma

A Wiestner - Hematology 2014, the American Society of …, 2014 - ashpublications.org
A Wiestner
Hematology 2014, the American Society of Hematology Education …, 2014ashpublications.org
Chronic lymphocytic leukemia (CLL) and lymphoplasmacytic lymphoma (LPL) are
malignancies of mature B cells. In LPL, mutations of the adaptor protein MYD88 (L265P) in
the Toll-like receptor pathway have been recognized recently as being a hallmark of the
disease and indicate a dependence of the tumor on this pathway. In CLL, functional studies
have implicated BCR activation in the tissue microenvironment as a pivotal pathway in the
pathogenesis. Bruton's tyrosine kinase (BTK) and the PI3Kδ isoform are essential for BCR …
Abstract
Chronic lymphocytic leukemia (CLL) and lymphoplasmacytic lymphoma (LPL) are malignancies of mature B cells. In LPL, mutations of the adaptor protein MYD88 (L265P) in the Toll-like receptor pathway have been recognized recently as being a hallmark of the disease and indicate a dependence of the tumor on this pathway. In CLL, functional studies have implicated BCR activation in the tissue microenvironment as a pivotal pathway in the pathogenesis. Bruton's tyrosine kinase (BTK) and the PI3Kδ isoform are essential for BCR signaling and also seem to be required for signal transduction in LPL cells, even if the role of BCR signaling in this disease remains less well defined. Ibrutinib, a covalent inhibitor of BTK approved by the Food and Drug Administration as a second-line treatment for CLL, and idelalisib, a selective inhibitor of PI3Kδ, achieve excellent clinical responses in both diseases irrespective of classic markers indicating high-risk disease. Several additional inhibitors targeting BTK and PI3Kδ, as well as the spleen tyrosine kinase, have entered clinical trials. This review discusses the biologic basis for kinase inhibitors as targeted therapy for CLL and LPL and summarizes the clinical experience with these agents.
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