Chronic Lymphocytic Leukemia (S O’Brien, Section Editor)

Current Hematologic Malignancy Reports

, Volume 7, Issue 1, pp 26-33

Inhibiting B-Cell Receptor Signaling Pathways in Chronic Lymphocytic Leukemia

  • Jan A. BurgerAffiliated withDepartment of Leukemia, Unit 428, The University of Texas M.D. Anderson Cancer Center Email author 

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Abstract

B-cell receptor (BCR) signaling is a central pathologic mechanism in B-cell malignancies, including chronic lymphocytic leukemia (CLL), in which it promotes leukemia cell survival and proliferation, and modulates CLL cell migration and tissue homing. BCR signaling now can be targeted with new, small molecule inhibitors of the spleen tyrosine kinase (Syk), Bruton’s tyrosine kinase (Btk), or phosphoinositide 3′-kinase (PI3K) isoform p110δ (PI3Kδ), which have recently entered the clinical stage and show promising results in patients with CLL. During the first weeks of therapy, these agents characteristically induce rapid resolution of lymphadenopathy and organomegaly, accompanied by a transient surge in lymphocyte counts due to “mobilization” of tissue-resident CLL cells into the blood. Then, often after months of continuous therapy, a major proportion of patients achieve remissions. This article reviews key biologic aspects of BCR-associated kinases in CLL and other B cell neoplasias, and develops perspectives for future development of this exciting new class of kinase inhibitors.

Keywords

Chronic lymphocytic leukemia CLL Signaling pathways Syk Btk PI3K delta B-cell receptor BCR Chemokine receptors CXCR4 CXCR5 Microenvironment Kinase inhibitors B lymphocytes ZAP-70 Fostamatinib PCI-32765 CAL-101 Therapy