Targeting B Cell Signaling in Chronic Lymphocytic Leukemia

Curr Oncol Rep. 2017 Sep;19(9):61. doi: 10.1007/s11912-017-0620-7.

Abstract

In recent years, a revolution in the management of chronic lymphocytic leukemia (CLL) has centered on the targeting of the B cell receptor (BCR) signaling pathway. Our improved understanding of the biology of cell signaling in CLL and the development of oral kinase inhibitors directed at the BCR pathway has led to the approval of two new agents and has the potential to radically change the treatment of CLL in both the relapsed/refractory and upfront settings. In this review, we will describe the underlying biology of the BCR signaling pathway. We will discuss the landmark clinical trials resulting in the approval of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib and the PI3Kδ inhibitor idelalisib. We will highlight ongoing trials that are evaluating the use of combinations of these agents with standard chemotherapy. We will evaluate some of the emerging data regarding toxicity, potential off-target effects, and mechanisms of resistance to BCR signaling pathway blockade. Finally, we will highlight some of the next-generation BCR pathway inhibitors currently in development.

Keywords: B cell receptor; Chronic lymphocytic lymphoma; Ibrutinib; Idelalisib.

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use*
  • B-Lymphocytes / drug effects*
  • B-Lymphocytes / metabolism
  • Clinical Trials as Topic
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
  • Leukemia, Lymphocytic, Chronic, B-Cell / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Protein-Tyrosine Kinases / metabolism
  • Receptors, Antigen, B-Cell / metabolism
  • Signal Transduction / drug effects*

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Receptors, Antigen, B-Cell
  • Protein-Tyrosine Kinases