Hide and Seek: The Game Between Chronic Lymphocytic Leukaemia Cells and B Cell Receptor Signalling Inhibitors

*Kumudha Balakrishnan,1 Krishna Bojja,1 William Decker,2 Michael J. Keating3

1. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
2. Baylor College of Medicine, Houston, Texas, USA
3. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
*Correspondence to kbalakr@mdanderson.org

Disclosure: The authors have declared no conflicts of interest.
Support: This work was supported in part by Sponsored Research Agreement from Infinity Pharmaceuticals Inc., Cambridge, Massachusetts, USA.
Received: 12.07.16 Accepted: 01.12.16
Citation: EMJ. 2017;2[1]:24-30.

Abstract

The emergence of B cell receptor (BCR) kinase inhibitors has recently changed the treatment landscape in chronic lymphocytic leukaemia (CLL). The inhibitors that selectively target potential kinases downstream from BCR (particularly Bruton’s tyrosine kinase [BTK] and phosphoinositide 3-kinase [PI3K]) have replaced conventional chemotherapy for high-risk CLL. Ibrutinib and idelalisib are the respective first-in-class BTK and PI3K-δ inhibitors that are US Food and Drug Administration (FDA) approved for CLL treatment, with promising second-generation molecules under development. Differing from idelalisib, duvelisib (IPI-145) inhibits both delta and gamma isoforms of PI3K. Kinase inhibitors have gained popularity in the clinic primarily due to their ability to induce remissions in the vast majority of patients, even in patients with high-risk disease features, without causing haematotoxicity. In particular, they interfere with the homing capabilities of CLL cells residing in their respective microenvironments and cause lymphocytosis via redistribution of tissue-resident CLL cells into the peripheral blood. Thereby, BCR inhibitors can seek out and target hiding CLL cells in the lymph node and marrow niches. In this review, we discuss laboratory and clinical aspects of the BCR inhibitors that have recently advanced the treatment of B cell malignancies, with a particular emphasis on CLL. Despite the excitement about this new class of compounds targeting BCR signalling, single agent therapy with kinase inhibitors has limitations, requiring continuous kinase suppression to maintain remissions, which generally are partial remissions, indicating that combination strategies will become important for moving the field forward.

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