Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765)

Abstract

Over the past 3 years, ibrutinib (PCI-32765) has emerged as a breakthrough in targeted therapy for patients with certain types of B cell malignancies. Early stage clinical trials found ibrutinib to be particularly active in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), providing the rationale for ongoing phase 3 trials. In contrast to conventional chemo-immunotherapy, ibrutinib is not myelosuppressive, and responses are not affected by disease features that predict failure to respond to or short remission durations after chemo-immunotherapy, such as del17p. In CLL, ibrutinib characteristically causes an early redistribution of tissue-resident CLL cells into the blood, with rapid resolution of enlarged lymph nodes, along with a surge in lymphocytosis. Later, after weeks to months of continuous ibrutinib therapy, the growth- and survival-inhibitory activities of ibrutinib result in the normalization of lymphocyte counts and remissions in a majority of patients. This review discusses the discovery, preclinical and clinical development of ibrutinib, its pathophysiological basis, and outlines perspectives for future use of ibrutinib.

Keywords::

• Chronic lymphocytic leukemia
• CLL
• microenvironment
• B cell receptor
• BCR
• BTK
• ibrutinib

Acknowledgements

The authors are grateful to Jeannice Theriot for expert editorial assistance.

Potential conflict of interest:

Disclosure forms provided by the authors are available with the full text of this article at http://www.informahealthcare.com/lal.

This manuscript was supported by a CLL Global Research Foundation grant and a Cancer Prevention and Research Institute of Texas (CPRIT) grant (to J.A.B.).