Ibrutinib: a paradigm shift in management of CLL

Abstract

B-cell receptor (BCR) signaling plays a vital role in B-cell malignancies; Bruton tyrosine kinase is a critical mediator of this signaling. BCR signaling, either constitutively or following antigen binding, leads to activation of several downstream pathways involved in cell survival, proliferation and migration. The efficacy observed in studies of the Bruton tyrosine kinase inhibitor, ibrutinib, confirms that BCR signaling is critical for the growth of B-cell malignancies. Ibrutinib characteristically induces redistribution of malignant B cells from tissues into the peripheral blood and rapid resolution of adenopathy. Furthermore, ibrutinib therapy results in normalization of lymphocyte counts and improvement in cytopenias. Ibrutinib has been shown to have an excellent safety profile and does not cause myelosuppression. Early data from combination studies of ibrutinib with anti-CD20 monoclonal antibodies have shown more rapid responses compared to those seen with ibrutinib monotherapy. Current data strongly support continued clinical evaluation of ibrutinib in B-cell malignancies.

Keywords::

• B-cell receptor signaling
• Bruton tyrosine kinase inhibitor
• chronic lymphocytic leukemia
• ibrutinib
• PCI-32765

Financial & competing interests disclosure

S O’Brien has received research support from Pharmacyclics. JA Burger has received research support from Pharmacyclics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• B-cell receptor signaling plays a vital role in the pathogenesis of B-cell malignancies.

• Numerous kinases in the B-cell receptor signaling pathway are being explored as therapeutic targets: PI3K, spleen tyrosine kinase, Lyn and Bruton tyrosine kinase.

• Ibrutinib is a selective, irreversible, oral Bruton tyrosine kinase inhibitor.

• Ibrutinib produces a high response rate in patients with relapsed/refractory chronic lymphocytic leukemia, including those with del 17p13.1.

• Ibrutinib has a good safety profile; the majority of adverse effects are grade 1–2 and do not require discontinuation of the drug.

• In Phase I/II ibrutinib studies, occasionally patients developed subdural hematomas and other serious bleeding episodes. Although there were multiple risk factors contributing to the incidence of subdural hematoma, use of warfarin excluded patients from subsequent ibrutinib trials and the package insert recommends against the use of ibrutinib in patients on warfarin. Further investigations on the risk of bleeding need to be performed.

• In patients with chronic lymphocytic leukemia, ibrutinib induces transient lymphocytosis which may persist for months during therapy; this should not be mistaken for disease progression.

• In contrast to chemoimmunotherapy, ibrutinib does not cause myelosuppression. In fact, most patients will have improvement in cytopenias with ibrutinib.

• The combination of ibrutinib with monoclonal antibodies has shown favorable early results.

• Mutation in Bruton tyrosine kinase and clonal evolution are identified as possible causes of ibrutinib resistance in patients who progress on ibrutinib therapy.

Notes