Effects of Ibrutinib on Rituximab and Ga-101 Induced Antibody-Dependent Cell Cytotoxicity (adcc) in Lymphoma Cells in Vitro

Introduction: Ibrutinib is a first-in-class, oral, once-daily, small molecule that covalently binds to and inhibits Bruton’s tyrosine kinase (BTK), an essential enzyme in the B-cell receptor signaling pathway. Ibrutinib has shown single-agent efficacy and good tolerability in patients with various B-cell malignancies, and has been approved for treatment of previously treated chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). In addition, ibrutinib is also being evaluated in combination with several other anticancer agents, including the anti-CD20 monoclonal antibodies rituximab and ofatumumab, as well as obinutumumab (GA-101), a next-generation anti-CD20 antibody recently approved to treat CLL. A previous report suggested that the combination of ibrutinib and rituximab under certain conditions results in antagonistic effects on ADCC, a possible mechanism of action of rituximab (Kohrt HE, et al. Blood. 2014;123:1957-1960). However, clinical data in high-risk CLL in combination with rituximab showed high response rates compared with available data on the single agents (Burger JA, et al. Blood. 2012;120 (21):187). As the variance could be due to experimental conditions that do not replicate well the unique pharmacokinetics (PK; such as short half-life and lower Cmax; Advani RH, et al. JCO. 2013;31:88-94) and selectivity profile of ibrutinib under clinical dosing conditions, we modified the assay to better mimic the physiological PK profile, and further, to test these possible effects of ibrutinib in combination with the newer anti-CD20 antibody obinutumumab.