Abstract 3519: Mobilization of follicular lymphoma cells into peripheral blood following BTK inhibition by ibrutinib.
Authors: Chang Betty Y. , Magadala Padmaja , Francesco Michelle , Balasubramanian Sriram , Elias Laurence , Buggy Joseph J. 
Published: August 2014

Abstract
Introduction: Ibrutinib is an orally administered, highly potent and specific inhibitor of Bruton tyrosine kinase (BTK) in clinical development for the treatment of B cell lymphoproliferative diseases. In the course of the Phase I study of ibrutinib, we found patients with follicular lymphoma (FL) have transient increases of the blood absolute lymphocyte count (ALC) following treatment with ibrutinib, as has been demonstrated with treatment of CLL and MCL patients (Advani et al., 2012a; Wang et al., 2011b., Chang et al., 2011c). We characterized the patterns and phenotypes of blood cells among patients with FL before and following ibrutinib for over 500 days, and further investigated the mechanism of these changes. The baseline ALC of patients with FL treated in the previously reported Phase I study was 1.11 ± 0.12 (x 109 /L, Mean ± SE, n=14). ALC increases of 40-150% (Mean ± SE=59 ± 20%, n=14) occurred following the first two weeks of drug treatments. Patients who were administered drug with 35-day cycles (29 days on, 7-days off) (n=10) exhibited decreases of lymphocytes during the week off treatment, and rapid increases after starting the next cycle of treatment. During this same time, patients experienced reductions in tumor burden as demonstrated by the decrease in Sum of Perpendicular Diameters (SPD). The cyclically increasing lymphocytes were confirmed to be CD19+CD20+CD10+ CD5− light chain restricted, and thus likely to represent circulating, mobilized lymphoma cells. After a single cycle of treatment, these CD19+CD10+ cells had reduced levels of CD38, Ki67 and pErk, consistent with a lower proliferation index. Functionally, ibrutinib inhibited BCR- and CXCL12-mediated adhesion and chemotaxis of FL cell lines in vitro (EC50 = 10-100 nM), and the pseudoemperipoleisis of FL cells in the presence of stromal cells.
Conclusion: Transient increases of lymphocytes in the peripheral blood are notable among FL patients treated with ibrutinib. These CD19+CD10+ cells had decreased CD38, Ki67 and pErk expression. The increase in ALC most likely reflects mobilization of FL cells from lymph nodes into the peripheral blood. We have demonstrated that inhibition of BTK activation by ibrutinib results in inhibition of FL cell chemotaxis, adherence and pseudo-emperipoleisis. We propose that Btk activity is essential for the homing of FL cells into secondary lymphoid organstissues, and that its inhibition results in the compartmental shift of FL cells from tissues into the periphery.
aAdvani R, J. Clin Oncol. 2012 10.1200/JCO 2012.42.7906.
bWang L, American Society of Hematology 2011.
cChang BY, in American Society of Hematology 2011.
Citation Format: Betty Y. Chang, Padmaja Magadala, Michelle Francesco, Sriram Balasubramanian, Laurence Elias, Joseph J. Buggy. Mobilization of follicular lymphoma cells into peripheral blood following BTK inhibition by ibrutinib. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3519. doi:10.1158/1538-7445.AM2013-3519