Combination Of Ibrutinib And Corticosteroids In B-Cell Non-Hodgkin Lymphomas (Nhl)

Introduction: The B-cell receptor (BCR) signaling pathway is a major driver in the pathogenesis of B-cell malignancies. A vast array of BCR-associated kinases have emerged as rational therapeutic targets, including Bruton9s tyrosine kinase (BTK), which plays a pivotal role in BCR signaling. Ibrutinib is a first-in-class, oral, covalent BTK inhibitor approved in the US for patients with mantle cell lymphoma and chronic lymphocytic leukemia (CLL) who have received at least 1 prior therapy, CLL patients with 17p deletion, and patients with Waldenstrom9s macroglobulinemia. While ibrutinib is efficacious as a single agent, combinations with other drugs may further enhance efficacy and increase response rates in patients with NHLs. Corticosteroids are included in nearly all combination regimens for NHL treatment, showing promising results when combined with chemotherapy and antibodies (Cunningham, Lancet 2013). We therefore evaluated corticosteroids in combination with ibrutinib in preclinical models of activated B cell-like (ABC) and germinal center B cell-like (GCB) diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma (FL). Methods: ABC-DLBCL, GCB-DLBCL, and FL cell lines were used in this study. Drug effect on cell growth was evaluated with CellTiter-Glo luminescent cell viability assay (Promega) following treatment with ibrutinib or the combinations for 3 days. Combination index (CI) was determined using CalcuSyn. Synergy score (SS) was calculated using the Chalice Analyzer (Horizon CombinatoRx). Mutation profiles were extracted from the Catalogue of Somatic Mutations in Cancer database. Results: Synergistic growth suppression of dexamethasone and ibrutinib was identified in 7 of 14 GCB-DLBCL cell lines. Dexamethasone had a stronger effect on cells with lower EC50 on ibrutinib treatment. Intriguingly, 4 of these 7 cell lines that showed synergy of the 2 compounds had BCL-2 nonsynonymous mutations, whereas only 1 of the cell lines with no combination effect had BCL-2 silent mutation. In addition to dexamethasone, other corticosteroids, including hydrocortisone, prednisolone, and mometasone, also showed synergy with ibrutinib in GCB-DLBCL (SU-DHL-4, CI = 0.219-0.668, SS = 5.08-15.15; SU-DHL-10, CI = 0.008-0.224, SS = 7.27-11.24), ABC-DLBCL (TMD-8, CI = 0.001-0.016, SS = 21.1), and FL cell lines (DoHH2, CI = 0.020-0.467, SS = 12.3-30.86; WSU-FSCCL, CI = 0.017-0.022, SS = 18.24). The in vivo effect and underlying mechanisms of the combinations are currently under investigation. Conclusions: We identified synergistic inhibitory effects of ibrutinib and corticosteroids on ABC-DLBCL, GCB-DLBCL, and FL cell growth, providing a rationale for the design of combination clinical trials in these NHL types. Further understanding of the mechanisms contributing to the synergy may help to stratify patient populations and expand treatment to other lymphoid neoplasms. Citation Format: Hsu-Ping Kuo, Sidney Hsieh, Karl J. Schweighofer, Leo WK Cheung, Mutiah Apatira, Mint Sirisawad, Shiquan Wu, Karl Eckert, Yu Liang, Jeff Hsu, Chun-Te Chen, Darrin Beaupre, Betty Y. Chang. Combination of ibrutinib and corticosteroids in B-cell non-Hodgkin lymphomas (NHL). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3072.