Data from Combination of YM155, a Survivin Suppressant, with Bendamustine and Rituximab: A New Combination Therapy to Treat Relapsed/Refractory Diffuse Large B-cell Lymphoma

Abstract

<div>Abstract<p><b>Purpose:</b> There remains an unmet therapeutic need for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). The purpose of this study was to evaluate the therapeutic potential of sepantronium bromide (YM155), a survivin suppressant, in combination with either bendamustine or both bendamustine and rituximab using DLBCL models.</p><p><b>Experimental Design:</b> Human DLBCL cell lines, DB, SU-DHL-8, and WSU-DLCL2, were treated with YM155 in combination with bendamustine. Cell viability, apoptosis induction, protein expression, and cell-cycle distribution were evaluated. Furthermore, antitumor activities of YM155, in combination with bendamustine or both bendamustine and rituximab, were evaluated in mice bearing human DLBCL xenografts.</p><p><b>Results:</b> The combination of YM155 with bendamustine showed greater cell growth inhibition and sub-G<sub>1</sub> population than either agent alone. YM155 inhibited bendamustine-induced activation of the ATM pathway and accumulation of survivin at G<sub>2</sub>–M phase, with greater DNA damage and apoptosis than either single agent alone. In a DLBCL DB murine xenograft model, YM155 enhanced the antitumor activity of bendamustine, resulting in complete tumor regression without affecting body weight. Furthermore, YM155 combined with bendamustine and rituximab, decreased FLT-PET signals in lymph nodes and prolonged overall survival of mice bearing disseminated SU-DHL-8, an activated B-cell–like (ABC)-DLBCL xenografts when compared with the combination of either rituximab and bendamustine or YM155 with rituximab.</p><p><b>Conclusions:</b> These results support a clinical trial of the combination of YM155 with bendamustine and rituximab in relapsed/refractory DLBCL. <i>Clin Cancer Res; 20(7); 1814–22. ©2014 AACR</i>.</p></div>