Abstract 3709: Synergistic effects of obatoclax (GX15-070) and bortezomib (BTZ) in non-Hodgkin's lymphoma
Authors: Thudium Karen E. , Wollenberg Lance , Mavis Cory , Czuczman Myron S. , Fetterly Gerald J. , Hernandez-Ilizaliturri Francisco 
Published: August 2012

Abstract
Non-Hodgkins Lymphoma (NHL) is the second most rapidly increasing cause of cancer-related death in the US, making selection of appropriate combinations against B-cell lymphoma increasingly important. Our aim was to develop a pharmacodynamic (PD) model to characterize the interaction of obatoclax and bortezomib (BTZ), which target pathways associated with acquired resistance to therapies of rituximab and chemotherapy in NHL. Primary tumor cells from patients (n=45) with previously untreated relapsed/refractory (rel/ref) B-cell lymphoma were utilized. Sample subtypes included: activated B-cell (ABC), diffuse large B-cell lymphoma (DLBCL), germinal center B-cell (GCB), Transformed DLBCL, Follicular lymphoma (FL), Hodgkin's lymphoma (HL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL) and small lymphocytic lymphoma (SLL). Primary tumor cells were exposed to obatoclax and BTZ for 48-hours, and cell viability was determined by luminescent cell viability assays. Single agent IC50 values for obatoclax (0.0003-6.3nM) and BTZ (0.0005-0.01nM) were determined across all cell lines. Tumors were exposed to combinations of obatoclax and BTZ and a PD interaction model was developed to assess synergy; (α=1, additive; Φ&lt;1, synergy; ≤ &gt;1, antagonism). Patient demographics, BCL-2 status, Ki67%, CD20 status, lifetime rituximab dose and response to therapy were described for all patients. A total of 14 male (M) and 9 female (F) tumor cells were evaluable for synergy. Values of ≤ were: 0.93-1.0 (DLBCL-ABC-Denovo (D)); 0.64-1.6 (DLBCL-ABC Refractory (R)); 0.64-0.71 (DLBCL/GCB-D); 0.48-1.1 (FL-D); 0.97-2.5 (FL-R); 0.58-1.2 (HL-D); and (1.0-1.2) SLL-D. Synergy was observed in both MCL-R (α = 0.55) and MZL-D (α = 0.56). Patients with progressive disease (n=3) after therapy all had Ψ&gt;1. Tumor cells from patients who had a complete (n=6) or partial response (n=8) post-biopsy had a synergistic or additive effect to obatoclax and BTZ. A non-significant difference in ≤ was observed between M and F (p=0.5510), D and R cell types (p=0.31), and CD20 expression (p=0.678) by a two tailed Mann-Whitney. The ≤ for the interaction between obatoclax and BTZ was correlated with lifetime rituximab dose (r =0.61, t-score = 2.4, p&lt;0.05), %Ki67 (r =0.50, t-score = 2.04, p&gt;0.05) and age (r =−0.21, t-score = 0.085, p&gt;0.05). A one-way ANOVA indicates a significant difference observed in ≤ with patients showing complete or partial response compared with progressive disease (p&lt;0.05). These results indicate combination of obatoclax and BTZ have a synergistic effect in GCB-DLBCL-D, MCL-R and MZL-D cell types. A partial synergy or additive effect was observed in FL-D, HL-D, SLL-D and ABC-DLBCL-D. This approach provides a modeling strategy that may serve as a framework for bridging in vitro and ex vivo work to provide clinical benefit to patients, and supports the use of obatoclax in combination with BTZ in the future.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3709. doi:1538-7445.AM2012-3709