Novel Pharmacodynamic Approach to Assess Obatoclax (GX15-070) and Bortezomib (BTZ) Synergism in Non-Hodgkin’s Lymphoma

Obatoclax (GX15-070) is a small molecule that binds to Bcl-2 family proteins (Bcl-2, Bcl- XL, and MCL-2) and has demonstrated efficacy in reinitiating programmed cell death. We previously demonstrated the synergistic effects of GX15-070 in combination with cytotoxic agents in rituximab sensitive and rituximab resistant models. Our aim was therefore to develop a pharmacodynamic model to characterize the degree of interaction between GX15-070 and Bortezomib (BTZ) on cells isolated from Non-Hodgkin’s Lymphoma (NHL) patients to understand the role of combination therapy. Cells were exposed to escalating concentrations of GX15-070 and BTZ for 48 hours; data were fit to pharmacodynamic model. Patient demographics, BCL-2 status, Ki67%, CD20, lifetime-rituximab dose and response to therapy were obtained for all patients and correlated with observed pharmacodynamic endpoints. The greatest degree of synergy was seen in the MCL, MZL, and untreated DLBCL-GCB. Previously un-treated B-cell lymphoma (DLBCL-ABC, DLBCL-GCB/transformed, FL) and relapsed refractory B-cell lymphoma (DLBCL-ABC, FL) demonstrate a combination shift towards a possible additive effect. The majority of the patients had DLBCL or FL, and 29% had relapsed/refractory disease. These results demonstrate synergism in NHL and may support the use of this combination in a future clinical trial.