Abstract 1693: The combination of romidepsin and bendamustin is synergistically cytotoxic and reverses the malignant phenotype in preclinical models of T-cell lymphoma

Background: Peripheral T-cell lymphomas (PTCLs) represent approximately 10-15% of all non-Hodgkin lymphomas (NHL) in the Western world, and their incidence is increasing. Cases of PTCL tend to have an aggressive clinical course, with poor patient responses to conventional chemotherapy and poor long-term survival. So far, treatment approaches have mirrored diffuse large B-cell lymphoma (DLBCL) and CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and CHOP-like chemotherapy are commonly used despite suboptimal results. Histone deacetylase inhibitors (HDACs) have been approved for the treatment of relapsed or refractory PTCLs given their single-agent activity in these diseases. To continue to improve responses in patients with PTCL, it is important to assess the utility of romidepsin as frontline therapy and as a component of combination therapies. Aim: Interactions between romidepsin (R) and bendamustine (B), a potent cytotoxic alkylating drug active against a panel of other lymphoproliferative disorders, was investigated in in preclinical models of T-cell Lymphoma. Experimental Design: Assays for cytotoxicity on 5 different T-cell lymphoma and leukemia cell lines (Jurkat, HD-MAR2, Karpas, Sup-T1, HH), mathematical analysis for synergism (Chou-Talalay equation), flow cytometry, and the Itk-Syk transgenic mouse model (K. Pechloff, 2010) were used to explore the in vitro and in vivo activities of R and B alone and in combination in T-cell lymphoid malignancies. Results: In vitro, romidepsin and bendamustine exhibited concentration- and time-dependent cytotoxicity against all the 5 different T-cell lymphoma and leukemia cell lines. Romidepsin showed synergism when combined with bendamustine in all cell lines studied. Romidepsin also induced potent apoptosis and caspase activation when combined with bendamustine across the panel. The impact of schedule on the activity of the combination was determined by assessing cell viability after treatment with B and R as follows: (1) simultaneous exposure; (2) B pretreatment followed by exposure to R; and (3) R pretreatment followed by exposure to B. In a new mouse model of PTCL in which a status of permanent T cell activation mediated by the Itk-Syk transcript induces highly malignant PTCLs with 100% penetrance that resemble the human disease, the combination of romidepsin and bendamustine enhanced efficacy compared with either drug alone. Conclusions: Collectively, these data strongly support the potentia