Based on the in vitro synergism observed for combinations of OTX015 with other compounds , we evaluated the activity of combinations of this bromodomain inhibitor in an in vivo model of ABC-DLBCL. Mice bearing xenografts of the ABC-DLBCL cell line SU-DHL-2 were treated with control or OTX015, BTK inhibitor ibrutinib, the mechanistic target of rapamycin (mTOR) inhibitor everolimus, the histone deacetylase inhibitor vorinostat, or the anti-CD20 monoclonal antibody rituximab as single agents or in OTX015-containing combinations. None of the mice showed any body weight loss during the treatment period. When given as single agents, OTX015 and all four other drugs caused tumor growth delay (Figure 1A). When given in combination, the antitumor activity was significantly greater, with an almost complete and immediate tumor eradication in mice receiving the OTX015-containing combinations, maintained throughout treatment (P<0.001) (Figure 1A). The degree of necrosis was also evaluated in three tumors per group. Tumors from mice treated with rituximab (P=0.0463), everolimus (P=0.0463) or ibrutinib (P=0.0431) as single agents, or with OTX015 combinations plus everolimus (P=0.0463), plus ibrutinib (P=0.0431), and plus vorinostat (P=0.0463) presented a higher percentage of necrotic cells than control mice (Figure 1B, 1C). Higher necrosis was observed in tumors from mice treated with the OTX015 and vorinostat combination compared to the single agent vorinostat group (P=0.0109). Together with our previous in vitro findings with OTX015 as a single agent and in combination , the OTX015 antitumor activity reported as single agent in the phase I hematologic study , and similar positive results of other combination regimens based on BET inhibitors [13, 16–18], these novel in vivo data confirm the combinability of OTX015 with classic cytotoxic and targeted therapies in lymphoma and provide supporting rationale for future clinical development strategies in lymphoma. Due to the direct effect of OTX015 and other BET inhibitors on MYC expression, independently of the presence of chromosomal translocations , also high-risk populations such the double-hit or double-expressor lymphomas  could be targeted.