Abstract
Abstract Introduction. Diffuse large B-cell lymphoma (DLBCL) is the commonest lymphoma and at least one quarter of patients still present with a refractory disease or relapse after first line chemotherapy. Pixantrone is an aza-anthracenedione with reduced cardiotoxicity, which has received a conditional marketing approval in the E.U. as a monotherapy for the treatment of adults with multiply relapsed or refractory aggressive B-cell non-Hodgkin lymphomas. Here, we evaluated the pre-clinical activity pixantrone as single agent and in combination with a series of additional anti-lymphoma drugs in cell lines derived from DLBCL. Methods. DLBCL cell lines derived from activated B-cell like (ABC) DLBCL (U2932, TMD8, HBL1, RIVA, OCI-LY-3), and from germinal center B-cell (GCB) DLBCL (DOHH-2, SU-DHL-4, OCI-LY-19, KARPAS422, OCI-LY-8, OCI-LY-7) were studied. Pix was used in combination with: bendamustine, ibrutinib, idelalisib, lenalidomide, rituximab, vorinostat, bortezomib and etoposide. Due to the mechanism of action, lenalidomide, bortezomib and ibrutinib were evaluated only in ABC-DLBCL cell lines. Cell lines were exposed (72 h) to increasing doses of the compounds alone or in combination, followed by MTT assay. The Chou-Talalay combination index (CI) was estimated using the Synergy R package: CI < 0.9, synergism; CI between 0.9 1.1, an additive effect; CI >1.1, no benefit. Results. The median IC50 of pixantrone as single agent was 200 nM among 11 DLBCL cell lines. GCB-DLBCL presented a trend for a higher sensitivity to the drug than ABC-DLBCL (P = 0.05). Pixantrone was evaluated in combination with targeted agents and with other chemotherapy agents. The combination with the BTK-inhibitor ibrutinib was effective in all five ABC-DLBCL (median CI = 0.7, range 0.53-1.04): synergism in 4 and additive effect in 1. The combination with the PI3K-delta inhibitor was beneficial in 9 out of 11 DLBCL (median CI = 0.7; range 0.1-1.35): synergism in 8 and additive effect in 1. Benefit was also observed when pixantrone was combined with lenalidomide in 2/2 ABC-DLBCL (synergism and additive effect, 1 each), with the anti-CD20 monoclonal antibody rituximab in 2/5 DLBCL (synergism in both) and with the HDAC-inhibitor vorinostat in 2/4 DLBCL. An additive effect was seen when pixantrone was combined with etoposide in 2/3 DLBCL, with bendamustine in 2/4 DLBCL and with bortezomib in 1/2 ABC-DLBCL. Conclusions. Pixantrone was very active in DLBCL cell lines as single agent and benefit was observed when the drug was combined with different additional anti-cancer agents. The combinations with the BTK inhibitor ibrutinib and with the PI3K-delta inhibitor idelalisib were the most effective and are worth of further studies at pre-clinical and clinical level. Citation Format: Chiara Tarantelli, Eugenio Gaudio, Ivo Kwee, Anastasios Stathis, Panteli Theocharous, Patrik Zintl, Emanuele Zucca, Francesco Bertoni. Combinations containing the aza-anthracenedione pixantrone show preclinical activity in diffuse large B-cell lymphoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4793.
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