MECHANISMS OF SECONDARY RESISTANCE TO IDELALISIB IN MARGINAL ZONE LYMPHOMA

Abstract

ALK+ cell lines achieved a synergism with copanlisib/ruxolitinib. Copanlisib/brentuximab vedotin was synergistic in the non ALCL-ALK + and Sezary Syndrome cell lines. Transcriptome analysis identified the PIM1 and PIM2 kinases and the anti-apoptotic gene MCL1 as up-regulated in the MZL cell line HAIRM exposed to copanlisib (5nM, for 4, 8 and 12h). Thus, we tested combinations with the PIM inhibitor AZD1208 and the MCL1 inhibitor MIK665 (S63845) in 3 MCL and 3 MZL cell lines. Both combinations were synergistic in the HAIR-M and beneficial in additional 5/5 and 3/5 cell lines, respectively. Conclusions: Our study identified a series of active copanlisibcontaining combinations and provided the rational for the design of the new SAKK 66/18 phase I study exploring copanlisib plus venetoclax in relapsed/refractory B-cell lymphomas.