Background: Decitabine (DEC) is a hypomethylating agent approved to treat acute myeloid leukemia (AML) that can reactivate tumor suppressor genes that are epigenetically silenced by DNA methylation. Selinexor (SEL) is a selective inhibitor of nuclear export that inhibits exportin 1 (XPO1/CRM1) from shuttling cargoes, including tumor suppressor proteins and oncogene mRNAs bound to eIF4e, from the nucleus to the cytoplasm. DEC priming has been previously found to increase the antileukemic effects of SEL in AML in vitro and in vivo, through DEC-mediated upregulation of tumor suppressor proteins such as CDKN1A (p21) and FOXO3A, which are XPO1 cargos localized in the nucleus after SEL treatment. The goal of this study was to determine the optimal dosing schedule for combination treatment of SEL and DEC in AML.

Methods: The efficacy of concomitant and sequential drug treatment using DEC and SEL was evaluated in the subcutaneous implanted MV4-11 xenograft models of AML in NOD-SCID mice. Tumor bearing mice were treated with vehicle, SEL once weekly at 15 mg/kg, DEC at 0.4 mg/kg (M-F, week 1 only) and combinations of DEC with SEL 15 mg/kg on Mondays only (DEC + SEL M, concomitant) or Fridays only (DEC + SEL F, sequential) starting from week 1. In the follow up experiment mice were treated similarly except for revised combination group schedules, SEL was administered once weekly starting either from Friday of week 1 (sequential A) or Monday of week 2 (sequential B). Tumor volume and body weight of mice were monitored for five weeks of treatment, and tumors were collected at the end of the study for immunohistochemistry (IHC) analysis.

Results: DEC and SEL effectively inhibited tumor growth as single agents. Concomitant administration of SEL and DEC did not enhance the anti-tumor effect, with no significant difference among the tumor growth inhibition (TGI) rate for mice treated with SEL alone (62.7%), DEC alone (60.0%) and the concomitant combination (DEC + SEL M, 62.6%) (p>0.05). Whereas sequential administration of SEL after DEC priming (DEC + SEL F) enhanced the anti-tumor effects, as TGI (81.7%) was significantly higher than each single agent alone (p<0.05). In the follow up experiment, TGI for the two sequential DEC and SEL combination groups was similar (86.19% for sequential schedule A and 86.17% for sequential schedule B, p>0.05).

Conclusions: The introduction of SEL post priming with DEC showed greater TGI than when SEL and DEC were dosed concomitantly. A delay of 4-7 days between the first dose of SEL after DEC priming demonstrated better antileukemic effect than concomitant dosing. This is relevant to potential future clinical trials because separation of dosing DEC and SEL has the potential to increase tolerability of the combination without affecting antileukemic activity.

Citation Format: Leah F. Henegar, Hua Chang, Christopher J. Walker, Trinayan Kashyap, Nicholas Fredette, Kathleen Martyn, Sharon Shacham, Yosef Landesman. Optimizing the treatment schedule of selinexor in combination with decitabine in AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1049.