Synergistic anti-tumor activity of the mTOR inhibitor everolimus and gemcitabine for the treatment of peripheral T cell lymphoma.

Abstract

e19538 Background: Patients with relapsed/refractory (R/R) peripheral T-cell lymphoma (PTCL) have dismal prognosis and limited treatment options. The mTOR inhibitor everolimus or gemcitabine as a single agent regimen had limited clinical efficacy in patients with R/R PTCL. Therefore, investigation of active combination therapies with everolimus for T cell lymphoma needs to be investigated. Methods: A retrospective analysis of 24 R/R PTCL patients were treated with everolimus and gemcitabine from December 2017 to March 2021. The primary endpoint was objective response rate (ORR). CellTiter Glo and AnnexinV FITC/PI were utilized to determine cell viability and apoptosis, respectively. Results: Here we demonstrated that combination treatment of everolimus and gemcitabine is effective in treating R/R PTCL patients, achieving an ORR of 70.8%, with 45.8% complete response rate. The median time to response was 1.7 months. With a median follow-up time of 22.3 months (95% confidence interval[CI], 5.7-39.0), the median PFS of all patients was 9.9 months (95%CI, 0-20.81), the median DOR was 16.8 months for responders. Patients with best response of CR and PR achieved superior PFS (18.7 vs. 1.2 months, P = 0.0007) and OS (30.9 vs. 5.8 months, P = 0.021) than that with SD and PD. Grade 3 or 4 neutropenia, thrombocytopenia and anaemia occurred in 13 (29.2% grade 3 and 25.0% grade 4), 11 (8.3% grade 3 and 37.5% grade 4) and 7 (16.6% grade 3 and 12.5% grade 4) patients, respectively. Functional in vitro studies showed that combination treatment synergistically inhibited cell viability and induced apoptosis in PTCL cell lines. Mechanistically, transcriptomic profiling indicated that the synergistic effect was induced through the abrogation of MYC pathway. Conclusions: Collectively, our study sheds light on synergistic antitumor effect of combinatorial therapy, providing a potential therapeutic strategy for patients with R/R PTCL.