Autologous Transplant Consolidation Vs. Immunotherapy Maintanance Therapy in Patients with Relapsed or Refractory NK/T Lymphoma Treated While in Complete Remission

Background: Extranodal natural killer (NK)/T-cell lymphoma (ENKTL) is a rare aggressive type of non-Hodgkin's lymphoma associated with Epstein-Barr virus infection, it is more prevalent in Asia than in other regions, accounting for ~6% of lymphoma subtypes in China. Relapsed or refractory ENKTL (RR-ENKTL) cases are characterized by a high rate of relapse and dismal prognosis with limited therapeutic options. The median survival in the relapsed/refractory setting is only slightly more than 6 months. Available data from retrospective and prospective studies have shown that high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) improves survival in patients with chemotherapy-sensitive disease, both upfront and salvage therapy. The use of immune checkpoint inhibitors (ICIs), represented by programmed cell death protein 1 (PD-1) antibodies, have produced a unique and significant remission rate in RR-ENKTL from 2018. We have previously reported superior outcomes in patients who received immunotherapy maintenance therapy (immuno-MT) in complete remission (CR). These findings have raised questions about the comparative performance of ASCT vs. immuno-MT in CR patients who experience refractory or relapse. Herein, to further investigate the comparative effectiveness of ASCT vs. immuno-MT in patients with RR-ENKTL. Method: We used the database of Sun Yat-sen University Cancer Center (SYSUCC) compare the outcome of patients with RR-ENKTL who failed from asparaginase containing regimens and received ASCT or immuno-MT after attaining a CR (CR2). Patients between ages 18 and 75 with a diagnosis of RR-ENKTL were included if they received ASCT between 2006-2023 or immuno-MT between 2018-2023 while in a CR by CT or PET scan and per the 2014 Lugano definition. Patients undergoing ASCT or immuno-MT with only one prior therapy line in CR (CR1) were excluded. Immuno-MT included PD-1/L1 antibody monotherapy or PD-1 antibody plus chidamide (an oral subtype-selective histone deacetylase inhibitor, HDACi). The primary endpoints of the study were progression-free survival (PFS) and overall survival (OS). PFS was defined as the time from either ASCT or immuno-MT to relapse, progression or death from any cause. OS1 was defined as the time from front-line treatment to death from any cause. OS2 was defined as the time from ASCT or immuno-MT to death from any cause. Results: We identified 63 patients with RR-ENKTL who received ASCT (n = 32) or immuno-MT (n = 31) while in a CR2, and key baseline characteristics are shown that, the two groups were balanced for patients' age (median 33.5 vs. 37 years; p = 0.32), female sex (13.6% vs. 15.3%; p = 0.87) and proportion of patients with advanced stage before ASCT or immuno-MT (56.3% vs. 45.2%; p = 0.38). Median lines of therapies before ASCT or immuno-MT were both 2. In the ASCT group, a smaller proportion of patients had PET or PET/CT performed prior to ASCT (68.8% vs. 96.8%; p = 0.003) and no patients were treated with immunotherapy before 2018. Three patients from the immuno-MT group received ASCT and 4 patients from the ASCT group received PD-1 antibody maintenance. As of last follow-up July 1, 2024, median follow-up was 43.6 months for ASCT group and 55.3 months for the immuno-MT group. Median cycles and time of immuno-MT were 17(5-80) cycles and 17.3 months (3-68). Patients who received immuno-MT had a superior PFS (median PFS not reached vs. 39.8 months, p=0.046), OS1 (median OS1 not reached vs. 78.7 months, p=0.023) and OS2 (median OS2 not reached vs. 74.2 months, p=0.031). The OS2 was numerically higher in the year 2018-2023 compared to the year 2006-2017 (median OS2 not reached vs. 74.2 months, p=0.09). Conclusion: These results may inform, or validate, clinical practices in select settings. Immunotherapy maintenance strategy alone may lead to improved long-term survival in patients with RR-ENKTL in CR2. Prospective randomized studies to make comparation between ASCT consolidation and immunotherapy maintenance worth exploring.