Clinical Characteristics and Treament Outcomes of 104 Cases of Extranodal NK/T-Cell Lymphoma Undergoing Primary Treatment in Novel Agents Era

Objective: Extranodal NK/T-cell lymphoma (ENKTL) is an aggressive malignancy with a low incidence and lacks a standardized treatment approach. This comprehensive study aimed to delineate the clinical characteristics of 104 ENKTL patients undergoing primary treatment, to evaluate the efficacy of asparaginase-based chemotherapy, both with and without novel agents such as PD-1 antibodies and histone deacetylase inhibitors (such as chidamide), and to compare the outcomes of ASCT and allo-HSCT in these patients.

Methods：ENKTL patients who received treatment for the first time in our center between January 2011 and June 2023, and had complete treatment records, were enrolled in the study. Comparisons of differences between groups were conducted by using the Pearson χ² test or Fisher's exact test for categorical variables, and the t-test or Mann-Whitney U test for continuous variables. Survival analysis was carried out by using the Kaplan-Meier method, with differences compared by using the log-rank test. Multivariable regression analyses were conducted by using the Cox proportional hazards model.

Results：

Patient Characteristics: study cohort comprised 104 patients with ENKTL, with a median age of 50 (36-60) years and a male predominance (62.5%). Nasal involvement was the most common presentation, observed in 86 patients (82.7%). Primary extranasal ENKTL was identified in 18 patients (17.3%), of whom 8 presented with skin nodules or ulcers as the initial clinical manifestation, and 5 presented with abdominal pain or intestinal perforation. According to the Ann Arbor staging system, there were 33 patients in stage I, 39 in stage II, 8 in stage III, and 24 in stage IV. Based on the PINK score, the cases were categorized into low-risk (48 patients), intermediate-risk (33 patients), and high-risk groups (23 patients). Advanced-stage patients had a higher rate of positive EBV-DNA compared to those with limited disease (67% vs. 18%, P < 0.001). The expression of Ki-67 ranged from 30% to 95%, with a median of 70%. The median expression level of Ki-67 was higher in patients with primary extranasal disease compared to those with nasal disease (83% vs. 70%, P < 0.001).

Treatment Efficacy: Ninety-three patients were evaluable for terminal efficacy. Asparaginase-based chemotherapy, when combined with novel agents (n=48), demonstrated superior efficacy in terms of ORR (96% vs 80%, P=0.0496) and CRR (91% vs 73% , P=0.0483) compared to asparaginase-based regimens alone (n=45).

Survival and Prognostic Factors: the median follow-up was 759 days, and the 2-year OS and PFS were 83% and 69% for all patients, 92% and 77% for patients with limited stage disease, and 65% and 54% for patients with advanced stage disease. Patients with advanced disease had a higher proportion of positive EBV-DNA than patients with limited disease, EBV-DNA was an independent prognostic factor affecting survival in multivariable analysis. Bone marrow involvement and pre-treatment ECOG score ≥2 were independent risk factors affecting OS and PFS. Additionally, first-line treatment combined with new drugs was an independent favorable prognostic factor for OS and PFS.

HSCT Outcomes: Among 56 patients undergoing HSCT, the allo-HSCT group (n=22) had a higher non-relapse mortality (NRM) and was more likely to present with advanced disease and bone marrow involvement prior to transplantation. The 3-year cumulative incidence of recurrence (CIR) was higher in the auto-HSCT group(n=34), contrasting with a better OS observed in the allo-HSCT group for patients achieving CR pre-transplantation. For patients with advanced ENKTL who achieved CR post-chemotherapy, both ASCT and allo-HSCT were effective in improving OS and PFS. Younger patients with bone marrow involvement may benefit from allo-HSCT, while older patients without bone marrow involvement might opt for ASCT.

Conclusions: ENKTL affects primarily middle-aged and elderly males, with extranasal presentations indicating higher proliferation indices. Asparaginase-based chemotherapy significantly improves survival, and the addition of novel agents enhances treatment efficacy. Pre-transplantation lymphoma control is pivotal for transplant outcomes, with CR status as an independent prognostic factor. Both ASCT and allo-HSCT are viable options for advanced ENKTL patients in CR, with selection guided by patient-specific factors and disease characteristics.