Serum Triglyceride and Apolipoprotein A1 as Biomarkers for Extranodal Natural Killer/T cell Lymphoma (ENKTL): A Multicenter Study

Background: Although clinical outcome of extranodal NK/T cell lymphoma (ENKTL) has been improved recently, some patients resistant to Asp-based chemotherapy suffered poorer survival. Therefore, reliable and convenient biomarkers become more important. Methods: We retrospectively analyzed 1017 ENKTL patients with available clinical data between December 2003 and August 2021. Demographics and serum lipid data of 500 healthy controls were reviewed. The median values at baseline were selected as the cutoff values for serum lipid. Results: The baseline serum levels of high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) and apolipoprotein A1 (ApoA1) were lower, while the levels of triglyceride (TG) was higher in ENKTL patients than those in age- and gender-matched healthy controls (all p < 0.001). Besides conventional predictive factors, baseline serum TG (PFS: p = 0.017; OS: p = 0.018) and ApoA1 (PFS: p = 0.007; OS: p = 0.002) were identified as independent prognostic factors. Among patients with high levels of TG (or low levels of ApoA1) at baseline, those who exhibited objective responses had a significant serum TG decrease (or ApoA1 increase) after treatment (all p < 0.001) (Figure A-B). However, no significant change of TG or ApoA1 was observed in patients without satisfactory response. Compared with baseline levels, further increased levels of TG and decreased levels of ApoA1 after first-line treatment were associated with significantly shorter PFS and OS (all p < 0.001) (Figure C-D). We developed and validated a pre-treatment nomogram containing TG and ApoA1 at baseline and a post-treatment nomogram containing serum lipid at best response (Figure E-F). Compared with pre-treatment nomogram and PINK, the post-nomogram prognostic model was proved to possess a higher predictive power of survival for ENKTL with significantly higher concordance index and the area under the curve (AUC) and lower integrated Brier score (IBS) for 5-year OS. Subgroup analysis showed that Asp-containing regimens were associated with significant survival benefits among patients with low levels of LDL-C and high levels of HDL-C and ApoA1 at baseline (all p < 0.001). Furthermore, the comprehensive transcriptome analysis provided evidence for intratumoral lipid metabolic disorders and dysregulated classical tumor-related signaling pathways, including NOTCH and MAPK, among patients with high levels of TG (or low levels of ApoA1) at baseline (Figure G-H) Conclusion: This study suggests that ENKTL is accompanied by dyslipidemia. Baseline levels and change trends of TG and ApoA1 could contribute to risk stratification, disease status monitoring and treatment outcome prediction. Patients with dyslipidemia also have intratumoral lipid metabolic disorders and dysregulated classical tumor-related signaling pathway. Encore Abstract - previously submitted to EHA 2023 The research was funded by: The research was funded by grants from the National Key Research and Development Program (2022YFC2502602), the National Natural Science Foundation of China (82230001 and 82270199), the Sun Yat-Sen University Clinical Research 5010 Program (2020009), the Special Support Program of Sun Yat-sen University Cancer Center (PT19020401), and the Clinical Oncology Foundation of Chinese Society of Clinical Oncology (Y-XD2019-124 and Y-SY2021ZD-0110). Keyword: Extranodal non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.