Extranodal NK/T Cell Lymphoma Patients Research Articles

Clinical Impact of Microbiome Characteristics in Treatment-Naïve Extranodal NK/T-Cell Lymphoma Patients.

Extranodal NK/T-cell lymphoma (ENKTL) predominantly manifests in East Asia and Latin America. Despite shared intrinsic factors, such as ethnic and genetic backgrounds, the progression of ENKTL can be influenced by extrinsic factors related to changing lifestyle patterns. This study collected stool samples from newly diagnosed (ND)-ENKTL patients (n=40) and conducted whole genome shotgun sequencing. ND-ENKTL revealed reduced alpha diversity in ND-ENKTL compared to healthy controls (HCs) (p=0.008), with Enterobacteriaceae abundance significantly contributing to the beta diversity difference between ENKTL and HCs (p<0.001). Functional analysis indicated upregulated aerobic metabolism and degradation of aromatic compounds in ND-ENKTL. Enterobacteriaceae were associated not only with clinical data explaining disease status (serum CRP, stage, prognosis index of natural killer cell lymphoma (PINK), and PINK-E) but also with clinical outcomes (early relapse and short progression-free survival). The relative abundance of Enterobacteriaceae at the family level was similar between ENKTL and diffuse large B-cell lymphoma (DLBCL) (p=0.140). However, the ENKTL exhibited a higher abundance of Escherichia, in contrast to the prevalence of Enterobacter and Citrobacter in DLBCL. Linear regression analysis demonstrated a significant association between Escherichia abundance and PD-L1 levels in tissue samples (p=0.025), whereas no correlation with PD-L1 was observed for Enterobacteriaceae at the family level (p=0.571). ND-ENKTL exhibited an abundance of Enterobacteriaceae and a dominant presence of Escherichia. These microbial characteristics correlated with disease status, treatment outcomes, and PD-L1 expression, suggesting the potential of the ENKTL microbiome as a biomarker and cause of lymphomagenesis, which warrants further exploration.

The role of auto-HSCT in extranodal natural killer/T cell lymphoma.

Autologous hematopoietic stem cell transplantation (auto-HSCT) is considered optional consolidation therapy especially for relapsed/refractory extranodal NK/T-cell lymphoma (ENKL), but its applications to newly diagnosed advanced-stage ENKL is currently limited. We collected 51 cases of newly diagnosed advanced-stage ENKL patients, including 26 with auto-HSCT and 25 with chemotherapy rather than HSCT, from our hospital between 2014/01 and 2023/12. We summarized the patients' characteristics, conducted survival analysis of the 51 cases, and analyzed the potential benefits of auto-HSCT to ENKL patients. It shows that after a median follow-up time of 39 months, the estimated 5-year overall survival (OS) of the 51 newly diagnosed advanced-stage ENKL patients is 73.4%, and their estimated 5-year progression-free survival (PFS) is 73.4%. For patients receiving auto-HSCT, the 5-year OS (91.7%) and PFS (91.0%) are significantly different from those of patients receiving chemotherapy without HSCT (OS 53.3%, PFS 54.5%) (p < 0.05). Univariate and multivariate analysis results suggest that only the l-asparaginase usage in chemotherapy showed significant impact on the OS, and none of concerned factors showed significant impact on the PFS. Auto-HSCT is indeed an option to newly diagnosed advanced-stage ENKL, but further studies are still required for more strict disease management.

Diverse Microbiome Characteristics in Treatment Naïve Extranodal NK/T-Cell Lymphoma Patients

Background: It is still unclear why extranodal NK/T cell lymphoma (ENKTL) emerged in certain regions, such as Asia and South America, and initiated ENKTL lymphomagenesis in restricted upper airway or aerodigestive tract regions. Recently, reports have highlighted the profound relationship between the gut microbiome and immune system modulation. These associations can potentially influence cancer development and impact the effectiveness of chemotherapy. Therefore, we conducted a stool analysis to determine the newly diagnosed ENKTL (ND-ENKTL) microbiome characteristics. Additionally, a comparison analysis of microbiome composition among healthy individuals, newly diagnosed diffuse large B-cell lymphoma (ND-DLBCL), and ND-ENKTL was performed to identify potential clues that could influence ENKTL development and outcomes. Methods: We have gathered and analyzed microbial data from 40 feces samples obtained from 40 ND-ENKTL patients from 2020 to 2022. Fecal samples from ENKTL patients were collected using a stool sampling kit (CJ Bioscience. Inc, Seoul, Korea) designed explicitly for microbial community analysis using shotgun sequencing. We used pre-analyzed gut microbiome data from the healthy control (HC) or newly diagnosed DLBCL (ND-DLBCL) group to compare the gut microbiome specificities. Results : 32 (80.0%) presented stage I/II, and 7 (17.5%) or 6 (15.0%) had a high PINK (≥2) or high PINK-E score (≥3). In the alpha diversity analysis, ENKTL exhibited significantly lower diversity than HC. Additionally, we observed significant differences in microbial composition between these two groups (PERMANOVA, P-value=0.001). Species such as Escherichia coli, Citrobacter portucalensis and Citrobacter freundii were identified as significant biomarkers associated with dysbiosis in ENKTL. All these species belong to the Enterobacteriaceae family, a facultative aerobic opportunistic bacteria group. In the functional analysis, we observed an increase in genes related to aerobic bacterial metabolism in the ENKTL group. Conversely, a trend of decreased short-chain fatty acid (SCFA) metabolism and folate biosynthesis was identified. The noteworthy observation in ENKTL is the dominant Enterobacteriaceae family presence, which bears similarity to the microbiome associated with gut microbial dysbiosis in DLBCL, previously reported. While no significant differences were observed at the family level, a notable distinction was found between ENKTL and DLBCL at the genera. Specifically, a significantly higher proportion of Escherichia was dominant in ENKTL compared to DLBCL, which was dominant in Enterobacter and Citrobacter. In the chi-square analysis, a high abundance of Enterobacteriaceae presented statistically correlated with advanced stage (p=0.001) and PINK-high (≥2, p=0.003). Moreover, statistically significant associations were observed between the high proportion of the Escherichia genus and advanced stage (p=0.037), PINK-High (≥2, p=0.020), and a high PD-L1 CPS (≥10, p=0.029). During the median 21.1 months (95% CI 16.2-25.9) follow-up duration, the patients with high Enterobacteriaceae abundance exhibited significantly poorer progression-free survival (PFS) compared to those without such abundance (5.6 months vs. NR, p=0.001). Furthermore, patients with high Escherichia abundance demonstrated inferior PFS compared to those without (5.2 months vs. NR, p=0.001). Conclusion: By comparing the intestinal microbes of ND-ENKTL with those of healthy individuals and ND-DLBCL, we could determine the distinct distribution of intestinal microbiome specific to ENKTL. Although the finding of the Enterobacteriaceae family was similar result with previously reported microbiome composition in DLBCL, we determined a high abundance of Escherichia genea in ENKTL but high Enterobacter and Citrobacter in DLBCL through subgroup analysis. Interestingly, Escherichia genea in ENKTL showed a statistical correlation with a high disease burden, PD-L1 expression, and inferior PFS. Based on the results, we expected that it would be possible to predict the disease characteristics and treatment susceptibility in ENKTL by intestinal microbes' composition and diversity in the future.

Survival Outcome of Autologous or Allogeneic Stem Cell Transplantation in 49 Patients with Extranodal NK/T-Cell Lymphoma

Objective:Extranodal NK/T-cell lymphoma (ENKTL) is an uncommon tumor featured by high invasiveness, the ease of developing drug resistance, low curative rate, and short survival time. Hematopoietic stem cell transplantation (HSCT) is now recommended for patients with advanced or relapsed/refractory (r/r) ENKTL, but which HSCT is the most suitable remains to be conclusively determined. Here, we performed a retrospective single-center study to compare the prognostic role of autologous and allogeneic HSCT after induction chemotherapy in ENKTL patients. Methods: Clinical data on 49 ENKTL patients who underwent HSCT in the First Affiliated Hospital of Soochow University from 8/2007 to 9/2022 was reviewed. We divided all patients into two subgroups: cohort A) auto-HSCT and cohort B) allo-HSCT. Observation period started from the day of stem cell infusion in both cohorts. The primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS) and non-relapse mortality (NRM). NRM was defined as death from any cause related to transplantation without evidence of lymphoma progression. Results: Of 49 patients included, 28 (57%) patients received auto-HSCT (cohort A), while 21 (43%) patients received allo-HSCT (cohort B). The two cohorts of patients were different in some terms of baseline characteristics (Figure A). A total of 8 patients with stageⅡdisease received transplantation due to r/r status or primary lesions beyond the nasal area. The patients in cohort B were younger at the time of transplant (median age: 33 years vs. 37 years, p=0.0031) and had a higher proportion of bone marrow involvement (7% vs. 43%, p=0.005). After a median follow-up of 35 months, patients who received allo-HSCT had a worse prognosis compared to patients who underwent auto-HSCT (2-year OS:61% vs 96%, p=0.0015). There was no transplantation-related mortality in the auto-HSCT group, while the NRM was 33.3% in the allo-HSCT group. Limiting the analysis to only patients with complete remission (CR) (allo-HSCT=13, auto-HSCT=25) before HSCT, no differences in 2-year OS and PFS were reported despite 61% vs 4% bone marrow involvement, respectively (76% vs 96% OS and 76.9% vs 84.1% PFS at +24 months, p&amp;gt;0.05). In the allo-HSCT group, patients who achieved first CR(CR1) before HSCT showed higher OS and lower NRM rates compared to those without CR1, with 2-year OS of 88.9% and NRM of 11.1% (p=0.028, p=0.06, respectively). In terms of donor sources, no significant difference in PFS and OS was observed in patients who received haploid conjugate (n = 14) vs. HLA-matched related and unrelated donors(p&amp;gt;0.05). Conclusions: Overall, consolidation therapy with HSCT improved OS in patients with advanced or relapsed/refractory ENKTL who achieved CR after induction therapy. Given the high NRM in the allo-HSCT, auto-HSCT is probably the preferred clinical option in most patients and allo-HSCT may be more appropriate for younger patients with bone marrow involvement and CR1 acquired before transplantation. Larger studies are needed to validate our results.

First-line immunotherapy with anti-PD-1 antibody for extranodal NK/T-cell lymphoma: A retrospective study.

Anti-PD-1 antibody has shown certain effects in patients with newly diagnosed extranodal NK/T-cell lymphoma (ENKTL). Here, we evaluated the clinical efficacy and safety of first-line anti-PD-1 antibody for the treatment of patients with ENKTL and explored biomarkers for treatment response. The clinical data of 107 patients with newly diagnosed ENKTL were retrospectively analysed. Patients received either first-line anti-PD-1 antibody induction treatment or anti-PD-1 antibody combined with asparaginase-based chemotherapy (immunochemotherapy). We found that immunochemotherapy was an independent prognostic factor for longer PFS (p < 0.001). The overall response rate and complete remission rate of immunochemotherapy group was higher than immunotherapy induction group (86.11% vs. 62.86% and 72.22% vs. 52.29%, respectively, p = 0.013). We also observed pretreatment CD4/CD8 ratio >0.83 was significant associated with better response and longer PFS in ENKTL patients received first-line anti-PD1-antibody. Plasma copy number of EBV decreased more significantly in patients with CD4/CD8 ratio >0.83 after treatment. PD-L1 expression was associated with better response and PFS, while elevated plasma IL-6, IL-10 and IFN-γ were associated with poor prognosis. Anti-PD-1 antibody treatment showed promising results in newly diagnosed ENKTL patients. The assessment of pretreatment CD4/CD8 ratio in ENKTL seems feasible for identifying responders to anti-PD-1 antibody treatment.

Improved prognosis of advanced‐stage extranodal NK/T‐cell lymphoma: results of the NKEA‐Next study

Background: Extranodal NK/T-cell lymphoma (ENKL) is a particular subtype of lymphoma that is characterized by the expression of multi-drug resistance-associated P-glycoprotein. Although the advent of non-anthracycline-based and L-asparaginase containing chemotherapy has contributed to enhancing the prognosis of ENKL patients, recent clinical results of ENKL patients have not been well assessed. Method: A cooperative NKEA-Next study (UMIN 000046300) was performed in Japan to gather data on ENKL patients diagnosed between 2014 and 2021. Data from advanced-stage ENKL patients were examined. Results of limited-stage patients were presented elsewhere (ASCO 2023). Results: A total of 351 patients with ENKL were included in the NKEA-Next study. Among these, 116 patients (33%; 5 with stage III and 111 with stage IV) were in an advanced stage. The median age of the advanced-stage patients was 59.5 years (range: 19–90) and 59% were male. Thirty-five percent of the advanced-stage patients had poor performance status (2–4), and 53% had B symptoms at diagnosis. Of the 111 patients with stage IV disease, 94 (85%) had two or more extranodal involvement, including nasal/paranasal area (65%), bone or bone marrow (44%), skin (44%), lung (18%), liver (17%), spleen (14%) and central nervous system (10%). The most common first-line treatment was SMILE (52%), followed by DeVIC (30%) and CHOP (10%), although 10 patients did not receive any treatments due to poor general condition. The 2-year overall survival (OS) of the advanced-stage patients was 38.2%, which was significantly improved in the recent era (25.2% for the year 2014–2017 vs. 49.8% for the year 2018–2021; P = 0.01). Patients treated with SMILE had significantly longer survival time than those treated with DeVIC or CHOP (2y-OS: 57.1%, 35.8% and 0%, respectively; P < 0.001). The overall response rate was significantly higher in patients treated with SMILE (74%) than those treated with DeVIC (58%) and CHOP (18%). The proportion of patients who underwent subsequent hematopoietic stem cell transplantation (HSCT) was also significantly higher in patients treated with SMILE than the other regimens (65% vs. 18%, P < 0.001). The prognosis was significantly better in patients who underwent HSCT than in those who did not (2-year OS: 66.8% vs. 17.6%, P < 0.001). Multivariate analysis confirmed that patients who underwent HSCT had significantly better OS [hazard ratio (HR) 0.2, 95% confidence interval (CI) 0.1–0.5, P < 0.001] and treatment with SMILE was identified as almost significant factor for better OS (HR 0.6, 95% CI: 0.3–1.0, P = 0.06). Keywords: Aggressive T-cell non-Hodgkin lymphoma, Chemotherapy, Extranodal non-Hodgkin lymphoma Conflicts of interests pertinent to the abstract. A. Fujimoto Honoraria: Chugai pharmaceutical co. ltd, Meiji Seika Pharma, Sanofi K. Miyazaki Honoraria: Chugai Pharma, SymBio Pharmaceuticals, Janssen, Eisai, Nippon Shinyaku, AstraZeneca, Bristol-Myers Squibb Japan, Meiji Seika Kaisha, Abbvie, Novartis, Incyte, and Asahi Kasei Research funding: Eisai, Takeda, Nippon Shinyaku, Otsuka, Chugai Pharma, Asahi Kasei, Sumitomo Dainippon Pharma Oncology and Zenyaku Kogyo N. Asano Honoraria: Takeda Pharmaceutical Company Limited K. Yakushijin Honoraria: Pfizer, Kyowa Kirin, Chugai W. Munakata Honoraria: Celgene, Janssen Pharmaceutical, Takeda Pharmaceutical, ONO PHARMACEUTICAL, Eisai Chugai Pharmaceutical, Novartis Pharma, Bristol-Myers Squibb, AstraZeneca, SymBio Pharmaceuticals Genmab, Mundipharma, NIPPON SHINYAKU, Gilead Sciences, Nippon Kayaku Research funding: Janssen Pharmaceutical, ONO PHARMACEUTICAL, Kyowa Kirin, Genmab, NIPPON SHINYAKU M. Hirano Honoraria: Eisai Co., Ltd T. Maeda Honoraria: Bristol Myers Squibb, Chugai, Janssen, Nippon Shinyaku, Novartis, Ono, Sanofi J. Takizawa Honoraria: AstraZeneca, Kyowa-Kirin, Abbvie, Chugai, Jansen, Novartis, Ono Research funding: AstraZeneca, Kyowa-Kirin, Abbvie, Eisai, Chugai, Jansen, Novartis R. Sakai Honoraria: Bristol Myers Squibb, Chugai Pharma, Janssen, Kyowa Kirin, Meiji Seika Pharma, Nippon Shinyaku, Mundipharma, SymBio pharmaceuticals, Takeda Pharmaceutical, CSL Behring K.K, Eisai, AstraZeneca plc, Nihon Medi-Physics, Sanofi S.A., Towa Phamaceutical, Research funding: Chugai Pharma, Kyowa Kirin, TAIHO Phamaceutical N. Fukuhara Honoraria: Chugai pharma, Genmab, Abbvie, Takeda, Eli Lilly, astrazeneca, Meiji Seika, Ono Pharmacuetical, Janssen, Bristol-Myers Squibb, Eisai, Kyowa-Hakko Kirin, Symbio and Novartis Research funding: Chugai pharma, Genmab, Abbvie, Takeda, Eli Lilly, Incyte and Chordia Therapeu M. Yamaguchi Honoraria: AbbVie, Bristol Myers Squibb, Chugai Pharma, Janssen, Kyowa Kirin, Meiji Seika Pharma, MSD, Nippon Shinyaku, SymBio pharmaceuticals, Takeda Pharmaceutical Research funding: Chugai pharma, Genmab, Abbvie, Takeda and Eli Lilly R. Suzuki Honoraria: Kyowa-kirin Chugai Bristol-Meyer Squib Eisai MSD Shionogi Janssen Abbvie Takeda Meiji Seika Ohtsuka Sumitomo Dainippon Novartis AstraZeneca Nippon Shinyaku Research funding: Kyowa-kirin Chugai Taiho Ohtsuka Takeda Shionogi Eisai Meiji Seika Sysmex

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

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.

Derivation and validation of a nutrition-covered prognostic scoring system for extranodal NK/T-cell lymphoma.

Patients with aggressive lymphomas are at high risk of losing body resources, resulting in malnutrition, immunodeficiency and inferior outcomes. Nutritional status is closely associated with survival, but often neglected in the prognostic assessment. This study aimed to explore the significance of nutritional status in extranodal NK/T-cell lymphoma (ENKTL). Univariate and multivariate Cox regression analyses were conducted to examine the significance of nutritional index on overall survival (OS) and progression-free survival (PFS). A nutrition-incorporated score system was constructed based on the multivariate results, and its calibration, discrimination and clinical utility were tested in the training and validation cohort. Multivariate analysis revealed controlling nutritional status (CONUT) score could independently predict OS (HR 10.247, P=0.001) and PFS (HR 5.587, P=0.001) in addition to prognostic index of natural killer lymphoma plus EBV (PINK-E). Herein, a reformative model, CONUT-PINK-E, was developed and further verified in external validation cohort. CONUT-PINK-E classified patients into three risk grades with significant survival differences (P < 0.001). Compared with the current models, CONUT-PINK-E presented superior discrimination, calibration and clinical benefit. In this study, we firstly verified that CONUT score was efficient to screen prognosis-related malnutrition in ENKTL. Moreover, we developed the first nutritional assessment-covered scoring system, CONUT-PINK-E, which might be a promising tool to provide references for clinical decision-making of ENKTL patients.

A controlling nutritional status score is an independent predictor for patients with newly diagnosed nasal-type extranodal NK/T-cell lymphoma based on asparaginase-containing regimens.

The controlling nutritional status (CONUT) score is a nutritional index that combines serum albumin, total cholesterol, and lymphocyte counts. The potential value of CONUT score for predicting clinical outcomes in patients with nasal-type extranodal NK/T-cell lymphoma (ENKTL) has not been explored. This study included 374 ENKTL patients treated with asparaginase-containing regimens from September 2012 to September 2017. Clinical characteristics, treatment efficacy, prognostic factors, and the predictive value of CONUT score were analyzed. The complete response (CR) and overall response rate (ORR) were 54.8% and 74.6%, respectively. Patients with CONUT scores <2 had higher CR and ORR compared to patients with scores ≥2 (69.1% vs. 48.9% for CR, p= 0.001; 90.0% vs. 74.6% for ORR, p< 0.001). The 5-year overall survival (OS) and progression-free survival (PFS) rates were 61.9% and 57.3%, respectively. Patients with CONUT scores <2 had better survival outcomes than those with scores ≥2 (5-year OS, 76.1% vs. 56.0%, p< 0.001; 5-year PFS, 74.4% vs. 50.1%, p< 0.001). CONUT score ≥2 was identified as an independent poor prognostic factor for both OS and PFS. A CONUT score ≥2 was also associated with poorer survival outcomes in low-risk ENKTL patients. A CONUT score ≥2 is a prognostic marker for poor survival in patients with ENKTL and could be used to stratify risk in low-risk patients.

Plasma EBV-DNA and peripheral blood mononuclear cell EBV-DNA have disparate clinical relevance in patients with extranodal NK/T-cell lymphoma.

Extranodal NK/T-cell lymphoma (ENKTCL) is an Epstein-Barr virus (EBV)-related hematological malignancy. The presence of EBV-DNA in peripheral blood is a widely used ENKTCL tumor marker. However, there is no consensus on the preferred blood specimen type for EBV testing. Furthermore, discordance between EBV-based and imaging-based disease assessments is common, and how to interpret this discordance is important. We retrospectively analyzed the data of ENKTCL patients in the Affiliated Cancer Hospital of Zhengzhou university and Sun Yat-sen University Cancer Center. All EBV-DNA and imaging-based disease assessment data were collected at diagnosis, during treatment, at the end of treatment, and during follow-up. We compared matched plasma EBV-DNA and peripheral blood mononuclear cell (PBMC) EBV-DNA and matched EBV-based and imaging-based assessments to uncover their clinical relevance. A total of 450 patients with adequate data were included, of whom 278 had plasma EBV-DNA data, 250 had PBMC EBV-DNA data, and 78 had matched plasma and PBMC EBV-DNA data. No significant correlations were found between PBMC and plasma EBV-DNA and between PBMC EBV-DNA and imaging-based assessment, but patients with positive PBMC EBV-DNA at diagnosis or intermittently/persistently positive PBMC EBV-DNA during follow-up had poorer survival. In contrast, plasma EBV-DNA strongly correlated with lymphoma status. Detectable pre- and post-treatment plasma EBV-DNA was associated with significantly worse survival. Patients with early-stage disease who had detectable plasma EBV-DNA at the end of treatment shared similar survival to those with advanced-stage disease, even if their imaging-based assessments were negative. For disease relapse monitoring, 78 (55.7%) episodes of relapse were detected by both imaging and plasma EBV-DNA; 58 (41.4%) detected by plasma EBV-DNA earlier than imaging, with a median time of 9.3 (0.3 - 37.8) months; and only 4 (2.9%) detected by plasma EBV-DNA later than imaging. The sensitivities of plasma EBV-DNA, PET/CT, and CT/MRI were 97.1%, 76.8%, and 45.1%, respectively, and their specificities were 91.7%, 84.2%, and 96.7%, respectively. Analysis of EBV kinetic patterns in EBV+/imaging- episodes revealed that relapse occurred only in patients with intermittently/persistently positive plasma EBV-DNA. Persistent plasma EBV+ was also seen in patients after autologous hematopoietic stem cell transplantation. Occasional EBV+ was not associated with relapse. Plasma and PBMC EBV-DNA have different clinical relevance in ENKTCL patients. PBMC EBV-DNA does not correlate with imaging-based disease assessment. PBMC or even whole blood should not be used for response evaluation and relapse monitoring. However, PBMC EBV-DNA still has prognostic value. Plasma EBV-DNA is strongly related to tumor status and is not only a prognosticator at diagnosis and end of treatment, but also a sensitive marker in relapse monitoring compared to PET/CT and CT/MRI. The specificity of plasma EBV-DNA is relatively low, but when EBV-DNA kinetic patterns are considered, it can identify at-risk patients.

Survival of Patients with Extranodal NK-Cell Lymphoma in the United States

Background: Extranodal NK/T-cell lymphoma (ENKL) is an EBV-associated malignancy of rare occurrence in Western countries. There is limited data on the survival of patients with ENKL in the United States (US). Objective: To describe survival of US patients with ENKL, to inquire if the long-term survival has improved in the most recent years, and to evaluate factors possibly associated with survival among ENKL patients. Design/Method: We used the National Cancer Institute' Surveillance Epidemiology and End Results (SEER-18) database to determine the survival of patients with ENKL. Inclusion criteria was the diagnosis of ENKL occurring at any age, as first malignant neoplasm diagnosed between 2000 and 2018. Follow-up data was available to the end of 2020. Cases were divided in two "eras", 2000-2009 and 2010-2018, with the latter being expected to reflect the use of asparaginase-base chemotherapy regimens. Survival was estimated using the method of Kaplan-Meier. The impact of era, age, race, gender, and stage on survival were accessed utilizing multivariate analysis. Results: A total of 967 cases were included. Median age of patients was 52 years, 267 (28%) were < 40 at time of diagnosis, 630 (65%) were male and 599 (62%) had early stage disease. There were 430 patients in the 2000-2009 era and 537 patients in the 2010-2018 era. A high proportion of patients was Hispanic (367, 38%) or Asian/Pacific Islander (215, 22%). The median survival for patients < 40 years was 30 months (95% C.I. 0-60.4), and 19 months for patients ≥ 40 (95% C.I. 11.8-26.1, P=0.047) (Figure). Median survival was better for patients diagnosed in the 2010-2018 era (35 months, 95% C.I. 21-48.9 vs. 13 months, 95% C.I. 8.2-17.7, P=0.003). For patients < 40, median survival was 16 months in 2000-2009 and 61 months in 2010-2018 (P=n.s.). For patients ≥ 40 years, median survival improved from 12 to 33 months respectively (P=0.003). Survival improved for those with limited disease (median n.r. vs. 31 months, P< 0.0001), but not for those with advanced stage (6 months in both eras, P=0.3). In multivariable analysis, diagnosis of ENKL in the 2010-2018 era (HR=0.8, 95% C.I. 0.65-0.91, P=0.003), age ≥ 40 (HR=1.2, 95% C.I. 1.0-1.4, P=0.036), and early stage (HR=0.54, 95% C.I. 0.3-0.7, P<0.01) were associated with survival. Conclusion: Survival improved for patients with ENKL in the US particularly for patients with localized disease. There is urgent need for different treatment strategies for ENKL patients, especially for those with advanced disease. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

IL-10 contributes to gemcitabine resistance in extranodal NK/T-cell lymphoma cells via ABCC4.

BackgroundChemotherapy resistance is a main reason for treatment failure in extranodal NK/T-cell lymphoma (ENKTL). Interleukin-10 (IL-10) is closely related to the occurrence and prognosis of ENKTL. We intended to study the role and molecular mechanism of IL-10 in ENKTL resistance. MethodsFifty serum samples were collected from patients with a histologically proven diagnosis of ENKTL. Fifty healthy volunteers were enrolled as a control group. The level of serum IL-10 was detected by ELISA. The NK/T-cell lymphoma cell lines YT and NK-92 were divided into the control group (untreated), IL-10 group (treated with IL-10), IL-10 + GEM group (treated with IL-10 and gemcitabine simultaneously) and GEM group (treated with gemcitabine). A CCK8 assay and flow cytometry were employed to detect the effects of IL-10 on each group. Western blotting was applied to detect the expression of ABC membrane transporter family proteins and signaling pathway proteins in each group. ResultsSerum IL-10 levels were higher in ENKTL patients as well asin patients with ineffective treatment. The IC50 value for gemcitabine in YT and NK-92 cells increased significantly in the presence of IL-10. The effects of gemcitabine resulting in cell killing, cell cycle arrest, and apoptosis promotion were also weakened by IL-10. The expression of ABCC4, STAT1, p-STAT1, Tyk2 and p-Tyk2 was significantly increased by IL-10. ConclusionOur results indicate that IL-10 contributes to the resistance of ENKTL cells via ABCC4 and that IL-10 regulates the JAK/STAT signaling pathway in YT and NK-92 cells.

The identification of gene signatures in patients with extranodal NK/T-cell lymphoma from a pair of twins

BackgroundThere is no unified treatment standard for patients with extranodal NK/T-cell lymphoma (ENKTL). Cancer neoantigens are the result of somatic mutations and cancer-specific. Increased number of somatic mutations are associated with anti-cancer effects. Screening out ENKTL-specific neoantigens on the surface of cancer cells relies on the understanding of ENKTL mutation patterns. Hence, it is imperative to identify ENKTL-specific genes for ENKTL diagnosis, the discovery of tumor-specific neoantigens and the development of novel therapeutic strategies. We investigated the gene signatures of ENKTL patients.MethodsWe collected the peripheral blood of a pair of twins for sequencing to identify unique variant genes. One of the twins is diagnosed with ENKTL. Seventy samples were analyzed by Robust Multi-array Analysis (RMA). Two methods (elastic net and Support Vector Machine-Recursive Feature Elimination) were used to select unique genes. Next, we performed functional enrichment analysis and pathway enrichment analysis. Then, we conducted single-sample gene set enrichment analysis of immune infiltration and validated the expression of the screened markers with limma packages.ResultsWe screened out 126 unique variant genes. Among them, 11 unique genes were selected by the combination of elastic net and Support Vector Machine-Recursive Feature Elimination. Subsequently, GO and KEGG analysis indicated the biological function of identified unique genes. GSEA indicated five immunity-related pathways with high signature scores. In patients with ENKTL and the group with high signature scores, a proportion of functional immune cells are all of great infiltration. We finally found that CDC27, ZNF141, FCGR2C and NES were four significantly differential genes in ENKTL patients. ZNF141, FCGR2C and NES were upregulated in patients with ENKTL, while CDC27 was significantly downregulated.ConclusionWe identified four ENKTL markers (ZNF141, FCGR2C, NES and CDC27) in patients with extranodal NK/T-cell lymphoma.

Nutrition-Incorporated Pink-E Predicts Survival of Extranodal NK/T-Cell Lymphoma

▪Introduction: Patients with aggressive lymphomas are at high risk of losing body resources, resulting in malnutrition, immunodeficiency, impaired life quality and inferior outcomes. Nutritional status is closely associated with the development and treatment arrangements of malignancies, but often neglected in the prognostic assessment. Thus, this study aimed to explore the prognostic significance of nutrition-related parameters in extranodal NK/T-cell lymphoma (ENKTL), an aggressive lymphoma with dismal outcomes.Methods: We retrospectively analyzed patients diagnosed with ENKTL between 2011 and 2020 from Shandong Provincial Hospital and Affiliated Hospital of Qingdao University. The observation endpoints were overall survival (OS) and progression-free survival (PFS). Univariate (UVA) and multivariate (MVA) Cox regression analyses were conducted to examine the significance of variables at diagnosis on OS and PFS. A reformative nutrition assessment-incorporated score system was constructed based on the MVA results. Its performance was tested in the training and validation cohort from multiple aspects, including calibration, discrimination and clinical utility.Results: A total of 160 patients with a median age of 50 (39, 58.75) years and male predominance (67.5%) were included. The prognostic significance of two emerging nutritional indexes, prognostic nutritional index (PNI) and controlling nutritional status (CONUT) score, was assessed. UVA analysis showed PNI was a meaningful marker to OS (HR 2.275, P=0.014) but not to PFS (HR 1.653, P=0.089) while CONUT score was a significant predictor not only to OS (HR 29.385, P＜0.001) but to PFS (HR 12.516, P＜0.001). MVA analysis further verified that CONUT score could independently predict OS (HR 10.247, P=0.001) and PFS (HR 5.587, P=0.001) in addition to prognostic index of natural killer lymphoma plus EBV (PINK-E), another independent marker (PINK-E=2, HR 3.842, P=0.034, PINK-E=3/4/5, HR 9.185, P=0.006 for OS; PINK-E=2, HR 2.308, P=0.06, PINK-E=3/4/5, HR 4.535, P=0.004 for PFS) (Figure 1).Based on this finding, a modified prognosis scoring tool, CONUT-PINK-E, was developed from the training cohort (TC) and tested in the independent external validation cohort (VC). The novel model contains six factors, age≥60 years old, Ann Arbor III/IV stage, distant lymph node involvement, non-nasal type, detectable EBV-DNA in blood and CONUT score≥5 (moderate and severe malnutrition). CONUT-PINK-E differentiated patients into low-, intermediate- and high-risk grades according to the imparities of survival probability revealed by Kaplan-Meier curves. Significant survival differences existed among three risk grades that the median OS was 74, 36, 5 months and median PFS was 31, 14, 4 months, respectively, for the low-, intermediate-, high-risk group (P＜0.001) in TC and the corresponding data were 72, 26, 7 months and 35, 14, 4 months in VC (P＜0.001, Figure 2).Subsequently, the superiority of CONUT-PINK-E was examined by comparison with international prognostic index (IPI), Korean Prognostic Index (KPI), Prognostic index of natural killer lymphoma (PINK) and PINK-E. The 1- to 5-year time-dependent areas under receiver operating characteristic curve (AUCs) hinted that CONUT-PINK-E (TC: 0.832-0.961, VC: 0.773-0.937) possessed higher discrimination than IPI (TC: 0.710-0.785, P<0.001; VC: 0.646-0.840, P<0.001), KPI (TC: 0.659-0.826, P<0.001; VC: 0.623-0.691, P<0.001), PINK (TC: 0.802-0.865, P<0.001; VC: 0.663-0.842, P<0.001) and PINK-E(TC: 0.815-0.902, P<0.001; VC: 0.741-0.894, P<0.001) (Figure 3A, 3B). Decision curve analysis plainly showed CONUT-PINK-E brought higher clinical net benefits than IPI, KPI, PINK and PINK-E in forecasting OS and PFS of ENKTL (Figure 3C, 3D). In addition, net reclassification index (NRI) and integrated discrimination improvement (IDI) conformably demonstrated that CONUT-PINK-E achieved significant improvements than the prior stratification tools.Conclusion: This is the first time that CONUT score was recognized capable of acting as an independent prognostic marker in newly-diagnosed ENKTL patients. More importantly, the first risk score covering nutritional status assessment for ENKTL, CONUT-PINK-E, was proposed and presented striking performance. The newly-built model could deliver vital reference to the risk stratification and comprehensive managements of ENKTL patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Clinical Characteristics and Prognostic Analysis of Extranodal NK/T-Cell Lymphoma Patients Treated with Pegaspargase Based Chemotherapy

To investigate the clinical characteristics of patients with extranodal NK/T-cell lymphoma (ENKL), and to analyze the factors that affecting the survival and prognostic of patients treated with pegaspargase based chemotherapy. The clinical data of 61 ENKL patients treated in Peking Union Medical College Hospital from January 2015 to June 2019 were enrolled and retrospectively analyzed. The clinical characteristics, survival rate and influencing factors of prognostic in patients were investigated. The male and female ratio in the whole group was 2.8∶1. The median age was 46 years old (range, 17-67 years old). 30 patients were in stage I/II, while 31 patients were in stage III/IV. The ratio of nasal and non-nasal type was 4.1∶1. The common sites of extranodal involvement were skin and subcutaneous tissue (26.2%), liver (14.8%), lung (13.1%) and gastrointestinal tract (13.1%). 9.8% of patients showed central nervous system involvement and 11.5% showed bone marrow involvement. The median follow-up time was 22 months (range, 1-53 months). The 2-year PFS and OS rates of patients in the whole group were 51.6% and 53.2%, respectively. The 2-year OS rate of patients at stage I/II was 87.5%, while that of patients at stage III/IV was only 21.2%, the difference showed statistically significant (P<0.0001). Patients with non-nasal type disease showed a higher proportion in adverse factors of prognosis, of whom the median OS was only 3 months. Multivariate analysis showed that age>60 years old and Ann Arbor stage III-IV were the independent adverse factors that affecting the prognosis of PFS and OS (HR=3.681, 95% CI 1.322-10.250; HR=4.611, 95% CI 1.118-19.009). The survival of ENKL patients has been significantly improved by pegaspargase based chemotherapy. Patients with stage I/II disease have achieved a relatively good 2-year OS rate of 87.5%, but the prognosis of stage III/IV and non-nasal type patients are still poor. Age>60 years old and Ann Arbor stage III/IV are independent adverse prognostic factors for ENKL patients.

Metabolic activity of extranodal NK/T cell lymphoma on 18F-FDG PET/CT according to immune subtyping

Disseminated extranodal NK/T cell lymphoma (ENKTL) is associated with dismal prognosis. Hence, distinct tumor immune microenvironment (TIME) subtypes were proposed to explain their influence on ENKTL progression and help predict treatment response. In this study, we investigated the capacity of FDG PET/CT to discern ENKTL TIME subtypes. A total of 108 pretreatment FDG PET/CT scans of 103 patients with newly diagnosed or relapsed ENKTL were retrospectively analyzed. TIME subtype was determined using three key immunohistochemical markers. SUVmax, MTV and TLG were measured, and metabolic features associated with TIME subtype were statistically extracted. TIME subtype was immune tolerance (IT) in 13.9%, immune evasion A (IE-A) in 56.5%, immune evasion B (IE-B) in 21.3%, and immune silenced (IS) in 8%. The IS group showed the highest SUVmax (15.9 ± 6.4, P = 0.037), followed by IE-A (14.1 ± 7.8), IE-B (10.9 ± 5.6), and IT groups (9.6 ± 5.1). Among 53 with only nasal FDG lesions, 52 had non-IS subtype. Among 55 with extra-nasal FDG lesions, those with IS subtype more often had adrenal (P = 0.001) or testis involvement (P = 0.043), greater MTV (P = 0.005), greater TLG (P = 0.005), and SUVmax located at extra-nasal sites. The presence of 0–2 and 3–4 of these four findings was associated with low probability (2/46) and high probability (6/9) of IS subtype, respectively. Furthermore, patients showing IS subtype-favoring PET/CT pattern had worse overall survival compared to their counterparts. These results demonstrate that FDG PET/CT can help predict immune subtype in ENKTL patients. The different patterns between glycolytic activity and involved site according to TIME subtype might be related to the interplay between tumor cells and immune cells in the tumor microenvironment.

Open-label, single arm, multicenter phase II study of VIDL induction chemotherapy followed by upfront autologous stem cell transplantation in patients with advanced stage extranodal NK/T-cell lymphoma

The clinical outcome of advanced-stage Extranodal NK/T cell lymphoma (ENKTL) patients using conventional chemotherapy is extremely poor. The aim of this study was to investigate the outcomes of advanced-stage ENKTL patients treated with non-anthracycline-based chemotherapy followed by upfront autologous stem cell transplant (ASCT). From 8 institutions, 27 patients were recruited from February 2016 to May 2019. Patients were treated with 4 cycles of VIDL induction chemotherapy. Patients who achieved complete response (CR) or partial response (PR) underwent upfront ASCT. This study is registered with clinicaltrial.gov, # NCT02544425. Twenty patients (74.1%) completed 4 cycles of VIDL induction. The overall response rate of VIDL was 74.1%, including 17 (63.0%) with CR and 3 (11.1%) with PR. Primary toxicity of the induction regimen was grade 3 or 4 neutropenia, and no treatment-related mortality was reported. Seventeen patients proceeded with upfront ASCT, and 9 patients relapsed after ASCT, among whom, 4 was central nervous system (CNS) relapse. The median duration of response was 15.2 months (95% CI, 6.3–24.1 months). This study suggested that VIDL induction chemotherapy followed by upfront ASCT is feasible and effective for the treatment of advanced-stage ENKTL. However, CNS relapse prevention is needed in the treatment of advanced-stage ENKTL.

Serum-Derived Exosomal MicroRNA Profiles Can Predict Poor Survival Outcomes in Patients with Extranodal Natural Killer/T-Cell Lymphoma.

Simple SummaryExosomes containing microRNAs (miRNAs) might have utility as biomarkers to predict the risk of treatment failure in extranodal NK/T-cell lymphoma (ENKTL). The aim of our study was to assess the prognostic value of serum-derived exosomal miRNA profiles in patients with ENKTL. The top 20 upregulated miRNAs in patients with poor outcomes and 16 miRNAs upregulated in tumor cell lines identified five candidate miRNAs (miR-320e, miR-4454, miR-222-3p, miR-21-5p, and miR-25-3p). Among these, increased levels of exosomal miR-4454, miR-21-5p, and miR-320e were associated with poor overall survival. These three miRNAs were overexpressed in NKTL cell lines that were resistant to etoposide, and the transfection of NKTL cell lines with miR-21-5p and miR-320e induced an increase in expression of the proinflammatory cytokines. Upregulation of these exosomal miRNAs in treatment-resistant cell lines suggests they have a role as biomarkers for the identification of ENKTL patients at high risk of treatment failure.Exosomes containing microRNAs (miRNAs) might have utility as biomarkers to predict the risk of treatment failure in extranodal NK/T-cell lymphoma (ENKTL) because exosomal cargo miRNAs could reflect tumor aggressiveness. We analyzed the exosomal miRNAs of patients in favorable (n = 22) and poor outcome (n = 23) groups in a training cohort. Then, using the Nanostring nCounter® microRNA array, we compared them with miRNAs identified in human NK/T lymphoma (NKTL) cell line-derived exosomes to develop exosomal miRNA profiles. We validated the prognostic value of serum exosomal miRNA profiles with an independent cohort (n = 85) and analyzed their association with treatment resistance using etoposide-resistant cell lines. A comparison of the top 20 upregulated miRNAs in the training cohort with poor outcomes with 16 miRNAs that were upregulated in both NKTL cell lines, identified five candidate miRNAs (miR-320e, miR-4454, miR-222-3p, miR-21-5p, and miR-25-3p). Among these, increased levels of exosomal miR-4454, miR-21-5p, and miR-320e were associated with poor overall survival in the validation cohort. Increased levels were also found in relapsed patients post-treatment. These three miRNAs were overexpressed in NKTL cell lines that were resistant to etoposide. Furthermore, transfection of NKTL cell lines with miR-21-5p and miR-320e induced an increase in expression of the proinflammatory cytokines such as macrophage inflammatory protein 1 alpha. These studies show that serum levels of exosomal miR-21-5p, miR-320e, and miR-4454 are increased in ENKTL patients with poor prognosis. Upregulation of these exosomal miRNAs in treatment-resistant cell lines suggests they have a role as biomarkers for the identification of ENKTL patients at high risk of treatment failure.

Prognostic value of bone marrow (18)F-FDG uptake pattern of pretreatment PET-CT in extranodal NK/T cell lymphoma

Objective: To investigate the prognostic value of bone marrow (BM) (18)F-fluorodeoxyglucose ((18)F-FDG) uptake pattern of pretreatment positron emission tomography/computed tomography (PET-CT) in extranodal NK/T cell lymphoma (ENKTL) patients. Methods: We retrospectively collected clinical data from a series of 63 ENKTL patients with stageⅡ~Ⅳ, who have received both (18)F-FDG PET-CT and bone marrow biopsy (BMB) prior to treatment. According the BM (18)F-FDG uptake pattern of PET-CT, the patients were divided into three groups: focal BM FDG uptake higher than liver (fPET+ ), diffuse BM uptake higher than liver (dPET+ ) and normal BM uptake (lower than liver) (nPET). The Kaplan-Meier method and Log-rank test were respectively used for survival analysis and univariate analysis, and COX proportional hazards model for multivariate analysis. Results: Among the 63 patients, 22 patients had nPET, 24 patients showed dPET+ , and 17 patients had fPET+ . BMB positive was found in 8 patients, and negative in 55 patients. Thirty-seven patients had disease progression or relapse, and 31 patients died. The 3-years progression free survival (3y-PFS) rates of fPET+ patients and nPET patients were 14.7% and 63.6% (P=0.006). The 3-years overall survival (3y-OS) rates were 18.8% and 64.8% (P=0.005). The 3y-PFS of dPET+ patients and nPET patients were 35.6% and 63.6% (P=0.161), 3y-OS were 47.9% and 64.8% (P=0.280). Univariate analysis showed that lactate dehydrogenase (LDH) level, Epstein-Barr virus DNA (EBV-DNA), Korean prognostic index (KPI) and BM (18)F-FDG were related with PFS and OS (all P<0.05). Multivariate analysis showed EBV-DNA and BM (18)F-FDG were independent predictors for PFS (P<0.05). EBV-DNA was also an independently predictor for OS (P<0.05). Conclusions: PET/CT-directed BM patterns are meaningful in predicting prognosis of newly diagnosed ENKTL patients. Focal BM (18)F-FDG uptake pattern is an independent predictor for PFS.

Prognostic value of pretreatment (18)F-FDG PET-CT metabolic parameters in patients with advanced extranodal NK/T cell lymphoma

Objective: To investigate the prognostic values of the maximum standardized uptake value (SUV(max)), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) calculated from pretreatment (18)F-fluorodeoxy glucose ((18)F-FDG) PET-CT results of patients with advanced extranodal NK/T cell lymphoma (ENKTL). Methods: The clinic data, follow-up data and pretreatment (18)F-FDG PET-CT data of 45 patients with ENKTL of stage Ⅳ were collected. The optimal cutoff value of progression-free survival (PFS) of SUV(max), MTV and TLG were analyzed by using receiver-operating characteristic (ROC) curve. The Kaplan-Meier method, Log-rank test and COX proportional hazards model were used for survival analysis, univariate analysis and multivariate analysis, respectively. Results: The median SUV(max), MTV and TLG of 45 ENKTL patients were 17.98, 70.18 and 755.42, respectively. ROC curve showed that the area under the curve (AUC) of SUV(max), MTV and TLG were 0.504 (P=0.970), 0.868 (P<0.001) and 0.848 (P=0.001), respectively. The value of SUV(max) was too small to fit for calculating the cutoff value of AUC. The cutoff value of MTV was 42.54 (sensitivity =78.1% and specificity =84.6%), and the cutoff value of TLG was 435.15 (sensitivity=75.0% and specificity =76.9%). Univariate analysis showed that lactate dehydrogenase (LDH) level, epstein-barr virus (EBV)-DNA, Eastern Cooperative Oncology Group (ECOG) score, bone marrow, Korean prognostic index (KPI), MTV, TLG were significantly related with PFS (all P<0.05), and lactate dehydrogenase (LDH) level, EBV-DNA, ECOG score, primary tumor location, KPI, MTV, TLG were significantly related with overall survival (OS) (all P<0.05). Multivariate analysis showed that KPI, MTV and TLG were independent prognostic predictors of PFS and OS (all P<0.05). Conclusions: MTV and TLG of pretreatment (18)F-FDG PET-CT are independent prognostic factors for PFS and OS of patients with advanced ENKTL. MTV and TLG may be more fit for evaluating the prognosis of ENKTL patients than SUV(max).