Extranodal Natural killer/T-cell Lymphoma Patients Research Articles

Serum aspartate aminotransferase, a novel potential biomarker of prognosis in extranodal natural killer/T cell lymphoma, nasal type.

Aspartate aminotransferase (AST), an indicator of liver cell damage, was related to the prognosis of certain malignant tumors. This study examined the predictive value of AST in patients with extranodal natural killer/T cell lymphoma (ENKTL). We reviewed 183 cases diagnosed with ENKTL and selected 26 U/L as the optimum cut-off value of AST. We used the univariate and multivariate Cox regression to compare the different AST groups' overall survival (OS) and progression-free survival (PFS). Prior to propensity score matching (PSM), Kaplan-Meier analysis showed that patients in the low AST subgroup had better OS and PFS than the high AST subgroup. Multivariate analysis revealed that AST was an independent indicator for prognosis. After PSM, the low AST subgroup maintained a significantly better OS and PFS than the high AST subgroup. AST might represent a significant prognostic marker for ENKTL patients.

Pulmonary extranodal natural killer/T-cell lymphoma: clinical presentation, CT characteristics, and patient outcomes.

Due to the extreme rarity of pulmonary extranodal natural killer/T-cell lymphoma (ENKTCL), studies on this lymphoma type are limited. We aimed to investigate the clinical presentations, computed tomography (CT) findings, CT dynamic changes, and outcomes of patients diagnosed with pulmonary ENKTCL. We conducted a retrospective cohort study on ENKTCL, nasal type, at West China Hospital, from January 2010 to January 2023. Out of 27 initial cases with pulmonary ENKTCL, we excluded 4 due to the lack of chest CT images, resulting in a final cohort of 23 patients. Our evaluation covered clinical features, laboratory findings, CT presentations, treatment strategies, and survival outcomes. Survival analyses were performed using the Kaplan-Meier method, with log-rank tests for survival curve comparisons. Given the small sample size, our interpretation of the data is mainly descriptive. The most common CT presentations in our institution was solitary or multiple nodules (7/23, 30.4%). The halo sign (78.3%) and floating vessels sign (83.3%) were commonly observed in pulmonary ENKTCL. Elevated lactate dehydrogenase (LDH) levels were observed in 20 (86.9%) patients. The median overall survival (OS) for pulmonary ENKTCL patients was 1 month; 3 cases displayed a favorable prognosis, maintaining complete remission (CR) status for 1.5-7 years after receiving chemotherapy. Chemotherapy led to improved prognosis, with a median survival of 5 months seen in patients who received chemotherapy. Patients with bilateral lung involvement had worse outcomes compared to those with unilateral lesions. Pulmonary ENKTCL is a rare and aggressive disease, often misdiagnosed due to nonspecific clinical and CT features. Laboratory tests, failure of antibiotic treatment, and "floating vessels sign" on enhanced CT scans may aid in diagnosis. Timely chemotherapy may improve survival, emphasizing the importance of early detection and prompt treatment.

Appropriate timing to perform an interim 18F-FDG PET/CT in patients with nasal-type extranodal natural killer/T cell lymphoma.

Interim 18F-FDG PET/CT (I-PET) has a role in response evaluation and treatment guidance in patients with nasal-type extranodal natural killer/T cell lymphoma (ENKTL). However, there was no agreement on the timing of I-PET performed, after chemotherapy or after chemoradiotherapy. We aimed to find the appropriate timing for I-PET by assessing the prognostic value of I-PET in response evaluation in ENKTL patients. Two hundred and twenty-seven ENKTL patients who had undergone I-PET were retrospectively included. All patients were grouped based on their therapeutic strategy received, chemotherapy or chemoradiotherapy. The Deauville 5-point score (DS) was used to interpret the I-PET images. The hazard ratio (HR) and C-index were used to measure the discriminatory and prognostic capacities of I-PET performed at different times. One hundred and six patients underwent the I-PET after chemotherapy (chemotherapy group), while I-PET was performed after chemoradiotherapy in 121 patients (chemoradiotherapy group). Eighty-seven patients were classified as metabolic remission (DS score of 1-3), while the other 140 were classified as non-metabolic remission (DS score of 4-5) according to the Deauville criteria. There were no significant survival differences between patients in metabolic remission and in non-metabolic remission in either progression-free survival (PFS, p = 0.406) or overall survival (OS, p = 0.350). In the chemotherapy group, patients in metabolic remission had significantly superior PFS than patients in non-metabolic remission (p = 0.012). For OS, a discriminative trend was also found on the survival curve between patients in metabolic remission and in non-metabolic remission (p = 0.082). In the chemoradiotherapy group, there was no significant difference in PFS (P = 0.185) or OS (P = 0.627) between patients in metabolic remission and in non-metabolic remission. I-PET after chemotherapy yields higher discriminative power and has the ability for prognostic prediction in nasal-type ENKTL patients. I-PET after radiochemotherapy has no prognostic value. Thus, the appropriate timing for I-PET is after chemotherapy but before radiotherapy for response evaluation in nasal-type ENKTL patients.

Analysis of Efficacy and Prognosis of Extranodal Natural Killer/T Cell Lymphoma

Objective: Extranodal natural killer/T cell lymphoma (ENKTCL) is one type of non-Hodgkin's lymphomas. It's highly malignant and aggressive. The survival rate of patients with ENKTCL is low and the prognosis is extremely pessimistic. With regard to the common therapeutic regimen, there is no absolute answer. Thus, this research aims to retrospectively analyze clinical features, efficacy and prognosis based on the data of ENKTCL patients from two different clinical centers, so as to provide real-world evidence for the clinical treatment of the disease. Methods : Clinical data of 18 ENKTCL patients treated in Hematological Department of Zhongda hospital Southeast University from January 2013 to December 2022 and 104 ENKTCL patients from Jiangsu Cancer Hospital from January 2017 to December 2022 were retrospectively collected. Clinical data included age at initial diagnosis, gender, stage, clinical classification, B symptom, number of extranodal involvement sites, the situation of regional lymph nodes involvement, the situation of bone marrow involvement, KPS, ECOG, PINK, NRI, immunohistochemistry, the clinical symptom, therapy regimen, laboratory and imaging test. Then analysis of efficacy and prognosis was done. Follow-up was conducted by telephone contact with the patient and/or family until April 2023. Results: 1. Among the different treatment options, the efficacy of a combination of chemotherapy with radiotherapy group was statistically significant compared with either single chemotherapy group (P=0.000) or single radiotherapy group (P= 0.009) for patients with limited-stage disease (stage I/II), but there was no significant difference in the efficacy between chemotherapy group and radiotherapy group (P>0.05).Similarly, the efficacy of chemotherapy with radiotherapy group was statistically higher than that of single chemotherapy group (P=0.012), and that of a combination of chemotherapy with targeted therapy group was statistically higher compared with single chemotherapy group (P= 0.041) for patients with advanced-stage disease (stage III/IV), but there was no statistical difference between the single chemotherapy group and its combination with radiotherapy and targeted therapy group, the combination of chemotherapy with radiotherapy group and their combinations with targeted therapy group, the combination of chemotherapy with targeted therapy group and their combinations with radiotherapy group (All P >0.05). For all patients receiving chemoradiotherapy, there was no statistical significance in the efficacy of the sequential chemoradiotherapy group compared with the sandwich chemoradiotherapy group (P=0.547). 2. Univariate analysis showed that age at initial diagnosis, stage, presence of B symptoms, lactate dehydrogenase (LDH), ECOG score, extranodal involved site and number, and therapy regimen were factors related to the prognosis of patients (All P<0.05). Multivariate analysis further showed that patients' age at initial diagnosis, LDH, ECOG score and therapy regimen were the main factors affecting the prognosis of ENKTCL patients (P<0.05). Conclusion: 1. In the treatment scheme of ENKTCL, the combination of radiotherapy and chemotherapy has a better effect for patients at stage I and II, whereas chemotherapy should be combined with radiotherapy or targeted therapy to improve the efficacy of patients at advanced stage III and IV. For all patients with chemoradiotherapy, the efficacy of sequential chemoradiotherapy is similar to sandwich chemoradiotherapy. 2. The age at initial diagnosis, LDH, ECOG score and therapy regimen are the main factors affecting the prognosis of ENKTCL patients.

Efficacy and Safety of Chemotherapy (DDGP vs VIPD) Followed Radiotherapy Vs Radiotherapy Followed Chemotherapy (DDGP vs VIPD) Vs Radiotherapy Alone for Newly Diagnosed Early Stage Extranodal Natural Killer/T Cell Lymphoma: Final Results of a Prospective, Multicenter, Randomized, Controlled Clinical Trial

Background: Extranodal Natural Killer/T Cell Lymphoma (ENKTL) is a highly aggressive form of non-Hodgkin lymphoma (NHL), primarily found in Asia and commonly linked to Epstein-Barr virus (EBV) infection. Despite the treatment efficacy for early stage ENKTL has been improved in recent years, there is no consistent approach for clinical treatment. Current guidelines includes radiotherapy (RT) alone, concurrent chemoradiation therapy (CCRT), sequential chemoradiation, and sandwich chemoradiation. Here we present the final results of the efficacy and safety of sequential therapies of DDGP (dexamethasone, cisplatin, gemcitabine, and pegaspargase) regimen or VIPD (etoposide, ifosfamide, cisplatin and dexamethasone) regimen combined with RT, and RT alone. M ethods: We conducted a prospective, multicenter, randomized, controlled clinical trial to compare the efficacy and safety of sequential chemotherapy (DDGP vs VIPD regimen) followed by RT, sequential RT followed by chemotherapy, and RT alone in eligible patients with newly diagnosed stage I/II ENKTL. Upon study entry, patients were randomized 1:1:1:1:1 to receive either DDGP regimen followed by RT (DDGP+RT), or VIPD regimen followed by RT (VIPD+RT), or RT followed by DDGP regimen (RT+DDGP), or RT followed by VIPD (RT+VIPD), or RT alone. Patients assigned to the DDGP group were administered cisplatin (20 mg/m 2, intravenous, days 1-4), dexamethasone (15 mg/m 2, intravenous, days 1-5), gemcitabine (800 mg/m 2, intravenous, on days 1 and 8), and pegaspargase (2500 IU/m 2, intramuscular, on day 1). Those in the VIPD group received etoposide (100 mg/m 2, intravenous, days 1-3), ifosfamide (1.2 g/m 2, intravenous, days 1-3), cisplatin (33 mg/m 2, intravenous, days 1-3), and dexamethasone (40mg, intravenous, days 1-4). Both the DDGP and VIPD regimens were repeated every 21 days. For the sequential chemotherapy followed by RT group, patients underwent 3 cycles of either DDGP or VIPD regimen, followed by 50 Gy (2 Gy * 25 times) of intensity modulated radiotherapy (IMRT). In the sequential RT followed by chemotherapy group, patients were first given 50 Gy (2 Gy * 25 times) of IMRT and then sequential either DDGP or VIPD regimen. Meanwhile, the RT alone group received 50 Gy (2 Gy * 25 times) of IMRT only. The primary end point of our study was progression free survival (PFS), with secondary end points including complete remission rate (CRR), objective response rate (ORR), overall survival (OS). R esults: Our study, spanning January 2011 to August 2020, involved 244 patients from 22 centers across China, with 200 randomly assigned to receive treatment (40 in each group). Both the demographic and disease characteristics of the patients at baseline were generally consistent across all treatment groups. During a median follow-up of 72.1 months, the median PFS (mPFS) was not reached in neither the DDGP + RT nor RT + DDGP groups, compared to 36.3 months in the VIPD + RT group, 78.3 months in the RT + VIPD group, and 89.6 months in the RT alone group. The 5-year PFS rates for the DDGP + RT, VIPD + RT, RT + DDGP, RT + VIPD, and RT alone groups were 81.5%, 46.1%, 79.8%, 53.1%, and 57.5% respectively. Similarly, the 10-year PFS rates were 81.5%, 42.8%, 74.1%, 45.9%, and 45.7% respectively. Compared with RT alone, PFS was improved in DDGP + RT group (p = 0.006) and RT + DDGP group (p = 0.024). Compared with VIPD + RT, PFS was improved in DDGP + RT group (p = 0.006) and RT + DDGP group (p = 0.026). Either between DDGP +RT and RT + DDGP group or between VIPD +RT and RT +VIPD group, PFS showed no differences. Median OS was not reached in 5 groups. OS showed no differences in 5 groups (p = 0.27). The patients who failed from either VIPD regimen or RT alone received DDGP regimen. This might be the reason why the OS showed no differences between 5 groups. The CRRs of 5 groups (DDGP + RT, VIPD +RT, RT + DDGP, RT +VIPD, RT alone) were 87.5%, 57.5%, 82.5%, 69.2%, and 67.5%, respectively. Similarly, the ORRs were 97.5%, 77.5%, 90.0%, 74.4%, and 87.5%, respectively. Conclusions: The DDGP regimen exhibited promising outcomes in this randomized clinical trial for newly diagnosed early-stage ENKTL patients. The sequential therapies with DDGP regimen could improve the efficacy compared with RT alone. Patients could also benefit more from therapies with DDGP regimen than those with VIPD regimen. The order in which chemotherapy and RT were applied has no fatal impact on the prognosis of early-stage ENKTL.

Comparative analysis of clinicopathologic characteristics and prognosis between nasal and nonnasal extranodal NK/T-cell lymphoma.

The clinicopathologic characteristics and prognosis of nasal and nonnasal extranodal natural killer T-cell lymphoma (ENKTL) are considered to be different. However, the underlying features responsible for these differences are not well clarified especially in the era of asparaginase therapy. In total, 1007 newly diagnosed ENKTL patients from 11 medical centers were included in this study. Clinicopathologic characteristics and survival data were collected. The chi-squared test and Kruskal-Wallis test were utilized for the comparison of different groups. Univariable and multivariable Cox proportional hazards models were used to screen prognostic factors. Overall, 869 (86.3%) patients were nasal forms. Compared to patients with nasal ENKTL, nonnasal patients were at more advanced stages and had poor performance status, bone marrow involvement, elevated serum lactate dehydrogenase (LDH), and CD56-negative status (p < 0.05). The 5-year overall survival (OS) for nasal and nonnasal patients were 65.6% and 45.0%, respectively. The OS of nasal forms patients were superior to nonnasal patients, especially in Eastern Cooperative Oncology Group performance status (ECOG PS) (≥2), advanced stage, KPI (HIR/HR), IPI (HIR/HR), PINK (HR), and high EBV DNA load groups. In patients treated with pegaspargase/L-asparaginase-based regimens, the OS of nasal patients was better than that of nonnasal patients. After adjusting the covariates of age, stage, ECOG PS score, LDH, B symptoms, and BM involvement, results showed that the nonnasal site was associated with poor survival of ENKTL. The clinicopathologic characteristics and prognosis of nasal and nonnasal ENKTL patients are different. Nasal forms patients had superior OS than nonnasal patients, especially in the era of asparaginase.

Development and Validation of Clinical-Metabolic-Radiomics Model Based on Nomogram-Revised Risk Index for Prognosis Prediction in Patients with Extranodal Natural Kill/T Cell Lymphoma

To identify clinical-metabolic-radiomics model using clinical data and 18F-FDG PET/CT image for predicting progression-free survival (PFS) of nasal-type extranodal natural killer/T cell lymphoma (ENKTCL) on the basis of the nomogram-revised risk index (NRI) model previously established and validated by our research group. A total of 133 ENKTCL patients were prospectively included and randomly divided into a training cohort (n = 73) and a validation cohort (n = 50). 107 features and 7 commonly used metabolic parameters (SUVmax, MTV, TLG, SD, TLR, TAR and TBR) were extracted from baseline PET images of the patients. Least absolute shrinkage and selection operator (LASSO) following Cox regression were used to select optimal features and parameters. NRI-metabolic-radiomics model was developed and validated in the two cohorts and compared with NRI model and NRI-metabolic model. TLG and 5 radiomics features were selected after LASSO and Cox regression. NRI-metabolic (NRI-TLG) model and NRI-metabolic-radiomics (NRI-TLG-RAD) model was developed based on NRI, TLG and selected 5 radiomics features. For PFS, NRI-TLG-RAD showed better PFS discrimination than NRI-TLG model and NRI model in both training cohort (C-index = 0.791, 0.743 and 0.690, respectively) and validation cohort (C-index = 0.785, 0.707, and 0.610 respectively). Moreover, NRI-TLG-RAD model and NRI-TLG model divided more patients into low-risk group (No. of patients: 66, 42 vs. 20) and very high-risk group (No. of patients: 25, 25 vs. 9), compared to preexisting NRI model. The addition of metabolic and radiomics information improved the prognostic performance of preexisting NRI model greatly. Better prognostic discrimination and more reasonable patient division of the new NRI-TLG and NRI-TLG-RAD model may provide the basis for more precise treatment modality in the future.

The predictive implication of programmed cell death ligand 1 expression in extranodal natural killer/T-Cell lymphoma and its correlation with clinicopathological features: a systematic review and meta-analysis.

Although programmed cell death ligand 1 (PD-L1) expression and function in hematologic malignancies have aroused extensive attention, its prognostic value for extranodal natural killer/T-cell lymphoma (ENKTL) is still unknown. Therefore, we conducted this meta-analysis to explore the predictive value of neoplastic PD-L1 expression for ENKTL. The PubMed, Embase, Web of Science, and CNKI databases were searched to identify eligible observational studies reporting PD-L1 expression and survival outcomes of ENKTL patients. The search was conducted in accordance with the Meta-analyses Of Observative Studies in Epidemiology (MOOSE) guidelines. The pooled hazard ratios (HRs) and 95% confidence intervals (95% CIs) were adopted to analyze survival outcomes, and the odds ratios (ORs) and 95% CIs were adopted for clinicopathological parameters. Review Manager 5.3 and STATA 17.0 were used for statistical analysis. Potential publication bias was evaluated by funnel plot and Egger's test. A total of 433 patients with ENKTL were included across seven studies. The pooled results showed no significant relationship between neoplastic PD-L1 expression and overall survival (OS) (HR =1.35, 95% CI: 0.49-3.75, P=0.559). We also performed subgroup analyses. However, increased PD-L1 expression was associated with a low international prognostic index (IPI) score of 0-1 (OR =2.46; 95% CI: 1.11-5.45, P=0.03), good performance status (OR =1.97; 95% CI: 1.11-3.51, P=0.02), and a good treatment effect (OR =2.61; 95% CI: 1.01-6.70, P=0.05). PD-L1-positive expression in patients with ENKTL was correlated with favorable clinical features. Thus, PD-L1-positive expression appears to be a potential predictor of treatment benefits. Additional large-scale, high-quality studies are needed to further explore its predictive value.

Multicenter real-world study of newly diagnosed advanced-stage extranodal natural killer/T-cell lymphoma (ENKTL): Proposal for intensive therapy.

e19523 Background: Advanced-stage ENKTL is characterized by its low prevalence, poor prognosis, and inconclusive optimal therapy. The present study investigated the treatment of newly diagnosed advanced-stage ENKTLs. Methods: Newly diagnosed stage III/IV ENKTL patients from two large-scale Chinese cancer centers in the last 10-15 years were retrospectively collected and analyzed. Results: With a median follow-up of 75.03 (range, 0.33-292.13) months, the median overall survival (mOS) for the 195 newly diagnosed stage III/IV ENKTL patients was 19.43 (range, 0.33-292.13) months, and estimated 1-, 2-, 3-, and 5-year OS were 59.5%, 46.3%, 41.8%, and 35.1%, respectively. First-line multi-modality therapy(n=89) significantly prolonged OS compared to single-modality therapy(n=106)( P&lt;0.001). Chemotherapy(CT)+radiotherapy(RT)(n=47) compared to CT alone(n=93)( P=0.007), and hematopoietic stem cell transplantation(HSCT)(n=20) compared to non-HSCT(n=175)( P&lt;0.001) both significantly improved OS. For patients ≤60 years and ineligible for HSCT, other therapies with complete remission(n=28) led to comparable OS( P=0.160), with no significant difference in baseline characteristics( P&gt;0.05). Four long-term survival patients treated with chidamide maintenance therapy(MT) achieved a median progression-free survival(PFS) of 55.83(range, 53.27-92.33) months and a mOS of 60.65(range, 53.70-95.70) months, preliminarily indicating its positive impact on prognosis. Regarding CT, anthracycline(ANT)-based regimens(n=60), compared to non-ANT-based ones(n=119), led to significantly inferior PFS( P=0.031) and OS( P=0.010); while asparaginase(ASP)-(n=123) compared to non-ASP-(n=56), and gemcitabine(GEM)-(n=56) compared to non-GEM-based(n=123) regimens, both prolonged PFS( P=0.005; P=0.009) and OS( P=0.086; P=0.003). Multivariate analysis further showed that GEM-based regimens improved PFS(HR=0.691, P=0.061) and OS(HR=0.624, P=0.037) compared to non-GEM-based ones. The GEM+ASP(n=42) combinations slightly improved PFS and OS compared to regimens containing either GEM(n=14) or ASP(n=56) alone( P&gt;0.05). The GEM+ASP combinations led to significantly superior PFS( P=0.058[log-rank test], P=0.036[Breslow test]) and OS( P=0.008) compared to the ANT+ASP combinations. First-line “intensive therapy”, including CT(particularly GEM+ASP regimens), RT, HSCT, and chidamide MT, was therefore proposed, and could improve long-term survival for advanced-stage ENKTLs. Conclusions: We propose the first-line “intensive therapy” for newly diagnosed advanced-stage ENKTLs, including CT, RT, HSCT, and chidamide MT. The GEM+ASP combinations appear to yield the optimal efficacy and survival. RT, consolidative HSCT, or chidamide MT are recommended.

A MULTI‐CENTER RETROSPECTIVE STUDY OF PEMBROLIZUMAB IN PATIENTS WITH RELAPSED OR REFRACTORY EXTRANODAL NK/T‐CELL LYMPHOMA

Background: Extranodal natural killer T-cell lymphoma (ENKTL) is an aggressive malignancy with a dismal prognosis. PD-1 blockade with pembrolizumab has shown promising activity in relapsed/refractory (R/R) ENKTL in case series. Real-world data about the efficacy of pembrolizumab in R/R ENKTL patients are limited. Methods: We performed a multicenter retrospective study to evaluate pembrolizumab efficacy and safety in patients with R/R ENKTL from 10 academic centers in South Korea. Pembrolizumab 100 mg was administered intravenously every 3 weeks. Results: A total of 24 patients were enrolled. The median age was 67 years old (range, 36–87) and 29.2% of patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or greater. Pembrolizumab was administered as 2nd-, 3rd- and 4th or greater line chemotherapy in 9 (37.5%), 9 (37.5%), and 6 (25.0%) patients, respectively, and median 3 cycles (range 1–21) of pembrolizumab were given. In response evaluation, complete remission (CR) and partial response (PR) was achieved in 6 (25.0%) and 3 (12.5%), respectively. The median progression-free survival and overall survival were 2.0 months (95% CI, 0.9–3.0) and 8.0 months (95% CI, 0.0–22.4), respectively. Multivariate analysis indicated that ECOG PS was the only significant predictor of PFS after pembrolizumab treatment (hazard ratio, 5.33; 95% confidence interval, 1.09–26.1; P = .039) Overall, 14 (58.3%) patients experienced adverse events (AEs), with fatigue (n = 7, 29.1%) being the most common Eight patients (33.3%) developed G3-4 AEs, the most frequent of which was neutropenia (4,16.7%) Conclusion: Pembrolizumab could be a therapeutic approach for the control of R/R ENKTL. Keyword: Aggressive T-cell non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.

The prognostic value of controlling nutritional status (CONUT) score–based nomogram on extranodal natural killer/T cell lymphoma patients

Controlling nutritional status (CONUT) score as an original nutritional assessment tool can be used to assess the prognosis of patients with a variety of malignancies. However, the predictive power of CONUT in extranodal natural killer/T cell lymphoma (ENKTL) patients has never been demonstrated. Our retrospective multicenter study aimed to explore the prognostic value of CONUT in newly diagnosed ENKTL. A total of 1085 newly diagnosed ENKTL patients between 2003 and 2021 were retrospectively retrieved. Cox proportional hazard model was used to explore the prognostic factors of overall survival (OS). The survival rate of ENKTL was evaluated using Kaplan-Meier analysis, and log-rank test was applied to the difference between groups. We investigated the prognostic performance of CONUT, the International Prognostic Index (IPI), the Korean Prognostic Index (KPI), and the Prognostic Index of Natural Killer Cell Lymphoma (PINK) using the receiver operating characteristic (ROC) curve and decision curve analysis (DCA). The median age at diagnosis for the whole cohort was 47 years, and the male to female ratio was 2.2:1. The 5-year OS for all patients was 72.2%. Multivariable analysis showed that CONUT, age, bone marrow involvement, ECOG PS score, and Chinese Southwest Oncology Group and Asia Lymphoma Study Group ENKTL stage were identified as independent predictive factors for OS. Based on multivariable results, a prognostic nomogram was developed. Subgroup analysis demonstrated that patients with severe malnutrition had poorest clinical outcome. In addition, ROC curves and DCA analysis proved that compared with IPI, KPI, and PINK models, the CONUT score-based nomogram showed a better prognostic predictive efficiency of ENKTL. CONUT could effectively stratify the prognosis of ENKTL and the proposed nomogram based on CONUT was an effective prognostic model for prediction.

Efficacy and safety of PD-1 inhibitor alone or combined with chemotherapy in patients with relapsed or refractory extranodal natural Killer/T cell lymphoma: A retrospective study.

Extranodal natural killer/T cell lymphoma (ENKTL) patients typically face a grim prognosis after relapse or progression following asparaginase-based chemotherapy. Currently, programmed cell death protein-1 (PD-1) immune checkpoint blockade has shown promising efficacy as an optimal regimen for relapsed or refractory ENKTL (rrENKTL) patients. This study retrospectively investigated the efficacy, safety, and factors influencing the survival of 26 rrENKTL patients who underwent monoclonal antibody treatment using PD-1 (Sintilimab or Camrelizumab) alone or combined with chemotherapy from January 2018 to February 2022. The disease control rate was 73.1%, and the objective response rate was 50.0%. 15.4% of the patients achieved complete remission, and 34.6% achieved partial remission (PR). After a median follow-up of 12 (range 3-47) months, the median progression-free survival (PFS) and overall survival (OS) were 6.5 and 13.3months. The 1-year PFS and OS rate were 23.1% and 53.8%. 96.2% of patients experienced at least one adverse event and 26.9% experienced grade 1-2 immune-related adverse events. PD-1 inhibitor improved rrENKTL patient survival, and the AEs were controlled. We also observed that the prognostic index for NK cell lymphoma including Epstein-Barr virus (EBV) (PINK-E) and the nomogram-revised risk indexz for ENKTL patients could help identify a potentially unfavorable prognosis in this era of immunotherapy. More attention should be paid to the presence of EBV after anti-PD-1 immunotherapy, as it more accurately indicates a poor prognosis.

High-dose extended-field radiotherapy plus chemotherapy improved survival in extranodal NK/T-cell lymphoma in a real-life setting: results from the multicenter T-Cell Brazil Project

Extranodal natural-killer/T-cell lymphoma (ENKTL) is a rare and aggressive Epstein-Barr virus related mature T-cell and natural-killer malignancy. Although highly prevalent in South America, few studies covering data from this geographic location have been published. Therefore, this study aims to report clinical characteristics, prognostic factors, and outcomes in a multicenter cohort of ENKTL patients from Brazil. This retrospective, observational and multicenter study included 98 ENKTL patients treated during two decades in Brazil. Data were extracted from the T-Cell Brazil Project database. In our cohort, 59/98 patients (60.2%) were male, with a median age of 50 years. Sixty-two patients (63.3%) had B-symptoms, 26/98 (26.5%) had Eastern Cooperative Oncology Group scale ≥ 2; 16/98 (16.3%) presented extranasal disease and 34.7% (34/98) were advanced-stage (Ann Arbor/Cotswolds III/IV). The median follow-up for the whole cohort was 49 months, with an estimated 2-year overall survival (OS) and progression-free survival (PFS) of 51.1% and 17.7%, respectively. In early-stage disease (IE/IIE), the median OS was 21.8 months for patients treated with concurrent radiotherapy plus chemotherapy (CCRT-VIPD [etoposide/vp-16, ifosfamide, cisplatin and dexamethasone), 16.2 months for sequential chemoradiotherapy (SCRT) followed by asparaginase-based regimens, and 56.7 months for SCRT followed by CHOP-like (cyclophosphamide, doxorrubicin, vincristine and prednisone) treatments, p = 0.211. CCRT was associated with higher rates of early-mortality, hematological toxicity, and mucositis. Median OS was 8.2 months for patients with advanced-stage disease receiving regimens containing asparaginase compared to 3.2 months for anthracycline-based therapy, p = 0.851. Chemo-radiotherapy (CRT) regimens demonstrated better OS (p = 0.001) and PFS (p = 0.007) than chemotherapy alone. Multivariate analysis revealed anemia, relapsed/refractory (R/R) disease and radiotherapy omission as poor outcome predictors for OS. Lymphopenia and radiotherapy omission adversely affected PFS. Concerning progression of disease within 24-months (POD-24), clinical stage III/IV was a poor outcome predictor. In this real-life Brazilian cohort, ENKTL presented dismal outcomes. Radiation therapy was an independent factor for increased OS and PFS, but CCRT regimens were associated with higher toxicities. Polychemotherapy based on anti-multi drug resistant agents was not associated with survival benefit in either early or advanced-stage disease in our patient cohort.

Exosomal and Soluble Programed Death-Ligand 1 (PD-L1) Predicts Responses to Pembrolizumab in Patients with Extranodal NK/T-Cell Lymphoma.

Soluble and exosomal programed death-ligand 1 (PD-L1) can be upregulated in extranodal natural killer/T-cell lymphoma (ENKTL). However, its clinical role in predicting outcomes after pembrolizumab treatment has yet to be studied in ENKTL patients. We investigated the association between pre-treatment soluble and exosomal PD-L1 and outcomes in ENKTL patients who received pembrolizumab as a salvage treatment. The production of soluble and exosomal PD-L1 was analyzed in vitro using an etoposide-resistant ENKTL cell line. Serum levels of soluble and exosomal PD-L1 were measured in patients with relapsed or refractory ENKTL prior to treatment with pembrolizumab. Relapsed or refractory ENKTL patients who received pembrolizumab as a salvage therapy between May 2017 and March 2021 were analyzed at our institute. Soluble and exosomal PD-L1 was significantly higher in serum samples of relapsed or refractory ENKTL patients compared with healthy controls, which is consistent with increased production of soluble and exosomal PD-L1 in an etoposide-resistant ENKTL cell line (SNK6R), which was found to show increased expression of soluble and exosomal PD-L1. Serum-soluble PD-L1 levels were significantly correlated with exosomal PD-L1, and were significantly lower in responders to pembrolizumab compared with non-responders. Longitudinal analysis after pembrolizumab also revealed a relationship between PD-L1 levels and responses. Treatment outcomes and overall survival after pembrolizumab were significantly better in patients with low soluble and exosomal PD-L1. In conclusion, soluble and exosomal PD-L1 can predict responses to pembrolizumab in ENKTL patients, making it a useful pre-treatment biomarker for ENKTL patients receiving pembrolizumab.

Interim PET-CT Scan to Improve Risk Modeling for Patients with Extranodal Natural Killer/T-Cell Lymphoma Treated with Non-Anthracycline Containing L-Asparaginase Based Regimen

Background Extranodal natural killer/T-cell lymphoma (ENKTL) is a rare and distinct subtype of non-Hodgkin lymphoma characterized by predominant involvement of the nasal cavity and nasopharynx and the application of L-asparaginase (L-asp) based non-anthracycline containing induction therapy has improved clinical outcomes of the patients. Currently, prognostic index of natural killer lymphoma plus Epstein-Barr virus is widely used to evaluate prognosis of patients with ENKTL. In this study, we evaluated the value of interim fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) for the better prognostication of ENKTL patients. Methods Patients with histologic diagnosis of ENKTL from May 2009 to May 2020 treated with L-asp based non-anthracycline containing induction regimen and who had interim PET-CT analysis at Asan Medical Center, Seoul, Korea were included. Response was assessed using the Deauville 5-point scales (DS). Progression-free survival (PFS) was defined as time from the induction therapy to disease progression or any cause of death, and overall survival (OS) was defined as time from the induction therapy to any cause of death. Survival curves were estimated by Kaplan-Meier method and compared using log-rank test. Key baseline characteristics and candidate prognostic factors including age, Eastern Cooperative Oncology Group performance status, Epstein-Barr virus (EBV) detection from blood at baseline, distant lymph node (LN) involvement, initial stage, location of disease (nasal vs. non-nasal), and serum lactate dehydrogenase level were included in the univariate analysis. In the multivariate analysis, variables exhibiting a potential association with survival (p < 0.05) in the univariate analysis were included. Results A total of 58 patients were included in the analysis. Median age was 55 years (range, 19-80), 34 patients (58.6%) were male, 19 patients (32.8%) had non-nasal disease and 43 patients (74.1%) had stage 4 disease at diagnosis. Among 43 patients with stage 4 disease, 19 patients (44.2%) received VIDL regimen consisting of etoposide, ifosfamide, dexamethasone and L-asp while 23 patients (55.8%) received SMILE regimen consisting of ifosfamide, etoposide, methotrexate, dexamethasone and L-asp as induction treatment. All 15 patients with stage 1 or 2 disease received combined modality treatment with cisplatin-based concurrent chemoradiation and L-asp containing chemotherapy. With median follow-up duration of 52.7 months (95% confidence interval [CI] 37.7-81.3), median PFS and OS were 9.9 months (95% CI 4.8-28.6) and 25.6 months (95% CI 13.3-not applicable), respectively. Thirty-two patients (55.2%) had interim PET-CT DS (iDS) of 4-5. Patients with iDS 4-5 showed significantly worse outcomes in terms of both PFS and OS compared to patients with iDS 1-3 with hazards ratio (HR) of 2.13 (95% CI 1.11-4.06, p = 0.019) and 2.51 (95% CI 1.19-5.33, p = 0.013), respectively. The 2-years PFS rates for patients with iDS 4-5 and iDS 1-3 were 27.3% (95% CI 15.3-44.8) and 49.0% (95% CI 32.9-69.3), respectively. The 2-years OS rates were 35.6% (95% CI 22.1-54.0) and 64.3% (95% CI 48.0-86.2), respectively. In the univariate analysis, age, EBV detection from blood at baseline, initial stage, location of disease (nasal vs. non-nasal), distant LN involvement and iDS showed potential association (p < 0.05) with OS. In multivariate analysis, iDS were independently associated with OS with HR of 3.96 (iDS 4-5 vs. 1-3, 95% CI 1.76-8.94, p < 0.001), along with location of disease with HR of 4.03 (non-nasal vs. nasal, 95% CI 1.83-8.91, p < 0.001). Conclusion The interim PET-CT response based on the DS is useful for predicting OS of patients with ENKTL in the era of non-anthracycline-based L-asp containing induction therapy.

Sintilimab Plus P-Gemox (Pegaspargase, Gemcitabine and Oxaliplatin) Regimen for Newly-Diagnosed Advanced, Extranodal Natural Killer/T Cell Lymphoma, Nasal Type: A Multicenter, Phase 2 Cohort of the Open-Label Spirit Study

Background: Extranodal Natural Killer/T Cell Lymphoma (ENKTL) is an aggressive non-Hodgkin lymphoma with a high incidence in Asian and south American populations. Pegaspargase, oxaliplatin plus gemcitabine are considered as the standard first-line therapy for advanced ENKTL, but the prognosis remains poor. In ENKTL, most patients overexpress PD-L1 protein, which is associated with a poor prognosis, and suggests that ENKTL should be sensitive to PD-1/PD-L1 axis blockade. In a phase II trial, the PD-1 mAb sintilimab showed promising efficacy as monotherapy in r/r ENKTL (Tao, Signal Transduct Target Ther, 2022). Additionally, we previously conducted a retrospective study of PD-1 mAb combined P-GEMOX for the treatment of advanced ENKTL patients (pts), which showing favorable antitumor activity with a non-overlapping toxicity profile (Cai, Signal Transduct Target Ther, 2020). Therefore, we conducted this prospective phase II trial to evaluate the efficacy and safety of sintilimab plus P-GEMOX as first-line therapy in pts with advanced ENKTL. Methods: This is a prospective, single-arm, open-label, multi-center, phase II clinical trial. Adult treatment-naive pts with histologically confirmed ENKTL nasal type had at least one measurable or evaluable lesion were enrolled to receive six cycles of sintilimab 200 mg plus pegaspargase 2000 U/m2 (day 1), gemcitabine 1g/m2 (days 1 and 8), and oxaliplatin 130 mg/m2 (day 1) (induction phase), followed by sintilimab 200 mg maintenance every 3 weeks (maintenance phase) for up to 2 years or until disease progression or unacceptable toxicities. Involved field radiotherapy (IFRT) is allowed for residual lesions after induction therapy. The primary endpoint was the proportion of pts who achieved complete response rate (CR) in response evaluable population. Secondary endpoints included overall response rate (ORR), response at the end of induction therapy (EoT), duration of response (DOR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety. Treatment related adverse events (TRAE) were rated according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) 5.0. This trial is registered with ClinicalTrials.gov, number NCT04127227. Results: From November 2019 to April 2022, 27 eligible pts were enrolled. Median age was 38 years (range, 25-72), 19 (70.4%) were male, 14 (22.2%) pts had PINK-E score ≥ 3 points (Table 1). Of 24 response evaluable pts, the ORR was 100% (24/24), and the CR rate reached 87.5% (21/24, figure 1, 2). At data cut-off, 18 pts completed 6 cycles of induction therapy and entered the maintenance phase, 1 patient experienced disease progression after 4 cycles of the treatment, and the EoT CR rate of induction phase is 13/19 (68.4%). The median time to response (TTR) was 1.6 (1.4-3.8) months. During the maintenance phase, 5 more pts achieved CR and at the time of analysis, The median follow-up time was 16.7 (3.0-32.0) months. The mOS and mPFS were not reached, estimated 1-year OS rate was 100%, 1-year PFS rate was 95%.All (100%) pts experienced TRAE at any grade. The most common toxicity was neutropenia (96.3%) and the majority of TRAEs were reported during the first two cycles of the induction therapy. Grade 3-4 TRAE reported in ≥5% of pts included neutropenia (48.1%), triglycerides increased (37.0%), leukopenia (29.5%), anemia (25.9%), thrombocytopenia (25.9%), albumin decreased (7.4%), and lipase increased (7.4%). Immune-related AEs (irAEs) were reported in 16 pts, including a grade 3 hypothyroidism which led to permanent treatment discontinuation in 1 (3.7%) patient, and the remaining irAEs were all grade 1-2. All TRAEs were manageable and only 1 patient discontinued treatment due to TRAEs during maintenance phase. Conclusions: Combination of sintilimab plus P-GEMOX Regimen yielded promising clinical activity with a manageable safety profile, supporting immunochemotherapy as a new first-line treatment option for pts with advanced ENKTL. Treatment and follow-up are currently ongoing and further studies have been initiated to explore biomarkers to better predict response and long-term survival. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Inhibition of SRPK1, a key splicing regulator, exhibits antitumor and chemotherapeutic-sensitizing effects on extranodal NK/T-cell lymphoma cells

BackgroundIncreasing evidence has convincingly shown that abnormal pre-mRNA splicing is implicated in the development of most human malignancies. Serine/arginine-rich protein kinase 1 (SRPK1), a key splicing regulator, is reported to be overexpressed in leukemia and other cancer types, which suggests the therapeutic potential of targeting SRPK1.MethodsSRPK1 expression was measured in 41 ENKTL patients by immunohistochemistry and mRNA expression was analyzed by qRT‒PCR. We knocked down SRPK1 expression in the ENKTL cell line YT by siRNA transfection and inhibited SRPK1 using inhibitors (SPHINX31 and SRPIN340) in YT cells and peripheral blood lymphocytes (PBLs) isolated from ENKTL patients to investigate its role in cell proliferation and apoptosis. Then, RNA-seq analysis was performed to predict the potential signaling pathway by which SRPK1 inhibition induces cell death and further verified this prediction by Western blotting.ResultsIn the present study, we initially evaluated the clinical significance of SRPK1 in extranodal natural killer/T-cell lymphoma (ENKTL), a very aggressive subtype of non-Hodgkin lymphoma. The expression of SRPK1 in ENKLT patients was examined by immunohistochemistry and qRT‒PCR, which revealed SRPK1 overexpression in more than 60% of ENKTL specimens and its association with worse survival. Cellular experiments using the human ENKTL cell line YT and PBLs from ENKTL patients, demonstrated that inhibition of SRPK1 suppressed cell proliferation and induced apoptosis. Subsequently, we investigated the downstream targets of SRPK1 by RNA-seq analysis and found that SRPK1 inhibition induced ATF4/CHOP pathway activation and AKT1 inhibition. Furthermore, ENKTL patients presenting high SRPK1 expression showed resistance to cisplatin-based chemotherapy. The association of SRPK1 expression with cisplatin resistance was also confirmed in YT cells. SRPK1 overexpression via pLVX-SRPK1 plasmid transfection dramatically decreased the sensitivity of YT cells to cisplatin, while siRNA-mediated SRPK1 knockdown or SRPK1 inhibitor treatment significantly increased cisplatin cytotoxicity.ConclusionIn summary, these results support that SRPK1 might be a useful clinical prognostic indicator and therapeutic target for ENKTL, especially for patients who relapse after cisplatin-based chemotherapies.

18F-FDG PET/CT Plays a Limited Role in Replacing Bone Marrow Biopsy for Newly Diagnosed Advanced-Stage Patients With Extranodal Natural Killer/T-Cell Lymphoma

PurposeThe role of 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) in evaluating bone marrow (BM) involvement (BMI) among patients with extranodal natural killer/T-cell lymphoma (ENKTL) is poorly understood. This study investigated whether PET/CT could replace bone marrow biopsy (BMB) in treatment-naive ENKTL patients.MethodsNewly diagnosed ENKTL patients (n = 356) who received BMB and PET/CT to evaluate BMI at the time of diagnosis were retrospectively reviewed at West China Hospital between August 2008 and January 2020. The BMI diagnosis was confirmed using BM histology. Clinical characteristics, survival outcomes, and prognostic indicators were summarized and analyzed.ResultsThe cohort included 356 cases, of whom 261 were diagnosed with early-stage and 95 with advanced-stage ENKTL by PET/CT before initial treatment. No early-stage patients were identified with BMI by either BMB or PET/CT. Among the advanced-stage patients, 26 were BMB positive, and 12 of 22 patients (54.5%) with positive PET/BM results were also BMB positive. The sensitivity and specificity of PET/CT to detect BMI were 46% and 97%, respectively. The progression-free survival (PFS) and overall survival (OS) of PET/BM-negative patients were markedly longer (p = 0.010 and p = 0.001 for PFS and OS, respectively), which was consistent with the results of the BMB (p = 0.000 for both PFS and OS).ConclusionAlthough 18F-FDG PET/CT showed the potential to replace BMB in the initial staging of early-stage ENKTL patients, baseline PET/CT cannot provide an accurate BMI evaluation for advanced-stage patients. A prospective study is required to confirm the diagnostic performance of BMI identification by PET/CT, along with targeted BMB and MRI for advanced-stage patients.

The Role of PD-L1 Expression in Prediction and Stratification of Recurrent or Refractory Extranodal Natural Killer/T-Cell Lymphoma.

Background and AimsThe clinical outcome of relapsed and refractory (RR) extranodal natural killer/T-cell lymphoma (ENKTL) is poor. It is necessary to identify RR patients in ENKTL and find novel therapeutic targets to improve the prognosis of patients with RR ENKTL.MethodsA total of 189 ENKTL patients with effective clinical characteristics were enrolled. Paraffin specimens were collected for PD-L1 expression identification. Kaplan-Meier curve analysis was performed for survival analysis. Whole exome sequencing (WES) was performed for identifying the mutational characterization of RR and effective treatment (ET) patients.ResultsUnivariate and multivariate Cox proportional hazards regression analysis showed that negative PD-L1 expression (HR = 1.132, 95% CI = 0.739-1.734, P = 0.036) was an independent predictor of poor prognosis in patients with ENKTL. The overall survival (OS) of PD-L1 positive patients was significantly higher than that of PD-L1 negative patients (P = 0.009). Then, we added PD-L1 expression as a risk factor to the model of Prognostic Index of Natural Killer Lymphoma (PINK), and named as PINK+PD-L1. The PINK+PD-L1 model can significantly distinguish RR patients, ET patients, and the whole cohort. Moreover, our data showed that PD-L1 expression was lower than 25% in most RR patients, suggesting that RR subtypes may be associated with low expression of PD-L1 (P = 0.019). According to the whole exome sequencing (WES), we found that the mutation frequencies of JAK-STAT (P = 0.001), PI3K-AKT (P = 0.02) and NF-kappa B (P < 0.001) pathways in RR patients were significantly higher than those in ET patients.ConclusionPatients tend to show RR when PD-L1 expression is lower than 25%. The model of PINK+PD-L1 can stratify the risk of different groups and predict OS in ENKTL patients. The mutational profile of ENKTL patients with RR is different from that of patients with ET.

The Effect of Chronic Rhinosinusitis on the Staging and Prognosis of Extranodal Natural Killer/T-Cell Lymphoma: A Single-Center Retrospective Analysis.

Clinically, extranodal natural killer/T-cell lymphoma (ENKTL) patients frequently had a history of chronic rhinosinusitis (CRS) before onset, and the correlation between the two diseases has not been systematically reported at present. In this study, we applied the method—retrospective analysis—to explore the relationship between CRS and ENKTL. We collected clinical data and the length of CRS history before onset in 214 patients diagnosed with ENKTL and found that the length of CRS history was correlated with the stage of 182 ENKTL patients whose primary sites were upper aerodigestive tract (UAT) (χ2 = 21.317, p = 0.046, n = 182); the Spearman correlation coefficient was 0.162 (p = 0.029). There was no significant difference in stage of the non-UAT-ENKTL patients (χ2 = 18.910, p = 0.091, n = 32). The COX multivariate regression analysis showed that CRS history was an independent prognostic predictor for PFS of the UAT-ENKTL patients (p = 0.004), and patients without CRS had significantly better PFS than the more than 15 years CRS history group (p = 0.001). Our findings suggested that we should not ignore the existence of chronic inflammation of the nasal cavity in ENKTL patients. It is better to treat CRS as soon as possible in clinical practice to reduce the possibility of the occurrence or progression of UAT-ENKTL.