Artificial intelligence for diagnosis and prognosis prediction of natural killer/T cell lymphoma using magnetic resonance imaging.

Accurate diagnosis and prognosis prediction are conducive to early intervention and improvement of medical care for natural killer/T cell lymphoma (NKTCL). Artificial intelligence (AI)-based systems are developed based on nasopharynx magnetic resonance imaging. The diagnostic systems achieve areas under the curve of 0.905-0.960 in detecting malignant nasopharyngeal lesions and distinguishing NKTCL from nasopharyngeal carcinoma in independent validation datasets. In comparison to human radiologists, the diagnostic systems show higher accuracies than resident radiologists and comparable ones to senior radiologists. The prognostic system shows promising performance in predicting survival outcomes of NKTCL and outperforms several clinical models. For patients with early-stage NKTCL, only the high-risk group benefits from early radiotherapy (hazard ratio = 0.414 vs. late radiotherapy; 95% confidence interval, 0.190-0.900, p = 0.022), while progression-free survival does not differ in the low-risk group. In conclusion, AI-based systems show potential in assisting accurate diagnosis and prognosis prediction and may contribute to therapeutic optimization for NKTCL.

First-line sintilimab with pegaspargase, gemcitabine, and oxaliplatin in advanced extranodal natural killer/T cell lymphoma (SPIRIT): a multicentre, single-arm, phase 2 trial.

BACKGROUND: Programmed cell death protein 1 (PD-1) inhibitor sintilimab is effective in relapsed and refractory extranodal natural killer/T cell lymphoma (ENKTL), nasal type. We aimed to assess the safety and activity of sintilimab plus P-GEMOX (pegaspargase, gemcitabine, and oxaliplatin) in the first-line setting for advanced ENKTL. METHODS: The multicentre, single-arm, phase 2 trial was done at three medical centres in China. Patients aged 18-75 years with treatment-naive pathologically confirmed advanced ENKTL and an with Eastern Cooperative Oncology Group performance status score of 0-2 were eligible. Patients received intravenous sintilimab (200 mg on day 1), intramuscular pegaspargase (2000 U/m2 on day 1), intravenous gemcitabine (1 g/m2 on days 1 and 8), and intravenous oxaliplatin (130 mg/m2 on day 1) every 3 weeks for six cycles, followed by intravenous sintilimab (200 mg) every 3 weeks for up to 2 years or until disease progression or unacceptable toxicities. The primary endpoint was the complete response rate in the intention-to-treat population. The secondary endpoints were overall response rate (ORR), progression-free survival (PFS), disease-free survival (DFS), and overall survival. This trial is registered with ClinicalTrials.gov, NCT04127227. Enrolment has been completed, and follow-up is ongoing. FINDINGS: Between Nov 29, 2019, and Sept 7, 2022, 34 eligible patients were enrolled (median age 39 years [IQR 32-55]; 25 [74%] of 34 patients were male; nine [26%] were female; and all were of Asian ethnicity). At the data cutoff (July 20, 2023), the median follow-up was 21 months (IQR 13-32). The complete response rate was 85% (29 of 34 patients, 95% CI 70-94). Five patients (15%; 95% CI 7-30) attained partial response and the ORR was 100% (34 of 34 patients). 24-month PFS was 64% (95% CI 48-86), 24-month DFS was 72% (54-95), and 36-month overall survival was 76% (52-100). The most common grade 3 or 4 treatment-related adverse events were neutropenia (17 [50%] of 34 patients), anaemia (10 [29%] patients), and hypertriglyceridemia (10 [29%] patients). Hypothyroidism was the most frequent immune-related adverse event (18 [53%]), including grade 3 hypothyroidism in one (3%) patient that caused treatment termination. No severe adverse events occurred. There were three deaths: one due to haemophagocytic syndrome, one due to disease progression, and one due to unknown cause, which were not considered to be treatment related. INTERPRETATION: Combination of sintilimab with P-GEMOX seems to be an active and safe first-line regimen for patients with advanced ENKTL. FUNDING: National Key Research and Development Program and National Natural Science Foundation of China, Guangzhou Science and Technology Program and the Clinical Oncology Foundation of Chinese Society of Clinical Oncology.

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

BACKGROUND: Aspartate aminotransferase (AST), an indicator of liver cell damage, was related to the prognosis of certain malignant tumors. OBJECTIVE: This study examined the predictive value of AST in patients with extranodal natural killer/T cell lymphoma (ENKTL). METHODS: 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). RESULTS: 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. CONCLUSION: AST might represent a significant prognostic marker for ENKTL patients.

GELAD chemotherapy with sandwiched radiotherapy for patients with newly diagnosed stage IE/IIE natural killer/T-cell lymphoma: a prospective multicentre study.

Early-stage natural killer/T-cell lymphoma (NK/TCL) patients usually receive a combination of chemotherapy and radiotherapy, but the optimal treatment approach has not yet been established. This study aimed to investigate the efficacy and safety profile of a novel chemotherapy regimen and sandwiched radiotherapy in early-stage NK/TCL. Patients with newly diagnosed stage IE/IIE disease were eligible. Patients were initially treated with two courses of the GELAD regimen (gemcitabine 1·0 g/m2 day 1, etoposide 60 mg/m2 days 1-3, pegaspargase 2000 units/m2 day 4, and dexamethasone 40 mg days 1-4), followed by intensity-modulated radiotherapy (IMRT; 50-56 Gy in 25-28 fractions) and two additional courses of GELAD chemotherapy. A total of 52 patients were enrolled. The overall response rate and complete response rate per Lugano 2014 criteria were 94·2% and 92·3% respectively. With a median follow-up of 32 months, the estimated four-year overall survival rate and progression-free survival rate were 94·2% [95% confidence interval (CI), 83·2% to 93·1%] and 90·4% (95% CI, 78·4% to 95·9%) respectively. The most common adverse events were related to pegaspargase. Haematological toxicities were mild, with grade 3/4 neutropenia in 15·4% of patients. Our study provides a new approach with high activity and improved safety for the treatment of early-stage NK/TCL patients. This study was registered at www.clinicaltrials.gov as NCT02733458.

Sintilimab for relapsed/refractory extranodal NK/T cell lymphoma: a multicenter, single-arm, phase 2 trial (ORIENT-4).

This study (ORIENT-4) aimed to assess the efficacy and safety of sintilimab, a humanized anti-PD-1 antibody, in patients with relapsed/refractory extranodal NK/T cell lymphoma (r/r ENKTL). ORIENT-4 is a multicenter, single-arm, phase 2 clinical trial (NCT03228836). Patients with r/r ENKTL who failed to at least one asparaginase-based regimen were enrolled to receive sintilimab 200 mg intravenously every 3 weeks for up to 24 months. The primary endpoint was the objective response rate (ORR) based on Lugano 2014 criteria. Twenty-eight patients with r/r ENKTL were enrolled from August 31, 2017 to February 7, 2018. Twenty-one patients (75.0%, 95% CI: 55.1-89.3%) achieved an objective response. With a median follow-up of 30.4 months, the median overall survival (OS) was not reached. The 24-month OS rate was 78.6% (95% CI, 58.4-89.8%). Most treatment-related adverse events (TRAEs) were grade 1-2 (71.4%), and the most common TRAE was decreased lymphocyte count (42.9%). Serious adverse events (SAEs) occurred in 7 (25.0%) patients, and no patient died of adverse events. Sintilimab is effective and well tolerated in patients with r/r ENKTL and could be a novel therapeutic approach for the control of ENKTL in patients.

EGR1 as a potential marker of prognosis in extranodal NK/T-cell lymphoma.

Extranodal natural killer T-cell lymphoma (ENKTL) is an aggressive malignancy with a dismal prognosis. In the present study, gene expression profiling was performed to provide more information on ENKTL molecular signature and offer a rationale for further investigation of prognostic markers in ENKTL. NanoString nCounter Analysis encompassing 133 target genes was used to compare gene expression levels of 43 ENKTL tumor samples. The majority of the patients were under 60 years of age (79.1%); 32 (74.4%) patients had nasal type ENKTL and 23 patients (53.5%) had intermediate/high risk ENKTL based on the prognostic index for natural killer cell lymphoma (PINK). The median follow-up was 15.9 months and the median overall survival (OS) was 16.1 months (95% CI 13.0-69.8). EGR1 upregulation was consistently identified in the localized stage with a low risk of prognostic index based on the PINK. Among the six significantly relevant genes for EGR1 expression, high expression levels of genes, including CD59, GAS1, CXCR7, and RAMP3, were associated with a good survival prognosis. The in vitro test showed EGR1 modulated the transcriptional activity of the target genes including CD59, GAS1, CXCR7, and RAMP3. Downregulation of EGR1 and its target genes significantly inhibited apoptosis and decreased chemosensitivity and attenuated radiation-induced apoptosis. The findings showed EGR1 may be a candidate for prognostic markers in ENKTL. Considerable additional characterization may be necessary to fully understand EGR1.

A composite single-nucleotide polymorphism prediction signature for extranodal natural killer/T-cell lymphoma.

Current prognostic scoring systems based on clinicopathologic variables are inadequate in predicting the survival and treatment response of extranodal natural killer/T-cell lymphoma (ENKTL) patients undergoing nonanthracyline-based treatment. We aimed to construct a classifier based on single-nucleotide polymorphisms (SNPs) for improving predictive accuracy and guiding clinical decision making. Data from 722 patients with ENKTL from international centers were analyzed. A 7-SNP-based classifier was constructed using LASSO Cox regression in the training cohort (n = 336) and further validated in the internal testing cohort (n = 144) and in 2 external validation cohorts (n = 142 and n = 100). The 7-SNP-based classifier showed good prognostic predictive efficacy in the training cohort and the 3 validation cohorts. Patients with high- and low-risk scores calculated by the classifier exhibited significantly different progression-free survival (PFS) and overall survival (OS) (all P < .001). The 7-SNP-based classifier was further proved to be an independent prognostic factor by multivariate analysis, and its predictive accuracy was significantly better than clinicopathological risk variables. Application of the 7-SNP-based classifier was not affected by sample types. Notably, chemotherapy combined with radiotherapy significantly improved PFS and OS vs radiotherapy alone in high-risk Ann Arbor stage I patients, whereas there was no statistical difference between the 2 therapeutic modalities among low-risk patients. A nomogram was constructed comprising the classifier and clinicopathological variables; it showed remarkably better predictive accuracy than either variable alone. The 7-SNP-based classifier is a complement to existing risk-stratification systems in ENKTL, which could have significant implications for clinical decision making for patients with ENKTL.

Dynamic evaluation of the prognostic value of 18F-FDG PET/CT in extranodal NK/T-cell lymphoma, nasal type.

Extranodal natural killer/T-cell lymphoma, nasal-type (ENKTL) is a type of rare and distinct entity of non-Hodgkin lymphoma with poor prognosis. It is important to evaluate the early treatment response accurately to decide further treatment strategy. 18F-FDG PET/CT plays an important role in response evaluation and prognostic prediction in some kinds of lymphomas. However, data available regarding patients with ENKTL are limited. Thus, in this prospective study, we analyzed the prognostic value of 18F-FDG PET/CT in ENKTL. Thirty-four patients with newly diagnosed ENKTL were enrolled in this phase 2 study (NCT02825147, July 7, 2016). The patients received pre-, mid-, and end-treatment 18F-FDG PET/CT scans. Deauville score (DS), maximal standardized uptake values (SUVmax), and the change in SUVmax (ΔSUVmax) were recorded for response assessment. The median follow-up period was 42.2 months. The 2-year overall survival (OS) and progression-free survival (PFS) were 82.4% and 73.5%, respectively. Univariate analysis revealed that Ann Arbor stage (P < 0.002), mid-treatment DS (P = 0.005), mid-SUVmax (P = 0.001), mid-∆SUVmax (P = 0.004), end-treatment DS (P < 0.001), and end-SUVmax (P = 0.014) were prognostic factors for OS. Ann Arbor stage (P = 0.001), mid-treatment DS (P = 0.008), mid-SUVmax (P = 0.029), mid-∆SUVmax (P < 0.001), and end-treatment DS (P =0.021) were of prognostic significance for PFS. Multivariate analysis showed that mid-SUVmax (P = 0.042) and DS at the middle (P = 0.050) and end (P = 0.044) of treatment were significant independent predictors of PFS. 18F-FDG PET/CT is useful for predicting the prognosis of ENKTL.

Nomograms based on SUVmax of 18F-FDG PET/CT and clinical parameters for predicting progression-free and overall survival in patients with newly diagnosed extranodal natural killer/T-cell lymphoma.

BACKGROUND: The prognostic value of 18F-FDG PET/CT in extranodal natural killer/T-cell lymphoma (ENKTL) is not well established. We aimed to develop nomograms for individualized estimates of progression-free survival (PFS) and overall survival (OS) in patients with ENKTL using 18F-FDG PET/CT parameters and clinical parameters. METHODS: A total of 171 patients with newly diagnosed ENKTL undergoing 18F-FDG PET/CT scanning were retrospectively analyzed. Nomograms were constructed according to multivariate Cox proportional hazards regression. The predictive and discriminatory capacities of the nomograms were then measured using the concordance index (C-index), calibration plots, and Kaplan-Meier curves. The C-index, the area under receiver operating characteristic (ROC) curve (AUC), and decision curve analysis (DCA) were used to contrast the predictive and discriminatory capacities of the nomograms against with the International Prognostic Index (IPI) and Korean Prognostic Index (KPI). RESULTS: Multivariate analysis demonstrated that pretreatment SUVmax≥9.5, disease stage II and III-IV, elevated lactate dehydrogenase (LDH), and elevated ß2-microglobulin (ß2-MG) had the strongest association with unfavorable PFS and OS. In addition, hemoglobin (Hb) < 120 g/L had a tendency to be associated with PFS. Both nomogram models incorporated SUVmax, Ann Arbor stage, LDH, and ß2-MG. The PFS nomogram also included Hb. The nomograms showed good prediction accuracies, with the C-indexes for PFS and OS were 0.729 and 0.736, respectively. The calibration plots for 3-year and 5-year PFS/OS reported good consistency between predicted and observed probabilities for survival time. The PFS and OS were significantly different according to tertiles of nomogram scores (p < 0.001). The C-index and AUCs of the nomograms were higher than that of IPI and KPI. Moreover, DCA showed that the predictive accuracy of the nomograms for PFS and OS were both higher than that of IPI and KPI. CONCLUSIONS: This study established nomograms that incorporate pretreatment SUVmax and clinical parameters, which could be effective tools for individualized prognostication of both PFS and OS in patients with newly diagnosed ENKTL.

Abnormal expression of p-ATM/CHK2 in nasal extranodal NK/T cell lymphoma, nasal type, is correlated with poor prognosis.

AIMS: The aim of this study is to investigate the expression profiles of cell cycle related proteins in nasal extranodal NK/T cell lymphoma, nasal type (ENKTCL). METHODS: The expression profiles of cell cycle related proteins were assessed with a cell cycle antibody array and validated by immunohistochemistry. Correlations between the expression levels of proteins and clinical outcomes of patients with nasal ENKTCL were evaluated. RESULTS: The expression of full length ataxia telangiectasia mutated (ATM) in nasal ENKTCL significantly decreased compared with that in nasal benign lymphoid proliferative disease (NBLPD), but the expression levels of p-ATM, CHK2 and RAD51 significantly increased in nasal ENKTCL compared with that in NBLPD. Kaplan-Meier analysis showed that the expression levels of p-ATM and CHK2 in nasal ENKTCL were inversely related to overall survival (p=0.011 and p=0.025, respectively). CONCLUSION: Abnormalities in the ATM pathway may play a crucial role in the oncogenesis and chemoradiotherapy resistance of nasal ENKTCL.

DDGP vs. SMILE in Relapsed/Refractory Extranodal Natural Killer/T-cell Lymphoma, Nasal Type: A Retrospective Study of 54 Patients.

Extranodal natural killer/T-cell lymphoma, nasal type (ENKL) is a rare peripheral T-cell lymphoma that predominantly occurs in Asian and South American populations. The treatment of ENKL has been a challenge for a long time. This study was conducted to compare the clinical efficacy and safety of cisplatin, dexamethasone, gemcitabine, and pegaspargase (DDGP) and methotrexate, dexamethasone, ifosfamide, L-asparaginase, and etoposide (SMILE) regimens for relapsed/refractory ENKL and explore the prognostic factors. From October 2014 to July 2019, 54 patients with relapsed/refractory ENKL who received DDGP or SMILE chemotherapy were retrospectively assessed in this study. Thirty-one patients received DDGP chemotherapy and 23 patients received SMILE chemotherapy. A higher complete response rate was observed in patients treated with DDGP regimen (61.3% vs. 30.4%, P = 0.025). The DDGP group (95% confidence interval (CI) of 5-year progression-free survival (PFS): 24.6-66.2%; 95% CI of 5-year overall survival (OS): 8.5-91.7%) was also significantly associated with longer 5-year PFS and 5-year OS (P = 0.008 for 5-year PFS, P = 0.023 for 5-year OS). More serious leucopenia (P = 0.021), neutropenia (P = 0.041), and allergy (P = 0.040) were observed in the SMILE group. Post-treatment Epstein-Barr virus (EBV)-DNA status (P = 0.001 for PFS, P = 0.018 for OS) was identified as a significant prognostic factor for PFS and OS in multivariate analysis. The present research suggested that compared with SMILE chemotherapy, DDGP chemotherapy can significantly improve the response and survival of relapsed/refractory ENKL with better tolerance. Post-treatment EBV-DNA status was identified as a significant prognostic factor for PFS and OS in relapsed/refractory ENKL.

Validation of nomogram-revised risk index and comparison with other models for extranodal nasal-type NK/T-cell lymphoma in the modern chemotherapy era: indication for prognostication and clinical decision-making.

Derived from our original nomogram study by using the risk variables from multivariable analyses in the derivation cohort of 1383 patients with extranodal NK/T-cell lymphoma, nasal-type (ENKTCL) who were mostly treated with anthracycline-based chemotherapy, we propose an easily used nomogram-revised risk index (NRI), validated it and compared with Ann Arbor staging, the International Prognostic Index (IPI), Korean Prognostic Index (KPI), and prognostic index of natural killer lymphoma (PINK) for overall survival (OS) prediction by examining calibration, discrimination, and decision curve analysis in a validation cohort of 1582 patients primarily treated with non-anthracycline-based chemotherapy. The calibration of the NRI showed satisfactory for predicting 3- and 5-year OS in the validation cohort. The Harrell's C-index and integrated Brier score (IBS) of the NRI for OS prediction demonstrated a better performance than that of the Ann Arbor staging system, IPI, KPI, and PINK. Decision curve analysis of the NRI also showed a superior outcome. The NRI is a promising tool for stratifying patients with ENKTCL into risk groups for designing clinical trials and for selecting appropriate individualized treatment.

Cytogenetic complexity and heterogeneity in intravascular lymphoma.

AIMS: To characterise the karyotypic abnormalities and heterogeneities in intravascular lymphoma (IVL). METHODS: G-banded karyotyping was performed on biopsy specimens from a single-centre IVL cohort comprising intravascular large B-cell lymphoma (IVLBCL, n=12) and NK/T-cell lymphoma (IVNKTCL, n=1). RESULTS: Five IVLBCL cases and one IVNKTCL case (total 46%) were found to have normal karyotypes, and the cytogenetic abnormalities observed in the other seven IVLBCL cases (54%) were investigated further. These seven karyotypes were uniformly complex with an average of 13 aberrations. The seven cases all had abnormalities involving chromosome 6, with 57% involving structural abnormalities at 6q13, and chromosome 8, with 43% involving abnormalities at 8p11.2. In addition, 71% had aberrations at 19q13. On average, 4.4 chromosomal gains and losses were detected per case. Cytogenetic heterogeneities were observed in six cases (86%) and tetraploidy in three cases (43%). There was no significant difference in progression-free survival (p=0.92) and overall survival (p=0.61) between the IVLBCL cases with complex and normal karyotypes. CONCLUSION: Approximately half of IVLBCL cases had a highly heterogeneous pattern of karyotypes with different clonal numerical and structural chromosome aberrations.

Progression-free survival at 24 months and subsequent survival of patients with extranodal NK/T-cell lymphoma: a China Lymphoma Collaborative Group (CLCG) study.

Limited evidence supports the use of early endpoints to evaluate the success of initial treatment of extranodal NK/T-cell lymphoma (ENKTCL) in the modern era. We aim to analyze progression-free survival at 24 months (PFS24) and subsequent overall survival (OS) in a large-scale multicenter cohort of patients. 1790 patients were included from the China Lymphoma Collaborative Group (CLCG) database. Subsequent OS was defined from the time of PFS24 or progression within 24 months to death. OS was compared with age- and sex-matched general Chinese population using expected survival and standardized mortality ratio (SMR). Patients who did not achieve PFS24 had a median OS of 5.3 months after progression, with 5-year OS rate of 19.2% and the SMR of 71.4 (95% CI, 62.9-81.1). In contrast, 74% patients achieved PFS24, and the SMR after achieving PFS24 was 1.77 (95% CI, 1.34-2.34). The observed OS rate after PFS24 versus expected OS rate at 5 years was 92.2% versus 94.3%. Similarly, superior outcomes following PFS24 were observed in early-stage patients (5-year OS rate, 92.9%). Patients achieving PFS24 had excellent outcome, whereas patients exhibiting earlier progression had a poor survival. These marked differences suggest that PFS24 may be used for study design and risk stratification in ENKTCL.

Prognostic value of 25-hydroxy vitamin D in extranodal NK/T cell lymphoma.

25-hydroxy vitamin D [25-(OH)D] is widely used to determine vitamin D status in clinic. The aim of our study was to evaluate the prognostic value of 25-(OH)D in extranodal NK/T cell lymphoma (ENKTL). Ninety-three (93) ENKTL patients with available serum 25-(OH)D values were enrolled in our study. Vitamin D deficiency is defined as a 25-(OH)D below 50 nmol/L (20 ng/ml). Univariate and multivariate regression analyses were performed to determine independent risk factors for progression-free survival (PFS) and overall survival (OS). Receiver operator characteristic (ROC) curves were plotted, and corresponding areas under the curves (AUC) were calculated to estimate the accuracy of PINK-E (prognostic index of natural killer lymphoma added with Epstein-Barr virus-DNA status) and 25-(OH)D deficiency in ENKTL risk-stratification. Our results suggested that the vitamin D deficiency was an independent inferior prognostic factor for both PFS [hazard ratio (HR), 2.869; 95% confidence interval (CI), 1.540 to 5.346; P = 0.003] and OS (HR, 3.204; 95% CI, 1.559 to 6.583; P = 0.006) in patients with ENKTL. Additionally, we demonstrated that adding 25-(OH)D deficiency to PINK-E score system indeed has a superior prognostic significance than PINK-E alone for PFS [AUC: 0.796 (95% CI: 0.699 to 0.872) vs. 0.759 (95% CI: 0.659 to 0.841), P = 0.020] and OS [AUC: 0.755 (95% CI: 0.655 to 0.838) vs. 0.721 (95% CI: 0.618 to 0.809), P = 0.040]. In conclusion, our study proved that 25-(OH)D deficiency was associated with inferior survival outcome of ENKTL patients.

Combination of anti-PD-1 antibody with P-GEMOX as a potentially effective immunochemotherapy for advanced natural killer/T cell lymphoma.

Advanced natural killer/T cell lymphoma (NKTL) has demonstrated poor prognosis with currently available therapies. Here, we report the efficacy of anti-programmed death 1 (PD-1) antibody with the P-GEMOX (pegaspargase, gemcitabine, and oxaliplatin) regimen in advanced NKTL. Nine patients underwent six 21-day cycles of anti-PD-1 antibody (day 1), pegaspargase 2000 U/m2 (day 1), gemcitabine 1 g/m2 (days 1 and 8) and oxaliplatin 130 mg/m2 (day 1), followed by anti-PD-1 antibody maintenance every 3 weeks. Programmed death-ligand 1 (PD-L1) expression and genetic alterations were determined in paraffin-embedded pretreatment tissue samples using immunohistochemistry and next-generation sequencing (NGS) analysis. Responses were assessed using 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) and computed tomography or magnetic resonance imaging. Eight patients exhibited significant responses, comprising of seven complete remissions and one partial remission (overall response rate: 88.9%). After a median follow-up of 10.6 months, 6/9 patients (66.7%) remained in complete remission. The most common grade 3/4 adverse events were anemia (33.3%), neutropenia (33.3%), and thrombocytopenia (33.3%); all of which were manageable and resolved. Immunochemotherapy produced a high response rate in patients with positive PD-L1 expression (5/6, 83.3%). NGS analysis suggested that STAT3/JAK3/PD-L1 alterations and ARID1A mutation were associated with immunochemotherapy efficacy. Mutation in DDX3X and alteration in epigenetic modifiers of KMT2D, TET2, and BCORL1 might indicate a poor response to immunochemotherapy. In conclusion, the anti-PD-1 antibody plus P-GEMOX regimen demonstrated promising efficacy in advanced NKTL. PD-L1 expression combined with specific genetic alterations could be used as potential biomarkers to predict therapeutic responses to immunochemotherapy.

Baseline SUVmax of 18F-FDG PET-CT indicates prognosis of extranodal natural killer/T-cell lymphoma.

To evaluate the prognostic value of the baseline SUVmax of F-FDG PET-CT in extranodal natural killer/T-cell lymphoma (NKTCL) patients.From January 2010 to December 2015, 141 extranodal NKTCL patients with staging F-FDG PET-CT scan were divided into two group based on SUVmax cutoff value obtained from operating characteristic (ROC) curves. All the patients received radiotherapy, chemotherapy or chemoradiation. Survival analysis was performed on the basis of SUVmax.The median baseline SUVmax of the tumors was 11.67 (range 2.6-34.6). The ROC curves showed that the optimal cutoff of the baseline SUVmax was 9.65. The patients were divided into two groups: low SUV group (SUVmax < 9.65) and high SUV group (SUVmax ≥ 9.65). Patients in high SUV group were more likely to have invasive disease outside the nasal cavity (P < .001), poorer ECOG scores (P = .012) and higher LDH levels (P = .034). The univariate survival analyses indicated that high SUVmax was a poor prognostic factor for overall survival (OS, P = .038), progression free survival (PFS, P = .006) and distant relapse free survival (DRFS, P = .001), but not for local recurrence free survival (LRFS, P > .05). These results were consistent with that of the survival analyses using the Kaplan-Meier method. The multivariate survival analyses showed that the baseline SUVmax was no longer a prognostic factor for OS (HR 1.99, 95% CI 0.81-4.88, P = .135), but it still indicated worse PFS (HR 2.6, 95% CI 1.24-5.46, P = .012) and DRFS (HR 4.58, 95% CI 1.83-11.46, P = .001) independent of other variables.For extranodal NKTCL patients, a higher baseline SUVmax of F-FDG PET-CT was associated with more aggressive clinical features. An SUVmax ≥ 9.65 was an independent poor prognostic factor for DRFS and PFS. Thus, the baseline SUVmax may be a valuable tool to help identify patients with a high risk of disease progression.

Avelumab for the treatment of relapsed or refractory extranodal NK/T-cell lymphoma: an open-label phase 2 study.

This study aimed to assess the efficacy and safety of treatment with avelumab, an anti-programmed death ligand 1 (PD-L1) antibody, in patients with relapsed or refractory extranodal natural killer/T-cell lymphoma (ENKTL). In this phase 2 trial, 21 patients with relapsed or refractory ENKTL were treated with 10 mg/kg of avelumab on days 1 and 15 of a 28-day cycle. The primary end point was the complete response (CR) rate based on the best response. Targeted sequencing and immunohistochemistry were performed using pretreatment tumor tissue, and blood samples were drawn before and after treatment for measurement of cytokines and soluble programmed cell death protein 1 (PD1), PD-L1, and PD-L2. The CR rate was 24% (5 of 21), and the overall response rate was 38% (8 of 21). Although nonresponders showed early progression, 5 responders currently continue to receive treatment and have maintained their response. Most treatment-related adverse events were grade 1 or 2; no grade 4 adverse events were observed. Treatment responses did not correlate with mutation profiles, tumor mutation burden, serum levels of cytokines, or soluble PD1/PD-L1 and PD-L2. However, the response to avelumab was significantly associated with the expression of PD-L1 by tumor tissue (P = .001). Therefore, all patients achieving CR showed high PD-L1 expression, and their tumor subtyping based on PD-L1 expression correlated with treatment response. In summary, avelumab showed single-agent activity in a subset of patients with relapsed or refractory ENKTL. The assessment of PD-L1 expression on tumor cells might be helpful for identifying responders to avelumab. This trial was registered at www.clinicaltrials.gov as #NCT03439501.

Aberrant Expression of Prohibitin Is Related to Prognosis of Nasal Extranodal Natural Killer/T Cell Lymphoma, Nasal Type.

INTRODUCTION: Nasal extranodal natural killer (NK)/T cell lymphoma, nasal type (ENKTCL) is a high-grade Epstein-Barr virus (EBV)-associated malignancy with poor outcomes. There are few biomarkers for the accurate diagnosis and prognostic prediction of the disease. The aim of this study was to investigate the clinicopathological significance of prohibitin (PHB) expression in nasal ENKTCL. METHODS: The expression level of PHB was detected via immunohistochemical staining in 49 nasal ENKTCL tissues and age- and sex-matched controls of 30 nasal mucosa-reactive lymphoid hyperplasia (NRLH) tissues. The correlations between the PHB expression and clinicopathological features of patients with nasal ENKTCL were evaluated. RESULTS: The results indicated a significantly decreased expression of PHB in nasal ENKTCL tissues compared with in NRLH tissues. Low-level PHB expression was significantly associated with younger age and fever (p = 0.008 and 0.018, respectively). The Kaplan-Meier analysis showed that the cytoplasm expression level of PHB in nasal ENKTCL was inversely related to overall survival (p = 0.046). CONCLUSIONS: PHB may be a potential diagnostic marker and prognostic predictor of nasal ENKTCL.

Radiotherapy followed by DICEP regimen in treatment of newly diagnosed, stage IE/IIE, extranodal NK/T-cell lymphoma patients.

BACKGROUND: The optimal treatment strategies for extranodal natural killer/ T-cell lymphoma (ENKTL) have not been defined. We conducted this prospective, open-label, phase II, single-center study aimed to explore the efficacy and safety of radiotherapy followed by DICEP (Dexamethasone, ifosfamide, cisplatin, etoposide, and pegaspargase) regimen in the treatment of patients with untreated, stage IE/IIE, extranodal NK/T-cell lymphoma. METHODS: Thirty eligible patients were enrolled in this study, receiving radiotherapy of 50Gy/25fx, and followed by chemotherapy with DICEP regimen for 3 cycles if tolerated. Median follow-up time of this study was 70.8 months. We constructed Kaplan-Meier survival curves for survival analyses. RESULTS: The most common manifestations at the onset of disease were nasal obstruction (80%), with or without fever, and pharyngalgia (20%). The overall response rate (ORR) was 96.7% (29/30). Four patients (13.3%) had progression of the disease (PD), the estimated 5-year progression-free survival (PFS) rate was 86%. Four patients (13.3%) died of disease, and the estimated 5-year cumulative overall survival (OS) was 87%. The most common hematological toxicity was grade 3 or grade 4 neutropenia, which could be successfully managed via using growth-stimulating factors or dose modifications. Hypoalbuminemia and decreased fibrinogen are the top two nonhematologic toxicities. No treatment-related death occurred in this study. CONCLUSIONS: Our present study showed that radiotherapy followed by DICEP chemotherapy could be an effective and tolerable treatment modality for newly diagnosed, stage IE/IIE ENKTL patients. Adverse events were predictable and manageable. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01667302. Registered: 1 July 2012.