TET2 regulates extranodal NK/T cell lymphoma progression through regulation of DNA methylation.

The biological role of Ten-11 translocation 2 (TET2) and the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in the development of extra-nodal natural killer/T-cell lymphoma (ENKTL) remains unclear. The level of 5mC and 5hmC was detected in 112 cases of ENKTL tissue specimens by immunohistochemical (IHC) staining. Subsequently, TET2 knockdown and the overexpression cell models were constructed in ENKTL cell lines. Biochemical analyses were used to assess proliferation, apoptosis, cell cycle and monoclonal formation in cells treated or untreated with L-Ascorbic acid sodium salt (LAASS). Dot-Blots were used to detect levels of genome 5mC and 5hmC. Additionally, the ILLUMINA 850k methylation chip was used to analyze the changes of TET2 regulatory genes. RNA-Seq was used to profile differentially expressed genes regulated by TET2. The global level of 5hmC was significantly decreased, while 5mC was highly expressed in ENKTL tissue. TET2 protein expression was negatively correlated with the ratio of 5mC/5hmC (p < 0.0001). The 5mC/5hmC status were related to the site of disease, clinical stage, PINK score and Ki-67 index, as well as the 5-year OS. TET2 knockdown prolonged the DNA synthesis period, increased the cloning ability of tumor cells, increased the level of 5mC and decreased the level of 5hmC in ENKTL cells. While overexpression of TET2 presented the opposite effect. Furthermore, treatment of ENKTL cells with LAASS significantly induced ENKTL cell apoptosis. These results suggest that TET2 plays an important role in ENKTL development via regulation of 5mC and 5hmC and may serve as a novel therapeutic target for ENKTL.

Optimization of immune checkpoint inhibitor treatment planning for relapsed or refractory extranodal NK/T cell lymphoma.

Pembrolizumab (anti-programmed cell death-ligand 1 inhibitor) is a promising salvage therapeutic option for relapsed/refractory extranodal NK/T-cell lymphoma (R/R ENKTL). However, the appropriate duration of pembrolizumab use in R/R ENKTL patients and the optimal timing for administering pembrolizumab remain undetermined. We collected and analyzed clinical information on R/R ENKTL 58 patients who received pembrolizumab to evaluate the optimal treatment durations and clinical information for considering treatment interruption. Treatment outcomes were assessed by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) and Epstein Barr virus DNA (EBV DNA) every 3 months. Nineteen (32.8%) patients had been treated with more than three chemotherapies before pembrolizumab administration. The best response rate towards the first try of pembrolizumab was 38.9% (31.5% complete response rate (CR), 7.4% partial response (PR)). During the 41.8-month median follow-up duration, the median progression-free survival (PFS) was 3.1 months, and the median overall survival (OS) was 7.1 months. The failure group, which was characterized by Deaville score (DS) 3-4 and circulating EBV detection, or DS 5 with/without EBV detection, had the worst PFS (p < 0.001) and OS (p < 0.001), followed by the high (DS 1-2 and EBV detection, or DS 3-4 and EBV not detected) and low-risk groups (DS 1-2 and EBV not detected). Among the 21 patients who achieved the best response at the first pembolizumab try, the patients who received planned 24 cycles presented better PFS than those who received incomplete cycles (57.6 months vs 20.9 months, P-value = 0.012). Among 13 patients who received avelumab or pembrolizumab in advance, a few who responded to the second trial of pembrolizumab administration had over one year of chemotherapy vacation. Determining the discontinuation or continuation of pembrolizumab would be considered in selected cases assessed by PET-CT and EBV monitoring. Disruption of pembrolizumab treatment may be advisable for the low-risk group(DS 1-2 and EBV not detected), whereas continuation could be warranted for the high-risk group (DS 1-2 and EBV detection, or DS 3-4 and EBV not detected). Moreover, it might be critical to maintain over 24 cycles to improve the survival outcome of R/R ENKTL.

Immunotyping of peripheral blood lymphocytes by flow cytometry reveals Th cell as a potential prognostic biomarker for extranodal NK/T-cell lymphoma.

This study aimed to explore the distribution, characteristics and prognostic value of baseline peripheral blood lymphocyte subsets in patients with extranodal NK/T-cell lymphoma (NKTCL). We conducted this cross-sectional study of 205 newly-diagnosed NKTCL patients receiving first-line chemotherapy and radiation at our institute between 2010 and 2020. Baseline peripheral blood lymphocytes were detected using flow cytometry, and the clinical value was analyzed. Compared with healthy controls, patients with NKTCL presented with a distinct peripheral immunity with higher levels of cytotoxic CD8+ T cells (33.230 ± 12.090% vs. 27.060 ± 4.010%, p < 0.001) and NKT cells (7.697 ± 7.219% vs. 3.550 ± 2.088%, p < 0.001) but lower proportions of suppressive regulatory T cells (Treg, 2.999 ± 1.949% vs. 3.420 ± 1.051%, p = 0.003) and CD4+ helper T cells (Th, 33.084 ± 11.361% vs. 37.650 ± 3.153%, p < 0.001). Peripheral lymphocytes were differentially distributed according to age, stage, and primary site in patients with NKTCL. The proportion of Th cells/lymphocytes was associated with tumor burden reflected by stage (p = 0.037), serum lactate dehydrogenase (p = 0.0420), primary tumor invasion (p = 0.025), and prognostic index for NK/T-cell lymphoma (PINK) score (p = 0.041). Furthermore, elevated proportions of T cells (58.9% vs. 76.4%, p = 0.005), Th cells (56.3% vs. 68.8%, p = 0.047), or Treg cells (49.5% vs. 68.9%, p = 0.040) were associated with inferior 5-year progression-free survivals (PFS) via univariable survival analysis. Multivariate cox regression revealed elevated Th cells as an independent predictor for unfavorable PFS (HR = 2.333, 95% CI, 1.030-5.288, p = 0.042) in NKTCL. These results suggested the proportion of Th cells positively correlated with tumor burden and was a potential non-invasive biomarker for inferior survival for patients with NKTCL.

Comprehensive population pharmacokinetic modelling of sugemalimab, an anti-programmed death-ligand 1 (PD-L1) human monoclonal antibody, in patients with solid tumours or lymphomas across multiple Phase I-III studies.

AIMS: The aim of this study was to develop a population pharmacokinetics model for sugemalimab, a monoclonal antibody that targets programmed death-ligand 1 (PD-L1), using data from Phase I-III trials and to assess clinical factors affecting sugemalimab exposure. METHODS: A nonlinear mixed-effect modelling approach was employed to analyse pooled data from nine studies involving 1628 subjects to characterize the PopPK of sugemalimab. This investigation examined the influence of various covariates on sugemalimab pharmacokinetics (PK), encompassing demographics, baseline hepatic and renal function-related covariates, and others (including anti-drug antibody [ADA], combination treatment, Eastern Cooperative Oncology Group [ECOG] performance score, tumour burden and tumour type). Estimation accuracy and predictive ability of the final model were evaluated using various methods. The influence of covariates on sugemalimab exposure was assessed by simulation from the final model. RESULTS: A two-compartment model with first-order elimination and time-varying clearance effectively described the PK of sugemalimab. Covariate analyses revealed significant relationships between sugemalimab clearance and body weight, albumin, gender, ADA, tumour burden and tumour type. The statistically significant covariates on central volume were body weight, albumin, gender and tumour type. No significant relationships were found in the final model for age, race, alanine aminotransferase, aspartate aminotransferase, creatinine, total bilirubin, alkaline phosphatase, combination treatment, creatinine clearance, ECOG, renal function or hepatic function. All significant covariates demonstrated less than a 20% effect on sugemalimab exposure. CONCLUSIONS: The PopPK model adequately described the pharmacokinetic profile of sugemalimab with no clinically meaningful impact observed on its exposure across all covariates. Dose adjustment does not appear to be necessary.

Primary cutaneous EBV+ extranodal NK/T-cell lymphoma of gamma/delta T-cell lineage in the posttransplantation setting.

Posttransplantation primary cutaneous T-cell lymphomas (PT-CTCL) are a rare complication of sustained immunosuppression in the posttransplant setting. When present, PT-CTCLs are typically EBV- and exhibit features of mycosis fungoides/Sézary syndrome or CD30+ lymphoproliferative disorders. We present a case of a 75-year-old individual who developed skin lesions 30 years after liver transplantation. Pathologic evaluation of the skin biopsy revealed involvement by a clonal, EBV+ T-cell population of gamma/delta lineage with no evidence of systemic disease. Comprehensive genomic profiling was performed, confirming focal one-copy loss of 6q23.3, altogether consistent with the extremely rare and unusual diagnosis of primary cutaneous EBV+ extranodal NK/T-cell lymphoma of gamma/delta T-cell lineage in the posttransplantation setting.

Quality of life in disease-free survived patients with early-stage extranodal nasal-type NK/T-cell lymphoma after definitive intensity-modulated radiotherapy: a cross-sectional study of 310 cases.

PURPOSE: Radiotherapy is a critical treatment for early-stage extranodal nasal-type NK/T-cell lymphoma (ENKTL) and has yielded favorable survival outcomes. However, their postradiotherapy quality of life (QOL) has not been investigated. Here, we conducted a cross-sectional study to assess the QOL of ENKTL patients with disease-free survival after definitive radiotherapy and to identify factors associated with QOL and treatment optimization. METHODS: This cross-sectional study included 310 patients with stage I-II ENKTL of the upper aerodigestive tract (UADT) who had received simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) with a consistent design and achieved disease-free survival. The median postradiotherapy time was 47.2 months (range, 3.1-115.7). The EORTC QLQ-H&N35 questionnaire was used to assess symptom-related QOL, and nine additional items were added to incorporate nasal, optical, and aural-related symptoms. The scores indicate the severity of the symptoms. RESULTS: The most common postradiotherapy symptoms among patients with ENKTL were nose problems (49.7%), dry mouth (44.8%), tooth problems (41.3%), sensory problems (32.6%), and less sexuality (25.8%). Tooth problems had the highest average score of 18.6, which is still acceptable. The severity of these symptoms decreased over time and reached a plateau in the second year after radiotherapy. Multivariable regression analysis showed that whole-neck irradiation was an independent predictive factor for xerostomia (P = 0.013, OR = 1.114), while age > 60 years was a predictive factor for lower sexuality (P < 0.001, OR = 1.32). CONCLUSION: The QOL of patients with early-stage ENKTL after radiotherapy was favorable, and most symptoms improved over time. Radiotherapy was correlated with specific symptoms, which may suggest a direction for further improvement in SIB-IMRT.

Expression of soluble CD27 in extranodal natural killer/T-cell lymphoma, nasal type: potential as a biomarker for diagnosis and CD27/CD70-targeted therapy.

The engagement of CD27 on lymphocytes with its ligand, CD70, on tumors is believed to mediate tumor immune evasion and the elevation of serum soluble CD27 (sCD27) levels in patients with CD70-positive malignancies. We previously showed that CD70 is expressed in extranodal natural killer/T-cell lymphoma, nasal type (ENKL), an Epstein-Barr virus (EBV)-related malignancy. However, little is known about serum sCD27 expression and its association with the clinical characteristics of, and the CD27/CD70 interaction in, ENKL. In the present study, we show that serum sCD27 is significantly elevated in the sera of patients with ENKL. The levels of serum sCD27 provided excellent diagnostic accuracy for discriminating patients with ENKL from healthy subjects, correlated positively with the levels of other diagnostic markers (lactate dehydrogenase, soluble interleukin-2 receptor, and EBV-DNA), and decreased significantly following treatment. Elevated serum sCD27 levels also correlated significantly with advanced clinical stage and tended to correspond with shorter survival, in patients with ENKL. Immunohistochemistry indicated that CD27-positive tumor-infiltrating immune cells exist adjacent to CD70-positive lymphoma cells. In addition, serum sCD27 levels in patients with CD70-positive ENKL were significantly higher than those in patients with CD70-negative ENKL, suggesting that the intra-tumoral CD27/CD70 interaction boosts the release of sCD27 in serum. Furthermore, the EBV-encoded oncoprotein latent membrane protein 1 upregulated CD70 expression in ENKL cells. Our results suggest that sCD27 may serve as a novel diagnostic biomarker and also may serve as a tool for evaluating the applicability of CD27/CD70-targeted therapies by predicting intra-tumoral CD70 expression and CD27/CD70 interaction in ENKL.

"Sandwich" protocol based on modified SMILE regimen for children with newly extranodal NK/T cell lymphoma, nasal type: a single-arm, single-center clinical study.

Extranodal NK/T-cell lymphoma, nasal type (ENKTL), which is a rare form of mature T/NK cell lymphoma in children, currently lacks a standardized first-line treatment approach. However, a treatment protocol known as the "sandwich" regimen has been used in children newly diagnosed with ENKTL. This protocol combines the administration of methotrexate, ifosfamide, etoposide, pegaspargase, and dexamethasone (referred to as SMILE) with the addition of radiotherapy (RT). From September 2017 to December 2020, a total of five patients were included in the study, consisting of three males and two females. The median age of onset was 10.6 years (range, 9.8 to 14.0 years). Among the patients, four had nasal/nasopharyngeal disease at stage II, while one patient had extra nasal disease involving the skin at stage IV. The median EBV-DNA level in plasma was 1.68 × 103 copies/ml (range, 0.44 to 21.1 × 103copies/ml). All the patients had good overall response after 2 cycles of chemotherapy and radiotherapy, including 4 of the patients who had a complete response and 1 of the patients with partial remission. The patient with stage IV received allogeneic hematopoietic stem cell transplantation after the EBV-DNA level was elevated again during treatment. One patient in the low-risk group experienced grade 4 oral mucositis, while no other severe complications or treatment-related deaths were observed. The median follow-up period was 22 months (range, 5 to 57 months). All five patients successfully completed their treatment, with four patients achieving event-free survival, and one patient was lost to follow-up. The median OS time and EFS time was 33 months (range: 18-57 months) and 20 months (range: 5-47 months), respectively. The sandwich protocol has demonstrated a high response rate, good tolerance to chemotherapy, and no treatment-related fatalities. However, further confirmation is necessary through additional clinical studies involving larger sample sizes. Clinical trial registration number: Due to modified SMILE regimens with sandwiched radiotherapy yielded promising outcomes in children ENKTL, we have carried out a phase II multicenter clinical trial (ChiCTR220005954) for children ENKTL in China to further verify the efficacy and safety.

Central nervous system involvement at initial diagnosis of extranodal NK/T-cell lymphoma: a retrospective study of a consecutive 12-year case series.

Patients with central nervous system (CNS) involvement at initial diagnosis of extranodal NK/T-cell lymphoma (ENKTL) are exceedingly rare, and the clinicopathologic features of CNS involvement have not been well characterized. In this study, we reviewed 662 patients with ENKTL from August 2008 to September 2019. Their clinical and pathological features, treatments, and survival outcomes were analyzed. The median follow-up time was 72 months. Nine of 662 (1.4%) patients were diagnosed with CNS involvement. Among them, the median age was 37 years, and seven patients were male. All patients had positive EBV-DNA, and three patients were asymptomatic at the time of diagnosis with CNS involvement. Common extranodal involved sites included bone, paranasal sinuses, breast, kidney, adrenal gland, and bone marrow. All patients were positive for cytoplasmic CD3ε, cytotoxic granule proteins, and EBER and negative for CD20. All patients received intrathecal chemotherapy and at least one cycle of systemic chemotherapy. Seven patients had died and two were still alive by the last follow-up. The median overall survival (OS) in patients with CNS involvement at initial diagnosis of ENKTL was 9 months, and the 1-year OS was 44.4%. Five patients achieved a complete response after asparaginase-based chemotherapy; two were still alive, one died of systemic progression, one died of ENKTL-associated hemophagocytic syndrome, and one died of treatment-related infections. In conclusion, CNS involvement at initial diagnosis of ENKTL is extremely rare with poor prognosis. There is no standard treatment, and asparaginase-based chemotherapy combined with intrathecal chemotherapy might yield good efficacy.

Primary central nervous system extranodal NK/T-cell lymphoma, nasal type with CD20 expression: Case report and review of the literature.

Primary central nervous system (PCNS) extranodal NK/T-cell lymphoma, nasal type (ENKTCL), is an exceedingly rare tumor. To the best of our knowledge, only 27 cases and only one reported aberrant CD20 expression have been documented in the literature. Here we present a second case of PCNS ENKTCL with aberrant CD20 expression in a 43-year-old immunocompetent Chinese female. The patient presented with tremors, weakness in the right upper limb, and a slow reaction. Magnetic resonance imaging revealed multiple brain lesions. A histological examination revealed a diffuse distribution of intermediate-sized pleomorphic lymphocytes with angiocentric growth. The tumor cells expressed CD2, CD3, CD56, T-cell intracellular antigen-1, granzyme B, and Epstein-Barr virus-encoded RNAs (EBERs), with additional partial and weak CD20 and CD30 expression. Despite a confirmatory pathological diagnosis, the patient refused treatment and was discharged, ultimately dying from the disease. In the literature review, the clinical, immunohistochemical, EBERs, treatment, and prognostic features of PCNS ENKTCL were summarized. Although PCNS ENKTCT is extremely rare, it does occur and should always be included in differential diagnoses. CD20 expression should be evaluated routinely with relevant markers. The accumulation of cases is crucial for developing an effective treatment strategy for this rare and aggressive malignancy.

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

Background Chemotherapy 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. Methods Fifty 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. Results Serum 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. Conclusion Our 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.

Long-term outcomes and central nervous system relapse in extranodal natural killer/T-cell lymphoma.

To elucidate the long-term outcomes of non-anthracycline-containing therapies and central nervous system (CNS) events in patients with extranodal NK/T-cell lymphoma, nasal type (ENKTL), the clinical data of 313 patients with ENKTL diagnosed between 2000 and 2013 in a nationwide retrospective study in Japan were updated and analyzed. At a median follow-up of 8.4 years, the 5-year overall survival (OS) and progression-free survival (PFS) were 71% and 64%, respectively, in 140 localized ENKTL patients who received radiotherapy-dexamethasone, etoposide, ifosfamide, and carboplatin (RT-DeVIC) in clinical practice. Nine (6.4%) patients experienced second malignancies. In 155 localized ENKTL patients treated with RT-DeVIC, 10 (6.5%) experienced CNS relapse (median, 12.8 months after diagnosis). In five of them, the events were confined to the CNS. Nine of the 10 patients who experienced CNS relapse died within 1 year after CNS relapse. Multivariate analysis identified gingival (hazard ratio [HR], 54.35; 95% confidence interval [CI], 8.60-343.35) and paranasal involvement (HR, 7.42; 95% CI, 1.78-30.89) as independent risk factors for CNS relapse. In 80 advanced ENKTL patients, 18 received steroid (dexamethasone), methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy as first-line treatment. Patients who received SMILE as their first-line treatment tended to have better OS than those who did not (p = 0.071). Six (7.5%) advanced ENKTL patients experienced isolated CNS relapse (median, 2.6 months after diagnosis) and died within 4 months of relapse. No second malignancies were documented in advanced ENKTL patients. In the entire cohort, the median OS after first relapse or progression was 4.6 months. 12 patients who survived 5 years after PFS events were disease-free at the last follow-up. Of those, 11 (92%) underwent hematopoietic stem cell transplantation. Our 8-year follow-up revealed the long-term efficacy and safety of RT-DeVIC and SMILE. The risk of CNS relapse is an important consideration in advanced ENKTL.

Comparison analysis of first-line asparaginase- versus non-asparaginase-based regimens for early-stage extranodal NK/T-cell lymphoma.

The present study investigated the efficacy and toxicity profile of first-line asparaginase (ASP)-based versus non-ASP-based regimens in treating early-stage extranodal NK/T-cell lymphoma (ENKTCL) in non-anthracycline therapy era. This multi-center, real-world retrospective study consisted 305 newly diagnosed localized ENKTCL patients who were treated with sequential chemoradiation between 2010 and 2020 in China: 190 cases received ASP-based regimens and 115 cases received non-ASP-based regimens. Propensity score matching and multivariable analyses were used to compare survivals and toxicities between the two treatment groups. Non-ASP-based regimens achieved comparable survivals compared with ASP-based regimens in the entire cohort. The 5-year overall survival (OS), progression-free survival (PFS) rates were 84.7% and 73.5% for non-ASP-based regimens, and 87.7% (P=0.464) and 74.6% (P=0.702) for ASP-based regimens. The non-inferior survivals of non-ASP-based regimens were consistent after adjustment using PSM and multivariable analyses. However, survival benefits of ASP varied in different treatment modalities. Among patients receiving sequential chemotherapy and radiation (CT+RT±CT), ASP-based regimens achieved higher complete remission rate (54.3 vs. 34.5%, P=0.047) and more favorable survivals compared with non-ASP-based regimens (5-year OS, 87.0 vs. 69.0%, P=0.028). However, for patients receiving sequential radiation and chemotherapy (RT+CT), non-ASP-based regimens achieved comparable favorable survivals as ASP-based regimens. Besides, liver injury, malnutrition, and coagulative dysfunction were significantly more commonly documented in ASP-based regimens. These findings suggested that ASP was an effective agent in treating ENKTCL, especially among those receiving induction CT and RT. For patients who received upfront RT, non-ASP-based regimens might be a comparably effective and more tolerable treatment option.

First-line LVDP (L-asparaginase, etoposide, dexamethasone, and cisplatin) regimen combined with radiotherapy is effective for early-stage extranodal natural killer/T-cell lymphoma, nasal type.

Chemotherapy combined with radiotherapy could reduce the risk of recurrence in early-stage extranodal NK/T lymphoma (ENKTL). However, the optimal combined chemotherapy regimen is still unknown. Our previous study reported that LVDP (L-asparaginase, etoposide, dexamethasone, and cisplatin) combined with radiotherapy was a potentially effective and safe treatment regimen for early-stage ENKTL. This study further validated the efficacy and safety of LVDP chemotherapy combined with radiation for early-stage ENKTL with more patients and longer follow-up. We retrospectively studied 112 patients with early-stage ENKTL from September 2010 to September 2019. All patients received the LVDP regimen, and 101 of them received radiotherapy. The patients' characteristics, treatment responses, survival outcomes, prognostic factors, and toxicities were analyzed. The median follow-up was 60 months (range, 4 to 117). All patients received median 4 cycles of the LVDP chemotherapy. At the end of therapy, the objective response rate and complete response rate were 88.3% and 77.6%, respectively. The 3- and 5-year OS were 79.6% and 73.2%, and the 3- and 5-year PFS were 75.4% and 71.6%, respectively. Among them, the LVDP regimen combined with radiotherapy yielded more favorable treatment outcomes (the 3-year OS and PFS were 83.1% and 80.8%). The most common severe hematologic toxicity was leukopenia (25% grade 3/4), and the most common severe non-hematologic toxicity was increased transaminase (4.5% grade 3/4). No pancreatitis or treatment-related death occurred. The LVDP regimen combined with radiotherapy had a good therapeutic response and long-term survival with tolerable toxicity for patients with early-stage ENKTL.

[Pretreatment evaluation of 18F-FDG PET-CT in extranodal NK/T-cell lymphoma].

Objective: To investigate the clinical value of pretreatment 18F-fluorodeoxy glucose positron emission tomography/computed tomography (18F-FDG PET-CT) in extranodal NK/T-cell lymphoma. Methods: Eighty-one patients with pathologically confirmed extranodal NK/T-cell lymphoma and pretreatment with PET-CT scan in Cancer Hospital, Chinese Academy of Medical Sciences from August 2006 to December 2017 were enrolled in the study. The clinical, follow-up and imaging data were analyzed retrospectively. The relationship between maximum standard uptake value (SUVmax) and prognosis were evaluated by Mann-Whitney U test and Spearman rank correlation analysis. Results: Among the 81 patients, 98.8% (80/81) were upper aerodigestive tract (UAT) involved. Lesions at extra-UAT sites were detected in 7 cases, involving parotid gland (n=1), breast (n=1), spleen (n=1), pancreas (n=1), skin and subcutaneous soft tissue (n=1), muscle (n=1), lung (n=2) and bone (n=3). Lymph node involvement were demonstrated in 33 cases. All of the lesions had increased uptake of PET, the median SUVmax was 8.6. PET-CT changed staging in 15 cases, and 12 cases were adjusted treatment methods. 21 cases were changed radiotherapy target because of PET-CT. The 1-, 2-year progression-free survival (PFS) rates were 88.7% and 80.3% while 1-, 2-year overall survival (OS) rates were 97.2% and 94.4% respectively. The median SUVmax of patients with local lymph nodes involvement was significantly higher than those without local lymph nodes involvement (P=0.007). The SUVmax was positively associated with Ann Arbor stage (r=0.366, P=0.001), lactate dehydrogenase (r=0.308, P=0.005) and Ki-67 level (r=0.270, P=0.017). The SUVmax was inversely associated with lymphocyte count (r=-0.324, P=0.003) and hemoglobin content (r=-0.225, P=0.043). Conclusions: Extranodal NK/T-cell lymphoma predominantly occurs in extra-nodal organs, mainly in the upper respiratory and gastrointestinal tracts, with marked FDG-addiction. Compared with conventional imaging, 18F-FDG PET-CT is sensitive and comprehensive in detecting extra-nodal NK/T-cell lymphoma involvement, assisting in accurate clinical staging and treatment planning. Pretreatment SUVmax is potential for prognosis evaluation since it is correlated with prognostic factors.

[Extranodal NK/T cell lymphoma, nasal type with local recurrence in the contralateral nasal cavity 15 years after initial sequential chemoradiotherapy].

A 72-year-old woman was diagnosed with extranodal NK/T cell lymphoma of the right nasal cavity and received sequential radiochemotherapy comprising focal radiotherapy and THP-COP chemotherapy. Showed a complete tumor response to the treatment; however, the tumor recurred in the contralateral right nasal cavity 15 years after the initial treatment. This was judged to be a marginal recurrence in the radiation field. After four cycles of dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy, a second complete response was achieved. It is possible that another recurrence occurs in the future, and if the lesion is localized at the time of recurrence, it may be possible to control the disease again. Careful follow-up is considered necessary.

[Induced pluripotent stem cell-derived rejuvenated cytotoxic T lymphocyte therapy for Epstein-Barr virus-associated lymphomas: application to clinical practice].

Epstein-Barr virus (EBV)-associated lymphomas are common in Asia and exhibit a poor prognosis. As EBV antigens LMP1 and LMP2 are often expressed in EBV-associated lymphomas, these lymphomas should be a good target for antigen-specific cytotoxic T lymphocyte (CTL) therapy. However, CTLs continuously exposed to viral or tumor antigens often become exhausted. Antigen-specific CTLs generated from induced pluripotent stem cells are functionally rejuvenated, showing a strong antitumor effect on EBV-associated lymphomas and persistence in vivo. For feasible "off-the-shelf" therapy, we generated allogeneic EBV-specific CTLs in the cell processing center and prepared them for actual use in clinical settings.

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

BACKGROUND: There 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. METHODS: We 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. RESULTS: We 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. CONCLUSION: We identified four ENKTL markers (ZNF141, FCGR2C, NES and CDC27) in patients with extranodal NK/T-cell lymphoma.

Autologous EBV-specific T cell treatment results in sustained responses in patients with advanced extranodal NK/T lymphoma: results of a multicenter study.

We conducted a phase II clinical trial to develop an autologous EBV-specific T cell product (baltaleucel T) for advanced, relapsed ENKTL. Among 47 patients who provided whole blood starting material for manufacturing the product, 15 patients received a median of 4 doses of baltaleucel T. Thirty-two (68%) patients did not receive baltaleucel-T due to manufacturing failure, rapid disease progression, and death. Of the 15 patients, 10 patients had measurable disease at baseline (salvage cohort), and 5 patients had no disease at baseline assessment (adjuvant cohort). In the 15 patients, the median follow-up duration was 10.2 months (range 2.0-23.5 months), median progression-free survival (PFS) was 3.9 months, and the median overall survival (OS) was not reached. Patients in the salvage cohort achieved a 30% complete response (CR) and a 50% overall response rate (ORR). In the adjuvant cohort, disease progression was reported in three patients and two patients did not relapse during study follow-up. When we compared survival outcomes of seven responders and eight non-responders, the PFS (P = 0.001) and OS (P = 0.014) of responders proved statistically superior to that of non-responders. Baltaleucel-T was well tolerated. We have performed a phase II clinical trial of autologous EBV-specific T cell treatment (baltaleucel-T) in R/R ENKTL. Autologous EBV-specific T cells were well tolerated and demonstrated single-agent activity in R/R ENTKL.

The optimal timing of radiotherapy in the combination treatment of limited-stage extranodal natural killer/T-cell lymphoma, nasal type: an updated meta-analysis.

This study was designed to explore the relative efficacy and toxicity of upfront radiotherapy (RT) and late RT in combination treatments for patients with limited-stage extranodal natural killer/T-cell lymphoma nasal type (LS-ENKTL). We searched for clinical trials in the PubMed database that compared upfront RT with late RT in the combined treatment of patients with LS-ENKTL. We systematically evaluated the differences in survival, treatment response, and treatment-related adverse events (AEs) between these two groups. Ten retrospective studies with a total of 1752 patients were included. Upfront RT significantly prolonged the overall survival (OS) and progression-free survival (PFS) of patients compared to late RT in combination with chemotherapy (CT) (HR = 0.72, 95% CI 0.59-0.88, P = 0.001 for OS; HR = 0.57, 95% CI 0.41-0.79, P = 0.0007 for PFS). The complete remission (CR) rate in the upfront RT group was superior to that in the late RT group (HR = 1.61, 95% CI 1.09-2.37, P = 0.02). Patients experienced similar local recurrence-free survival (LRFS), objective response rates (ORR), and toxicity between these two arms (P > 0.05 for all) in the analysis of each subgroup. The survival benefit of upfront RT was not correlated with the RT dose, concurrent chemoradiotherapy (CCRT) (or not), or the CT regimen (P > 0.05 for all). Without compromises in terms of toxicity, RT dose, and treatment modality, upfront RT can significantly benefit OS, PFS, and CR compared to late RT in combination treatment. These findings verified that the upfront RT regimen is more suitable for patients with LS-ENKTL.