Extranodal Natural Killer (NK)/T-cell Lymphoma Research Articles

A novel prognostic model based on ferritin and nomogram-revised risk index could better stratify patients with extranodal natural killer/T-cell lymphoma.

Extranodal natural killer (NK)/T-cell lymphoma (ENKTCL) is an aggressive lymphoma with marked heterogeneity, resulting in a distinct prognosis even in patients with the same disease stage. The nomogram-revised risk index (NRI) has been proposed to stratify patients with ENKTCL. Numerous reports have revealed the prognostic role of serum ferritin in various cancers. We aimed to evaluate the role of NRI in our single cohort of patients with ENKTCL treated uniformly, explore the prognostic value of ferritin, and establish a new prognostic model to better stratify patients with ENKTCL. We included 326 patients with ENKTCL with detailed data regarding clinical characteristics and survival outcomes. All patients were treated with asparaginase-based chemotherapy with or without radiotherapy. Multiple R packages were used to analyze the prognostic factors and derive a novel prognostic model. In the training cohort comprising 236 patients with ENKTCL, NRI significantly correlated with progression-free survival (PFS) and overall survival (p < 0.0001). Using a ferritin level of 400 μg/L as the cutoff value, patients with high ferritin levels had significantly inferior PFS (p=0.00028). Integrating the NRI score and four easily accessible clinical parameters, namely ferritin, hemoglobin, albumin, and D-dimer, a new prognostic model was constructed, stratifying patients with ENKTCL into three risk groups. This new prognostic model was independent of disease stage and NRI and performed better than NRI. Furthermore, this model helped to stratify patients within the same NRI risk groups. Finally, the role of this novel prognostic model was validated in the external validation cohort comprising 90 patients with ENKTCL. Serum ferritin level could be a novel prognostic factor in patients with ENKTCL. The new prognostic model combining NRI and clinical parameters could better predict the prognosis of ENKTCL, thereby warranting further validation and potentially guiding individualized treatment in future prospective clinical trials.

Long-Term Outcomes of Definitive Chemoradiotherapy for Early-Stage Extranodal Natural Killer/T-cell Lymphoma, Nasal Type: A Retrospective Analysis From a Single Center.

Background Nasal extranodal natural killer (NK)/T-cell lymphoma (ENKTL) is a rare type of lymphoma with characteristic histological features. Although radiotherapy can achieve a high response rate, long-term efficacy and safety are yet to be established. Methodology Using electronic health records, we identified relevant patients treated at our hospital from August 2005 to August 2015. We enrolled patients with pathologically confirmed ENKTL treated with curative intent radiotherapy. Results We included 13 patients who underwent definitive radiotherapy in the analysis, comprising 11 males and 2 females and a median age of 53 years (range: 28-73). The median follow-up period was 113.4 months. The overall survival at 5 and 10 years was 92.3% (95% confidence interval [CI]: 57-99 %) and 68.4% (95% CI: 29-89 %), respectively. The most common radiation-related late-term toxicity was sinus disorder (Grade 1-2) in 11 patients (85%). Radiation-related grade 3 to 5 toxicities were not observed. Conclusion The present retrospective study elucidated the long-term safety and effectiveness of curative intent radiotherapy in patients with localized ENKTL.

DNA-Demethylating Agents Combined with Anti-PD-1 Inhibitors Showed Activity in Patients with Relapsed or Refractory Extranodal NK/T Cell Lymphoma Who Have Failed Immunotherapy: An Exploratory Study

Background: Extranodal natural killer (NK)/T-cell lymphoma (ENKTL) is a rare aggressive type of non-Hodgkin's lymphoma associated with Epstein-Barr virus infection. Relapse or refractory (RR)-ENKTL cases are characterized by a high rate of relapse and dismal prognosis with limited therapeutic options. Immune check point inhibitors (ICIs) represent the cornerstone of treatment for RR-ENKTL; however, limited information is available of a rechallenge with ICIs after ICIs are discontinued due to disease progression. Epigenetic aberrations are critical as genetic abnormalities is the hallmarks of ENKTL. One of current promising strategies is that combining epigenetic and ICIs can overcome tumor resistance and enhance immunotherapy responses. Here, we assess the efficacy and safety of DNA methyltransferases inhibitors (DNMTi) plus anti-PD-1 therapy in RR-ENKTL. Methods: This trial enrolled eligible patients with histologically confirmed RR-ENKTL failing from asparaginase-based regimen or ICIs therapy; adequate organ function and bone marrow function; and at least one measurable or evaluable lesion or symptoms. Patients received standard dosage of anti-PD-1 antibodies plus decitabine (10mg/d, d1-5) or azacytidine (100mg/d, d1-5) every 21 days until disease progression, death, intolerable toxicity. Patients accept ASCT as consolidation after they obtained CR. The primary endpoints were objective response rate (ORR) based on Lugano 2016 criteria and clinical benefit rate. Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Adverse events (AEs) were defined according to CTCAE 5.0. Results: From March 2020 to May 2022, 27 eligible patients were enrolled. Median age 40 years (range, 12-77), 15 (55.6%) male, 13 (48.1%) patients with stage IV of disease at screening, 11 (40.7%) patients with PINK-E score ≥ 3 points. Among them, 5(18.5%) patients had no imaging lesions, but all peripheral blood ctDNA were positive, they had high plasma EBV-DNA level(n=3), persistent fever(n=2) associated with ENKTL. The median number of prior systemic therapies was 2 (1-5), 21（77.8%）patients received ≥ 2 lines of prior systemic therapy. Twenty-two (81.5%) patients experienced prior ICIs therapy, 23(85.2%) previously received HDACi. The median time between the last dose of prior ICIs and initiation of this trial was 0.8 months (0.8 -23). Seven (25.9%) patients received decitabine, 20 (74.1%) received azacytidine. Of 22 imaging objective response evaluable patients, 13 (59.1%) achieved response (iORR) including 10 (45.5%) patients with CR (iCR). Clinical benefit analysis of 27 patients showed that clinical response(cORR) was 63.0% (17/27), 14 (59.1%) got CR (cCR). Among 5 patients with positive ctDNA alone, 4 patients achieve clinical improvement ,ctDNA negativity(n=4), EBV clearance(n=2) or fever disappearance (n=2). Among 22 patients previously received ICIs (20 patients previously received anti-PD-1 antibody plus HDACi), of these, 11 (50%) had response. After anti-PD-1 antibodies rechallenge plus DNMTi, iORR and cORR were 58.8% (10/17), 63.6% (14/22), iCR and cCR were 41.2% (7/17), 50.0% (11/22), respectively. Anti-PD-1 antibodies rechallenge plus DNMTi yielded iORR were 72.7% (8/11) and 55.6% (5/9) in patients responded to prior ICIs therapy. The difference of efficacy between decitabine and azacytidine was no significant, iORR and cORR were 60% (3/5), 58.8% (10/17) and 71.4% (5/7), 60.0% (12/20), respectively in this study. The median follow-up time was 12.1 (1.9-28.0) months, 1-year OS rate was 70.4%, median PFS rate was 12.8months. Survival results were similar with decitabine and azacytidine cohort. Sixteen (59.3%) patients reported treatment-related AEs (TRAEs). The most frequently observed (≥10%) TRAEs were lymphopenia (44.4%), neutropenia (37.0%), hypothyroidism (25.9%), nausea (18.5%), hyperglycemia (11.1%). Conclusion: DNMTi combined with anti-PD-1 immunotherapy showed promising efficacy and manageable safety profile in RR-ENKTL for the first time. ICIs rechallenge is still an active and feasible strategy, further prospective studies are needed to clarify the role of rechallenge ICIs in this population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Loss of LEF-1 expression as a diagnostic indicator for extranodal NK/T-cell lymphoma: An immunohistochemical study of 88 cases.

Extranodal natural killer (NK)/T-cell lymphoma (ENKTL) is not a uniform entity but consists of various disease subtypes associated with Epstein-Barr virus (EBV) infection. Lymphoid enhancer binding factor-1 (LEF-1), a member of the T-cell factor/LEF family of transcription factors, plays a significant role in NK-cell and T-cell development. We aimed to explore the expression of LEF-1 in ENKTL and evaluate the applicability of LEF-1 in the diagnosis of ENKTL. The expression of LEF-1 was investigated in tissue samples harvested from patients with ENKTL by immunohistochemistry. LEF-1 staining was not observed in 85 of 88 ENKTL cases (97%). Eighty-six of the 88 cases (98%) were positive for CD56, whereas all the tested cases were negative for both CD16 and CD27. Of the cytotoxic T-cell-like features studied, 81 cases (92%) were negative for CD8, 85 of 88 cases (97%) were immunoreactive for the recombinant linker for activation of T cells (LAT), all (100%) were immunoreactive for TIA-1, 85 (97%) were immunoreactive for granzyme B and 65 (74%) were immunoreactive for perforin. Loss of LEF-1 expression is a highly specific diagnostic indicator of ENKTL.

Clinicopathologic and Genetic Features of Primary T-cell Lymphomas of the Central Nervous System: An Analysis of 11 Cases Using Targeted Gene Sequencing.

Primary central nervous system lymphoma (PCNSL) of peripheral T-cell lineage (T-PCNSL) is rare, and its genetic and clinicopathologic features remain unclear. Here, we present 11 cases of T-PCNSL in immunocompetent individuals from a single institute, focusing on their genetic alterations. Seven cases were subject to targeted panel sequencing covering 120 lymphoma-related genes. Nine of the eleven cases were classified as peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), of which one was of γδT-cell lineage. There was one case of anaplastic lymphoma kinase-positive anaplastic large cell lymphoma and another of extranodal natural killer (NK)/T-cell lymphoma (ENKTL) of αβT-cell lineage. The male to female ratio was 7 : 4 and the age ranged from 3 to 75 years (median, 61 y). Most patients presented with neurological deficits (n=10) and showed multifocal lesions (n=9) and deep brain structure involvement (n=9). Tumor cells were mostly small-to-medium, and T-cell monoclonality was detected in all nine evaluated cases. PTCL-NOS was CD4-positive (n=4), CD8-positive (n=3), mixed CD4-positive and CD8-positive (n=1), or CD4/CD8-double-negative (n=1, γδT-cell type). Cytotoxic molecule expression was observed in 4 (67%) of the 6 evaluated cases. Pathogenic alterations were found in 4 patients: one PTCL-NOS case had a frameshift mutation in KMT2C, another PTCL-NOS case harbored a truncating mutation in TET2, and another (γδT-cell-PTCL-NOS) harbored NRAS G12S and JAK3 M511I mutations, and homozygous deletions of CDKN2A and CDKN2B. The ENKTL (αβT-cell lineage) case harbored mutations in genes ARID1B, FAS, TP53, BCOR, KMT2C, POT1, and PRDM1. In conclusion, most of the T-PCNSL were PTCL-NOS, but sporadic cases of other subtypes including γδT-cell lymphoma, anaplastic lymphoma kinase-positive anaplastic large cell lymphoma, and ENKTL were also encountered. Immunophenotypic analysis, clonality test, and targeted gene sequencing along with clinicoradiologic evaluation, may be helpful for establishing the diagnosis of T-PCNSL. Moreover, this study demonstrates genetic alterations with potential diagnostic and therapeutic utility in T-PCNSL.

Low absolute CD4+ T cell counts in peripheral blood: an independent predictor of inferior survival in natural killer/T-cell lymphoma-a retrospective cohort study.

Lymphopenia at diagnosis is considered a negative prognostic factor for patients with extra-nodal natural killer (NK)/T-cell lymphoma (ENKTL), especially that of the absolute cluster of differentiation 4+ T cell count (ACD4C), which has previously been identified as an independent prognostic factor in other hematologic malignancies. However, there is limited data available regarding the prognostic value of peripheral blood T lymphocyte subsets in ENKTL patients. The purpose of this study was to investigate the prognostic value of lymphocyte subsets, especially the ACD4C in ENKTL as a clinical biomarker. We analyzed the clinical data of 176 patients who met the inclusion criteria in Cancer Center of Integrated Hospital of Traditional Chinese Medicine, Southern Medical University from 2000 to 2018, including baseline clinical factors and ACD4C detected by flow cytometry, and examined the correlation between the results and clinical parameters and long-term outcomes. The complete response rate of the high ACD4C group was 57.6%, which was significantly higher than that of the low ACD4C group (15.1%, P<0.001). The univariate analysis results showed that at a median follow-up time of 58.2 months, patients with a high ACD4C had significantly superior progression-free survival (PFS) and overall survival (OS) (P=0.034 and P=0.001, respectively). The multivariate analysis results revealed that Eastern Cooperative Oncology Group performance status (ECOG PS) and the ACD4C were independent prognostic factors for OS [RR (95% CI): 2.288 (1.209-4.328), P=0.011 and RR (95% CI): 2.058 (1.070-3.968), P=0.031, respectively]. ECOG PS was also an independent prognostic factor for PFS [RR (95% CI): 1.858 (1.064-3.244), P=0.029], while ACD4C tended to be independently correlated with PFS (P=0.085). In this large cohort study, we found that the ACD4C was associated with survival outcomes in ENKTL patients. It is a potential biomarker, which may potentially be applied to clinical.

Review on natural killer/T-cell lymphoma.

Extranodal natural killer (NK)/T-cell lymphoma (ENKTL) is strongly associated with Epstein-Barr virus (EBV) and has a high prevalence in Asian and in Central and South America. About 85% of ENKTLs derive from NK cells and 15% from T-cells. Various factors have been implicated in the development of ENKTL. Molecular pathogenesis of NK/T-cell lymphomas include mutations of genes, involving in the Janus Kinase/signal transducer and activator of transcription pathway, RNA helicase family, epigenetic regulation, and tumor suppression. The relationship between ENKTL and human leukocyte antigen has been demonstrated. Radiotherapy plays a key role in the first-line treatment of early-stage. In stage III/IV diseases, non-anthracycline-regimens-containing L-asparaginase are recommended. Although clinical remission after L-asparaginase-based combination therapy has been achieved in the majority of patients with advanced-stage or relapsed/refractory extranodal NK/T-cell lymphoma-nasal type, the long-term overall survival is still poor. Recently, immunotherapy and new therapeutic targets have gained much attention. In this article, we discuss the pathogenesis, diagnosis, prognostic models and management options of ENKTL.

Interleukin-6 reverses Adriamycin resistance in nasal NK/T-cell lymphoma via downregulation of ABCC4 and inactivation of the JAK2/STAT3/NF-κB/P65 pathway

Chemotherapy is generally effective for extranodal natural killer (NK)/T-cell lymphoma (ENKTCL), nasal type. Nevertheless, multidrug resistance (MDR) remains a key challenge in treating nasal NK/T-cell lymphoma. Interleukin-6 (IL-6) is reportedly an important regulator of MDR in many cancers, implicating a role of IL-6 in the chemotherapy response. However, the effects and mechanism of IL-6 in nasal NK/T-cell lymphoma remain unclear. Herein, we demonstrated that the IL-6 serum level was decreased in nasal NK/T-cell lymphoma patients compared to chronic rhinitis patients. Lower serum levels of IL-6 were closely correlated with Ki67 expression and patient survival. ATP-binding cassette (ABC) drug transporter ABCC4 in patients was abnormally upregulated. IL-6 significantly inhibited resistance to Adriamycin (ADM) in ADM-resistant SNK-6 cells (SNK-6/ADM). Moreover, IL-6 resulted in cell cycle arrest and led to apoptosis in SNK-6/ADM cells. Furthermore, IL-6 decreased ABCC4, p-JAK2, p-STAT3, and phospho-NF-κB p65 expression in SNK-6/ADM cells. IL-6 in combination with ADM inhibited tumor growth and increased the survival of SNK-6/ADM xenograft mice. In conclusion, our findings suggest that IL-6 can inhibit the upregulation of ABCC4 and inactivate the JAK2/STAT3/NF-κB/P65 pathway to sensitize NK/T-cell lymphoma to ADM, indicating that combination therapy with IL-6 and other chemotherapeutic drugs may be effective in reversing acquired resistance in nasal NK/T-cell lymphoma.

Study of Radiotherapy on Extranodal Natural Killer (NK)/T-Cell Lymphoma of Stage IE

In this study, we will examine whether prophylactic cervical node irradiation (PCNI) is necessary for stage IE nasal type Extranodal natural killer (NK)/T-cell lymphoma (ENKTCL) and investigate the survival difference between patients with primary tumors originating from nasal cavity and the Waldeyer ring. From January 2009 to December 2015, 152 pathologically confirmed stage IE ENKTCL patients with nasal cavity and Waldeyer ring primary tumors were retrospectively analyzed. Those patients were divided into three groups according to their primary tumor locations: limited to the nasal cavity (NC group), originating from nasal cavity and invading the Waldeyer ring (NCWR group) and originating from the Waldeyer ring (WR group). All cases were treated with extended-field radiotherapy alone and no PCNI was performed. The overall survival (OS), progression-free survival (PFS) and distant recurrence free survival (DRFS) were obtained after long-term follow-up. Pearson’s chi-square test or Fisher’s exact test was used to analyze the distribution difference of clinical features among the three groups. Univariate and multivariate analyses were performed using the Kaplan-Meier method and the Cox proportional hazards regression. There were 140 cases with primary tumor originating from nasal cavity, including 122 cases in NC group and 18 cases in NCWR group. In addition, there are 12 cases in WR group. For NC group, NCWR group and WR group, the failure rates of cervical lymph nodes were 5.74%, 11.11% and 8.33%. The local recurrence rates were 6.56%, 11.11% and 8.33%. The distant metastasis rates were 11.48%, 22.22% and 41.67%, respectively. There was no significant difference in cervical lymph node failure rates and local recurrence rates among the three groups, but the distant metastasis rates were significantly different (P = 0.014).Survival analyses using Kaplan-Meier method and univariate COX model showed that the three groups had significantly different OS (P = 0.010), PFS (P = 0.019) and DRFS (P = 0.015). OS, PFS and DRFS in NC group was significantly better than those in WR group. However, there was no survival difference in OS, PFS and RFS between the NC group and NCWR group, as well as the NCWR group and WR group. Furthermore, multivariate COX survival analyses demonstrated that the primary site group and ECOG score were independent prognostic factors of OS. And the primary site group and B symptom were independent prognostic factors of PFS and DRFS. Stage IE ENKTCL patients with primary tumors originating from nasal cavity and the Waldeyer ring showed a similar low risk of cervical lymph node recurrence without PCNI, thus there is no need of PCNI for stage IE ENKTCL patients. The main cause of treatment failure was distant recurrence. Moreover, the OS, PFS and DRFS of the Waldeyer ring primary patients were inferior to the nasal cavity primary patients independent from other features, which indicated that they may need more systemic chemotherapy.

CD20-positive extranodal NK/T cell lymphoma: clinicopathologic and prognostic features.

Extranodal natural killer (NK)/T cell lymphoma (ENKTCL) with aberrant CD20 expression is extremely rare. Here, we describe the clinicopathologic features of 11 CD20-positive ENKTCLs from three institutions in China along with a literature review. Membranous expression of CD20 was identified in 1.29% (11/851) of ENKTCLs. CD20-positive ENKTCLs primarily occurred in extra-nasal sites (72.2%, 13/18) rather than in the nasal cavity (27.8%, 5/18). Most evaluated patients (71.4%, 10/14) presented ENKTCL at advanced stage IV. The percentage of CD20-positive tumor cells ranged from 20 to 90%, and the CD20 staining intensity was dimmer in tumor cells than in normal B cells. Among four cases with multiple biopsies, three cases showed discordant expression of CD20 between the disseminated and primary lesions. All evaluated cases were negative for other B cell markers, including PAX5, CD79a, and CD19, except for one case that showed focally positive for CD79a. Patients with CD20-positive ENKTCL more frequently had advanced diseases (stage III/IV: 70% vs 17%, p= 0.001), with older age (median age at diagnosis: 60years vs. 43.5years, p= 0.006) and had inferior outcome (median survival: 18.7moths vs 36.0moths, p= 0.017) compared with CD20-negative cases. Four nonsynonymous single nucleotide variants (C > T) and one stop-gain mutation (C > T) in the exonic region of CD20 gene (MS4A1) were detected in one of seven cases with target region next-generation sequencing. Thus, ENKTCL with aberrant CD20 expression is rare, tends to occur in older patients, and is characterized by a highly aggressive clinical course and poor outcomes. The mechanism underlying the expression of CD20 in ENKTC still remains unknown.

Survival outcomes of patients with extranodal natural-killer T-cell lymphoma: a prospective cohort study from the international T-cell Project

Extranodal natural killer (NK) T-cell lymphoma (ENKTL) is a unique clinicopathological entity, typically associated with poor survival outcomes. Most published data have come from east Asian study groups, with little information available from international cohorts. The effects of treatment advances on routine clinical practice across continental territories has not been clear. We aimed to improve understanding of the clinical characteristics and outcomes of patients with ENKTL. We did a substudy of patients with ENKTL from the T-cell Project, a global prospective cohort study. The T-cell Project registered consecutively diagnosed adults (>18 years) with newly diagnosed, untreated mature T-cell or NK lymphomas (WHO 2001 or 2008 classifications) from 74 centres in 13 countries (in Asia, Europe, North America, and South America). In total, 1695 patients with mature T-cell or NK lymphomas were enrolled between Oct 12, 2006 and Feb 28, 2018 in the T-cell Project. The first patient with ENKTL was enrolled on Feb 15, 2007, and the last on May 26, 2017. Data on baseline characteristics, first-line treatment, treatment response, and survival outcomes were recorded in a central database (locked March 30, 2019). The primary outcome was 5-year overall survival. The T-cell Project is registered on ClinicalTrials.gov, NCT01142674. 166 patients were diagnosed with ENKTL, comprising 11% of 1553 eligible registered cases and distributed across 40 participating centres in four continents. At a median follow-up of 44 months (IQR 20-61), overall survival at 5 years was 54% (95% CI 44-63) in patients with nasal disease (n=98) and 34% (27-46) in patients with extranasal disease (n=68). To our knowledge, this study presents the largest international cohort of patients with ENKTL. We describe a clinically significant improvement in the survival of patients with ENKTL treated in routine clinical practice over the past decade, likely to be attributable to the increasing use of treatment protocols specific for ENKTL. The Fondazione Cassa di Risparmio di Modena, the Associazione Angela Serra per la Ricerca sul Cancro, the Fondazione Italiana Linfomi, Allos Therapeutics, Spectrum Pharmaceuticals, Associazione Italiana per la Ricerca sul Cancro, and the National Cancer Institute at the National Institutes of Health.

The correlation of clinicopathological features and prognosis in extranodal natural killer/T cell lymphoma: a report of 42 cases in the early stage.

This study aimed to explore the clinicopathological features and prognostic correlation of extranodal natural killer (NK)/T cell lymphoma (ENKTCL) in the early stage, screen out the prognostic markers of ENKTCL, and to establish the molecular model of ENKTCL prognosis. A retrospective study was conducted in 88 patients from May 1999 to Dec 2013 in Chinese Academy of Medical Sciences Cancer Hospital, who were diagnosed with ENKTCL according to WHO lymphoid hematopoietic tumor classification (published in 2008). The clinical data and paraffin-embedded tissue blocks were collected. The expressions of CD56, MLH1, PDGFRA, VEGF, PD-L1, PD-1, CyclinD1, p53, and Ki-67 were detected by high-throughput tissue microarray and immunohistochemistry (IHC) staining. The relationship between nine protein expressions and the clinicopathological features and prognosis of patients with ENKTCL were analyzed. The survival time of the 42 patients with complete clinical and follow-up data was 0~153months. The average survival time was 60.1months. The survival rates of 1year, 2years, and 3year were 85.7%, 78.6%, and 71.4%, respectively. Single factor survival analysis showed that the increase of serum lactate dehydrogenase (LDH ≥ 240UI/L) before treatment was associated with poor prognosis, and there was a significant difference in survival rate (P = 0.006). Different therapy methods were related with prognosis (P = 0.011); in specifically, radiotherapy alone had the best treatment effect, followed by concurrent chemoradiotherapy, and the worst was chemotherapy alone. But, multivariate statistics indicated that the LDH level and the treatment approach were not independent prognostic factors of ENKTCL. There was no statistical difference between epidemiological factors such as gender, age, and other clinicopathological factors including tumor location, B symptoms, β2-microglobulin levels before treatment, and prognosis. Survival analysis of single factor showed that the positive expression of PDGFRA and PD-L1 was, respectively, related to the poor prognosis of patients with ENKTCL (P = 0.040, 0.007). The patients with Ki-67 overexpression (≥ 50%) had a worse prognosis than those with lower expression (< 50%), and the difference of survival rate between the two groups has statistical significance (P = 0.038). The expression of CD56, MLH1, VEGF, PD-1, CyclinD1, and p53 has no effect on survival rate (P > 0.05). Multivariate survival analysis showed that the expression levels of PDGFRA, PD-L1, and Ki-67 were independent factors in the prognosis of patients with ENKTCL. And the positive expressions of these three proteins were risk factors for prognosis of patients with ENKTCL (PDGFRA: P = 0.045, HR = 8.265, 95% CI: 1.050-65.054; PD-L1: P = 0.005, HR = 9.369, 95% CI: 1.950-45.003; Ki-67: P = 0.023, HR = 3.545, 95% CI: 1.187-10.585). The elevation of serum lactate dehydrogenase (LDH ≥ 240UI/L) before treatment and the treatment approach were associated with poor prognosis, which could be used as adjunct indexes to the prognosis. However, they were not independent factors for the prognosis of patients with ENKTCL. The expressions of PDGFRA, PD-L1, and Ki-67 were independent factors in the prognosis of patients with ENKTCL and these three proteins were risk factors of prognosis. The above markers combined with clinical factors may establish the prognosis model of ENKTCL.

Pembrolizumab in newly diagnosed EBV-negative extranodal natural killer/T-cell lymphoma: A case report.

Extranodal natural killer (NK)/T-cell lymphoma (ENKTL) is a rare subtype of non-Hodgkin's lymphoma with a dismal prognosis. The pathogenesis almost invariably involves Epstein-Barr virus (EBV) infection, although EBV-negative ENKTLs are frequently reported in the western hemisphere. Treatment of these lymphomas consists of aggressive chemotherapy with dexamethasone, methotrexate, ifosfamide, L-asparaginase and etoposide (SMILE regimen). However, the SMILE regimen is poorly tolerated by elderly patients; therefore, treatment options are limited to palliative radiation and chemotherapy and/or hospice care. Recently, binding of programmed death (PD)-1 with its ligand (PD-L1) expressed on tumor cells was shown to downregulate effector T-cell function and may represent a potent mechanism of immune evasion in classical Hodgkin's lymphoma and aggressive B-cell lymphomas. Thus, targeting PD-L1/PD-1 to inhibit effector T-cell signaling may be a promising therapeutic strategy for these NK/T-cell lymphomas. We herein report the clinical efficacy and feasibility of the anti-PD-1 inhibitor pembrolizumab used concurrently with radiation therapy and as maintenance therapy in an elderly female patient. The findings demonstrated that pembrolizumab may be an effective and well-tolerated treatment for this type of lymphoma.

Clinical presentation, treatment, and outcomes of patients with central nervous system involvement in extranodal natural killer/T-cell lymphoma

Extranodal natural killer (NK)/T-cell lymphoma (ENKTCL) is a rare type of Non-Hodgkin’s lymphoma which rarely metastasizes to the central nervous system (CNS). Ten of 60 patients (16.7%) with ENKTCL followed at Memorial Sloan Kettering Cancer Center (MSKCC) were diagnosed with CNS involvement between 1995 and 2016. Eight patients had systemic disease at the time of CNS diagnosis; one patient never developed systemic disease and another was in remission at the time of CNS relapse. Median overall survival was 3.8 months; at time of this report 9 patients have died and one who underwent autologous stem cell transplant (ASCT) is alive 27 months after CNS diagnosis. Five patients achieved a complete response in the CNS; one is still alive, one died of systemic disease, and three died of infection. CNS ENKTCL portends a grim prognosis, with no standard treatment. Prospective study on ASCT and immunotherapy in CNS ENKTCL is warranted.

Expression of T-cell receptor signalling pathway components in extranodal NK/T-cell lymphoma.

Although the neoplastic cells of extranodal natural killer (NK)/T-cell lymphoma (ENKTL) usually do not express T-cell antigens, the T-cell receptor (TCR) gene might be rearranged and TCR protein expressed. The aim is to elucidate the expression of the downstream TCR pathway components and their importance in ENKTL. We used formalin-fixed paraffin-embedded tissues from 91 ENKTL samples to immunohistochemically characterise the expression of TCR pathway components. The following proteins were variably expressed: ZAP70 (94%; 83/88), GRAP2/GADS (68%; 60/88), DOK2 (42%; 38/90), LCK (35%; 31/88), and ITK (10%; 9/90). When these tumours were classified as being of T lineage (16%), NK lineage (45%), or indeterminate lineage (38%), the GRAP2/GADS expression rate was higher in T lineage tumours (versus NK, P = 0.0073; versus indeterminate, P = 0.00082). GRAP2/GADS-positive NK lineage tumours more frequently expressed DOK2 (P = 0.0073), and were more often confined to the nasal areas (P = 0.014). Furthermore, when these tumours were immunophenotypically classified into a T signature (42%) or NK signature (58%), the expression rates of GRAP2/GADS and ITK were higher in T signature tumours (P = 0.00074 and P = 0.067, respectively), whereas that of LCK was higher in NK-signature tumours (P = 0.10). Although some ENTKL cases were polyclonal for TCR rearrangement and others lacked TCR expression, we speculate that the TCR pathway might be functioning in ENKTLs. A T signature versus a NK signature might be better for delineating the physiology of ENKTL than cellular lineage. Furthermore, ITK may represent a potential therapeutic target for patients with ITK-expressing tumours.

Asparagine synthetase expression is associated with the sensitivity to asparaginase in extranodal natural killer/T-cell lymphoma in vivo and in vitro.

BackgroundAlthough asparagine synthetase (AsnS) is associated with drug resistance in leukemia, its function in extranodal natural killer (NK)/T-cell lymphoma (ENKTL) remains unclear.MethodsThe present study investigated the relationship between baseline AsnS mRNA levels and response to asparaginase in ENKTL cell lines. It also determined whether upregulating or downregulating the AsnS mRNA level induces or reverses asparaginase-resistant phenotype.ResultsInterestingly, considerable differences were observed in the sensitivity to asparaginase of the five ENKTL cell lines. The AsnS expression levels were positively correlated with the IC50 values. In addition, the asparaginase resistance was induced or reversed by upregulating or downregulating the AsnS mRNA level in vivo and in vitro. Functional analyses indicated that AsnS did not affect the proliferation and apoptosis of ENKTL cells in the absence of asparaginase.ConclusionTogether, the data stress the importance of AsnS in the sensitivity to asparaginase in ENKTL and suggest a different therapeutic strategy for patients with a different level of AsnS expression.

Primary pulmonary NK/T-cell lymphoma: A case report and literature review.

Extranodal natural killer (NK)/T-cell lymphoma (ENKTL) is an aggressive disease with poor prognosis. The lung is a relatively rare site of involvement. The current study presents a case of primary pulmonary ENKTL with fever and dyspnea, mimicking pneumonia and initially treated with empirical antibiotics. The patient demonstrated rapid deterioration and died shortly following diagnosis. To the best of our knowledge, large-scale investigations referring to primary pulmonary ENKTL are not available. As a result, the exact incidence and clinical features of primary pulmonary ENKTL are unknown. In the current report, a literature review is presented to discuss the clinical characteristics, diagnosis, treatment, and prognosis factors of this malignant disease.

Correlation between the clinicopathological features and prognosis in patients with extranodal natural killer/T cell lymphoma

ObjectiveTo investigate the correlation between the clinicopathological features and prognosis in patients with extranodal natural killer (NK)/T-cell lymphoma (ENKTCL). MethodsOne hundred and four patients diagnosed with ENKTCL at the Department of Pathology, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China from November 1991 to September 2011 were included in the study. The clinicopathological features and their correlations with disease prognosis were evaluated in these patients. ResultsThe number of effective follow-up cases was 56 (53.8%) by the end of last follow-up in October 2015. Univariate survival analysis showed that granzyme B, perforin, and Bcl-2 expression was significantly associated with a poor prognosis in ENKTCL (P = 0.033, 0.004, and 0.034, respectively), whereas platelet-derived growth factor receptor-alpha (PDGFRA) expression was significantly associated with a better prognosis (P = 0.034). Ki-67 overexpression (≥50%) was significantly associated with a poor prognosis (P = 0.017). Different treatment approaches were also associated with prognosis (P = 0.014); specifically, the efficacies of combination treatments including chemotherapy and radiotherapy, and autologous hematopoietic stem cell transplantation were significantly better than those involving radiotherapy and chemotherapy alone. Patient gender, age, tumor location, staging, the presence of B symptoms, pretreatment lactate dehydrogenase levels, and β2-microglobulin levels were not associated with the prognosis of ENKTCL (P > 0.05). However, multivariate analyses showed that the treatment approach and all the immune markers were not independent prognostic factors for ENKTCL. ConclusionGranzyme B, perforin, and Bcl-2 expression and Ki-67 overexpression (≥50%) might be adverse prognostic factors for ENKTCL, whereas PDGFRA-positivity suggested a better disease prognosis. In addition, different treatment approaches might be closely related to patient prognosis.

Prognostic role of ABO blood type in patients with extranodal natural killer/T cell lymphoma, nasal type: a triple-center study

BackgroundThe prognostic significance of ABO blood type for lymphoma is largely unknown. We evaluated the prognostic role of ABO blood type in patients with extranodal natural killer (NK)/T-cell lymphoma (ENKTL).MethodsWe retrospectively analyzed clinical data of 697 patients with newly diagnosed ENKTL from three cancer centers. The prognostic value of ABO blood type was evaluated using Kaplan–Meier curves and Cox proportional hazard models. The prognostic values of the International Prognostic Index (IPI) and the Korean Prognostic Index (KPI) were also evaluated.ResultsCompared with patients with blood type O, those with blood type non-O tended to display elevated baseline serum C-reactive protein levels (P = 0.038), lower rate of complete remission (P = 0.005), shorter progression-free survival (PFS, P < 0.001), and shorter overall survival (OS, P = 0.001). Patients with blood type O/AB had longer PFS (P < 0.001) and OS (P = 0.001) compared with those with blood type A/B. Multivariate analysis demonstrated that age >60 years (P < 0.001), mass ≥5 cm (P = 0.001), stage III/IV (P < 0.001), elevated serum lactate dehydrogenase (LDH) levels (P = 0.001), and blood type non-O were independent adverse predictors of OS (P = 0.001). ABO blood type was found to be superior to both the IPI in discriminating patients with different outcomes in the IPI low-risk group and the KPI in distinguishing between the intermediate-to-low- and high-to-intermediate-risk groups.ConclusionsABO blood type was an independent predictor of clinical outcome for patients with ENKTL.

Increased body mass index is associated with improved overall survival in extranodal natural killer/T-cell lymphoma, nasal type

Objectives: The role of body mass index (BMI) in lymphoma survival outcomes is controversial. The prognostic significance of BMI in extranodal natural killer (NK)/T-cell lymphoma (ENKTL) is unclear. We evaluated the prognostic role of BMI in patients with ENKTL.Methods: We retrospectively analyzed 742 patients with newly diagnosed ENKTL. The prognostic value of BMI was compared between patients with low BMIs (< 20.0 kg/m2) and patients with high BMIs (≥ 20.0 kg/m2). The prognostic value of the International Prognostic Index (IPI) and the Korean Prognostic Index (KPI) was also evaluated and compared with that of the BMI classification.Results: Patients with low BMIs tended to exhibit higher Eastern Cooperative Oncology Group performance status (ECOG PS) scores (≥ 2) (P = 0.001), more frequent B symptoms (P < 0.001), lower albumin levels (P < 0.001), higher KPI scores (P = 0.03), and lower rates of complete remission (P < 0.001) than patients with high BMIs, as well as inferior progression-free survival (PFS, P = 0.003), and inferior overall survival (OS, P = 0.001). Multivariate analysis demonstrated that age > 60 years, mass > 5 cm, stage III/IV, elevated LDH levels, albumin levels < 35 g/L and low BMIs were independent adverse predictors of OS. The BMI classification was found to be superior to the IPI with respect to predicting patient outcomes among low-risk patients and the KPI with respect to distinguishing between intermediate-low- and high-intermediate-risk patients.Conclusions: Higher BMI at the time of diagnosis is associated with improved overall survival in ENKTL. Using the BMI classification may improve the IPI and KPI prognostic models.