Expression of CD6 in Aggressive NK/T-cell Neoplasms and Assessment as a Potential Therapeutic Target: A Bone Marrow Pathology Group Study.

BACKGROUND: Aggressive NK/T-Cell neoplasms are rare hematological malignancies characterized by the abnormal proliferation of NK or NK-like T (NK/T) cells. CD6 is a transmembrane signal transducing receptor involved in lymphocyte activation and differentiation. This study aimed to investigate the CD6 expression in these malignancies and explore the potential of targeting CD6 in these diseases. MATERIALS AND METHODS: We conducted a retrospective study with totally 41 cases to investigate the expression of CD6 by immunohistochemistry, including aggressive NK-cell leukemia/lymphoma (ANKLL: N = 10) and extranodal NK/T-cell lymphoma (ENKTL: N = 31). A novel ANKLL model was applied for proof-of-concept functional studies of a CD6 antibody-drug-conjugate (CD6-ADC) both in vitro and in animal trial. RESULTS: CD6 was expressed in 68.3% (28/41) of cases (70% (7/10) of ANKLL and 67.7% (21/31) of ENKTL). The median overall survival (OS) for ANKLL and ENTKL cases was 1 and 12 months, respectively, with no significant difference in OS based on CD6 expression (p > 0.05, Kaplan-Meier with log-rank test). In vitro exposure of the CCANKL cell line, derived from an ANKL patient, to an anti-CD6ADC resulted in dose dependent induction of apoptosis. Furthermore, CCANKL engraftment in NSG mice could be blocked by treatment with the anti-CD6 ADC. CONCLUSION: To date, this is the first report to explore the expression of CD6 in ANKLL and ENKTL and confirms its expression in the majority of cases. The in vitro and in vivo data support further investigation of CD6 as a potential therapeutic target in these aggressive NK/T-cell malignancies.

Extranodal natural killer/T-cell lymphoma with tonsil involvement: a case report.

BACKGROUND: Extranodal natural killer/T-cell lymphoma (ENKTL) with tonsil involvement is not common, especially in children. CASE PRESENTATION: A 13-year-old girl presented with an unexplained sore throat for more than 2 months, together with intermittent fever and suppurative tonsilitis. Nasopharyngoscopy revealed a pharyngeal mass. Enhanced computed tomography (CT) scan showed tonsillar hypertrophy and punctate calcification. Chronic pyogenic granulomatous inflammation with pseudoepithelial squamous epithelial hyperplasia was observed in left tonsil, and pyogenic granulomatous inflammation and a small number of T-lymphoid cells were detected in the right tonsil. The immunohistochemical results showed CD2+, CD3+, CD4+, CD5+, CD8+, granzyme B+, and TIA-1+. The Ki-67 proliferation index was 20%. The case showed T cell receptor gene rearrangement. Finally, the case was diagnosed as ENKTL of stage II with tonsil involvement. The patient received 6 cycles of chemotherapy with SMILE regimen, and showed complete response with no recurrence in the follow-up. CONCLUSION: We presented a rare case of ENKTL with tonsil involvement in a child. The patient showed complete response to the SMILE chemotherapy with no recurrence.

A novel prognostic index for extranodal natural killer/T-cell lymphoma in the era of pegaspargase/L-asparaginase.

Aim: This multicenter retrospective study aimed to develop a novel prognostic system for extranodal natural killer/T-cell lymphoma (ENKTL) patients in the era of pegaspargase/L-asparaginase. Materials & methods: A total of 844 newly diagnosed ENKTL patients were included. Results: Multivariable analysis confirmed that Eastern Cooperative Oncology Group performance status, lactate dehydrogenase, Chinese Southwest Oncology Group and Asia Lymphoma Study Group ENKTL (CA) system, and albumin were independent prognostic factors. By rounding up the hazard ratios from four significant variables, a maximum of 7 points were assigned. The model of Huaihai Lymphoma Working Group-Natural killer/T-cell Lymphoma prognostic index (NPI) was identified with four risk groups and the 5-year overall survival was 88.2, 66.7, 54.3 and 30.5%, respectively. Conclusion: Huaihai Lymphoma Working Group-NPI provides a feasible stratification system for patients with ENKTL in the era of pegaspargase/L-asparaginase.

[Box: see text].

Incidence trends for common subtypes of T-cell lymphoma in Taiwan and the United States from 2008-2020.

The incidence of T-cell lymphoma (TCL) has been continually increasing in Taiwan and the United States (US) in recent years. This epidemiological study using population-based registry data aimed to determine the incidence patterns of common subtypes of TCL in Taiwan from 2008-2020 and compare them with those in the US and the Asian/Pacific Islander (API) population. Subtypes included angioimmunoblastic T-cell lymphoma (AITL); extranodal NK/T-cell lymphoma, nasal or other type (ENKTL); peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS); and anaplastic large cell lymphoma (ALCL). The total number of patients newly diagnosed with TCL during 2008-2020 was 4477, 3171, and 48,889 in Taiwan, API, and the US, respectively. Except the incidence rate of AITL in Taiwan, the incidence rates of these common TCL subtypes showed downward trends in all studied populations. There was also a significant increase in the relative frequency of AITL among TCL in Taiwan, with an annual percent change of 4.44 (p < 0.001), from 8.44% in 2002 to 20.63% in 2020. The rapid development of diagnostics may be the main factor contributing to this rise in incidence.

Histone methyltransferase KMT2D inhibits ENKTL carcinogenesis by epigenetically activating SGK1 and SOCS1.

BACKGROUND: Epigenetic alteration plays an essential role in the occurrence and development of extranodal natural killer/T cell lymphoma (ENKTL). Histone methyltransferase (HMT) KMT2D is an epigenetic regulator that plays different roles in different tumors, but its role and mechanism in ENKTL are still unclear. METHODS: We performed immunohistochemical staining of 112 ENKTL formalin-fixed paraffin-embedded (FFPE) samples. Then, we constructed KMT2D knockdown cell lines and conducted research on cell biological behavior. Finally, to further investigate KMT2D-mediated downstream genes, ChIP-seq and ChIP -qPCR was performed. RESULTS: The low expression of KMT2D was related to a decreased abundance in histone H3 lysine 4 mono- and trimethylation (H3K4me1/3). In KMT2D knockdown YT and NK-YS cells, cell proliferation was faster (P < 0.05), apoptosis was decreased (P < 0.05), the abundance of S phase cells was increased (P < 0.05), and the level of H3K4me1 was decreased. Notably, ChIP-seq revealed two crucial genes and pathways downregulated by KMT2D. CONCLUSIONS: KMT2D is a tumor suppressor gene that mediates H3K4me1 and influences ENKTL proliferation and apoptosis by regulating the cell cycle. Moreover, in ENKTL, serum- and glucocorticoid-inducible kinase-1 (SGK1) and suppressor of cytokine signaling-1 (SOCS1) are downstream genes of KMT2D.

Aggressive Biology of Extra-Nodal NK/T Cell Lymphoma: A Case Report.

Extra-nodal NK/T cell lymphoma, nasal type (ENKTL) is a rare and aggressive non-Hodgkin lymphoma primarily seen in Asian and South American populations. Diagnosis involves methods like biopsy and molecular testing, with treatment typically combining systemic and radiation therapy. We present the rare case of a 62-year-old female who was diagnosed with localized ENKTL upon initial presentation of nasal congestion. She was started on radiation therapy and responded favorably at first, with decreased congestion and facial swelling. After five weeks of treatment, she developed significant dysphagia and anorexia, which was initially attributed to being a side effect of chemotherapy. After pausing radiation treatment, her condition worsened until she was hospitalized for obstructive jaundice. CT scans and biopsy confirmed metastasis of the cancer to her pancreas. Her condition rapidly declined until she was ultimately sent to hospice care.

Discovery and biological evaluation of a potent small molecule CRM1 inhibitor for its selective ablation of extranodal NK/T cell lymphoma.

Background: The overactivation of NF-κB signaling is a key hallmark for the pathogenesis of extranodal natural killer/T cell lymphoma (ENKTL), a very aggressive subtype of non-Hodgkin's lymphoma yet with rather limited control strategies. Previously, we found that the dysregulated exportin-1 (also known as CRM1) is mainly responsible for tumor cells to evade apoptosis and promote tumor-associated pathways such as NF-κB signaling. Methods: Herein we reported the discovery and biological evaluation of a potent small molecule CRM1 inhibitor, LFS-1107. We validated that CRM1 is a major cellular target of LFS-1107 by biolayer interferometry assay (BLI) and the knockdown of CRM1 conferred tumor cells with resistance to LFS-1107. Results: We found that LFS-1107 can strongly suppresses the growth of ENKTL cells at low-range nanomolar concentration yet with minimal effects on human platelets and healthy peripheral blood mononuclear cells. Treatment of ENKTL cells with LFS-1107 resulted in the nuclear retention of IkBα and consequent strong suppression of NF-κB transcriptional activities, NF-κB target genes downregulation and attenuated tumor cell growth and proliferation. Furthermore, LFS-1107 exhibited potent activities when administered to immunodeficient mice engrafted with human ENKTL cells. Conclusions: Therefore, LFS-1107 holds great promise for the treatment of ENKTL and may warrant translation for use in clinical trials. Funding: Yang's laboratory was supported by the National Natural Science Foundation of China (Grant: 81874301), the Fundamental Research Funds for Central University (Grant: DUT22YG122) and the Key Research project of 'be Recruited and be in Command' in Liaoning Province (Personal Target Discovery for Metabolic Diseases).

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

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

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

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

Toxicity of a Modified PEG-Asparaginase-Based SMILE Regimen Is Comparable to L-Asparaginase-Based SMILE in a Non-Asian Population.

INTRODUCTION: L-asparaginase-based chemotherapy regimens are effective for treating chemotherapy-resistant natural killer- (NK-) cell neoplasms. To treat these lymphoma subtypes in Asia, where NK/T-cell lymphomas are more prevalent, the NK-Cell Tumor Study Group developed the SMILE regimen, which includes a steroid, methotrexate, ifosfamide, L-asparaginase, and etoposide. In the US however, the only commercially available form of asparaginase is the pegylated form (PEG-asparaginase) which has been incorporated into a modified SMILE (mSMILE). We sought to study the toxicity associated with replacing L-asparaginase with PEG-asparaginase in mSMILE. PATIENTS AND METHODS: We retrospectively identified all adult patients treated with the mSMILE chemotherapy regimen in our database at Moffitt Cancer Center (MCC) between December 1, 2009, and July 30, 2021. Patients were included if they were treated with mSMILE irrespective of their underlying diagnosis. Toxicity was assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 5. The rate of toxicity in our mSMILE treatment group was numerically compared to data published in a metanalysis of the SMILE regimen's toxicity (Pokrovsky et al., 2019). RESULTS: A total of 21 patients were treated with mSMILE at MCC during the 12-year analysis window. Compared to patients receiving the L-asparaginase-based SMILE, patients receiving mSMILE experienced grade 3 or 4 leukopenia less often, with a toxicity rate of 62% (median with SMILE, 85% [95% CI, 74%-95%]); thrombocytopenia, however, was more common, with a toxicity rate of 57% (median with SMILE, 48% [95% CI, 40%-55%]). Other hematological, hepatic and coagulation related toxicities were also reported. CONCLUSION: In a non-Asian population, the mSMILE regimen with PEG-asparaginase is a safe alternative to the L-asparaginase-based SMILE regimen. There is a comparable risk of hematological toxicity, and no treatment-related mortality was seen in our population.

Diagnostic and prognostic value of pretreatment PET/CT in extranodal natural killer/T-cell lymphoma: a retrospective multicenter study.

PURPOSE: The objective of this research was to assess the utility of positron emission tomography combined with computed tomography (PET/CT) to detect bone marrow invasion (BMI) and the predictive value of PET/CT in extranodal natural killer/T-cell lymphoma (ENKTL) patients. PATIENTS AND METHODS: This multicentre study enrolled ENKTL patients who underwent pretherapy PET/CT and bone marrow biopsy (BMB). The specificity, sensitivity, negative predictive value (NPV), and positive predictive value (PPV) of PET/CT and BMB for BMI were evaluated. Multivariate analysis was used to identify predictive parameters for constructing a nomogram. RESULTS: Seven hundred and forty-eight patients were identified from four hospitals, with eighty (10.7%) having focal skeletal lesions on PET/CT and fifty (6.7%) having positive BMB. When BMB is considered as the gold standard, the specificity, sensitivity, PPV, and NPV of PET/CT for diagnosing BMI were found to be 93.8%, 74.0%, 46.3%, and 98.1%, respectively. PET/CT-positive individuals showed significantly worse OS than PET/CT-negative patients in the subgroup of BMB-negative cases. The nomogram model created according to the significant risk factors from multivariate analysis performed well in predicting survival probability. CONCLUSION: PET/CT offers a superior degree of precision for determining BMI in ENKTL. A nomogram model including the parameters of PET/CT can predict survival probability and may help in applying appropriate personalized therapy.

Rational Targets of Therapy in Extranodal NK/T-Cell Lymphoma.

Extranodal NK/T-cell lymphoma (ENKTL) is an aggressive extranodal non-Hodgkin lymphoma (NHL) with poor outcomes, particularly in advanced-stage and relapsed/refractory disease. Emerging research on molecular drivers of ENKTL lymphomagenesis by next-generation and whole genome sequencing has revealed diverse genomic mutations in multiple signaling pathways, with the identification of multiple putative targets for novel therapeutic agents. In this review, we summarize the biological underpinnings of newly-understood therapeutic targets in ENKTL with a focus on translational implications, including epigenetic and histone regulatory aberrations, activation of cell proliferation signaling pathways, suppression of apoptosis and tumor suppressor genes, changes in the tumor microenvironment, and EBV-mediated oncogenesis. In addition, we highlight prognostic and predictive biomarkers which may enable a personalized medicine approach toward ENKTL therapy.

Up-front autologous hematopoietic stem cell transplantation after first complete remission improved prognosis of advanced extra-nodal NKT cell lymphoma: A multicenter real-world study in China.

OBJECTIVES: The advanced extra-nodal NK/T-cell lymphoma (ENKTL) is highly aggressive and lacks effective treatment with a poor prognosis. This study aimed to investigate the effectiveness and safety of autologous hematopoietic stem cell transplantation (ASCT) in CR1. METHODS: Forty of 121 patients with advanced ENKTL from four Chinese hospitals between January 2006 to December 2021 who achieved first complete remission (CR1) and received at least 4 cycles chemotherapy, were enrolled for analysis. Twenty patients received ASCT as up-front consolidation therapy (Group A), and 20 patients only received chemotherapy (Group B). Clinical features, treatment and follow-up information were collected. RESULTS: With a median follow-up of 27 months (range, 4-188 months), the 2-year overall survival (OS) in Group A, 61% (95% CI 37%-85%), was better than that in Group B, 26% (95% CI 2%-50%), p = .018. The 2-year progression-free survival (PFS) was 56% (95% CI 32%-80%) in Group A, 26% (95% CI 2%-50%) in Group B, p = .026. III-IV grade hematological toxicity was the most common adverse event. No treatment-related deaths were observed in both groups. CONCLUSION: Up-front ASCT could improve survival of advanced ENKTL patients in first complete remission, but need be confirmed by a prospective clinical trial.

Establishment and comprehensive analysis of a new human cell line (NK-NJ) with NK-cell characteristics established from extranodal natural killer cell lymphoma/leukemia.

Extranodal NK/T cell lymphoma, nasal type (ENKTL) is an aggressive and heterogeneous disease. With standard treatment containing pegaspargase-based regimen, patients who were resistant to pegaspargase have rapidly disease progression and worse prognosis. Thus, there is an urgent requirement for constructing ENKTL cell line model to explore the mechanism of pegaspargase resistance and new molecular targeted drugs to improve prognosis. We report here on the establishment of a novel ENKTL cell line, NK-NJ. The cells were isolated from a 52-year-old Chinese man who was diagnosed with relapse/refractory (R/R) ENKTL and grow steadily in vitro. The NK-NJ cells express CD56, CD2, CD45RA with no expression of CD3, CD16, CD57, CD4, CD8, CD26, CD28, CD5, TCR, CD45RO and CD161 and showed a TCR gene unrearrangement, which suggested an origin in the NK-lineage but not T-lineage. The immunophenotypes of NK-NJ cells were consistent with the patient. Moreover, short tandem repeat (STR) profiling results also demonstrated that NK-NJ originated from the patient. NK-NJ showed complex karyotype. Target sequencing method indicated that the main mutation genes of the first-time disease progression of lymph nodal were the same as main mutation genes of the primary nasal lesions. Moreover, NK-NJ was recognized as latency I with EBER positivity and carried high EBV-DNA viral load. The chemosensitivity results suggested synthetic lethality of epigenetic drugs and PD-1 inhibitor for ENKTL patients by reasons of epigenetic drugs promoting PD-L1 expression. In conclusion, we established a new ENKTL cell line in the era of new targeted drugs. We hope that this cell line can help to further understand underlying pathogenesis of ENKTL especially for advanced ENKTL and the functional role of EBV in ENKTL pathogenetic process.

18F-FDG PET/CT in extranodal natural killer/T-cell lymphoma: a comprehensive evaluation method.

Extranodal NK/T-cell lymphoma (ENKTL) is an uncommon subtype of non-Hodgkin's lymphoma that is closely related to Epstein-Barr virus (EBV) infection. ENKTL exhibits distinctive clinicopathological features among lymphomas and has poor overall survival in the absence of effective treatment. The timely and accurate diagnosis of ENKTL is crucial for effective treatment and a positive prognosis. 18F-Fluorodeoxyglucose-positron emission tomography/computed tomography (18F-FDG PET/CT) has emerged as an invaluable diagnostic modality for staging, curative effect evaluation, and prognosis analysis in ENKTL. We herein provide a comprehensive overview of the advances in the application of 18F-FDG PET/CT in patients with ENKTL.

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.

Background: 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. Methods: 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. Results: 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). Conclusions: 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.