Elevated serum IL-6 and total IgEAb are associated with poor survival in natural killer/T-cell lymphoma.

Natural killer/T-cell lymphoma (NKTCL) is an aggressive and malignant condition with a high mortality rate. Prognostic factors may assist to evaluate the outcome of the disease and may also be useful in selecting appropriate therapeutic strategies for patients. The study aims to describe NKTCL in terms of its clinical features, laboratory examinations, and immunophenotypes and to analyze relevance affecting patient survival outcomes. The patients diagnosed as NKTCL in Jinling Hospital from Jan. 2012 to Dec. 2022 were reviewed retrospectively in this study basing on histopathology. The analysis was performed to evaluate overall survival (OS). A total of 125 NKTCL patients were included, which mainly affected male more than female with the onset median age of 51.00 years old (range, 14 ~ 85 y). NKTCL commonly affects the nasopharynx and upper aerodigestive tract, intestines, and skin. The median overall survival was 13.00 months (range, 2-156 m), and the 5-year survival rate was 9.8%. Under univariable analysis revealed the following factors at diagnosis age: serum total IgEAb ≥ 54.6 IU/mL, IL-6 ≥ 32.445 ng/L, elevated PINK score, smoking, and extranasopharyngeal site were statistically significant predictors for OS. Compared to the patients who received radiotherapy alone or chemotherapy alone, the patients who received combined chemoradiotherapy had longer OS. We found that IL-6 and total IgEAb were significant prognostic factors in NKTCL patients. Also, extranasopharyngeal site was correlated with advanced disease.

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

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

Evidence of cure for extranodal nasal-type natural killer/T-cell lymphoma with current treatment: an analysis of the CLCG database.

Survival from extranodal nasal-type NK/T-cell lymphoma (ENKTCL) has substantially improved over the last decade. However, there is little consensus as to whether a population of patients with ENKTCL can be considered "cured" of the disease. We aimed to evaluate the statistical "cure" of ENKTCL in the modern treatment era. This retrospective multicentric study reviewed the clinical data of 1,955 patients with ENKTCL treated with non-anthracycline-based chemotherapy and/or radiotherapy in the China Lymphoma Collaborative Group multicenter database between 2008 and 2016. A non-mixture cure model with incorporation of background mortality was fitted to estimate cure fractions, median survival times and cure time points. The relative survival curves attained plateau for the entire cohort and most subsets, indicating that the notion of cure was robust. The overall cure fraction was 71.9%. The median survival was 1.1 years in uncured patients. The cure time was 4.5 years, indicating that beyond this time, mortality in ENKTCL patients was statistically equivalent to that in the general population. Cure probability was associated with B symptoms, stage, performance status, lactate dehydrogenase, primary tumor invasion, and primary upper aerodigestive tract site. Elderly patients (>60 years) had a similar cure fraction to that of younger patients. The 5-year overall survival rate correlated well with the cure fraction across risk-stratified groups. Thus, statistical cure is possible in ENKTCL patients receiving current treatment strategies. Overall probability of cure is favorable, though it is affected by the presence of risk factors. These findings have a high potential impact on clinical practice and patients' perspective.

Few and far between: clinical management of rare extranodal subtypes of mature T-cell and NK-cell lymphomas.

While all peripheral T-cell lymphomas are uncommon, certain subtypes are truly rare, with less than a few hundred cases per year in the USA. There are often no dedicated clinical trials in these rare subtypes, and data are generally limited to case reports and retrospective case series. Therefore, clinical management is often based on this limited literature and extrapolation of data from the more common, nodal T-cell lymphomas in conjunction with personal experience. Nevertheless, thanks to tremendous pre-clinical efforts to understand these rare diseases, an increasing appreciation of the biological changes that underlie these entities is forming. In this review, we attempt to summarize the relevant literature regarding the initial management of certain rare subtypes, specifically subcutaneous panniculitis-like T-cell lymphoma, hepatosplenic T-cell lymphoma, intestinal T-cell lymphomas, and extranodal NK/T-cell lymphoma. While unequivocally established approaches in these diseases do not exist, we make cautious efforts to provide our approaches to clinical management when possible.

Prognostic value of prognostic nutritional index on extranodal natural killer/T-cell lymphoma patients: A multicenter propensity score matched analysis of 1022 cases in Huaihai Lymphoma Working Group.

Prognostic nutritional index (PNI), comprised of serum albumin level and lymphocyte count, is associated with the prognosis of several malignant diseases, while the prognostic value of PNI in extranodal natural killer/T cell lymphoma, nasal type (ENKTL) remains unclear. This retrospective multicenter study aimed to investigate the value of PNI in predicting the prognosis of newly diagnosed ENKTL patients by using propensity score matched analysis (PSM). A total of 1022 newly diagnosed ENKTL patients were retrieved from Huaihai Lymphoma Working Group and clinicopathological variables were collected. MaxStat analysis was used to calculate the optimal cut-off points of PNI and other continuous variables. The median age at diagnosis was 47 years and 69.4% were males, with the 5-year OS of 71.7%. According to the MaxStat analysis, 41 was the optimal cut-off point for PNI. The Pseudo R2 before matching was 0.250, and it decreased to less than 0.019 after matching. Confounding factors of the two groups were well balanced after PSM. Multivariable analysis revealed that PNI, Korean Prognostic Index (KPI), eastern cooperative oncology group performance status (ECOG PS), the prognostic index of natural killer lymphoma (PINK) and hemoglobin were independent prognostic factors for ENKTL. The results of subgroup analysis demonstrated that patients with low PNI could predict worse prognosis and re-stratify patients in ECOG PS ≥ 2, EBER-positive, the International Prognostic Index (IPI) (HIR + HR), and PINK (HR) groups. PNI combined with IPI, PINK and KPI could improve the prediction efficiency. In conclusion, PNI could accurately stratify the prognosis of ENKTL by PSM analysis and patients with low PNI had poorer prognosis.

Clinical analysis of patients with primary and secondary extranodal natural killer/T-cell lymphoma of central nervous system.

Extranodal natural killer (NK)/T-cell lymphoma (NKTL) is a rare non-Hodgkin lymphoma that rarely arise exclusively in or metastasizes to the central nervous system (CNS). Globally, CNS involvement of NKTL heralds a serious prognosis and there is no standard treatment. 19 of 414 patients (4.59%) with ENKL followed were diagnosed with CNS involvement between 2006 and 2020. Two patients had primary CNS (PCNS) NKTL, and 17 patients had secondary CNS (SCNS) invasion. A total of 9 patients survived and 10 patients died. The median overall survival time was 55 months, and the median survival time after CNS invasion was 17 months. The 5-year cumulative survival probability was 45.7%. In conclusion, CNS risk evaluation and prophylaxis treatment can be carried out for patients with NK/T-cell lymphoma prognostic index risk group III/IV. In terms of treatment, systemic therapy based on methotrexate combined with radiotherapy and intrathecal chemotherapy can be selected.

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.

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

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

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

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

Extranodal natural killer/T-cell lymphoma nasal type in a western population: Molecular profiling identifies new therapeutic targets.

(A) Correlation matrix of unsupervised co-regulated genes, based on the 208 genes included in the NanoString platform. Some of the clusters of co-regulated genes corresponded to the following: Inflammatory cells; Epstein-Barr virus; B-cells; Cytotoxic T-cells; T-cells; and Proliferation. (B) Analysis of genomic alterations by targeted sequencing. Distribution of mutations in the 62 analyzed genes. Rows correspond to sequenced genes, columns represent individual patients. Color coding: green, missense; blue, synonymous; pink, frameshift; violet, Indel; red, stop gained; yellow, UTR.

EBV-associated NK and T-cell lymphoid neoplasms.

PURPOSE OF REVIEW: Epstein-Barr virus (EBV)-associated neoplasms derived from natural killer (NK) or T cells comprise a group of clinically and biologically heterogenous disorders affecting children and adults, which are overall rare but more prevalent in Asia and South America. This review focuses on neoplasms presenting in the adulthood, addressing recent genomic discoveries as well as therapeutic developments in these highly aggressive disorders. RECENT FINDINGS: Distinct molecular subtypes of extranodal NK/T-cell lymphomas (ENKTCLs) have been described, with differences in cell of origin, EBV pattern, genomic alterations, clinical characteristics, response to asparaginase-based therapies and to more recent approaches targeting molecular aberrations of the lymphoma. For the last two decades, progress in the clinical management of ENKTCL was based on L-asapraginase containing combinations and the incoroperation of radiotherapy. A subset of cases with PDL1-2 structural alterations may be more responsive to treatment with immune checkpoint inhibitors. Primary nodal EBV+ lymphomas derived from T or NK cells have distinctive features separating them from both peripheral T-cell lymphoma not otherwise specified and ENKTCL. Treatment algorithms correspond to those for advanced ENKTCL. SUMMARY: With better understanding of lymphomagenesis, genomic landscape and immunologic aspects of the diseases, future treatment options will include targeted therapies including immune checkpoint inhibitors and novel antibodies.

The value of prognostic nutritional index in nasal-type, extranodal natural killer/T-cell lymphoma.

Extranodal natural killer/T-cell lymphoma (ENKTL) is an aggressive disorder with heterogeneous clinical characteristics and poor prognosis. The combined value of baseline serum albumin level and absolute peripheral lymphocyte count showed prognostic information in a variety of malignancies, but its evidence is limited in ENKTL. The purpose of this study is to evaluate the impact of prognostic nutritional index (PNI) in ENKTL, and to provide some nutritionally and immunologically relevant information for better risk stratification. We conducted a retrospective study in 533 patients newly diagnosed with ENKTL. The PNI was calculated as albumin (g/L) + 5 × lymphocyte count (109/L). The optimal cutoff values for serum albumin and lymphocyte count were 40.6 g/L and 1.18 × 109/L, respectively, and 47.3 for PNI. After a median follow-up of 70 months, the 5-year overall survival (OS) and progression-free survival (PFS) were 56.2% and 49.5%, respectively. Patients in low PNI group had more unfavorable clinical features, and tended to have worse 5-year OS and PFS compared with those in high PNI group. According PNI-associated prognostic score, patients were classified into different risk groups. Significant difference has been found in 5-year OS and PFS in different risk groups. When PNI and PNI-associated prognostic score were superimposed on the International Prognostic Index (IPI), prognostic index of natural killer lymphoma (PINK), or nomogram-revised risk index (NRI) categories, the PNI and PNI-associated prognostic score provided additional prognostic information. Therefore, PNI and PNI-associated prognostic score could be independent prognostic factors for ENKTL and may be useful for risk stratification and clinical decision-making.

Nomograms to predict progression of disease within 24 months in patients with localized natural killer/T-cell lymphoma.

Aims: Progression of disease within 24 months (POD24) is associated with poor survival in some subtypes of lymphoma.The aim is to identify high-risk patients with localized extranodal natural killer/T-cell lymphoma (ENKTL) and to define clinical factors associated with the risk of early recurrence after antitumor treatment. Methods: The authors retrospectively analyzed 330 cases with localized ENKTL, of which 89 experienced POD24. Results: The 5-year overall survival of the POD24 group was extremely inferior to that of the non-POD24 group. Risk factors for POD24 were Eastern Cooperative Oncology Group performance status ≥2, response evaluation (non-complete remission) after first-line treatment and elevated lactate dehydrogenase concentrations. Also, higher Epstein-Barr virus DNA titer was related to POD24. Based on these data with or without the availability of Epstein-Barr virus DNA, the authors conducted two nomograms to predict POD24, which showed good accuracy with high C statistics. Conclusion: The results showed that POD24 could serve as a marker to identify patients whose medical needs were unmet in ENKTL.

Does the primary tumor site in stage I extranodal natural killer/T-cell lymphoma matter?

The purpose of this study was to investigate whether the primary tumor site in stage I extranodal natural killer/T-cell lymphoma (ENKTCL) had a prognostic value. Between January 2009 and December 2015, 152 stage I ENKTCL patients with primary disease in the nasal cavity and Waldeyer's ring were enrolled for this retrospective study. All patients received extended field intensity-modulated radiotherapy alone without prophylactic cervical node irradiation at a total dose of 50 Gy. In this study, there were 122 patients whose primary tumors were localized in the nasal cavity (NC group), and no adjacent structures were involved. A total of 18 patients had a primary disease involving the nasal cavity and Waldeyer's ring (NC-WR group), and the remaining 12 patients had primary tumors confined to Waldeyer's ring (WR group). We found that there was no significant difference in cervical lymph node failure rates among the NC, NC-WR, and WR groups. In terms of the 5-year overall survival (OS) rates, there was a significant difference among the NC, NC-WR, and WR groups (p=0.004), with the WR group having the worst OS. Multivariate analyses showed that the primary site (p=0.011) and ECOG (Eastern Cooperative Oncology Group) score (p=0.013) were independent prognostic factors for OS. In summary, patients with stage I ENKTCL had a good local control rate with radiotherapy alone and without prophylactic cervical node irradiation (PCNI), regardless of the site of the primary tumor. So, we think PCNI for stage I ENKTCL patients is not necessary. Patients with a primary tumor site located in Waldeyer's ring had the worst prognosis. And combined treatment with radiotherapy and chemotherapy should be considered in patients with primary tumors located outside the nasal cavity.

[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.

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.

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.

Outcome after hematopoietic stem cell transplantation in patients with extranodal natural killer/T-Cell lymphoma, nasal type: A French study from the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC).

We evaluated the outcome of 65 French patients with Extranodal NK/T-cell lymphoma, nasal type (ENKTL) undergoing hematopoietic stem cell transplantation (HSCT) (19 allogeneic and 46 autologous). Fifty-four patients (83%), most of which receiving L-asparaginase (L-aspa) containing regimens (81%), achieved complete or partial response at time of HCST. After a median follow-up of 79.9 months, 4-years progression-free survival (PFS) and overall survival (OS) were similar in both autologous and allogeneic groups (PFS: 34% vs. 26%, p = .12 and OS: 52% vs. 53%, p = .74). Response status at HSCT was the major independent prognostic factor on survival (OS: HR: 4.013 [1.137; 14.16], p = .031 and PFS: HR: 5.231 [1.625; 16.838], p = .006). As compared to control patients receiving chemotherapy and/or radiotherapy containing regimens only, upfront HSCT did not improve the outcome of responder patients, including those treated by L-aspa. However, it tends to provide survival benefit for relapsed patients with initial high-risk clinical features who achieved second remission. Whereas the place of HSCT in upfront therapy has still to be clarified, these data confirm that HSCT should be considered for consolidation in selected patients with relapsed ENKTL. Based on a large non Asian ENKTL cohort since the L-aspa era, this study provides some insight into the survival patterns of ENKTL patients with HSCT in the Western hemisphere and may give future direction for the next clinical trial design.

Advances in the treatment of extranodal NK/T-cell lymphoma, nasal type.

Extranodal natural killer/T-cell lymphoma, nasal type (ENKL) is a subtype of mature T- and natural killer cell lymphomas characterized by its association with Epstein-Barr virus and extranodal involvement. Although there is geographic variance in the frequency of ENKL, its clinical features are similar between Western countries and endemic areas, such as East Asia. Anthracycline-containing chemotherapy is not recommended to treat ENKL. No standard treatment has been established based on the results of randomized controlled trials. In patients with localized disease, radiotherapy is a core component of the recommended first-line therapy. Radiotherapy administered at 50 to 54 Gy, extended involved-site radiotherapy considering tumor invasiveness, and the use of intensity modulated radiation therapy or volumetric modulated arc therapy are associated with efficacy of radiotherapy. Although the use of concurrent chemoradiotherapy has been supported by the results of clinical trials, accumulating evidence supports the use of sequential chemoradiotherapy with non-anthracycline-containing regimens that include l-asparaginase and/or platinum anticancer agents. l-asparaginase-containing chemotherapy is a key component of first-line treatments for systemic ENKL. Hematopoietic stem cell transplantation is recommended as a front-line consolidation therapy for newly diagnosed advanced-stage ENKL. Newer agents including immune checkpoint inhibitors are being investigated for treating ENKL. In this modern ENKL treatment era, multidisciplinary efforts are needed to identify the best timing and sequencing of radiotherapy, l-asparaginase, platinum, newer agents, and hematopoietic stem cell transplantation.

Long-term eradication of extranodal natural killer/T-cell lymphoma, nasal type, by induced pluripotent stem cell-derived Epstein-Barr virus-specific rejuvenated T cells in vivo.

Functionally rejuvenated induced pluripotent stem cell (iPSC)-derived antigen-specific cytotoxic T lymphocytes (CTL) are expected to be a potent immunotherapy for tumors. When L-asparaginase-containing standard chemotherapy fails in extranodal natural killer/T-cell lymphoma, nasal type (ENKL), no effective salvage therapy exists. The clinical course then is miserable. We demonstrate prolonged and robust eradication of ENKL in vivo by Epstein-Barr virus-specific iPSC-derived antigen-specific CTL, with iPSC-derived antigen-specific CTL persisting as central memory T cells in the mouse spleen for at least six months. The anti-tumor response is so strong that any concomitant effect of the programmed cell death 1 (PD-1) blockade is unclear. These results suggest that long-term persistent Epstein-Barr virus-specific iPSC-derived antigen-specific CTL contribute to a continuous anti-tumor effect and offer an effective salvage therapy for relapsed and refractory ENKL.