Natural Killer Cell Lymphoma Research Articles

Inhibition of SRPK1, a key splicing regulator, exhibits antitumor and chemotherapeutic-sensitizing effects on extranodal NK/T-cell lymphoma cells

BackgroundIncreasing evidence has convincingly shown that abnormal pre-mRNA splicing is implicated in the development of most human malignancies. Serine/arginine-rich protein kinase 1 (SRPK1), a key splicing regulator, is reported to be overexpressed in leukemia and other cancer types, which suggests the therapeutic potential of targeting SRPK1.MethodsSRPK1 expression was measured in 41 ENKTL patients by immunohistochemistry and mRNA expression was analyzed by qRT‒PCR. We knocked down SRPK1 expression in the ENKTL cell line YT by siRNA transfection and inhibited SRPK1 using inhibitors (SPHINX31 and SRPIN340) in YT cells and peripheral blood lymphocytes (PBLs) isolated from ENKTL patients to investigate its role in cell proliferation and apoptosis. Then, RNA-seq analysis was performed to predict the potential signaling pathway by which SRPK1 inhibition induces cell death and further verified this prediction by Western blotting.ResultsIn the present study, we initially evaluated the clinical significance of SRPK1 in extranodal natural killer/T-cell lymphoma (ENKTL), a very aggressive subtype of non-Hodgkin lymphoma. The expression of SRPK1 in ENKLT patients was examined by immunohistochemistry and qRT‒PCR, which revealed SRPK1 overexpression in more than 60% of ENKTL specimens and its association with worse survival. Cellular experiments using the human ENKTL cell line YT and PBLs from ENKTL patients, demonstrated that inhibition of SRPK1 suppressed cell proliferation and induced apoptosis. Subsequently, we investigated the downstream targets of SRPK1 by RNA-seq analysis and found that SRPK1 inhibition induced ATF4/CHOP pathway activation and AKT1 inhibition. Furthermore, ENKTL patients presenting high SRPK1 expression showed resistance to cisplatin-based chemotherapy. The association of SRPK1 expression with cisplatin resistance was also confirmed in YT cells. SRPK1 overexpression via pLVX-SRPK1 plasmid transfection dramatically decreased the sensitivity of YT cells to cisplatin, while siRNA-mediated SRPK1 knockdown or SRPK1 inhibitor treatment significantly increased cisplatin cytotoxicity.ConclusionIn summary, these results support that SRPK1 might be a useful clinical prognostic indicator and therapeutic target for ENKTL, especially for patients who relapse after cisplatin-based chemotherapies.

High Efficacy and Drug Synergy of HDAC6-Selective Inhibitor NN-429 in Natural Killer (NK)/T-Cell Lymphoma.

NK/T-cell lymphoma (NKTCL) and γδ T-cell non-Hodgkin lymphomas (γδ T-NHL) are highly aggressive lymphomas that lack rationally designed therapies and rely on repurposed chemotherapeutics from other hematological cancers. Histone deacetylases (HDACs) have been targeted in a range of malignancies, including T-cell lymphomas. This study represents exploratory findings of HDAC6 inhibition in NKTCL and γδ T-NHL through a second-generation inhibitor NN-429. With nanomolar in vitro HDAC6 potency and high in vitro and in cellulo selectivity for HDAC6, NN-429 also exhibited long residence time and improved pharmacokinetic properties in contrast to older generation inhibitors. Following unique selective cytotoxicity towards γδ T-NHL and NKTCL, NN-429 demonstrated a synergistic relationship with the clinical agent etoposide and potential synergies with doxorubicin, cytarabine, and SNS-032 in these disease models, opening an avenue for combination treatment strategies.

CircKIF4A Is a Prognostic Factor and Modulator of Natural Killer/T-Cell Lymphoma Progression.

Simple SummaryCircKIF4A is significantly upregulated in NKTL cell lines and its upregulation correlates with the poor prognosis of NKTL. CircKIF4A regulates PDK1 and BCL11A expressions by sponging miR-1231. Our data indicated that circKIF4A is oncogenic in NKTL and that it is a predictor of poor prognosis of NKTL. Background: Natural killer/T-cell lymphoma (NKTL) is difficult to treat. Circular RNAs (circ RNAs) have been implicated in tumorigenesis. However, the function of circKIF4A in NKTL has not been investigated. Methods: QPCR analysis was used to compare circKIF4A levels in NKTL cell lines versus normal cell lines. Kaplan–Meier survival analysis was used to assess the effect of circKIF4A on the prognosis of NKTL. The correlation between clinicopathological features and circKIF4A expression was examined using cox regression analysis. Luciferase reporter, RNA immunoprecipitation and immunohistochemistry assays were also used to investigate the mechanisms of circKIF4A in NKTL. Results: Our analyses revealed that circKIF4A is significantly upregulated in NKTL cell lines and that its upregulation correlates with the poor prognosis of NKTL. The silencing of circKIF4A significantly suppressed glucose uptake and lactate production in NKTL cells. Moreover, we showed that circKIF4A, PDK1, and BCL11A bind miR-1231 and that circKIF4A regulates PDK1 and BCL11A expressions by sponging miR-1231. Conclusions: During NKTL progression, circKIF4A regulated PDK1 and BCL11A levels by sponging miR-1231. Our data indicated that circKIF4A is oncogenic in NKTL and that it is a predictor of poor prognosis of NKTL.

Sinonasal lymphoma: A primer for otolaryngologists.

Sinonasal lymphomas are a rare entity that commonly present with nonspecific sinonasal symptoms and are often recognized immediately. Through this review, we aim to summarize important principles in diagnosis and treatment of sinonasal lymphomas, with the goal of disseminating the current knowledge of this under-recognized malignancy to otolaryngologists. Systemic review using PRISMA guidelines of foundational scholarly articles, guidelines, and trials were reviewed focusing on clinical characteristics of key sinonasal lymphoma subtypes, along with available treatments in the otolaryngology, medical oncology, and radiation oncology literature. Sinonasal lymphoma are derived from clonal proliferation of lymphocytes at various stages of differentiation, of which diffuse large B-cell lymphoma (DLBCL) and extranodal natural killer/T-cell lymphoma (ENKTL) are the most common. Diagnosis and staging require biopsy with immunohistochemistry in conjunction with imaging and laboratory studies. Treatment is ever evolving and currently includes multi-agent chemotherapy and/or radiation therapy. Otolaryngologists may be the first to recognize sinonasal lymphoma, which requires a comprehensive workup and a multidisciplinary team for treatment. Symptoms are nonspecific and similar to many sinonasal pathologies, and it is crucial for otolaryngologists to keep a broad differential. 5.

CLINICAL OUTCOMES, PROGNOSTIC FACTORS AND THERAPEUTIC MANAGEMENT IN EXTRANODAL NATURAL-KILLER/T-CELL LYMPHOMA, NASAL-TYPE (ENKTL-NT) – RESULTS OF THE MULTICENTER T-CELL BRAZIL PROJECT

Extranodal natural-killer / T-cell lymphoma, nasal-type (ENKTL-NT) is an aggressive, angiocentric, and extensively necrotic malignancy, universally associated with Epstein-Barr virus (EBV) infection. Although highly prevalent in South America, few studies involving cohorts from this region have been published. Brazil is the largest and most populous country in South America, but Brazilian data on ENKTL-NT are extremely scare. In order to fill this gap, the current study aims to describe clinical and laboratory characteristics, assess clinical outcomes, determine predictors of survival and compare responses between different therapeutic modalities applied in a multicenter cohort of Brazilian patients with ENKTL-NT. This is a retrospective, observational and multicenter study, involving 98 patients with ENKTL-NT diagnosed and treated at 20 different Brazilian institutions between January 2000 and December 2021. Endpoints included overall response rate (ORR), overall survival (OS) and progression-free survival (PFS). Survival curves were constructed using the Kaplan-Meier method and the Log-Rank test was used to assess the relationship between variables and outcomes. Univariate analysis was performed using the semi-parametric Cox test and multivariate analysis by Cox regression method or proportional ratios model. The median age was 50 years (IqR 40-58) and 60.2% (59 / 98) were male. Sixty-three percent (62 / 98) had B-symptoms, 26.5% (26 / 98) had ECOG ≥ 2, 16.3% (16 / 98) had extranasal disease, 34.7% had advanced-stage III / IV, and 30.2% (29 / 98) had high-risk PINK score. With a median follow-up of 49.0 months (95% CI: 35.8-62.3), the estimated 2-year OS and PFS were 51.1% (95% CI: 40.4-61.6) and 17.7% (95% CI: 4.5-30.8), respectively. Among early-stage disease (IE / IIE) patients, the estimated 2-year OS were 81.3% (95% CI: 64.8-97.7) for SCRT (sequential chemoradiotherapy) followed by CHOP-like, 53.2% (95% CI: 29.3-77.1) for CCRT (concurrent chemoradiotherapy) followed by VIPD, and 50.5% (95% CI:21.4-79.5) for SCRT followed by asparaginase-based regimens, p = 0.221. CCRT-VIPD was associated with higher early-mortality (p = 0.034), and higher rates of neutropenia (p = 0.075), febrile neutropenia (p = 0.043) and mucositis (p < 0.001). Among advanced-stage (III / IV) disease, the estimated 2-year OS were 37.0% (95% CI: 8.9-65.0) for asparaginase-based regimens and 33.0% (95% CI: 1.9-68.5) for anthracycline-based regimens, p = 0.851. Chemoradiotherapy (CRT) was associated with benefit for OS (p = 0.001) and PFS (p = 0.007) compared to chemotherapy alone. In multivariate analysis, anemia (HR 2.052, p = 0.038), lymphopenia [HR 3.600, p = 0.012], advanced- stage disease (III / IV) [HR 3.101, p = 0.007], bone marrow infiltration [HR 5.406, p = 0.034] and omission of RT in up-front therapy [HR 2.791, p = 0.023] were independent factors associated with decreased survival. High-dose EF-RT proved to be the cornerstone for the treatment of early-stage ENKTL-NT, and omission of this therapeutic modality was associated with decreased OS and PFS in Brazilian patients. In our real-life study, CCRT-VIPD regimen was poorly tolerated, and surprinsingly protocols based on anti-MDR agents were not associated with increased survival either in early- or advanced-stage disease. We also found that anemia, lymphopenia, advanced-stage (III/IV) and bone marrow involvement were independent predictors associated with poor clinical outcomes.

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

Aims: Progression of disease within24 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.

The value of routine bone marrow examination in patients with extranodal NK/T-cell lymphoma staged with PET/CT.

Limited evidence supports the omission of routine bone marrow (BM) examination (biopsy and aspiration) in patients with nasal-type extranodal NK/T-cell lymphoma (ENKTCL). This study was aimed at assessing whether BM examination provides valuable information for positron emission tomography/computed tomography (PET/CT)-based staging in this patient population. Patients newly diagnosed with ENKTCL who underwent initial staging with both PET/CT and BM examination between 2013 and 2020 were retrospectively identified in two Chinese institutions. Overall, 742 patients were included; the BM examination was positive in 67 patients. Compared with BM biopsy alone, the combination of BM biopsy and aspiration assessment did not afford any additional diagnostic value. No patient with a positive BM biopsy was found to have early-stage disease by PET/CT. BM biopsy or PET/CT led to upstaging from stage III to IV as a result of BM involvement in 21 patients. In 135 patients with distant organ involvement, BM involvement was associated with worse overall survival (OS) and progression-free survival (PFS) compared with the corresponding durations in patients without BM involvement (2-year OS: 35.9% vs. 60.4%, p<.001; PFS: 26% vs. 40.7%, p=.003). No difference in survival was noted between groups judged positive based on PET/CT and BM biopsy. Compared with aspiration, BM biopsy led to the detection of more BM lesions. Baseline PET/CT can be safely used to exclude BM involvement in early-stage disease. Overall, routine BM examination affords diagnostic or prognostic value over PET/CT in patients with advanced-stage nasal-type ENKTCL.

TCL-276 Outcome of NK/T-Cell Lymphoma - Retrospective Analysis from a Tertiary Care Cancer Center.

Extra-nodal natural killer (NK)/T-cell lymphoma is a rare, distinctive clinicopathologic entity with an aggressive clinical course. High expression of multidrug-resistant (MDR) P-gp on NK lymphoma cells renders this disease resistant to anthracycline-based chemotherapy regimens. Over the years, based on retrospective analysis and phase II studies, regimens with L-asparaginase and non-MDR drugs have been used. To evaluate the outcome of patients with extra-nodal NK/T-cell lymphoma treated in a tertiary cancer care center in India from 2012 to 2021. Retrospective, observational, single-center study. Hematolymphoid Department, Tata Memorial Hospital. From January 2010 to December 2021, all consecutive patients with NK/T-cell lymphoma were analyzed. Relapse-free survival and overall survival. A total of 78 patients with a diagnosis of extra-nodal NK/T-cell lymphoma were treated from 2010 to 2021. Amongst them, 56 (71.8%) were male, with a median age of 40 years (15-71 years). The most common presenting symptom was nasal swelling (9%), followed by dysphagia (3.8%). B symptoms were present in 35 patients (45%). Only 5% had HLH anytime during the treatment. One-third of the patients had an ECOG performance status >1. Nasal type constituted 80% of the cohort, regional node was involved in 60%, distant node was involved in 28%, 33% had more than 1 extra-nodal site involved, 23% had bulky disease, and 40% had advanced stage (stage 3-4) at presentation. EBV LMP1 was positive in 19 patients (24%). EBERISH was available in 9 patients, of which 7 were positive. Fifteen patients received treatment prior to presentation to our center (CHOP in 10 patients). At our center, the SMILE chemotherapy protocol was administered to 52 patients (66.7%). Consolidative radiation therapy was administered in 43 patients (55.1%). The best radiological response of CR was achieved in 49 patients (62.8%). After a median follow-up of 30 months, 30 (38.5%) patients relapsed and 30 (38.5%) died. Median relapse-free survival was 45 (95%CI: 5.1-84.8) months. Overall survival at 36 months was 53.4% (95%CI: 41.7%-68.4%). The outcome of NK/T-cell lymphoma in our cohort is comparable to the outcomes found in the literature.

High plasma EBV-DNA load and positive EBER status associated with viral recurrence and persistent infection in early treatment of lymphoma.

The relationship between plasma EBV-DNA load (PEDL) and Epstein-Barr virus (EBV)-encoded small RNA (EBER) during the early treatment of lymphoma remains unclear. We explored discrepancies in PEDL and variables associated with EBER and evaluated the consistency between EBER and qualitative analysis of PEDL (qPEDL). Serial measurements of PEDL were performed to determine the dynamic changes of PEDL in early treatment of lymphoma. As a result, the median PEDL of non-Hodgkin's lymphoma NKT cell subtype (NHL-NKT) was higher than that of non-Hodgkin's lymphoma B cell subtype (NHL-B), the median PEDL of extranodal NK/T cell lymphoma (ENKTCL) was higher than that of diffuse large B cell lymphoma (DLBCL), and the median PEDL of EBER positive was higher than that of EBER negative. Age, Ki-67 ≧ 80%, Bcl-2 ≧ 80%, p53, and qPEDL were related to EBER. The PEDL could distinguish NHL-B, DLBCL, NHL-NKT, and ENKTCL from other lymphoma subtypes. EBER-positive patients spent more time with viral "turn negative (TN)" and "continuous positive (CP)" and less time with viral "continuous negative (CN)." The median PEDL of CP was higher than that of TN. In conclusion, although EBER affects the levels of PEDL in general, it has poor concordance with qPEDL. Our results show, for the first time, that high PEDL and positive EBER present a strong association with viral recurrence and persistent infection in the early treatment of lymphoma.

Cutaneous Involvement of Extranodal NK/T Cell Lymphoma, Nasal Type, a Clinical and Histopathological Mimicker of Various Skin Diseases

Background: Extranodal NK/T cell lymphoma, nasal type (ENK/T) with cutaneous involvement has various histopathological findings and diverse clinical manifestations. Methods: A retrospective study of cutaneous involvement of ENK/T lymphoma between 2006 and 2018 was conducted. Results: Twenty-two cases were eligible for this study. Twelve cases could be proven as secondary cutaneous involvement by ENK/T lymphoma, while the remaining could not be confirmed as primary cutaneous ENK/T lymphoma. The histopathological patterns included dermal and subcutaneous nodular infiltration pattern in 11/22 cases (50%), lobular panniculitis pattern in 6/22 cases (27.3%), interface dermatitis pattern in 4/22 cases (18.2%), and granulomatous dermatitis pattern in 1/22 case (4.5%). The median follow-up was 18.3 months. Overall, the one-year and five-year survival rates were 31.3% and 13.3%, respectively. Conclusions: A variety of histopathological patterns of cutaneous involvement by ENK/T lymphoma should be differentiated from other cutaneous lymphomas, dermatitis, and infection. When atypical medium or large-sized lymphoid cells are encountered within skin lesions, pathologists should realize these lesions can be ENK/T lymphoma, especially in cases with coexisting tumor necrosis or angioinvasion. A complete evaluation of the upper aerodigestive tract is mandatory to identify the occult primary site of ENK/T lymphoma before establishing primary cutaneous ENK/T lymphoma.

625MO Combination of mitoxantrone hydrochloride liposome with pegaspargase in patients with extranodal NK/T-cell lymphoma: A phase I/II clinical trial

Extranodal NK/T-cell lymphoma (ENKTCL) remains a high unmet clinical need for improving outcome. This trial aimed to explore the safety, pharmacokinetics (PK) and efficacy of mitoxantrone hydrochloride liposome (PLM60) plus pegaspargase in patients (pts) with ENKTCL.

Integrated driver mutations profile of chinese gastrointestinal-natural killer/T-cell lymphoma.

One of the most common nasal external sites in extranodal Natural Killer/T-cell lymphoma (NKTCL) is in the gastrointestinal (GI) system. Despite this, reports on gastrointestinal-Natural Killer/T-cell lymphoma (GI-NKTCL) are very few. To obtain a better understanding of this manifestation of NKTCL, we conducted a retrospective study on GI-NKTCL to analyze its clinical features, genomic changes and immune infiltration. We retrospectively collected patients diagnosed with GI-NKTCL in the Sixth Affiliated Hospital of Sun Yat-sen University from 2010 to 2020. From this cohort we obtained mutation data via whole exome sequencing. Genomic analysis from 15 patients with GI-NKTCL showed that the most common driving mutations were ARID1B(14%, 2/15), ERBB3(14%, 2/15), POT1(14%, 2/15), and TP53(14%, 2/15). In addition, we found the most common gene mutation in patients with GI-NKTCL to be RETSAT(29%, 4/15) and SNRNP70(21%, 3/15), and the most common hallmark pathway mutations to be G2M checkpoint pathway (10/15, 66.7%), E2F targets (8/15, 53.3%), estrogen response late (7/15, 46.7%), estrogen response early (7/15, 46.7%), apoptosis (7/15, 46.7%) and TNFA signaling via NFKB (7/15, 46.7%). In the ICIs-Miao cohort, SNRNP7-wild-type (WT) melanoma patients had significantly prolonged overall survival (OS) time compared with SNRNP7 mutant type (MT) melanoma patients. In the TCGA-UCEC cohort, the patients with RETSAT-MT or SNRNP7-MT had significantly increased expression of immune checkpoint molecules and upregulation of inflammatory immune cells. In this study, we explored GI-NKTCL by means of genomic analysis, and identified the most common mutant genes (RETSAT and SNRNP70), pathway mutations (G2M checkpoint and E2F targets) in GI-NKTCL patients. Also, we explored the association between the common mutant genes and immune infiltration. Our aim is that our exploration of these genomic changes will aid in the discovery of new biomarkers and therapeutic targets for those with GI-NKTCL, and finally provide a theoretical basis for improving the treatment and prognosis of patients with GI-NKTCL.

Dynamic Prediction of Survival for Sinonasal Extranodal Natural Killer/T-cell Lymphoma.

Extranodal natural killer/ T-cell lymphoma (ENKTL) is a rare malignant tumor. This study aimed to develop a predictive nomogram and a web-based survival rate calculator for dynamically predicting the survival of patients with sinonasal ENKTL (SN-ENKTL). This study investigated patients (n=134) with SN-ENKTL who had been initially treated in our hospital between Jan 2008 and Dec 2016. The patients were randomly divided into training and validation cohorts, in a 7:3 ratio. Independent prognostic factors were identified and integrated to build a predictive nomogram and a web-based calculator using the Cox-regression model. The nomogram was evaluated by consistency index and calibration curve. Age, lactate dehydrogenase, hemoglobin, Epstein-Barr virus DNA, and Ann Arbor stage were identified as independent risk factors. We constructed a predictive nomogram for survival and a web-based calculator (https://taiqinwang.shinyapps.io/DynNomapp/). This study developed a prognostic model and a web-based calculator specifically focused on SN-ENKTL for otolaryngologists to use to facilitate timely treatment decisions for the disease. 4 Laryngoscope, 133:1645-1651, 2023.

EBV-associated NK and T-cell lymphoid neoplasms.

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. 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. 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.

18F-FDG PET/CT Plays a Limited Role in Replacing Bone Marrow Biopsy for Newly Diagnosed Advanced-Stage Patients With Extranodal Natural Killer/T-Cell Lymphoma

PurposeThe role of 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) in evaluating bone marrow (BM) involvement (BMI) among patients with extranodal natural killer/T-cell lymphoma (ENKTL) is poorly understood. This study investigated whether PET/CT could replace bone marrow biopsy (BMB) in treatment-naive ENKTL patients.MethodsNewly diagnosed ENKTL patients (n = 356) who received BMB and PET/CT to evaluate BMI at the time of diagnosis were retrospectively reviewed at West China Hospital between August 2008 and January 2020. The BMI diagnosis was confirmed using BM histology. Clinical characteristics, survival outcomes, and prognostic indicators were summarized and analyzed.ResultsThe cohort included 356 cases, of whom 261 were diagnosed with early-stage and 95 with advanced-stage ENKTL by PET/CT before initial treatment. No early-stage patients were identified with BMI by either BMB or PET/CT. Among the advanced-stage patients, 26 were BMB positive, and 12 of 22 patients (54.5%) with positive PET/BM results were also BMB positive. The sensitivity and specificity of PET/CT to detect BMI were 46% and 97%, respectively. The progression-free survival (PFS) and overall survival (OS) of PET/BM-negative patients were markedly longer (p = 0.010 and p = 0.001 for PFS and OS, respectively), which was consistent with the results of the BMB (p = 0.000 for both PFS and OS).ConclusionAlthough 18F-FDG PET/CT showed the potential to replace BMB in the initial staging of early-stage ENKTL patients, baseline PET/CT cannot provide an accurate BMI evaluation for advanced-stage patients. A prospective study is required to confirm the diagnostic performance of BMI identification by PET/CT, along with targeted BMB and MRI for advanced-stage patients.

The clinical characteristics and prognostic factors of 410 patients with natural killer/T-cell lymphoma.

To investigate the clinical characteristics and prognostic factors of natural killer/T-cell lymphoma (NKTCL). We retrospectively reviewed 410 NKTCL patients admitted to our lymphoma center from 2000 to 2019. Overall survival (OS)and progression-free survival (PFS) were estimated with the Kaplan-Meier method, and the differences between the study groups were compared by the log-rank test. The median age of the 410 patients was 44(range 8-84), and the 5-year OS and PFS were 61.2% and 38.4%, respectively. For patients with stage I/II, the 5-year PFS rate was 57.5%, and the 5-year OS rate was 77.2%. For patients with stage III/IV, the 5-year PFS rate was 17.4%, and the 5-year OS rate was 43.7%. Compared to the patients who received radiotherapy alone or chemotherapy alone as their initial treatment, the patients who received combined chemoradiotherapy had longer PFS (P = 0.013). Independent prognostic factors for OS were stage III/IV (P = 0.001), elevated IPI/aaIPI score (P = 0.019), elevated PINK score (P < 0.001) and elevated plasma EBV-DNA (P = 0.003). An elevated PINK score (P < 0.001) was an independent prognostic factor for PFS. Stage III/IV, elevated IPI/aaIPI score, elevated PINK score and elevated plasma EBV-DNA were independent prognostic factors for OS. Elevated PINK score was an independent prognostic factor for PFS. In stage III/IV patients, the patients who received combined chemoradiotherapy had significantly longer PFS.

Brentuxinmab vedotin, alone or combine with bendamustine in the treatment of natural killer T cell lymphoma.

Natural killer (NK)/T cell lymphoma is a highly aggressive subtype of non-Hodgkin lymphoma. The prognosis of patients with natural killer T cell lymphoma (NKTCL) remains poor. More potent treatment strategies are urgently needed to improve the survival of these patients with R/R NKTCL. CD30 expression has been reported to occur in about 40% of NK/T cell lymphoma. Brentuximab vedotin (BV), a monomethyl auristatin E conjugated CD30 antibody, targets CD30 to kill cancer cells. Therapeutic combination of BV and bendamustine has been shown to be highly effective in Hodgkin lymphoma. We investigated efficacy of BV in treating NKTCL as a single therapy, and in combination with bendamustine in vitro and in vivo. We determined CD30 expression levels in 6 NKTCL cell lines. The efficiency of lymphoma cell inhibition by BV correlates with CD30 expression. We also determined the efficacy of BV in combination with bendamustine and found synergistic effects with bendamustine in NKTCL. Combined BV and bendamustine treatment exerted synergistic antiproliferation effect and enhanced cell apoptotic in vitro and in vivo. Brentuximab vedotin and bendamustine synergistically arrested cell cycle at the G2/M phase in NKTCL cell lines. The combination of BV and bendamustine was demonstrated to synergistically damage DNA in NKTCL. This study provides a reference for possible application on using BV for the treatment of NKTCL, either as a single agent or in combination with bendamustine.

The clinical features, treatment, and prognostic factors for peripheral T-cell lymphomas: A single-institution analysis of 240 Chinese patients.

This study aimed to analyze the clinical features, treatment, survival, and prognostic factors of Chinese patients with peripheral T-cell lymphoma (PTCL) excluding natural killer/T-cell lymphoma (NKTCL). Data on patients with newly diagnosed PTCLs between January 1, 2006 and December 31, 2017 at our hospital were retrospectively reviewed. Patients with NKTCL were excluded. A total of 240 patients were included. PTCL, not otherwise specified (PTCL-NOS), was the most frequent subtype (42.5%), followed by angioimmunoblastic T-cell lymphoma (AITL) (21.3%), anaplastic lymphoma kinase (ALK)-negative anaplastic large-cell lymphoma (ALK-ALCL) (16.7%), ALK-positive ALCL (ALK+ALCL) (10.8%) and others (8.8%). With a median follow-up of 81.1 months, the 5-year progression-free survival (PFS) and overall survival (OS) rates for all patients were 30.4% (95% CI 25.0%-37.0%) and 48.8% (95% CI 42.6%-55.7%), respectively. On multivariate analysis, no consolidative autologous stem cell transplantation (ASCT) and not achieving complete response after first-line chemotherapy retained independently prognostic value for inferior PFS and OS. Besides, bone marrow involvement and serum albumin level were independent factors for PFS, and Eastern Cooperative Oncology Group performance status ≥2 was significantly predictive of inferior OS. Compared with PTCL-NOS, significantly superior PFS and OS were observed for ALK+ALCL and ALK-ALCL. The survival outcomes with current treatment for most PTCL subtypes are still unsatisfactory. Prospective randomized studies are needed to establish the value of consolidative ASCT in PTCL, and novel therapeutic approaches should be explored.

The emerging role of anti-PD-1 antibody-based regimens in the treatment of extranodal NK/T-cell lymphoma-associated hemophagocytic lymphohistiocytosis.

Anti-PD-1 antibody (anti-PD-1 mAb) showed favorable outcomes in some patients with relapsed/refractory (r/r) extranodal NK/T-cell lymphoma (ENKTL). However, the role of anti-PD-1 antibody in NK/T-cell lymphoma-associated hemophagocytic lymphohistiocytosis (NK/T-LAHS) remains unclear. Here, we evaluated the efficacy and toxicity of anti-PD-1 antibody-based treatment in NK/T-LAHS patients. The clinical data of 98 patients diagnosed with NK/T-LAHS at Sun Yat-sen University Cancer Center and the First Affiliated Hospital of Guangdong Pharmaceutical University from May 2014 to November 2021 were retrospectively analyzed. All patients received anti-HLH [HLH-2004 (etoposide, dexamethasone, cyclosporine A) or DEP-based (liposomal doxorubicin, etoposide, methylprednisolone)] regimen and sequential anti-ENKTL chemotherapy (ChT) combined with anti-PD-1 antibody or not. The overall response rate (ORR) of the anti-PD-1 mAb plus ChT regimens was higher than that of the ChT regimens (73.3% vs. 45.5%, P = 0.041). The toxicity of the anti-PD-1 mAb plus ChT regimens was tolerable. Except for higher rate of neutropenia, no significant difference in adverse events (AEs) was observed between the two groups. When the optimal response to anti-ENKTL was achieved, the median EBV DNA levels in patients who received anti-PD-1 mAb plus ChT were significantly lower than patients who received ChT only (878 copies/mL vs. 18,600 copies/mL, P = 0.001). With a median follow-up of 26.6months (range 0-65.9months), the median overall survival (mOS) was 3.5months (95% CI：2.3-4.7months). Patients treated with anti-PD-1 mAb plus ChT experienced a longer mOS than those who received ChT only [5.2months (95% CI: 2.5-7.8months) vs. 1.5months (95% CI: 0.5-2.6months), P = 0.002]. Cox multivariate analysis found that anti-PD-1 mAb was an independent prognostic factor for all NK/T-LAHS patients. In conclusion, anti-PD-1 mAb combined with ChT regimens seemed to be associated with prolonged survival in NK/T-LAHS patients and may represent a potentially promising treatment strategy for this population.

A genomic-augmented multivariate prognostic model for the survival of natural-killer/T-cell lymphoma patients from an international cohort.

With lowering costs of sequencing and genetic profiling techniques, genetic drivers can now be detected readily in tumors but current prognostic models for Natural-killer/T cell lymphoma (NKTCL) have yet to fully leverage on them for prognosticating patients. Here, we used next-generation sequencing to sequence 260 NKTCL tumors, and trained a genomic prognostic model (GPM) with the genomic mutations and survival data from this retrospective cohort of patients using LASSO Cox regression. The GPM is defined by the mutational status of 13 prognostic genes and is weakly correlated with the risk-features in International Prognostic Index (IPI), Prognostic Index for Natural-Killer cell lymphoma (PINK), and PINK-Epstein-Barr virus (PINK-E). Cox-proportional hazard multivariate regression also showed that the new GPM is independent and significant for both progression-free survival (PFS, HR: 3.73, 95% CI 2.07-6.73; p < .001) and overall survival (OS, HR: 5.23, 95% CI 2.57-10.65; p=.001) with known risk-features of these indices. When we assign an additional risk-score to samples, which are mutant for the GPM, the Harrell's C-indices of GPM-augmented IPI, PINK, and PINK-E improved significantly (p < .001, χ2 test) for both PFS and OS. Thus, we report on how genomic mutational information could steer toward better prognostication of NKTCL patients.