Natural Killer Cell Lymphoma Research Articles

Outcomes and prognostic factors of patients with Extranodal NK T cell lymphoma (ENKTL)

The staging, prognostication, and treatment of ENKTL has evolved over the years with better understanding of the disease biology. There is significant heterogeneity in the treatment followed across the world. Literature from India have been few with small number of patients. We studied the outcomes and prognostic factors of patients with ENKTL treated between May 2010 and December 2021 at our center. A total of 78 patients diagnosed with ENKTL were treated at our center. L-asparaginase based chemotherapy was administered in 84% of the patients. Close to 2/3rd patients received SMILE chemotherapy. After a median follow-up of 30 months (18.5–41.4 months), the median relapse free survival and overall survival for the overall population was 45 months (12–118 months) and 45 months (14–118 months) respectively. By multivariate analysis, PINK score of 2–4, non-receipt of RT and non-achievement of CR were associated with poor survival.

Diagnostic significance of dysregulated miRNAs in T-cell malignancies and their metabolic roles.

T-cell malignancy is a broad term used for a diverse group of disease subtypes representing dysfunctional malignant T cells transformed at various stages of their clonal evolution. Despite having similar clinical manifestations, these disease groups have different disease progressions and diagnostic parameters. The effective diagnosis and prognosis of such a diverse disease group demands testing of molecular entities that capture footprints of the disease physiology in its entirety. MicroRNAs (miRNAs) are a group of noncoding RNA molecules that regulate the expression of genes and, while doing so, leave behind specific miRNA signatures corresponding to cellular expression status in an altered stage of a disease. Using miRNAs as a diagnostic tool is justified, as they can effectively distinguish expressional diversity between various tumors and within subtypes of T-cell malignancies. As global attention for cancer diagnosis shifts toward liquid biopsy, diagnosis using miRNAs is more relevant in blood cancers than in solid tumors. We also lay forward the diagnostic significance of miRNAs that are indicative of subtype, progression, severity, therapy response, and relapse. This review discusses the potential use and the role of miRNAs, miRNA signatures, or classifiers in the diagnosis of major groups of T-cell malignancies like T-cell acute lymphoblastic lymphoma (T-ALL), peripheral T-cell lymphoma (PTCL), extranodal NK/T-cell lymphoma (ENKTCL), and cutaneous T-cell lymphoma (CTCL). The review also briefly discusses major diagnostic miRNAs having prominent metabolic roles in these malignancies to highlight their importance among other dysregulated miRNAs.

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.

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. 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. 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). 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.

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

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. 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. 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. 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.

Enhanced efficacy of combined fluzoparib and chidamide targeting in natural killer/T-cell lymphoma.

The treatment of natural killer/T-cell lymphoma (NKTCL) presents an onerous challenge, and a search for new therapeutic targets is urgently needed. Poly ADP-ribose polymerase inhibitors (PARPi) were initially used to treat breast and ovarian cancers with BRCA1/2 mutations. Their excellent antitumor efficacy led to a series of clinical trials conducted in other malignancies. However, the exploration of PARPi and their potential use in combination treatments for NKTCL remains unexplored. We treated NKTCL cell lines with fluzoparib (a novel inhibitor of PARP) and chidamide (a classical inhibitor of HDACs) to explore their cytotoxic effects in vitro. Then, their antitumor efficacy in vivo was confirmed in YT-luciferin xenograft mouse models. Fluzoparib or chidamide alone inhibited NKTCL cell proliferation in a dose-dependent manner. Cotreatment with both drugs synergistically induced excessive accumulation of DNA double-strand breaks and massive apoptotic cell death by inhibiting the DNA damage repair pathway, as shown by the decreased protein levels of p-ATM, p-BRCA1, p-ATR, and Rad51. Moreover, the combination treatment apparently increased the level of intracellular reactive oxygen species (ROS) to enhance apoptosis, and pretreatment with an ROS scavenger reduced the proapoptotic effect by 30-60% in NKTCL cell lines. In vivo, this combined regimen also showed synergistic antitumor effects in xenograft mouse models. The combination of fluzoparib and chidamide showed synergistic effects against NKTCL both in vitro and in vivo and deserves further exploration in clinical trials.

Extranodal NK-/T-cell lymphoma, nasal type: what advances have been made in the last decade?

Extranodal NK-/T-cell lymphoma (ENKTCL) is a rare and highly aggressive malignancy with significant racial and geographic variations worldwide. In addition to the formerly "nasal-type" initial description, these lymphomas are predominantly extranodal in origin and typically cause vascular damage and tissue destruction, and although not fully understood, Epstein-Barr virus (EBV) has an important role in its pathogenesis. Initial assessment must include a hematopathology review of representative and viable tumor areas without necrosis for adequate immunohistochemistry studies, including EBV-encoded small RNA (EBER) in situ hybridization (ISH). Positron emission tomography with 18-fluorodeoxyglucose (18F-FDG-PET/CT) for accurate staging is essential, and most patients will have localized disease (IE/IIE) at diagnosis. Apart from other T-cell malignancies, the best treatment even for localized cases is combined modality therapy (chemotherapy plus radiotherapy) with non-anthracycline-based regimens. For advanced-stage disease, l-asparaginase-containing regimens have shown improved survival, but relapsed and refractory cases have very poor outcomes. Nowadays, even with a better understanding of pathogenic pathways, up-front therapy is completely based on chemotherapy and radiotherapy, and treatment-related mortality is not low. Future strategies targeting signaling pathways and immunotherapy are evolving, but we need to better identify those patients with dismal outcomes in a pre-emptive way. Given the rarity of the disease, international collaborations are urgently needed, and clinical trials are the way to change the future.

PARP inhibitor exerts an anti-tumor effect via LMO2 and synergizes with cisplatin in natural killer/T cell lymphoma

BackgroundPARP inhibitor (PARPi), as a kind of DNA damage repair inhibitor, has been shown to be effective in various solid tumors and hematologic malignancies. Natural killer/T cell lymphoma (NKTCL) is a highly aggressive malignancy, the treatment of which has long been a major challenge in the clinic. Here, we investigated the efficacy and mechanism of PARPi, and the therapeutic value of PARPi combined with cisplatin in NKTCL.MethodsThe cell proliferation, cell apoptosis, and cell cycle of NKTCL cells were detected respectively by CCK-8 and flow cytometry. The changes of mRNA expression and protein level were measured respectively by mRNA-sequencing, quantitative real-time PCR, western blotting, and immunofluorescence. LMO2 expression was detected by immunohistochemistry and western blotting. Targeted knockdown of LMO2 was conducted by short hairpin RNA. The tumor xenograft models were established to evaluate the efficacy of drugs in vivo.ResultsPARPi inhibited cell proliferation, promoted cell apoptosis, and induced S-phase cell cycle arrest in NKTCL cells. PARPi led to the accumulation of DNA damage by blocking DNA repair and DNA replication. Additionally, LMO2 deficiency reduced the sensitivity of NKTCL cells to PARPi. Finally, the combination of PARPi and cisplatin exhibited significant synergistic effects both in vitro and in vivo.ConclusionsIn summary, we found that PARPi exerted an anti-tumor effect via LMO2 and synergized with cisplatin in NKTCL, which provides the theoretical basis for the clinical application of PARPi.

Nasal-Type Extranodal Natural Killer/T-Cell Lymphoma Recurrence at Penile Glans Masquerading Urinary Contamination on 18F-FDG PET/CT.

A 69-year-old man with a history of extranodal NK/T-Cell lymphoma, nasal type (ENKTL-NT) performed an interim 18F-FDG PET/CT for response evaluation. It showed an intense focal uptake at his penile glans, which was suspected as urinary contamination initially. However, he complained with redness and swelling of his penis during further history inquiry. After careful observation, the diagnosis of ENKTL-NT recurrence at penile glans was highly suspected. It was confirmed by percutaneous biopsy of the penile glans finally.

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.

Circulating tumor DNA in NK/T and peripheral T cell lymphoma

Natural killer (NK)/T-cell lymphomas (NK/TCL) and peripheral T-cell lymphomas (PTCL) are aggressive hematological malignancies. With the development of next-generation sequencing, circulating tumor DNA (ctDNA) can be detected by several techniques with clinical implications. So far, the effect of ctDNA in pretreatment prognosis prediction, longitudinal monitoring of treatment response and surveillance of long-term remission or relapse in NK/TCL and PTCL has been reported in several researches.

Clinical characteristics analysis of sinonasal diffuse large B-cell lymphoma and extranodal NK/T-cell lymphoma.

Extranodal NK/T-cell lymphoma (ENKL) was the most common sinonasal lymphoma at our hospital. ENKL occurs at a younger age, and is more prevalent in the nasal cavity. ENKL had a lower Ann Arbor stage, and a better prognosis than diffuse large B-cell lymphoma (DLBLC).

Prognostic value of soluble programmed cell death ligand-1 (sPD-L1) in lymphoma: a systematic review and meta-analysis.

Previous studies on the prognostic value of soluble programmed cell death ligand 1 (sPD-L1) in lymphoma patients have yielded inconsistent results. Here, we conducted a meta-analysis and systematic review to investigate the prognostic significance of sPD-L1 in lymphoma, especially in diffuse large B-cell lymphoma (DLBCL) and NK/T-cell lymphoma (NK/TCL). A total of 11 studies with 1185 patients were included in the meta-analysis, and the combined results indicated that high sPD-L1 levels were associated with worse overall survival (OS) (HR=2.27, 95%CI: 1.70-3.04) and progression-free survival (PFS) (HR=2.68, 95%CI: 1.92-3.75). Furthermore, subgroup analysis showed that sPD-L1 remained a significant prognostic factor for OS. The meta-analysis indicated that sPD-L1 may be a potential prognostic biomarker for lymphoma, especially in DLBCL and NK/TCL, and high sPD-L1 levels were associated with worse survival prognosis.

Comparative analysis of upper aerodigestive tract and non-upper aerodigestive tract in NK/T-cell lymphoma.

Nasal or extranasal natural killer/T-cell lymphoma (NKTCL) is a very rare aggressive lymphoma, but it is increasingly diagnosed. To evaluate some specificity by comparative analysis between primary upper aerodigestive tract (UAT) and non-upper aerodigestive tract (NUAT)NKTCL. A retrospective analysis was performed on NKTCL patients from January 2013 to November 2022 in our cancer center. The majority of the lesions were UAT-NKTCL 70 cases (92.1%), the primary NUAT occurred in 6 cases. Patients in the UAT group were mainly in the early stage and in the low and medium risk, while those in the NUAT group were late stage and in high risk (p = 0.000). The expressions of CD3 and TIA-1 in UAT group were higher than those in NUAT group (p = 0.031, p = 0.003), while CD7 was dominant in NUAT group (p = 0.009). For early stage NKTCL, multivariate analysis suggested that gender and PINK score were independent factors affecting PFS and OS (p < 0.05). The 3year OS rate in initial CR group was 90.1% versus 46.4% in non-CR group (p = 0.000). In advanced stage, KI67% and bone marrow involvement were independent factors affecting OS (p = 0.022, p = 0.038). It was difficult to distinguish between UAT and NUAT-NKTCL from histopathology. NUAT-NKTCL patients did have advanced stage and poor outcome. The prognostic value of PINK score and bone marrow involvement was proposed. We aimed to improve initial CR rates, as well as to find new predictive models to predict the whole population.

Preclinical characterization of WB737, a potent and selective STAT3 inhibitor, in natural killer/T-cell lymphoma.

Natural killer/T-cell lymphoma (NKTL) is an uncommon malignancy with poor prognosis and limited therapeutic options. Activating mutations of signal transducer and activator of transcription 3 (STAT3) are frequently found in patients with NKTL, suggesting that targeted inhibition of STAT3 is a potential therapeutic option for this disease. Here, we have developed a small molecule drug WB737 as a novel and potent STAT3 inhibitor that directly binds to the STAT3-Src homology 2 domain with high affinity. In addition, the binding affinity of WB737 to STAT3 is 250-fold higher than STAT1 and STAT2. Interestingly, WB737 is more selective for NKTL with STAT3-activating mutations in terms of growth inhibition and apoptotic induction when compared with Stattic. Mechanistically, WB737 inhibits both canonical and noncanonical STAT3 signaling via suppression of STAT3 phosphorylation at Tyr705 and Ser727, respectively, thereby inhibiting the expression of c-Myc and mitochondria-related genes. Moreover, WB737 inhibited STAT3 more potently than Stattic, resulting in a significant antitumor effect with undetectable toxicity, followed by almost complete tumor regression in an NKTL xenograft model harboring a STAT3-activating mutation. Taken together, these findings provide preclinical proof-of-concept for WB737 as a novel therapeutic strategy for the treatment of NKTL patients with STAT3-activating mutations.

Laryngeal NK/T Cell Lymphoma, Nasal Type: Case Report and Literature Review

Extranodal Natural Killer T-cell lymphoma, nasal type represent a rare and aggressive entity of the non-Hodgkin's lymphomas. Laryngeal localization is rare and has a poor prognosis. We report the case of a 66-year-old patient who consulted for dyspnea, dysphonia and dysphagia. Endoscopic examination revealed an endo-laryngeal lesion. Anatomopathological study with immunohistochemistry concluded to a peripheral T NK/T-cell lymphoma nasal type. The extension workup was without abnormalities. Induction chemotherapy without anthracyclines was administered followed by conformal radiotherapy with intensity modulation in arctotherapy. Significant advances have been made over the past decade including better clarification of clinical heterogeneity, more accurate classification using imaging modalities, establishment of new prognostic models, and sequential use of anthracycline-free radiotherapy and chemotherapy in early stages and risk-adapted first-line treatment strategies in advanced stages.

National population-based analysis of demographics and outcomes of patients diagnosed with extranodal NK/T-cell nasal type lymphoma in the US: Does ethnicity play a role?

e18772 Background: Extranodal Natural Killer/T-cell Lymphoma Nasal Type (ENKTL-NT) in an uncommon malignancy with rising incidence in the United States (US) despite previously being described only in Asia and Latin America (J Oral Maxillofac Pathol PMC3125667 Crit Rev Oncol Hematol PMID33493634). Although primarily occupying the nasal cavity, other locations may be affected, which makes its presentation ambiguous. Diagnosis is important as omitting radiation has been associated with detrimental survival (J Oncol Pract PMID31600462). This is the first national population-based analysis evaluating ethnic differences for Hispanics (HI) diagnosed with ENKTL-NT. Methods: Data were analyzed on ENKTL-NT patients in the US reported to the Surveillance, Epidemiology, and End Results (SEER) database between 2000-2018. Demographic, clinical and survival patterns were analyzed. Kaplan-Meier and Cox regression analyses were used when appropriate. Multivariate analysis and propensity score matching were performed with adjustment for age, stage and B-symptoms. Results: 1,205 patients (HI=409, Non HI (NH)=796) were diagnosed with ENKTL-NT. Male sex predominated in both. HI were diagnosed at younger median age, 43 years (y) vs 59y in NH [p &lt;0.001]. Most of HI and NH were whites 98% vs 58%; however, for NH other races were noted. Most of the patients were diagnosed between 2010-2014. For both, the presence of B symptoms was predominantly unknown. At diagnosis stage I was mainly for HI while unknown stage was most likely noted for NH [p = 0.013]. HI were less likely than NH to receive radiation as part of their treatment, 47% vs 57% respectively [p = 0.003]. Median survival for HI was 1.7y vs 1.2y for NH; survival probability at 2, 5 and 10y for HI corresponded to 0.467, 0.413 and 0.355, while for NH it was 0.444, 0.352 and 0.292, respectively. OS probability at 10y had no statistically significant difference [p = 0.06]. On multivariate analysis, those who were older than 80y and between 60-80y, had worse OS compared to those younger than 60y (HR 2.3 - 95% CI: 1.7 – 3 and 1.2 - 95% CI: 1 – 1.5). Regarding stage, those who were at stage III/IV had worse OS than those at early stage I/II (HR 2.4 -95% CI: 1.7 - 3.2 and HR 3.4 -95% CI: 2.7 - 4.30). Conclusions: This national population-based study identified statistical differences in HI diagnosed with ENKTL-NT. Interestingly, HI were less likely to receive radiation therapy which is the mainstay treatment and key determinant for survival. The fact that there was no statistical difference in survival for HI and NH may underrepresent the improved survival from HI as they are not optimally treated and still living as longer as the NH. Additional research with biological variables should be carried out to better understand this oncological outcome and potentially offer improved targeted treatments for this ethnic minority.

A MULTI‐CENTER RETROSPECTIVE STUDY OF PEMBROLIZUMAB IN PATIENTS WITH RELAPSED OR REFRACTORY EXTRANODAL NK/T‐CELL LYMPHOMA

Background: Extranodal natural killer T-cell lymphoma (ENKTL) is an aggressive malignancy with a dismal prognosis. PD-1 blockade with pembrolizumab has shown promising activity in relapsed/refractory (R/R) ENKTL in case series. Real-world data about the efficacy of pembrolizumab in R/R ENKTL patients are limited. Methods: We performed a multicenter retrospective study to evaluate pembrolizumab efficacy and safety in patients with R/R ENKTL from 10 academic centers in South Korea. Pembrolizumab 100 mg was administered intravenously every 3 weeks. Results: A total of 24 patients were enrolled. The median age was 67 years old (range, 36–87) and 29.2% of patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or greater. Pembrolizumab was administered as 2nd-, 3rd- and 4th or greater line chemotherapy in 9 (37.5%), 9 (37.5%), and 6 (25.0%) patients, respectively, and median 3 cycles (range 1–21) of pembrolizumab were given. In response evaluation, complete remission (CR) and partial response (PR) was achieved in 6 (25.0%) and 3 (12.5%), respectively. The median progression-free survival and overall survival were 2.0 months (95% CI, 0.9–3.0) and 8.0 months (95% CI, 0.0–22.4), respectively. Multivariate analysis indicated that ECOG PS was the only significant predictor of PFS after pembrolizumab treatment (hazard ratio, 5.33; 95% confidence interval, 1.09–26.1; P = .039) Overall, 14 (58.3%) patients experienced adverse events (AEs), with fatigue (n = 7, 29.1%) being the most common Eight patients (33.3%) developed G3-4 AEs, the most frequent of which was neutropenia (4,16.7%) Conclusion: Pembrolizumab could be a therapeutic approach for the control of R/R ENKTL. Keyword: Aggressive T-cell non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.

Influence of Pre-treatment Lymphocyte/Monocyte Ratio and Neutrophil/Lymphocyte Ratio on the Prognosis of Patients with Extranodal NK/T-Cell Lymphoma

To explore the influence of lymphocyte-to-monocyte ratio (LMR) and neutrophil-to-lymphocyte ratio (NLR) on the prognosis of patients with extranodal NK/T cell lymphoma (ENKTL). The clinical data of 203 patients with ENKTL admitted to the First Affiliated Hospital of Zhengzhou University from January 2011 to January 2020 were retrospectively analyzed. The ROC curve determined the limit values of LMR and NLR; Categorical variables were compared using a chi-square test, expressed as frequency and percentage (n,%). Continuous variables were expressed as medians and extremes and compared with the Mann-Whitney U test; Progression-free survival (PFS) and overall survival (OS) of different grouped LMR and NLR patients were analyzed using Kaplan-Meier curves and compared with log-rank tests. The COX proportional risk regression model was used to perform one-factor and multi-factor analysis of PFS and OS. The optimal critical values of LMR and NLR were determined by the ROC curve, which were 2.60 and 3.40, respectively. LMR≤2.60 was more likely to occur in patients with bone marrow invasion (P=0.029) and higher LDH (P=0.036), while NLR≥3.40 was more likely to occur in patients with higher ECOG scores (P=0.002), higher LDH (P=0.008), higher blood glucose (P=0.024), and lower PLT (P=0.010). Kaplan-Meier survival analysis showed that PFS and OS of patients in the high LMR group were significantly better than the low LMR group, while PFS and OS in the low NLR group were significantly better than the high NLR group. The results of multivariate COX analysis showed that EBV-DNA positive (P=0.047), LMR≤2.60 (P=0.014), NLR≥3.40 (P=0.023) were independent risk factors affecting PFS in patients with ENKTL. LMR≤2.60 (P<0.001), NLR≥3.40 (P=0.048), and high β2-MG (P=0.013) were independent risk factors affecting OS in patients with ENKTL. Low LMR and high NLR before treatment are associated with poor prognosis in patients with ENKTL, which also can be used as an easily testable, inexpensive, and practical prognostic indicator in the clinic.

THE OUTCOME OF MODIFIED‐SMILE REGIMEN AS THE FIRST‐LINE TREATMENT FOR NEWLY DIAGNOSED FRAIL ADVANCED HIGH‐RISK NK/T CELL LYMPHOMA: A RETROSPECTIVE OBSERVATION STUDY

Introduction: To explore an effective and well-tolerant treatment for newly diagnosed advanced high-risk extranodal natural killer/T cell lymphoma (NKTCL) patients with poor performance status. We analyzed the efficacy and toxicity of modified-SMILE (dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide) regimen in untreated advanced high-risk NKTCL patients retrospectively. Methods: Ten newly diagnosed advanced high-risk extranodal natural killer/T cell lymphoma (NKTCL) patients with a performance status of 2 were included in Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology from May 2017 to May 2019. At least two cycles of modified-SMILE chemotherapy were administered as the first-line treatment. The primary endpoint was overall survival (OS) and progression-free survival (PFS). The secondary endpoint was the adverse effects of the treatment. Results: A total of 10 patients with newly diagnosed advanced high-risk NKTCL were enrolled, with a median age of 31.5 years (18-57 years). The male: female ratio was 7:3. The performance status of all patients was 2. Seven patients had B symptoms at the initial diagnosis, all presenting as hyperpyrexia. Extranodal organs involvement at the initial diagnosis included nasal cavity (8/10), skin (5/10), bone (4/10), lung (3/10), breast (2/10), pancreas (2/10), liver (1/10), stomach (1/10), intestine (2/10), adrenal glands (1/10) and uterine adnexa (1/10). Bone marrow involvement was present in 3 patients, and the spleen was involved in 2 patients. The prognostic index of NKTCL with Epstein-Barr virus DNA (PINK-E) of all patients was higher than 3. The median OS and PFS were 9 months (2-53 months) and 3 months (1-53 months), respectively. The main adverse effects were hematological toxicities including neutropenia, thrombocytopenia, and decreased fibrinogen. The grade 3/4 neutropenia happened in 2 patients, and the grade 4 thrombocytopenia happened in 1 patient. All toxicities were tolerable. To Mar 2023, the median follow-up period was 9 months (2-53 months), and the median OS was 9 months (2-53 months). Nine patients died and 1 patient survived. Of the 9 patients who died, all patients were diagnosed with Lymphoma-associated haemophilic syndrome (LAHS). Conclusions: The prognosis of advanced high risk NKTCL is very poor because of the poor tolerance to the intensive chemotherapy and the high incidence of LAHS. The modified-SMILE regimen might be an effective and well-tolerance chemotherapy to this intractable condition. Keywords: Chemotherapy, Combination Therapies No conflicts of interests pertinent to the abstract.

CAR-T cells targeting CD38 and LMP1 and anti-tumor activity against NK/T cell lymphoma.

e19529 Background: Natural killer/T-cell lymphoma (NKTCL) is an aggressive lymphoma with poor prognosis. In the past decade, chimeric antigen receptor transduced T (CAR-T) cell therapy has been a promising strategy against hematologic malignancies. Researchers have evaluated the efficacy of CAR-T cell targeting CD38 in multiple myeloma and NKTCL. LMP1 may induce a malignant transformation in B cells and epithelial cells, making it a non-negligible molecule in NKTCL. These suggest the potential clinical administration of CD38 and LMP1 targeting therapy. Methods: Four second-generation CAR-T cells including two single-targeted CAR (CD38-CAR and LMP1-CAR) and two tandem CAR (CD38-LMP1 Tan CAR 1 and Tan CAR 2) were constructed. Then the effects of four CAR-T cells on NKTCL cells were evaluated both in vitro and in vivo. Results: Four CAR-T cells could effectively eliminate malignant target-positive NKTCL cells in vitro. They could be activated and produce inflammatory cytokines in a target-dependent manner. Stimulated by CD38+LMP1+ NKTCL cells, two Tan CAR-T cells produced more IL-13, Granzyme B, IFN-γ and TNF-α than LMP1-CAR-T cells. In vivo test showed that CAR-T cells also exhibit significant anti-tumor effects in a xenotransplant NKTCL mice models. Two Tan CAR-T cells showed higher cytolytic activity against CD38+LMP1+ NKTCL cells than single-targeted CAR-T cells both in vitro and in vivo. Conclusions: We explored the feasibility of CAR-T cell therapy targeting both CD38 and LMP1 molecule. Our results indicated a promising effective therapeutic strategy for NKTCL.