Natural Killer Cell Lymphoma Research Articles

Single-Cell Analysis Reveals Malignant Cells Reshape the Cellular Landscape and Foster an Immunosuppressive Microenvironment of Extranodal NK/T-Cell Lymphoma.

Extranodal natural killer/T-cell lymphoma (NKTCL) is an aggressive type of lymphoma associated with Epstein-Barr virus (EBV) and characterized by heterogeneous tumor behaviors. To better understand the origins of the heterogeneity, this study utilizes single-cell RNA sequencing (scRNA-seq) analysis to profile the tumor microenvironment (TME) of NKTCL at the single-cell level. Together with in vitro and in vivo models, the study identifies a subset of LMP1+ malignant NK cells contributing to the tumorigenesis and development of heterogeneous malignant cells in NKTCL. Furthermore, malignant NK cells interact with various immunocytes via chemokines and their receptors, secrete substantial DPP4 that impairs the chemotaxis of immunocytes and regulates their infiltration. They also exhibit an immunosuppressive effect on T cells, which is further boosted by LMP1. Moreover, high transcription of EBV-encoded genes and low infiltration of tumor-associated macrophages (TAMs) are favorable prognostic indicators for NKTCL in multiple patient cohorts. This study for the first time deciphers the heterogeneous composition of NKTCL TME at single-cell resolution, highlighting the crucial role of malignant NK cells with EBV-encoded LMP1 in reshaping the cellular landscape and fostering an immunosuppressive microenvironment. These findings provide insights into understanding the pathogenic mechanisms of NKTCL and developing novel therapeutic strategies against NKTCL.

Pembrolizumab for Patients with Relapsed or Refractory Extranodal NK/T-Cell Lymphoma in Korea.

Programmed death-1 blockade with pembrolizumab has shown promising activity in relapsed/refractory (R/R) extranodal natural killer/T-cell lymphoma (NKTCL), but studies are limited, with small patient numbers. Thirteen institutes involved with the Consortium for Improving Survival of Lymphoma, a Korean lymphoma study group, collected the clinical data of 59 patients treated with pembrolizumab as salvage therapy between 2016 and 2022. The median age of the patients was 60 years (range, 22 to 87 years), and 76.3% had advanced Ann Abor stage disease. Pembrolizumab was given to 35.6%, 40.7%, and 23.7% of the patients as second-, third-, and fourth- or higher-line chemotherapy, respectively. The overall response rate was 40.7%, with 28.8% having complete response. The estimated 2-year progression-free survival (PFS) and overall survival rates for all patients were 21.5% and 28.7%, respectively; for responders, the rates were 53.0% and 60.7%, respectively. Although not statistically significant, Eastern Cooperative Oncology Group performance status ≥ 2 (hazard ratio [HR], 1.91; 95% confidence interval [95% CI], 0.93 to 3.94; p=0.078) and stage III or IV disease (HR, 2.59; 95% CI, 0.96 to 6.96; p=0.060) were associated with a trend toward shorter PFS in multivariate analysis. Grade 3 or 4 adverse events (AEs) were noted in 12 patients (20.3%); neutropenia (10.2%), fatigue (6.8%), and pneumonitis (5.1%) were most common AEs. In conclusion, while pembrolizumab had a modest effect on patients with R/R NKTCL, it may be a useful salvage therapy for patients with localized disease and good performance status.

Phase 2 Clinical Trial of Simultaneous Boost Intensity Modulated Radiation Therapy With 3 Dose Gradients in Patients With Stage I-II Nasal Type Natural Killer/T-Cell Lymphoma: Long-Term Outcomes of Survival and Quality of Life

The aim of this study was to investigate the treatment results and long-term quality of life in patients with early-stage extranodal natural killer/T-cell lymphoma who were prospectively treated with simultaneous boost intensity modulated radiation therapy (SIB-IMRT) with 3 dose gradients. Sixty patients with stage I-II nasal cavity natural killer/T-cell lymphoma (NKTCL) and Waldeyer's ring NKTCL were enrolled in a single-arm, prospective, phase 2 clinical trial from August 2011 to April 2015. All patients were treated with definitive radiation therapy combined with short-course induction chemotherapy. A newly designed SIB-IMRT scheme was uniformly adopted, with 54.6 Gy for the gross tumor volume (GTV) of the primary tumor and GTV of the positive lymph nodes, 50.7 Gy for the high-risk clinical target volume (CTV), and 45.5 Gy for the low-risk CTV, all delivered in 26 daily fractions. Before SIB-IMRT, L-asparaginase-based induction chemotherapy was used in 95.0% (57/60) of patients. With a median follow-up time of 95.8 months, the 5-year locoregional recurrence-free survival, progression-free survival, and overall survival rates were 83.3%, 81.7%, and 88.3%, respectively. Dosimetric analysis in the first 21 patients showed satisfying conformality for planning target volume of GTV, high-risk CTV, and low-risk CTV, while the organs at risk were well protected. The results of long-term quality-of-life investigations in patients without progression were favorable, and nasal discomfort was the most common symptom. No grade 3 or 4 acute or late toxicities were observed. The scheme of target volume delineation and dose setting that we designed has favorable clinical effects with mild side effects in treating patients with stage I-II nasal cavity NKTCL and Waldeyer's ring NKTCL.

Efficacy and Safety Analysis of Combination Therapy Based on Liposomal Mitoxantrone (Lipo-MIT) in Relapsed/Refractory NK/T-Cell Lymphoma

Background: Currently, there is no standard treatment for relapsed/refractory NK/T-cell lymphoma (NKTCL), which is characterized by highly aggressive and poor prognosis. New drugs are urgently needed to improve the therapeutic effect. Liposomal mitoxantrone (Lipo-MIT) is approved in China for the treatment of relapsed or refractory peripheral T-cell lymphoma patients who have received at least one line standard therapy previously. Phase II study data showed that the objective response rate (ORR) of patients after monotherapy was 41.7% and the complete response rate (CR) was 23.1%. Progression-free survival (PFS) was 8.5 months. Lipo-MIT showed excellent anti-tumor effect in patients with NKTCL subtype, with an ORR of 42.9%, which broke the limitation of natural resistance of NKTCL to anthracyclines. To further improve the efficacy, we tried a combination therapy based on Lipo-MIT in patients with relapsed/refractory NKTCL. Herein we will report its efficacy and safety. Methods: Nine patients with relapsed/refractory NKTCL were enrolled in this study, all of whom had previously received pegaspargase-based combination chemotherapy. The salvage treatment was a combination regimen based on Lipo-MIT. The efficacy was evaluated after every 2 cycles using PET-CT or MRI scan, and hematological and non-hematological adverse events were collected after treatment. Progression-free survival (PFS) was defined as the time from initiation of Lipo-MIT to disease progression, recurrence, death, or last follow-up. Overall survival time (OS) was defined as the time from initiation of Lipo-MIT to death from all causes or the last follow-up. Results: The median age of the nine patients was 53 years old (17-67 years old), and the male-female ratio was 7:2. Eight patients had stage IV NKTCL, one was stage II NKTCL, and all patients had an NRI score of ≥3. The median number of previous treatment lines was 2 (1-4). Three patients had recurrent NKTCL, and six patients had refractory disease to previous treatments, among whom two patients had concurrent hemophagocytic syndrome. The salvage treatment regimens were as follows: Lipo-MIT + pegaspargase + dexamethasone (N=3); Lipo-MIT + pegaspargase + dexamethasone +PD1 monoclonal antibody (N=2); Lipo-MIT +PD1 monoclonal antibody + dexamethasone (N=2); Lipo-MIT + etoposide + pegaspargase + dexamethasone (N=2). Efficacy was evaluable in all patients and the median number of treatment cycles was 3 (2-6). The best response rates were as follows: complete response in 3 (33.3%) patients, partial response in 4 (44.4%) patients, stable disease in 1 (11.1%) patient, and progressive disease in 1 (11.1%) patient. At a median follow-up of 4 months (2-13 months), 6 patients died, including 5 from disease progression and 1 from pegaspargase -associated acute pancreatitis, with a median PFS of 5 months and a median OS of 7 months. One patient underwent allogeneic hematopoietic stem cell transplantation after achieving a complete response and has been disease-free for more than 13 months now. The main adverse reactions of Lipo-MIT combination regimen were grade 3 or more bone marrow suppression (N=7), skin cyanosis (N=4), liver insufficiency (N=4), coagulation dysfunction (N=4), acute pancreatitis (N=1). The median recovery time from myelosuppression was 17 days (6-35 days). There was no correlation between skin cyanosis and efficacy. Conclusion: Combination therapy based on Lipo-MIT has a high remission rate for relapsed/refractory NKTCL, but the duration of remission needs to be further extended, and subsequent allogeneic hematopoietic stem cell transplantation may prolong survival. Lipo-MIT has obvious myelosuppression toxicity, and active supportive therapy should be given when combined with other cytotoxic drugs. In the future, it is worthwhile to conduct prospective clinical trials to explore the optimal combination therapy based on Lipo-MIT in relapsed/refractory NKTCL.

Combination of Mitoxantrone Hydrochloride Liposome with Tislelizumab in Patients with Relapsed or Refractory NK/T Cell Lymphoma: A Phase Ib/Ⅱ Clinical Trial

Background : Extranodal NK/T cell lymphoma (ENKTL) is a highly aggressive malignancy associated with Epstein-Barr virus (EBV) infection, and remains a high unmet clinical need for improving prognosis. Mitoxantrone hydrochloride liposome (PLM60) is a nano-drug that has been approved as the first treatment option for relapsed/refractory (r/r) PTCL, and has shown certain efficacy and safety in a pivotal phase Ⅱ study. Tislelizumab is a humanized immunoglobulin G4 variant monoclonal antibody against PD-1. This trial aims to investigate the safety and efficacy of combining PLM60 with tislelizumab in patients (pts) with r/r ENKTL. Methods: Pts with r/r ENKTL were recruited in this ongoing, prospective, multicenter, open-label phase Ib/Ⅱ study (NCT05464433). Phase Ib was 3+3 design with two dose levels of PLM60 (d1, 16 mg/m 2 and 20 mg/m 2) plus tislelizumab 200 mg (d1, Q4W) induction therapy for up to 6 cycles, then tislelizumab 200 mg (Q3W) to continue maintenance therapy until disease progression, discontinuation, withdrawal or one year of therapy (including induction therapy period). Phase II was a dose expansion at the recommended phase II dose (RP2D). The primary endpoints were to assess the tolerability (i.e. dose-limiting toxicity (DLT)) and explore RP2D of PLM60 in phase Ib, and the objective response rate (ORR) of phase II. Secondary endpoints were complete response (CR) rate, ORR, disease control rate (DCR) and safety of phase Ib, and DCR, progression-free survival (PFS), overall survival (OS) and safety of phase II. Results: At data cut-off on 11 July 2023, 13 eligible pts were enrolled (phase Ib, n=6 and phase II, n=7). 6 pts of phase Ib were evaluable for response with a median age of 29.5 (range, 22-47) years, and 5 pts (83.3%) were ECOG 1. 3 pts (50.0%) had advanced stage III or IV (Ann Arbor). No DLT occurred at 16 mg/m 2 and 20 mg/m 2in phase Ib study. RP2D was PLM60 20 mg/m 2 plus tislelizumab 200 mg. The CR rate, ORR and DCR were 33.3% (2/6, 95% CI 4.3%-77.7%), 100.0% (6/6, 95% CI 54.1%-100.0%) and 100.0% (6/6, 95% CI 54.1%-100.0%), respectively. At data cutoff, the phase II study is being enrolled. Overall, the 11 pts evaluated in phase Ib and phase II had an ORR of 81.8% (9/11) (Figure 1). Furthermore, a decrease in EBV viral load was observed during treatment with PLM60 and tislelizumab except for one pt who experienced viral load rebounded and disease progression after 3 cycles of therapy (Figure 2). With a median follow-up of 2.1 (range, 1.0-5.6) months currently, the median PFS and OS will be reported after long-term follow-up. Treatment-related adverse events (TRAEs) of any grade occurred in all 13 enrolled pts, in which 7 (53.8%) pts were grade 3/4. The common grade 3/4 TRAEs were leucopenia (38.5%), neutropenia (30.8%), lymphocyte count decreased (30.8%), thrombocytopenia (7.7%), alanine aminotransferase increased (7.7%) and diarrhea (7.7%). Three patients had treatment delayed because of AEs. Moreover, no adverse cardiac events occurred during this study. Conclusions: PLM60 plus tislelizumab proves an encouraging efficacy in r/r ENKTL pts with manageable safety profiles.

Efficacy and Safety of Chemotherapy (DDGP vs VIPD) Followed Radiotherapy Vs Radiotherapy Followed Chemotherapy (DDGP vs VIPD) Vs Radiotherapy Alone for Newly Diagnosed Early Stage Extranodal Natural Killer/T Cell Lymphoma: Final Results of a Prospective, Multicenter, Randomized, Controlled Clinical Trial

Background: Extranodal Natural Killer/T Cell Lymphoma (ENKTL) is a highly aggressive form of non-Hodgkin lymphoma (NHL), primarily found in Asia and commonly linked to Epstein-Barr virus (EBV) infection. Despite the treatment efficacy for early stage ENKTL has been improved in recent years, there is no consistent approach for clinical treatment. Current guidelines includes radiotherapy (RT) alone, concurrent chemoradiation therapy (CCRT), sequential chemoradiation, and sandwich chemoradiation. Here we present the final results of the efficacy and safety of sequential therapies of DDGP (dexamethasone, cisplatin, gemcitabine, and pegaspargase) regimen or VIPD (etoposide, ifosfamide, cisplatin and dexamethasone) regimen combined with RT, and RT alone. M ethods: We conducted a prospective, multicenter, randomized, controlled clinical trial to compare the efficacy and safety of sequential chemotherapy (DDGP vs VIPD regimen) followed by RT, sequential RT followed by chemotherapy, and RT alone in eligible patients with newly diagnosed stage I/II ENKTL. Upon study entry, patients were randomized 1:1:1:1:1 to receive either DDGP regimen followed by RT (DDGP+RT), or VIPD regimen followed by RT (VIPD+RT), or RT followed by DDGP regimen (RT+DDGP), or RT followed by VIPD (RT+VIPD), or RT alone. Patients assigned to the DDGP group were administered cisplatin (20 mg/m 2, intravenous, days 1-4), dexamethasone (15 mg/m 2, intravenous, days 1-5), gemcitabine (800 mg/m 2, intravenous, on days 1 and 8), and pegaspargase (2500 IU/m 2, intramuscular, on day 1). Those in the VIPD group received etoposide (100 mg/m 2, intravenous, days 1-3), ifosfamide (1.2 g/m 2, intravenous, days 1-3), cisplatin (33 mg/m 2, intravenous, days 1-3), and dexamethasone (40mg, intravenous, days 1-4). Both the DDGP and VIPD regimens were repeated every 21 days. For the sequential chemotherapy followed by RT group, patients underwent 3 cycles of either DDGP or VIPD regimen, followed by 50 Gy (2 Gy * 25 times) of intensity modulated radiotherapy (IMRT). In the sequential RT followed by chemotherapy group, patients were first given 50 Gy (2 Gy * 25 times) of IMRT and then sequential either DDGP or VIPD regimen. Meanwhile, the RT alone group received 50 Gy (2 Gy * 25 times) of IMRT only. The primary end point of our study was progression free survival (PFS), with secondary end points including complete remission rate (CRR), objective response rate (ORR), overall survival (OS). R esults: Our study, spanning January 2011 to August 2020, involved 244 patients from 22 centers across China, with 200 randomly assigned to receive treatment (40 in each group). Both the demographic and disease characteristics of the patients at baseline were generally consistent across all treatment groups. During a median follow-up of 72.1 months, the median PFS (mPFS) was not reached in neither the DDGP + RT nor RT + DDGP groups, compared to 36.3 months in the VIPD + RT group, 78.3 months in the RT + VIPD group, and 89.6 months in the RT alone group. The 5-year PFS rates for the DDGP + RT, VIPD + RT, RT + DDGP, RT + VIPD, and RT alone groups were 81.5%, 46.1%, 79.8%, 53.1%, and 57.5% respectively. Similarly, the 10-year PFS rates were 81.5%, 42.8%, 74.1%, 45.9%, and 45.7% respectively. Compared with RT alone, PFS was improved in DDGP + RT group (p = 0.006) and RT + DDGP group (p = 0.024). Compared with VIPD + RT, PFS was improved in DDGP + RT group (p = 0.006) and RT + DDGP group (p = 0.026). Either between DDGP +RT and RT + DDGP group or between VIPD +RT and RT +VIPD group, PFS showed no differences. Median OS was not reached in 5 groups. OS showed no differences in 5 groups (p = 0.27). The patients who failed from either VIPD regimen or RT alone received DDGP regimen. This might be the reason why the OS showed no differences between 5 groups. The CRRs of 5 groups (DDGP + RT, VIPD +RT, RT + DDGP, RT +VIPD, RT alone) were 87.5%, 57.5%, 82.5%, 69.2%, and 67.5%, respectively. Similarly, the ORRs were 97.5%, 77.5%, 90.0%, 74.4%, and 87.5%, respectively. Conclusions: The DDGP regimen exhibited promising outcomes in this randomized clinical trial for newly diagnosed early-stage ENKTL patients. The sequential therapies with DDGP regimen could improve the efficacy compared with RT alone. Patients could also benefit more from therapies with DDGP regimen than those with VIPD regimen. The order in which chemotherapy and RT were applied has no fatal impact on the prognosis of early-stage ENKTL.

Predictors of Outcome for Allogeneic Stem Cell Transplantation with a Reduced Intensity Pentostatin/TBI Conditioning Regimen in T-Cell Lymphomas: A Single Center Experience

Background: Allogeneic hematopoietic stem cell transplantation (alloSCT) is a potential curative option for patients with relapsed/refractory T-cell lymphoma (TCL).A reduced intensity conditioning (RIC) regimen of infusional pentostatin and 6 Gy of total body irradiation (TBI) has been shown to be well-tolerated and to have favorable engraftment kinetics 1. We utilized this regimen for patients with aggressive TCL undergoing alloSCT due to the demonstrated activity of pentostatin as a single agent in TCL and its potential impact, along with TBI, on eradicating residual TCL. Methods: This retrospective review includes adult patients with Nodal TCL (PTCL , AITL, ALCL), rare aggressive TCL [(T-ALL, natural killer/T-cell lymphoma (NKTL), adult T-cell leukemia/lymphoma (ATLL), and subcutaneous panniculitis-like T-cell lymphoma (SPTCL)], and T-Prolymphocytic leukemia (TPLL) who underwent alloSCT between 2006 and 2021. The primary objective was to determine transplant related outcomes including grade 3-4 acute graft-versus-host disease (aGVHD), extensive chronic GVHD (cGVHD), relapse, non-relapse mortality (NRM), and overall (OS), relapse-free (RFS), and GVHD-free, relapse-free survival (GRFS) following transplant. A subgroup analysis was conducted to evaluate the impact of disease status at the time of transplant and other factors, including age and subtype of TCL. Results: We report results for 40 patients (Nodal TCL: 21, Rare aggressive TCL: 10, T-PLL: 10) with a median age of 56.6 years ( range 24-71). Seventy-five percent were in clinical CR at the time of transplant. The 1-y cumulative incidence rate (CIN) of aGVHD was 42.5%. The 3-y CIN for cGVHD was 22.9. The median OS was 3.18 years with a 3-y OS rate of 51.9%. The median RFS was 1.24 years, with a 3-year RFS rate of 41.4%. OS and RFS were significantly higher in patients <65 compared to ≥65 (p-value 0.050 and 0.010 respectively), with no difference between the complete response (CR) and non-CR groups or different subtypes of TCL. The median GRFS was 0.52 years, with a 3-year GRFS rate of 20%. There was no statistically significant difference in GRFS or the incidence of GVHD between groups. Renal toxicity was noted in 10 patients. No cases of pulmonary or central nervous system (CNS) toxicities were observed. By day 100, 15 patients had an infection, including 8 bacterial infections and 5 viral infections. A total of 12 patients had reactivation of cytomegalovirus. Twelve patients died within the first year: 4 from relapse, 3 from aGVHD, 3 from infection, 1 from a subdural hematoma after a fall, and 1 from bladder perforation in the setting of hemorrhagic cystitis. Of 13 patients who relapsed, all received salvage therapy and 3 received DLI. Four are alive and in remission. Conclusions: In patients with TCL, RIC for alloSCT was well tolerated and compared favorably with retrospective data from larger groups of patients from CIBMTR and EBMT who were transplanted with different regimens 2. Interestingly, transplant-related outcomes were similar for patients with CR vs partial response (PR) at the time of transplant, and outcomes were better in patients younger than 65. Relapsed patients had a poor outcome despite salvage therapy with only a 30% OS at 3 years. 1. Foss et al, Transfusion 2020 2. Hamadani et al, Blood Advances 2022

Ksd-101 in Patients with EBV-Associated Hematologic Neoplasms: Results from an Ongoing Phase I Clinical Study

Background: The Epstein-Barr Virus (EBV), which has been confirmed by WHO as the first human tumor-associated virus, is a lifelong carrier once infected. EBV-associated Hematologic Neoplasms seriously threats human health, with rapid disease progression, poor prognosis, easy to relapse, and high mortality rate. KSD-101 is a First-in-class autologous dendritic cell (DC) vaccine which is developed to control EBV-associated hematological diseases. Autologous DCs were loaded with the EBV-transformed B-LCL (B-Lymphoblastoid Cell Line) lysates which contains a broad-spectrum EBV antigen to prepare KSD-101 for the treatment of EBV-associated diseases. Methods: In this study, patients (pts) with EBV-associated Hematologic Neoplasms who fail to respond to or relapse after conventional treatment will be recruited and undergo leukapheresis to collect autologous peripheral blood mononuclear cell (PBMC). The enriched monocytes will be induced to differentiate into DCs and prepared as KSD-101 after loading with EBV-transformed B-LCL. Pts will undergo monotherapy with KSD-101, without the need for pre-treatment of lymphodepletion or prophylactic medication. Administration route of KSD-101 is subcutaneous injection, once every 2 weeks for 3-5 vaccinations in total. The study used a 3+3 dose-escalation design. Safety assessment is conducted according to NCI-CTCAE 5.0 grading criteria. The primary objective is to assess the tolerability and safety of KSD-101 in the treatment of EBV-associated Hematologic Neoplasms, explore the dose-limiting toxicities (DLT) and the maximum tolerated dose (MTD). The secondary objective is to explore the clinical efficacy and immune responses of KSD-101 in the patients with EBV-associated Hematologic Neoplasms. Results: As of July 2023, 9pts were enrolled in the study and 8 pts DC vaccine preparations were completed. Three pts were injected 5.0 × 10 6 cells/dose without exploring any DLT. The first two pts in the second dose level were injected 7.5 × 10 6 cells/dose. However, the third pt in second dose level was injected 5.0 × 10 6 cells/dose due to insufficient apheresis collection. Based on the safety and preliminary efficacy data, we decided not to proceed with dose-escalation to the third dose group. In the expansion phase, all pts were injected with a dose of 5.0 × 10 6 cells. Currently observed KSD-101-related toxicities were pyrexia (grade ≤ 2), injection site reactions (grade 1), and lymphadenopathy (grade 1). In all the pts who were injected, neither DLT nor MTD were explored. Based on the comprehensive considerations of safety, efficacy and easibility, we propose that the most appropriate dose is 5.0 × 10 6 cells. Of all pts enrolled, one was excluded due to hemophagocytic lymphohistiocytosis (HLH), among whom 4 pts completed the 12-week follow-up after the first injection for clinical and laboratory assessments. The results showed an overall response rate (ORR):100%, complete response (CR):100%, including 1 case of AITL (EBV infected T, B, NK),1case of CAEBV (EBV infected T, NK),2cases of NK-T cell lymphoma (1 EBV infected B, NK, and the other EBV infected NK). After vaccinations, the total number of lymphocytes of these four pts increased by 1.5 to3.4 times, including 1.6 to 4.2 times of T cells, 2.1 to 6.5 times of activated T cells (CD3 + HLA -DR +), 1.4 to 5.0 times of CD8 + T cells, 1.2 to 3.7 times of CD4 + T cells, 1.7 to 2.0 times of NK cells, and 1.2 to 32.4 times of B cells; meanwhile, the proportion of EBV-specific CTLs increased significantly (ranging from a 2.51% to 4.16% increase), and the proportion of Tregs significantly decreased compared with the baseline (ranging from a 32.49% to 73.81% reduction). Conclusions：Our current study shows that KSD-101 has excellent safety and good preliminary efficacy against EBV-associated Hematologic Neoplasms with efficient induction of immune responses. The results indicate that KSD-101 is a promising therapeutic reagent for the treatment of EBV-associated Hematologic Neoplasms. Larger prospective studies and longer follow-up time is needed to be conducted.

338P Multicenter real-world study of advanced-stage non-nasal type NK/T cell lymphoma (NKTCL): Clinical features, treatment and prognosis

338P Multicenter real-world study of advanced-stage non-nasal type NK/T cell lymphoma (NKTCL): Clinical features, treatment and prognosis

Comparative analysis of clinicopathologic characteristics and prognosis between nasal and nonnasal extranodal NK/T-cell lymphoma.

The clinicopathologic characteristics and prognosis of nasal and nonnasal extranodal natural killer T-cell lymphoma (ENKTL) are considered to be different. However, the underlying features responsible for these differences are not well clarified especially in the era of asparaginase therapy. In total, 1007 newly diagnosed ENKTL patients from 11 medical centers were included in this study. Clinicopathologic characteristics and survival data were collected. The chi-squared test and Kruskal-Wallis test were utilized for the comparison of different groups. Univariable and multivariable Cox proportional hazards models were used to screen prognostic factors. Overall, 869 (86.3%) patients were nasal forms. Compared to patients with nasal ENKTL, nonnasal patients were at more advanced stages and had poor performance status, bone marrow involvement, elevated serum lactate dehydrogenase (LDH), and CD56-negative status (p < 0.05). The 5-year overall survival (OS) for nasal and nonnasal patients were 65.6% and 45.0%, respectively. The OS of nasal forms patients were superior to nonnasal patients, especially in Eastern Cooperative Oncology Group performance status (ECOG PS) (≥2), advanced stage, KPI (HIR/HR), IPI (HIR/HR), PINK (HR), and high EBV DNA load groups. In patients treated with pegaspargase/L-asparaginase-based regimens, the OS of nasal patients was better than that of nonnasal patients. After adjusting the covariates of age, stage, ECOG PS score, LDH, B symptoms, and BM involvement, results showed that the nonnasal site was associated with poor survival of ENKTL. The clinicopathologic characteristics and prognosis of nasal and nonnasal ENKTL patients are different. Nasal forms patients had superior OS than nonnasal patients, especially in the era of asparaginase.

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

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

A case of extranodal NK/T-cell lymphoma, nasal type, diagnosed by scraping cytology of the maxillary gingiva.

Extranodal NK/T-cell lymphoma (ENKTL), nasal type, is often seen in the head and neck region, but there have been rare instances of this disease with initial presentation as a lesion in the oral mucosa. The patient, a woman in her seventh decade of life, presented with an ulcer in the maxillary gingiva, and scraping cytology and biopsy were performed. Cytological specimens showed solitary or small aggregating cells with marked atypia in a necrotic background. Tumor cells were detected that had various nuclear shapes and azure granules in the cytoplasm. Biopsy showed that the tumor cells had diffusely infiltrated or interdigitated into the subepithelium. Immunohistochemistry revealed that the tumor cells had T- and NK cell phenotypes and were Epstein-Barr virus-encoded small RNA (EBER) positive, leading to a diagnosis of ENKTL. Thus, when nonepithelial tumor cells in a necrotic background and prominent atypia are found, as in this case, it is important to carefully observe for azurophil granules in the cytoplasm for differential diagnosis considerations.

Use of PD-1 blockade in refractory/relapsed natural killer T-cell lymphomas: a systematic review and synthesis of case reports

Natural killer/T-cell lymphoma (NK/T-cellL) is an aggressive non-Hodgkin’s lymphoma with limited treatment options for patients who experience disease progression or recurrence after second-line treatment. The use of new therapies, such as pembrolizumab, which involves immune checkpoint blockade mechanisms, is proposed. This systematic review followed the MOSE guidelines and searched PUBMED/MEDLINE, EMBASE, and Scopus databases. Fourteen articles were found, reporting on the use of pembrolizumab anti PD-1 in NK/T-cellL patients. The objective response rate was 84.50%, with disease-free survival ranging from two to 48 months. The complete response rate was 61.6%, and the quality of the reported studies was evaluated to be of high and moderate confidence bias levels in case reports and high bias in clinical trials. Pembrolizumab and others anti PD-1 are treatment options for refractory/recurrent NK/T-cellL, regardless of PD-L1 expression, with good short- and long-term results and low adverse events.

842P Multicenter real-world study of newly diagnosed advanced-stage extranodal natural killer/T cell lymphoma (ENKTL): Proposal for intensive therapy

842P Multicenter real-world study of newly diagnosed advanced-stage extranodal natural killer/T cell lymphoma (ENKTL): Proposal for intensive therapy

Development and Validation of Clinical-Metabolic-Radiomics Model Based on Nomogram-Revised Risk Index for Prognosis Prediction in Patients with Extranodal Natural Kill/T Cell Lymphoma

To identify clinical-metabolic-radiomics model using clinical data and 18F-FDG PET/CT image for predicting progression-free survival (PFS) of nasal-type extranodal natural killer/T cell lymphoma (ENKTCL) on the basis of the nomogram-revised risk index (NRI) model previously established and validated by our research group. A total of 133 ENKTCL patients were prospectively included and randomly divided into a training cohort (n = 73) and a validation cohort (n = 50). 107 features and 7 commonly used metabolic parameters (SUVmax, MTV, TLG, SD, TLR, TAR and TBR) were extracted from baseline PET images of the patients. Least absolute shrinkage and selection operator (LASSO) following Cox regression were used to select optimal features and parameters. NRI-metabolic-radiomics model was developed and validated in the two cohorts and compared with NRI model and NRI-metabolic model. TLG and 5 radiomics features were selected after LASSO and Cox regression. NRI-metabolic (NRI-TLG) model and NRI-metabolic-radiomics (NRI-TLG-RAD) model was developed based on NRI, TLG and selected 5 radiomics features. For PFS, NRI-TLG-RAD showed better PFS discrimination than NRI-TLG model and NRI model in both training cohort (C-index = 0.791, 0.743 and 0.690, respectively) and validation cohort (C-index = 0.785, 0.707, and 0.610 respectively). Moreover, NRI-TLG-RAD model and NRI-TLG model divided more patients into low-risk group (No. of patients: 66, 42 vs. 20) and very high-risk group (No. of patients: 25, 25 vs. 9), compared to preexisting NRI model. The addition of metabolic and radiomics information improved the prognostic performance of preexisting NRI model greatly. Better prognostic discrimination and more reasonable patient division of the new NRI-TLG and NRI-TLG-RAD model may provide the basis for more precise treatment modality in the future.

Treatment Outcomes and Prognostic Factors of Chemotherapy Combined with Radiotherapy for Patients with Stage I-II Nasal-Type Natural Killer/T-Cell Lymphoma

The purpose of this study was to assess the treatment outcome and the potential prognostic factors for patients with stage I-II nasal ENKTL treated with radiotherapy (RT) combined chemotherapy (CT). From July, 2005 to January, 2019, 118 eligible patients were retrospective included in the study. Among the 118 patients, 84 were male and 34 were female. The median age was 45 years (range: 14-77 years). According to the Ann Arbor staging system, 66 patients had stage I disease (Primary tumor invasion (PTI) was present in 29 patients), and 52 patients had stage II disease. B symptoms were observed in 61 patients. The Eastern Cooperative Oncology Group (ECOG) performance score was 0 to 1 in 88 patients. Cervical lymph node involvement was observed in 51 patients. The primary lesions were located in the nasal cavity in 92 cases and in the Waldeyer ring in 26 cases. Five patients had received RT followed by CT (RT + CT), 20 patients had received CT followed by RT (CT + RT), 90 patients had received CT followed by RT, again followed by CT (CT+RT+CT), and 3 patients had received concurrent chemoradiotherapy (CRT) (1 patient received CRT + CT, other 2 patients received CT+CRT+CT). Patients were irradiated with a median dose of 50 Gy (range, 24-61.2). All patients received chemotherapy, 91 received non-anthracycline-based chemotherapy, whereas 27 patients received anthracycline-based chemotherapy. The median number of courses of chemotherapy was four (range: 1-10). Patients were scored as having low-risk disease (n = 50), intermediate-risk disease (n = 60) or high-risk disease (n = 8) according to the prognostic index of natural killer cell lymphoma (PINK). Among the 118 patients, after initial therapy, the complete response (CR) rate was 82.2% (n = 97), and the partial response (PR) rate was 11.0% (n = 13). The stable disease (SD) rate was 2.5% (n = 3), and the progressive disease (PD) rate was 4.2% (n = 5). With a median follow-up of 43 months (range, 4-201) after irradiation, the 3-year PFS and OS were 76.9% and 82.9%, respectively. The 3-year OS rate was 75.0% for RT + CT, 70.0% for CT + RT, 87.1% for CT + RT+ CT, and 50.0% for CRT (P = 0.052). Three-year OS and PFS were 88.6% and 83.4%, respectively, for non-anthracycline-based chemotherapy regimen compared to 61.6% (P = 0.001) and 58.4% (P = 0.003), respectively, for the anthracycline-based chemotherapy regimen. Three-year OS and PFS were 84.0% and 79.0%, respectively, for patients receiving high-dose RT (≥50 Gy, n = 111) compared to 71.4% (P = 0.076) and 71.4% (P = 0.228), respectively, for low-dose RT (<50 Gy, n = 7). In multivariate analysis, adverse factors associated with OS in our study were chemotherapy regimen and response to RT and CT (P = 0.047, <0.001). Radiotherapy combined with chemotherapy reported promising response rate and a favorable survival for patients with stage I-II nasal ENKTL. Anthracycline-based chemotherapy regimen and no remission after RT and CT were adverse factors of OS.

GPCR signaling contributes to immune characteristics of microenvironment and process of EBV-induced lymphomagenesis

Epstein-Barr virus (EBV) is the oncogenic driver of multiple cancers. However, the underlying mechanism of virus-cancer immunological interaction during disease pathogenesis remains largely elusive. Here we reported the first comprehensive proteogenomic characterization of natural killer/T-cell lymphoma (NKTCL), a representative disease model to study EBV-induced lymphomagenesis, incorporating genomic, transcriptomic, and in-depth proteomic data. Our multi-omics analysis of NKTCL revealed that EBV gene pattern correlated with immune-related oncogenic signaling. Single-cell transcriptome further delineated the tumor microenvironment as immune-inflamed, -deficient, and -desert phenotypes, in association with different setpoints of cancer-immunity cycle. EBV interacted with transcriptional factors to provoke GPCR interactome (GPCRome) reprogramming. Enhanced expression of chemokine receptor-1 (CCR1) on malignant and immunosuppressive cells modulated virus-cancer interaction on microenvironment. Therapeutic targeting CCR1 showed promising efficacy with EBV eradication, T-cell activation, and lymphoma cell killing in NKTCL organoid. Collectively, our study identified a previously unknown GPCR-mediated malignant progression and translated sensors of viral molecules into EBV-specific anti-cancer therapeutics.

Contribution of the Epstein-Barr virus to the oncogenesis of mature T-cell lymphoproliferative neoplasms.

EBV is a lymphotropic virus, member of the Herpesviridae family that asymptomatically infects more than 90% of the human population, establishing a latent infection in memory B cells. EBV exhibits complex survival and persistence dynamics, replicating its genome through the proliferation of infected B cells or production of the lytic virions. Many studies have documented the infection of T/NK cells by EBV in healthy individuals during and after primary infection. This feature has been confirmed in humanized mouse models. Together these results have challenged the hypothesis that the infection of T/NK cells per se by EBV could be a triggering event for lymphomagenesis. Extranodal NK/T-cell lymphoma (ENKTCL) and Epstein-Barr virus (EBV)-positive nodal T- and NK-cell lymphoma (NKTCL) are two EBV-associated lymphomas of T/NK cells. These two lymphomas display different clinical, histological and molecular features. However, they share two intriguing characteristics: the association with EBV and a geographical prevalence in East Asia and Latin America. In this review we will discuss the genetic characteristics of EBV in order to understand the possible role of this virus in the oncogenesis of ENKTCL and NKTCL. In addition, the main immunohistological, molecular, cytogenetic and epigenetic differences between ENKTCL and NKTCL will be discussed, as well as EBV differences in latency patterns and other viral molecular characteristics.

Clinical and prognostic role of sarcopenia based on masticatory muscle index on MR images in patients with extranodal natural killer/T cell lymphoma, nasal type.

Sarcopenia is known to be associated with an increased risk of adverse outcomes in a variety of malignancies, but its impact in extranodal natural killer/T cell lymphoma, nasal type (ENKTL-NT) is unknown. The aim of this study was to explore the prognostic relevance of sarcopenia defined by MRI-based masticatory muscle index in ENKTL-NT patients. A total of 112 patients with newly diagnosed ENKTL-NT who underwent cranial magnetic resonance imaging (MRI) were enrolled. The masticatory skeletal muscle index (M-SMI) was measured based on T2-weighted MR images and sarcopenia was defined by M-SMI<5.5 cm2/ m2. The median M-SMI was 5.47 (4.91-5.96) cm2/m2; 58 were identified with sarcopenia in this cohort. On multivariate analyses, sarcopenia was the only independently risk factor predicting overall survival (HR, 4.590; 95% CI, 1.657-12.715; p = 0.003), progression-free survival (HR, 3.048; 95% CI, 1.515-6.130; p = 0.002), and treatment response (HR, 0.112; 95% CI, 0.042-0.301; p < 0.001). In addition, we found that integrating sarcopenia into prognostic indices could improve the discriminative power of the corresponding original model. Stratification analysis showed that sarcopenia was able to further identify survival differences in patients that could not be distinguished by prognostic models. In summary, our study suggests that sarcopenia defined by MRI-based M-SMI represents a new and routinely applicable prognostic indicator of clinical outcome or predictor of treatment response in ENKTL-NT patients, and may aid in risk stratification and treatment decisions.

Selinexor With Anti-PD-1 Antibody as a Potentially Effective Regimen for Patients With Natural Killer/T-Cell Lymphoma Failing Prior L-Asparaginase and PD-1 Blockade.

Natural killer/T-cell lymphoma (NKTCL) is a rare and heterogeneous tumor type of non-Hodgkin's lymphoma (NHL) with a poor clinical outcome. There is no standardized salvage treatment failing l-asparaginase-based regimens. Here we report our retrospective results of the combined use of selinexor and PD-1 blockade (tislelizumab) in 5 patients with NKTCL who had exhausted almost all available treatments. A total of 5 patients with relapsed/refractory(R/R) NK/T-cell lymphomas failing prior l-asparaginase and anti-PD-1 antibody were retrospectively collected. They were treated with at least one cycle of XPO1 inhibitor plus the same anti-PD-1 antibody. Anti-PD-1 antibody (Tislelizumab) was administrated at 200 mg on day 1 every 3 weeks and selinexor doses and schedules ranged from 40 mg weekly for 2 weeks per 21-day cycle to 60 mg weekly per cycle. Five patients with relapsed NKTCL with extensive organ involvement including 4 central nervous system (CNS) infiltration patients were included. Four patients achieved objective responses including 3 complete responses (CR) and 1 partial response (PR). After a median follow-up time of 14.5 (range, 5-22) months, 1 patient was still in remission with CR, and the other 4 patients discontinued due to disease progression with a median progression-free survival (PFS) of 6 months and median overall survival (OS) of 12 months. Four patients with CNS involvement achieved a median OS of 8 months. Our data suggest that selinexor in combination with an anti-PD-1 antibody is a promising small molecule and immunotherapy combination regimen for patients with relapsed or refractory NKTCL.