Natural Killer Cell Lymphoma Research Articles

Succinylation of 14–3–3 theta by CPT1A promotes survival and paclitaxel resistance in nasal type extranodal natural killer/T-cell lymphoma

BackgroundThe aggressive and refractory extranodal natural killer/T-cell lymphoma, nasal type (ENKTL-NT) is a subtype of non-Hodgkin's lymphoma. Succinylation promotes progression in a variety of tumors, but its mechanism in ENKTL-NT is unclear. MethodsBioinformatic analysis was performed to screen differentially expressed genes in the ENKTL dataset. Cell transfection techniques were used for knockdown and overexpression of genes. The mRNA and protein expression were detected using RT-qPCR and western blot, respectively. Immunohistochemical staining was used to assess protein expression in situ. For the detection of cell proliferation activity, CCK-8, clonal formation, and EDU staining assays were used. Flow cytometry was employed to detect apoptosis. Co-immunoprecipitation was utilized for the identification of protein interactions and succinylation modifications. ResultsSuccinyltransferase CPT1A was highly elevated in ENKTL-NT and was associated with a dismal prognosis. CPT1A knockdown suppressed SNK-6 cells’ proliferation and induced apoptosis, while these effects were reversed by the overexpression of 14–3–3theta. Co-immunoprecipitation results showed that CPT1A caused succinylation of 14–3–3theta at site of K85, thereby enhancing the protein stability. Suppression of CPT1A-induced succinylation of 14–3–3theta by ST1326 resulted in the inhibition of SNK-6 cell proliferation and increased apoptosis. Paclitaxel combined with knockdown of CPT1A significantly inhibited the proliferation of ENKTL-NT compared to paclitaxel alone. ConclusionCPT1A induces succinylation of 14–3–3theta at the K85 site, promoting ENKTL-NT proliferation. The anti-ENKTL activity of paclitaxel was improved when combined with CPT1A knockdown.

Identification of PATL1 as a prognostic and immunotherapeutic predictive factor for nasal-type natural killer/T-cell lymphoma and head and neck squamous cell carcinoma

This research examines the function of protein associated with topoisomerase II homolog 1 (PATL1) in nasal-type natural killer/T-cell lymphoma (NKTCL) and head and neck squamous cell carcinoma (HNSCC). We analyzed bulk RNA-seq data from NKTCL, nasal polyps, and normal nasal mucosa, identifying 439 differentially expressed genes. Machine learning algorithms highlighted PATL1 as a hub gene. PATL1 exhibited significant upregulation in NKTCL and HNSCC tumor samples in comparison to normal tissues, showing high diagnostic accuracy (AUC = 1.000) for NKTCL. Further analysis of local hospital data identified PATL1 as an independent prognostic risk factor for NKTCL. Data analysis of TCGA and GEO datasets revealed that high PATL1 expression correlated with poorer prognosis in HNSCC patients (p < 0.05). We also constructed a PATL1-based nomogram, which emerged as an independent prognostic predictor for HNSCC after addressing missing values. Additionally, we found a strong correlation between PATL1 and various immune cell infiltrates (e.g., activated.CD4 T cell), and a significant association with the expression of 37 immune checkpoints genes (e.g., CTLA4, PDCD1) and 20 N6-methyladenosine-related genes (e.g., ZC3H13, METTL3) (all p < 0.05). Both TCIA and TIDE algorithms suggested that PATL1 could potentially predict immunotherapy efficacy (p < 0.05). Cellular experiments demonstrated that transfection with a silencing plasmid of PATL1 significantly inhibited the malignant behaviors of SNK6 and FaDu cell lines(p < 0.05). In conclusion, our findings suggest that PATL1 may serve as a valuable prognostic and predictive biomarker in NKTCL and HNSCC, highlighting its significant role in these cancers.

Sintilimab (anti-PD-1 antibody) plus chidamide (histone deacetylase inhibitor) in relapsed or refractory extranodal natural killer T-cell lymphoma (SCENT): a phase Ib/II study.

Anti-PD-1 antibodies are a favorable treatment for relapsed or refractory extranodal natural killer T cell lymphoma (RR-ENKTL), however, the complete response (CR) rate and the duration of response (DOR) need to be improved. This phase 1b/2 study investigated the safety and efficacy of sintilimab, a fully human anti-PD-1 antibody, plus chidamide, an oral subtype-selective histone deacetylase inhibitor in 38 patients with RR-ENKTL. Expected objective response rate (ORR) of combination treatment was 80%. Patients received escalating doses of chidamide, administered concomitantly with fixed-dose sintilimab in 21-days cycles up to 12 months. No dose-limiting events were observed, RP2D of chidamide was 30 mg twice a week. Twenty-nine patients were enrolled in phase 2. In the intention-to-treat population (n = 37), overall response rate was 59.5% with a complete remission rate of 48.6%. The median DOR, progression-free survival (PFS), and overall survival (OS) were 25.3, 23.2, and 32.9 months, respectively. The most common grade 3 or higher treatment-emergent adverse events (AEs) were neutropenia (28.9%) and thrombocytopenia (10.5%), immune-related AEs were reported in 18 (47.3%) patients. Exploratory biomarker assessment suggested that a combination of dynamic plasma ctDNA and EBV-DNA played a vital prognostic role. STAT3 mutation shows an unfavorable prognosis. Although outcome of anticipate ORR was not achieved, sintilimab plus chidamide was shown to have a manageable safety profile and yielded encouraging CR rate and DOR in RR-ENKTL for the first time. It is a promising therapeutic option for this population.

BiZact-Assisted Endoscopic Resection of a Sinonasal Tumor.

The BiZact device, a bipolar electrosurgical scissor designed for tonsillectomy, minimizes thermal tissue damage and seals blood vessels <3 mm in diameter while dividing the soft tissue. This study describes the authors' experience with sinonasal tumor surgery using a BiZact and discusses its clinical utility and advantages. The authors analyzed BiZact-assisted endoscopic sinonasal tumor surgery cases between January 2021 and May 2023. Data were collected on patients' demographics, histopathology, extent of tumor involvement, surgical records, and postoperative medical records. Clinical utility was assessed using the success rate of complete tumor excision, estimated blood loss during surgery, device-related complications, and operation time. A survey of the surgeons' BiZact experience was also conducted. The diagnoses of the 20 patients in this study included squamous cell carcinoma (n = 2), malignant melanoma (n = 1), sarcoma (n = 1), natural killer cell lymphoma (n = 1), inverted papilloma (n = 12), angiofibroma (n = 2), and schwannoma (n = 1). This pilot study demonstrated a shortened operative time, with a median of 0.8 hours and <100 mL of intraoperative blood loss. In addition, no BiZact-related complications were observed. The BiZact device allows efficient sinonasal surgery because it has the unique advantage of one-step sealing and cutting. BiZact-assisted endoscopic sinonasal tumor surgery is a beneficial and safe procedure that reduces blood loss during surgery, shortens the operative time, and minimizes postoperative complications.

Artificial intelligence for diagnosis and prognosis prediction of natural killer/T cell lymphoma using magnetic resonance imaging

Accurate diagnosis and prognosis prediction are conducive to early intervention and improvement of medical care for natural killer/T cell lymphoma (NKTCL). Artificial intelligence (AI)-based systems are developed based on nasopharynx magnetic resonance imaging. The diagnostic systems achieve areas under the curve of 0.905-0.960 in detecting malignant nasopharyngeal lesions and distinguishing NKTCL from nasopharyngeal carcinoma in independent validation datasets. In comparison to human radiologists, the diagnostic systems show higher accuracies than resident radiologists and comparable ones to senior radiologists. The prognostic system shows promising performance in predicting survival outcomes of NKTCL and outperforms several clinical models. For patients with early-stage NKTCL, only the high-risk group benefits from early radiotherapy (hazard ratio= 0.414 vs. late radiotherapy; 95% confidence interval, 0.190-0.900, p= 0.022), while progression-free survival does not differ in the low-risk group. In conclusion, AI-based systems show potential in assisting accurate diagnosis and prognosis prediction and may contribute to therapeutic optimization for NKTCL.

Recent Advances in Nanobiotechnology for the Treatment of Non-Hodgkin's Lymphoma.

Lymphoma is the eighth most common type of cancer worldwide. Currently, lymphoma is mainly classified into two main groups: Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL), with NHL accounting for 80% to 90% of the cases. NHL is primarily divided into B, T, and natural killer (NK) cell lymphoma. Nanotechnology is developing rapidly and has made significant contributions to the field of medicine. This review summarizes the advancements of nanobiotechnology in recent years and its applications in the treatment of NHL, especially in diffuse large B cell lymphoma (DLBCL), primary central nervous system lymphoma (PCNSL), and follicular lymphoma (FL). The technologies discussed include clinical imaging, targeted drug delivery, photodynamic therapy (PDT), and thermodynamic therapy (TDT) for lymphoma. This review aims to provide a better understanding of the use of nanotechnology in the treatment of non-Hodgkin's lymphoma.

Analysis of mutation profiles in extranodal NK/T-cell lymphoma: clinical and prognostic correlations.

The molecular pathogenesis of extranodal NK/T-cell lymphoma (NKTCL) remains obscured despite the next-generation sequencing (NGS) studies explored on ever larger cohorts in the last decade. We addressed the highly variable mutation frequencies reported among previous studies with comprehensive amplicon coverage and enhanced sequencing depth to achieve higher genomic resolution for novel genetic discovery and comparative mutational profiling of the oncogenesis of NKTCL. Targeted exome sequencing was conducted to interrogate 415 cancer-related genes in a cohort of 36 patients with NKTCL, and a total of 548 single nucleotide variants (SNVs) and 600 Copy number variances (CNVs) were identified. Recurrent amplification of the MCL1 (67%) and PIM1 (56%) genes was detected in a dominant majority of patients in our cohort. Functional mapping of genetic aberrations revealed that an enrichment of mutations in the JAK-STAT signaling pathway, including the cytokine receptor LIFR (copy number loss) upstream of JAK3, STAT3 (activating SNVs), and downstream effectors of MYC, PIM1 and MCL1 (copy number gains). RNA in situ hybridization showed the significant consistence of MCL1 RNA level and copy number of MCL1 gene. We further correlated molecular and clinical parameters with overall survival (OS) of these patients. When correlations were analyzed by univariate followed by multivariate modelling, only copy number loss of LIFR gene and stage (III-IV) were independent prognostic factors of reduced OS. Our findings identified that novel loss of LIFR gene significantly correlated with the adverse clinical outcome of NKTCL patients and provided therapeutic opportunities for this disease through manipulating LIFR.

Comprehensive Genetic Profiling Reveals Frequent Alterations of Driver Genes on the X Chromosome in Extranodal NK/T-cell Lymphoma.

Extranodal NK/T-cell lymphoma (ENKTCL) is an Epstein-Barr virus (EBV)-related neoplasm with male dominance and a poor prognosis. A better understanding of the genetic alterations and their functional roles in ENKTCL could help improve patient stratification and treatments. In this study, we performed a comprehensive genetic analysis of 178 ENKTCL cases to delineate the landscape of mutations, copy number alterations (CNA), and structural variations, identifying 34 driver genes including six previously unappreciated ones, namely, HLA-B, HLA-C, ROBO1, CD58, POT1, and MAP2K1. Among them, CD274 (24%) was the most frequently altered, followed by TP53 (20%), CDKN2A (19%), ARID1A (15%), HLA-A (15%), BCOR (14%), and MSN (14%). Chromosome X losses were the most common arm-level CNAs in females (∼40%), and alterations of four X-linked driver genes (MSN, BCOR, DDX3X, and KDM6A) were more frequent in males and females harboring chromosome X losses. Among X-linked drivers, MSN was the most recurrently altered, and its expression was lost in approximately one-third of cases using immunohistochemical analysis. Functional studies of human cell lines showed that MSN disruption promoted cell proliferation and NF-κB activation. Moreover, MSN inactivation increased sensitivity to NF-κB inhibition in vitro and in vivo. In addition, recurrent deletions were observed at the origin of replication in the EBV genome (6%). Finally, by integrating the 34 drivers and 19 significant arm-level CNAs, nonnegative matrix factorization and consensus clustering identified two molecular groups with different genetic features and prognoses irrespective of clinical prognostic factors. Together, these findings could help improve diagnostic and therapeutic strategies in ENKTCL. Significance: Integrative genetic analyses and functional studies in extranodal NK/T-cell lymphoma identify frequent disruptions of X-linked drivers, reveal prognostic molecular subgroups, and uncover recurrent MSN alterations that confer sensitivity to NF-κB inhibition.

Serum aspartate aminotransferase, a novel potential biomarker of prognosis in extranodal natural killer/T cell lymphoma, nasal type.

Aspartate aminotransferase (AST), an indicator of liver cell damage, was related to the prognosis of certain malignant tumors. This study examined the predictive value of AST in patients with extranodal natural killer/T cell lymphoma (ENKTL). We reviewed 183 cases diagnosed with ENKTL and selected 26 U/L as the optimum cut-off value of AST. We used the univariate and multivariate Cox regression to compare the different AST groups' overall survival (OS) and progression-free survival (PFS). Prior to propensity score matching (PSM), Kaplan-Meier analysis showed that patients in the low AST subgroup had better OS and PFS than the high AST subgroup. Multivariate analysis revealed that AST was an independent indicator for prognosis. After PSM, the low AST subgroup maintained a significantly better OS and PFS than the high AST subgroup. AST might represent a significant prognostic marker for ENKTL patients.

Abstract P07: Extracellular Vesicles Secreted from Daratumumab Resistant Cells Promote Resistance and Proliferation of Daratumumab Sensitive cells, possibly Through the Transfer of miRNA Cargo

Abstract Daratumumab (dara) is an anti-CD38 monoclonal antibody used for Multiple Myeloma (MM) treatment, but responses are heterogeneous, and resistance is inevitable. We established three dara resistant (dara R) cell lines in Natural Killer T-cell Lymphoma (NKTL), T-cell acute lymphoblastic leukaemia (T-ALL) and MM via long-term exposure to increasing concentrations of dara. We have previously demonstrated that the exosome biogenesis pathway plays a significant role in the survival of dara R cell lines. Coculture of dara sensitive (dara S) cell lines with dara R cell lines separated by a cell-impermeable transwell insert promoted cell proliferation and reduced response to dara treatment in dara S cell lines thereby suggesting a potential role for extracellular vesicles (EVs) in mediating these responses. To assess the specific role of EVs, we isolated dara R EVs and added it to the culture of dara S cells. We observed that uptake of dara R EVs directly promote proliferation and reduced cytotoxic response to dara treatment in dara S cells. In this study, we seek to investigate the role of EVs secreted by dara R cells, in particular, that of EV-derived miRNAs. Exosomal miRNAs are known to play a role in regulating cellular pathways driving cancer cell resistance and survival. To evaluate the potential role of EV-derived miRNA cargo, we performed miRNA sequencing of EVs isolated from the plasma fraction of bone marrow samples obtained from MM patients. We found that the EVs from patients with a progression free survival (PFS) of less than 2 years after dara based therapy had an enrichment of mir-155 and mir-181a as compared to those with a PFS longer than 2 years. These data align with our findings in the cell lines and suggest that these miRNAs may be utilised as potential biomarkers for daratumumab resistance. Citation Format: Muhamad Irfan Bin Azaman, Wee Joo Chng, Sanjay de Mel, Nurulhuda Mustafa. Extracellular Vesicles Secreted from Daratumumab Resistant Cells Promote Resistance and Proliferation of Daratumumab Sensitive cells, possibly Through the Transfer of miRNA Cargo [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P07.

Retrospective review of the toxicities and change in dosing patterns for pegaspargase in patients with acute lymphoblastic leukemia/lymphoma and T-cell lymphoma.

Pegaspargase (PEG) is a key component of standard regimens for acute lymphoblastic leukemia/lymphoma (ALL) and extranodal natural killer/T-cell lymphoma (NKTCL). Emerging evidence suggests an opportunity to decrease incidence of PEG-associated toxicities with dose capping, but evidence is limited. This study aims to evaluate whether a significant difference in PEG-associated toxicities related to dosing strategy exists and to identify patient-specific or regimen-specific factors for PEG-related toxicity. A retrospective analysis of PEG-associated toxicities was completed in adult patients with ALL or NKTCL who received PEG within Cancer and Leukemia Group B (CALGB) 10403 or modified dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide (mSMILE) regimens at the UW Medical Center/Fred Hutchinson Cancer Center. PEG-associated toxicities that occurred through 8 weeks after PEG doses were noted. Twenty-eight patients received dose-capped PEG, and 29 received noncapped PEG. Fewer all-grade and grade 3/4 toxicities were observed in the dose-capped cohort. Grade 3/4 toxicities observed were hepatotoxicity, hyperglycemia, hypersensitivity, and hypertriglyceridemia. In addition, fewer grade 3/4 pancreatitis and thrombosis events occurred in the dose-capped cohort. Hypertriglyceridemia and hepatotoxicity were associated with the highest cumulative incidence proportions among all toxicities. Dose capping of PEG was associated with a similar or later median onset for most toxicities, a less heterogeneic toxicity profile, and a lower recurrence of most toxicities upon PEG rechallenge compared to the non-dose-capped cohort. Standardizing PEG dose capping in the CALGB 10403 and mSMILE regimens may translate to improved tolerance compared to a historical standard of no dose capping PEG.

Somatic mutations in FAS pathway increase hemophagocytic lymphohistiocytosis risk in patients with T- and/or NK-cell lymphoma

AbstractAlthough significant progress has been made in understanding the genetic basis of primary hemophagocytic lymphohistiocytosis (HLH), the pathogenesis of secondary HLH, the more prevalent form, remains unclear. Among the various conditions giving rise to secondary HLH, HLH in patients with lymphoma (HLH-L) accounts for a substantial proportion. In this study, we investigated the role of somatic mutations in the pathogenesis of HLH-L in a cohort of patients with T- and/or natural killer–cell lymphoma. We identified a 3-time higher frequency of mutations in FAS pathway in patients with HLH-L. Patients harboring these mutations had a 5-time increased HLH-L risk. These mutations were independently associated with inferior outcome. Hence, our study demonstrates the association between somatic mutations in FAS pathway and HLH-L. Further studies are warranted on the mechanistic role of these mutations in HLH-L.

Clinical characteristics and prognostic analysis of primary extranodal non-Hodgkin lymphoma of the head and neck.

Primary extranodal non-Hodgkin's lymphoma (PE-NHL) of the head and neck is the second common site of extranodal lymphoma, accounting for approximately one-third of all extranodal non-Hodgkin's lymphoma (E-NHL). However, in recent years, large-scale PE-NHL case studies in China and worldwide are rare and not comprehensive enough. This work analyzed the clinical manifestations, pathological features, immunophenotypes and diagnosis of PE-NHL, as well as the factors affecting the treatment and prognosis. A retrospective study was performed on 74 patients who were diagnosed with head and neck PE-NHL and treated for the first time. The clinical manifestations, pathological features, and immunophenotypes were summarized, and the factors related to the treatment and prognosis were analyzed. The most common site of this disease was the Waldeyer's ring, followed by the nasal cavity. Diffuse large B-cell lymphoma was the most common type, followed by extranodal NK T-cell lymphoma nasal type. The 1-year, 2-year, and 5-year progression-free survival (PFS) rates were 76.4%, 67.9%, and 59.3%. The 1-year, 2-year, and 5-year overall survival (OS) rates were 89.4%, 85.6%, and 63.2%. ECOG score ≥ 2, Ann Arbor stage III or IV and IPI risk stratification identifying patients as the high-risk group were independent risk factors affecting the OS of patients with PE-NHL of the head and neck. The most common site of PE-NHL in these Chinese patients was the Waldeyer's ring, but the incidence in the nasal cavity was higher than that reported in Western countries. Radiotherapy combined with chemotherapy had better efficacy than chemotherapy alone, and the prognosis depended on the ECOG score and clinical stage. IPI had a better prognostic value in patients in the high-risk group of head and neck PE-NHL.

Primary isolated extranodal NK/T-cell lymphoma of the orbit: A case report and diagnostic dilemma

Natural killer T-cell lymphoma (NKTL) is associated with Epstein-Barr virus, a highly malignant tumor that typically arises in the nose and/or paranasal sinuses isolated orbital involvement by NKTL is extremely rare. Herein, we report a case of primary orbital NKTL in a young female patient. A 32-year-old female presented with gradually increasing painful swelling of the right eye. On examination, abaxial proptosis, inferolateral displacement of the eyeball, restricted extraocular muscle movement, and solid mass in the subconjunctival fornix and superior quadrant. The rest of the ocular and systemic examination was unremarkable. Magnetic resonance imaging with contrast of the orbit shows a lobulated mass lesion 35×30×18 mm involving the medial aspect of the right orbit extraconal and superior intraconal space extending up to the preseptal region. Informed consent and biopsy were done and sent for histopathology examination. Histopathological examination shows the spectrum of atypical lymphoid cells, indented or cleaved nuclei and pale to clear cytoplasm, few histiocytes, giant cells, and apoptotic body. To rule out lymphoma, immunohistochemistry (IHC) was advised. On IHC, tumor cells were positive for CD3, D56, CD4 focally, CD7, Ki-67–90% and negative for CD20, CD2, Tdt, PAX5, CD34, CD5, Cd8 leading to a diagnosis of extranodal NKTL of the orbit. To the best of our knowledge, around 20 cases of isolated orbital extranodal NKTL were reported in the literature review. Polymorphic lymphoid cell in a young patient often mimics the inflammatory conditions of orbit. The rarity of this tumor and inflammatory signs make it challenging to identify these tumors early.

A Nomogram Model Based on the Inflammation-Immunity-Nutrition Score (IINS) and Classic Clinical Indicators for Predicting Prognosis in Extranodal Natural Killer/T-Cell Lymphoma.

Systemic inflammation, immunity, and nutritional status are closely related to patients' outcomes in several kinds of cancers. This study aimed to establish a new nomogram based on inflammation-immunity-nutrition score (IINS) to predict the prognosis of extranodal natural killer/T-cell lymphoma (ENKTL) patients. The clinical data of 435 patients with ENTKL were retrospectively reviewed and randomly assigned to training cohort (n=305) and validation cohort (n=131) at a ratio of 7:3. Cox regression analysis was employed to identify independent prognostic factors and develop a nomogram in the training cohort. Harrell's concordance index (C-index), calibration curve, receiver operating characteristic (ROC) curve, and decision curve analysis (DCA) curve were employed to assess the performance of the nomogram and compare it with traditional prognostic systems (PINK, IPI, KPI). Internal validation was performed using 1000 bootstrap resamples in the validation cohort. Kaplan-Meier survival analyses were conducted to compare the overall survival (OS) of patients in different risk groups. In the training cohort, in addition to several classic parameters, IINS was identified as an independent prognostic factor significantly associated with the OS of patients. The nomogram established based on the independent prognostic indicators showed superior survival prediction efficacy, with C-index of 0.733 in the training cohort and 0.759 in the validation cohort compared to the PINK (0.636 and 0.737), IPI (0.81 and 0.707), and KPI (0.693 and 0.639) systems. Furthermore, compared with PINK, IPI, and IPI systems, the nomogram showed relatively superior calibration curves and more powerful prognostic discrimination ability in predicting the OS of patients. DCA curves revealed some advantages in terms of clinical applicability of the nomogram compared to the PINK, IPI, and IPI systems. Compared with traditional prognostic systems, the nomogram showed promising prospects for risk stratification in ENKTL patient prognosis, providing new insights into the personalized treatment.

Extranodal, nasal, natural Killer T-cell lymphoma of the lacrimal gland: A case report

Natural killer T-cell lymphomas involving the lacrimal gland are extremely rare. The prognosis of this type of lymphoma is poor, with 12-month mortality rates over 87%. In this case report, we present a patient with an isolated compromise of the right lacrimal gland by an extranodal, nasal, natural killer T-cell lymphoma treated with stereotactic radiotherapy with a free event follow-up of 12 years, an uncommonly long survival.

MYC overexpression in natural killer cell lymphoma: prognostic and therapeutic implications.

The current clinical management of extranodal natural killer (NK)/T-cell lymphoma (ENKTL) primarily depends on conventional chemotherapy and radiotherapy, underscoring the need for innovative therapeutic strategies. This study explores the clinical significance and therapeutic implication of c-MYC (MYC) in ENKTL. Initially, we identified MYC protein overexpression in approximately 75% of cases within a large cohort of 111 patients. MYC overexpression was strongly correlated with lymphoma cell proliferation and poor clinical outcomes. Intriguingly, integrating MYC expression into the prognostic index of NK cells lymphoma with Epstein-Barr virus (PINK-E) prognostic model significantly enhanced its predictive power. Subsequently, we implemented MYC knockdown in NK malignancy cell lines with MYC overexpression, resulting in significant viability reduction. RNA sequencing used to determine MYC function revealed a high overlap with canonical MYC-regulated genes and enrichment in metabolism and cell cycle regulation. Integrative analysis of the RNA-sequencing data upon MYC knockdown with gene expression profiles of primary ENKTL cases identified a subset of genes closely associated with MYC overexpression. Among these, CDK4 emerged as a potential therapeutic target, and its inhibition not only abrogated MYC function but also decreased MYC expression in NK malignancy cells. Furthermore, the clinical-grade CDK4/6 inhibitor palbociclib exhibited a potent anti-tumor effect in xenograft mouse models, especially when combined with gemcitabine. In summary, our study firmly establishes MYC as an oncogene with prognostic significance in ENKTL and highlights CDK4 inhibition as a promising therapeutic strategy for treating ENKTL with MYC overexpression.

First-line sintilimab with pegaspargase, gemcitabine, and oxaliplatin in advanced extranodal natural killer/T cell lymphoma (SPIRIT): a multicentre, single-arm, phase 2 trial

Programmed cell death protein 1 (PD-1) inhibitor sintilimab is effective in relapsed and refractory extranodal natural killer/T cell lymphoma (ENKTL), nasal type. We aimed to assess the safety and activity of sintilimab plus P-GEMOX (pegaspargase, gemcitabine, and oxaliplatin) in the first-line setting for advanced ENKTL. The multicentre, single-arm, phase 2 trial was done at three medical centres in China. Patients aged 18-75 years with treatment-naive pathologically confirmed advanced ENKTL and an with Eastern Cooperative Oncology Group performance status score of 0-2 were eligible. Patients received intravenous sintilimab (200 mg on day 1), intramuscular pegaspargase (2000 U/m2 on day 1), intravenous gemcitabine (1 g/m2 on days 1 and 8), and intravenous oxaliplatin (130 mg/m2 on day 1) every 3 weeks for six cycles, followed by intravenous sintilimab (200 mg) every 3 weeks for up to 2 years or until disease progression or unacceptable toxicities. The primary endpoint was the complete response rate in the intention-to-treat population. The secondary endpoints were overall response rate (ORR), progression-free survival (PFS), disease-free survival (DFS), and overall survival. This trial is registered with ClinicalTrials.gov, NCT04127227. Enrolment has been completed, and follow-up is ongoing. Between Nov 29, 2019, and Sept 7, 2022, 34 eligible patients were enrolled (median age 39 years [IQR 32-55]; 25 [74%] of 34 patients were male; nine [26%] were female; and all were of Asian ethnicity). At the data cutoff (July 20, 2023), the median follow-up was 21 months (IQR 13-32). The complete response rate was 85% (29 of 34 patients, 95% CI 70-94). Five patients (15%; 95% CI 7-30) attained partial response and the ORR was 100% (34 of 34 patients). 24-month PFS was 64% (95% CI 48-86), 24-month DFS was 72% (54-95), and 36-month overall survival was 76% (52-100). The most common grade 3 or 4 treatment-related adverse events were neutropenia (17 [50%] of 34 patients), anaemia (10 [29%] patients), and hypertriglyceridemia (10 [29%] patients). Hypothyroidism was the most frequent immune-related adverse event (18 [53%]), including grade 3 hypothyroidism in one (3%) patient that caused treatment termination. No severe adverse events occurred. There were three deaths: one due to haemophagocytic syndrome, one due to disease progression, and one due to unknown cause, which were not considered to be treatment related. Combination of sintilimab with P-GEMOX seems to be an active and safe first-line regimen for patients with advanced ENKTL. National Key Research and Development Program and National Natural Science Foundation of China, Guangzhou Science and Technology Program and the Clinical Oncology Foundation of Chinese Society of Clinical Oncology.

Abstract 7276: Potent anti-proliferative activity of brincidofovir in Diffuse Large B-cell Lymphoma with overexpression of transcriptional repressor TLE1

Abstract Introduction: Brincidofovir (BCV) is a biologically-active acyclic nucleoside phosphonate and clinically-approved anti-viral agent. Recently, BCV has been demonstrated to display potent anti-proliferative and immunogenic properties in NK/T cell lymphoma (NKTCL). However, its effect on other lymphoma types remain unclear. Methods: We investigated BCV in an expanded cohort of B-cell lymphoma cell-lines (diffuse large B-cell lymphoma [DLBCL], n = 16; Burkitt lymphoma, n = 2; Hodgkin lymphoma, n = 1), in comparison with NKTCL cell lines (n = 11). Mouse xenograft models were deployed to assess in vivo effects. Whole transcriptomic sequencing (RNAseq) was performed to examine Epstein-Barr virus (EBV) status and explore potential mechanisms of action. Results: BCV inhibited viability in all B-cell lymphoma cell-lines in a dose-dependent manner (IC50 0.0798 to 8.414 µg/ml). Marked sensitivity (IC50 &amp;lt; 1 µg/ml) was demonstrated in nine cell-lines, including the MYC/BCL2-rearranged double-hit DLBCL cell-line OCI-LY18 (IC50 0.5 µg/ml). Intraperitoneal BCV (40 mg/kg, 2X per week) inhibited tumor growth in NOD/SCID mice OCI-LY18 xenografts, compared with vehicle alone (p &amp;lt; 0.001, two-tailed t-test). RNAseq showed that most cell-lines (n = 16) were EBV negative. Interestingly, the transcriptional repressor TLE1 was amongst the top upregulated genes in the BCV-sensitive cell-lines (log2foldchange = 8.12, adjusted p = 0.0004). DLBCL patient samples from two independent datasets showed that TLE1-high tumors conferred worse overall survival (GSE11318, n = 200: HR 2.77, 95%CI 1.78 to 4.30, p &amp;lt; 0.0001; GSE10846, n = 414: HR 1.94, 95%CI 1.35 to 2.80, p = 0.0004). Gene set enrichment analysis showed that pathways involved in oxidative phosphorylation and oncogenic signaling were significantly upregulated in the BCV-resistant cell-lines compared to the rest. Notably, these findings are in stark contrast to NKTCL, in which TLE1 loss instead confers BCV sensitivity in vitro and is associated with poor survival outcomes in patients (n = 36; HR 3.44, 95% CI 1.23-10.49, p = 0.0301). Conclusions: Taken together, these results suggest that BCV may be a potential novel therapeutic agent for the treatment of B-cell lymphomas. Further work will be required to investigate the role of TLE1 and other molecular features as potential predictive biomarkers. Citation Format: Jing Yi Lee, Tun Kiat Ko, Elizabeth Chun Yong Lee, Bavani Kannan, Boon Yee Lim, Zhimei Li, Zexi Guo, Jui Wan Loh, Cedric Chuan-Young Ng, Kelila Xin Ye Chai, Nur Ayuni Binte Muhammad Taib, Kerry Lim, Dachuan Huang, Jing Quan Lim, Masatoshi Hazama, Koji Fukushima, Bin Tean Teh, Soon Thye Lim, Choon Kiat Ong, Jason Yongsheng Chan. Potent anti-proliferative activity of brincidofovir in Diffuse Large B-cell Lymphoma with overexpression of transcriptional repressor TLE1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7276.

Update on T-Cell Lymphoma Epidemiology.

T-cell lymphomas (TCLs) are a group of rare subtypes of non-Hodgkin lymphoma derived from mature T-lymphocytes. Recent updates in lymphoma classification based on the cell-of-origin pathogenesis have shed new light on TCL epidemiology and outcomes. Contemporary regional consortia and international studies, including those conducted recently in Asia and South America, have provided an updated delineation of the major subtypes across various global regions. Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), remains the most common subtype globally except in Asia, where extra-nodal NK-T cell lymphoma (ENKTL) has emerged as the most prevalent. Angioimmunoblastic T-cell lymphoma (AITL) is the second most common subtype globally except in South America where its incidence falls behind adult T-cell leukemia/lymphoma (ATLL) and ENKTL. ALK-negative anaplastic large cell lymphoma (ALCL) has been recognized as the second most common subtype in some parts of South America. Studies on the newly classified breast implant-associated ALCL (BIA-ALCL) are beginning to reveal its distribution and risk factors. Deciphering the epidemiology of TCLs is a challenging endeavor due to the rarity of these entities and ongoing refinement in classification. Collaborative efforts on prospective registries based on the most current WHO classifications will help capture the true epidemiology of TCL subtypes to better focus resources for diagnostic, prognostic, and therapeutic efforts.