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•Tislelizumab monotherapy showed modest efficacy in R/R mature T- and NK-cell neoplasms with some long-lasting remissions.•Tislelizumab was well tolerated and demonstrated promising efficacy in R/R mycosis fungoides and Sézary syndrome.

Hepatitis B virus (HBV) infection has been associated with an increased risk for B-cell lymphomas. We previously showed that 20% of diffuse large B-cell lymphoma (DLBCL) patients from China, an endemic area of HBV infection, have chronic HBV infection (surface antigen–positive, HBsAg+) and are characterized by distinct clinical and genetic features. Here, we showed that 24% of follicular lymphoma (FL) Chinese patients are HBsAg+. Compared with the HBsAg− FL patients, HBsAg+ patients are younger, have a higher histological grade at diagnosis, and have a higher incidence of disease progression within 24 months. Moreover, by sequencing the genomes of 109 FL tumors, we observed enhanced mutagenesis and distinct genetic profile in HBsAg+ FLs, with a unique set of preferentially mutated genes (TNFAIP3, FAS, HIST1H1C, KLF2, TP53, PIM1, TMSB4X, DUSP2, TAGAP, LYN, and SETD2) but lack of the hallmark of HBsAg− FLs (ie, IGH/BCL2 translocations and CREBBP mutations). Transcriptomic analyses further showed that HBsAg+ FLs displayed gene-expression signatures resembling the activated B-cell–like subtype of diffuse large B-cell lymphoma, involving IRF4-targeted genes and NF-κB/MYD88 signaling pathways. Finally, we identified an increased infiltration of CD8+ memory T cells, CD4+ Th1 cells, and M1 macrophages and higher T-cell exhaustion gene signature in HBsAg+ FL samples. Taken together, we present new genetic/epigenetic evidence that links chronic HBV infection to B-cell lymphomagenesis, and HBV-associated FL is likely to have a distinct cell-of-origin and represent as a separate subtype of FL. Targetable genetic/epigenetic alterations identified in tumors and their associated tumor microenvironment may provide potential novel therapeutic approaches for this subgroup of patients.

Hepatitis B virus (HBV) infection has been associated with an increased risk for B-cell lymphomas. We previously showed that 20% of diffuse large B-cell lymphoma (DLBCL) patients from China, an endemic area of HBV infection, have chronic HBV infection (surface antigen–positive, HBsAg+) and are characterized by distinct clinical and genetic features. Here, we showed that 24% of follicular lymphoma (FL) Chinese patients are HBsAg+. Compared with the HBsAg−FL patients, HBsAg+patients are younger, have a higher histological grade at diagnosis, and have a higher incidence of disease progression within 24 months. Moreover, by sequencing the genomes of 109 FL tumors, we observed enhanced mutagenesis and distinct genetic profile in HBsAg+FLs, with a unique set of preferentially mutated genes (TNFAIP3, FAS, HIST1H1C, KLF2, TP53, PIM1, TMSB4X, DUSP2, TAGAP, LYN, and SETD2) but lack of the hallmark of HBsAg−FLs (ie, IGH/BCL2translocations and CREBBPmutations). Transcriptomic analyses further showed that HBsAg+FLs displayed gene-expression signatures resembling the activated B-cell–like subtype of diffuse large B-cell lymphoma, involving IRF4-targeted genes and NF-κB/MYD88 signaling pathways. Finally, we identified an increased infiltration of CD8+memory T cells, CD4+Th1 cells, and M1 macrophages and higher T-cell exhaustion gene signature in HBsAg+FL samples. Taken together, we present new genetic/epigenetic evidence that links chronic HBV infection to B-cell lymphomagenesis, and HBV-associated FL is likely to have a distinct cell-of-origin and represent as a separate subtype of FL. Targetable genetic/epigenetic alterations identified in tumors and their associated tumor microenvironment may provide potential novel therapeutic approaches for this subgroup of patients.

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.

Background

The lymphocyte subsets activation profiles in peripheral blood may contribute to the diagnosis of natural killer/T-cell lymphoma-associated hemophagocytic lymphohistiocytosis

Introduction

Abstract

Background:Follicular lymphoma (FL) is the most common form of indolent non-Hodgkin lymphoma (NHL). Several treatment options are approved by the US Food and Drug Administration for second- or later-line FL therapy, including rituximab + lenalidomide (R 2). However, advanced-stage FL remains incurable and new treatment options for relapsed or refractory (R/R) disease are needed. Epcoritamab, a subcutaneously administered, bispecific antibody that binds CD3 on T lymphocytes and CD20 on B cells, induces potent and selective T-cell-mediated killing of malignant CD20 +B cells (van der Horst et al, Blood Cancer J2021). In the first-in-human, phase 1/2 EPCORE NHL-1 trial (NCT03625037) in heavily pretreated patients with B-cell NHL (N=68), epcoritamab showed manageable safety and promising single-agent anti-tumor activity (Hutchings et al, Lancet2021). Among 10 patients with R/R FL, objective response rate (ORR) was 90% (95% CI: 55-100) and complete response (CR) rate was 50%. In the ongoing phase 1b/2 trial evaluating epcoritamab + R 2for R/R FL (EPCORE NHL-2 arms 2a and 2b; NCT04663347), ORR was 98% among 104 efficacy-evaluable patients, with a complete metabolic response in 87%. Most cytokine release syndrome (CRS) events were low grade (n=111; grade 1-2, 46%; grade 3, 2%) and occurred in cycle 1; all CRS events resolved with routine management. These encouraging data, and the distinct mechanisms of action of epcoritamab and R 2, support ongoing evaluation of this combination for its potential to improve clinical outcomes in patients with R/R FL. The phase 3 EPCORE FL-1 trial was designed to evaluate epcoritamab in combination with R 2vs R 2alone in patients with R/R FL with ≥1 prior line of anti-lymphoma therapy. We present an updated protocol, reflecting recent developments and revisions implemented in this study.

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.

Background

Background:Indolent B-cell lymphoma (iBCL) are clinically heterogeneous and accounts for 10-15% of all kinds of subtypes in NHL in China. Although iBCL have a relatively good survival, majority of these lymphomas is considered incurable. The favorable activity and safety profile of rituximab monotherapy in the initial treatment of iBCL has been proven. Interferon alpha (IFN-α) was effective in modulating immune responses and may enhance the clinical efficacy of rituximab in vitro and in vivo studies. Clinical combination of rituximab and conventional IFN-α was associated with fewer early treatment failures compared to single agent rituximab. Peginterferon-α-2(peg-IFN-α2) has a longer half-life with less toxicity. It is also recommended as one of the therapeutic options for chronic hepatitis B virus (CHB) infection. The RIPPLE study (ClinicalTrials. gov identifier: NCT04246359) was initiated to evaluate the efficacy and safety of rituximab plus pegylated interferon α-2b for treatment-naive patients with iBCL. This publication provides long-term follow-up data.

Background:

Hepatitis B virus (HBV) infection is endemic in some parts of Asia, Africa, and South America and remains to be a significant public health problem in these areas. It is known as a leading risk factor for the development of hepatocellular carcinoma, but epidemiological studies have also shown that the infection may increase the incidence of several types of B-cell lymphoma. Here, by characterizing altogether 275 Chinese diffuse large B-cell lymphoma (DLBCL) patients, we showed that patients with concomitant HBV infection (surface antigen positive [HBsAg+]) are characterized by a younger age, a more advanced disease stage at diagnosis, and reduced overall survival. Furthermore, by whole-genome/exome sequencing of 96 tumors and the respective peripheral blood samples and targeted sequencing of 179 tumors from these patients, we observed an enhanced rate of mutagenesis and a distinct set of mutation targets in HBsAg+ DLBCL genomes, which could be partially explained by the activities of APOBEC and activation-induced cytidine deaminase. By transcriptome analysis, we further showed that the HBV-associated gene expression signature is contributed by the enrichment of genes regulated by BCL6, FOXO1, and ZFP36L1. Finally, by analysis of immunoglobulin heavy chain gene sequences, we showed that an antigen-independent mechanism, rather than a chronic antigenic simulation model, is favored in HBV-related lymphomagenesis. Taken together, we present the first comprehensive genomic and transcriptomic study that suggests a link between HBV infection and B-cell malignancy. The genetic alterations identified in this study may also provide opportunities for development of novel therapeutic strategies.

Blockade of the programmed cell death 1-programmed cell death ligand 1 pathway is a new and promising therapeutic approach in Hodgkin lymphoma (HL). To our knowledge, the impact of soluble programmed cell death ligand 1 (sPD-L1) serum levels on HL patient prognosis has not yet been investigated. In this study, the prognostic value of sPD-L1 was assessed in patients with HL. We measured serum sPD-L1 levels and identified their prognostic value in 108 newly diagnosed HL patients using an enzyme-linked immunosorbent assay (ELISA). We found higher serum sPD-L1 concentrations in HL patients than in healthy controls. The best sPD-L1 cutoff value for predicting disease progression risk was 25.1674 ng/ml. The 4-year progression-free survival (PFS) rates for the high-sPD-L1 and low-sPD-L1 groups were 78.8% and 93.3%, respectively. Multivariate survival analysis showed that advanced stage and higher sPD-L1 levels (>25.1674 ng/ml) were independent prognostic factors for shorter PFS. In addition, higher sPD-L1 levels were positively correlated with advanced stage and negatively correlated with peripheral blood monocyte number. The serum sPD-L1 level is an independent prognostic factor for PFS in HL patients and may allow identification of a subgroup of patients who require more intensive therapy and who may benefit from anti-PD-1 agents.

Hemophagocytic syndrome (HPS) is a fatal hyperinflammatory disease with a poorly understood mechanism that occurs most frequently in extranodal natural killer/T cell lymphoma (ENKTL). Through exome sequencing of ENKTL tumor–normal samples, we have identified a hotspot mutation (c.419T>C) in the evolutionarily conserved signaling intermediate in Toll pathway (ECSIT) gene, encoding a V140A variant of ECSIT. ECSIT-V140A activated NF-κB more potently than the wild-type protein owing to its increased affinity for the S100A8 and S100A9 heterodimer, which promotes NADPH oxidase activity. ECSIT-T419C knock-in mice showed higher peritoneal NADPH oxidase activity than mice with wild-type ECSIT in response to LPS. ECSIT-T419C-transfected ENKTL cell lines produced tumor necrosis factor (TNF)-α and interferon (IFN)-γ, which induced macrophage activation and massive cytokine secretion in cell culture and mouse xenografts. In individuals with ENKTL, ECSIT-V140A was associated with activation of NF-κB, higher HPS incidence, and poor prognosis. The immunosuppressive drug thalidomide prevented NF-κB from binding to the promoters of its target genes (including TNF and IFNG), and combination treatment with thalidomide and dexamethasone extended survival of mice engrafted with ECSIT-T419C-transfected ENKTL cells. We added thalidomide to the conventional dexamethasone-containing therapy regimen for two patients with HPS who expressed ECSIT-V140A, and we observed reversal of their HPS and disease-free survival for longer than 3 years. These findings provide mechanistic insights and a potential therapeutic strategy for ENKTL-associated HPS.

Background:

Background:Peripheral T cell lymphoma (PTCL) and Extranodal NK/T cell lymphoma (ENKTCL) are rare types of non-Hodgkin’s lymphoma (NHL), with a higher incidence in Asian countries. Outcomes for patients with relapsed or refractory (R/R) PTCL and ENKTCL are very poor. There is still a lack of effective treatment for these patients. Mitoxantrone is a synthetic anthracenedione anti-cancer drug that is effective in lymphoma, leukemia, and other solid tumors. Liposome preparations have shown higher anti-tumor effect and lower toxicities due to modified drug release and particle shape. Mitoxantrone hydrochloride liposome (PLM60) was manufactured by Shijiazhuang Pharmaceutical Group Co., Ltd. (CSPC). High accumulation in tumor tissue was a key characteristic of PLM60 in our preclinical investigation. The pharmacokinetic parameters, especially half-life of PLM60 was prolonged significantly in phase I trial. Phase II exploratory clinical trial showed promising results in R/R PTCL. Therefore, we conducted this pivotal registration phase II trial to evaluate the efficacy and safety of PLM60 in patients with R/R PTCL and ENKTCL. At the present time, this was the first clinical trial to assess PLM60 in treating R/R PTCL and ENKTCL worldwide.

Xia: CSPC ZhongQi Pharmaceutical Technology (Shijiazhuang) Co., Ltd.: Current Employment. Xue:CSPC ZhongQi Pharmaceutical Technology (Shijiazhuang) Co., Ltd.: Current Employment. Li:CSPC ZhongQi Pharmaceutical Technology (Shijiazhuang) Co., Ltd.: Current Employment.

No relevant conflicts of interest to declare.Sintilimab is medication that is indicated for the treatment of relapsed or refractory classical Hodgkin's lymphoma after failure of at least second-line systemic chemotherapy.

Background:ENKTL is a highly aggressive NHL related to Epstein-Barr virus, with a higher incidence in Asia. Patients with r/r-ENKTL have a poor prognosis after failing asparaginase based regimen, and there is lack of effective treatment. Anti-PD-1 antibody represented a favorable treatment for rr-ENKTL. ORIENT-4 trial demonstrated Sintilimab was effective and well tolerated in r/r-ENKTL. The efficacy of Chidamide, an oral HDACi was reported on rr-ENKTL(CHIPEL trial, 2017 ASH). Here we present preliminary results of Sintilimab plus Chidamide for r/r-ENKTL.

Macrophages are polarized into two functionally distinct forms, M1 and M2, in response to different microenvironment. Tumor-associated macrophages (TAMs) generally have M2 phenotype and promote tumor progression. Few studies to date have described the infiltration of M2-polarized macrophages in ovarian cancer. We used two macrophages markers, CD68 and CD163, to analyze the expression of TAMs and to clarify the relationship between the M2 form and survival in advanced ovarian cancer. Clinical data of 110 patients with stages III-IV epithelial ovarian cancer at Sun Yat-sen University Cancer Center between 1999 and 2007 were retrospectively reviewed. Immunohistochemical staining of CD68 and CD163 was performed. Correlations between macrophage density and patient survival were analyzed. Our data showed that no significant difference was observed in survival between patients in the high- and the low-CD68 expression groups. In contrast, the progression-free survival (PFS) rates (p= 0.003) and overall survival (OS) rates (p= 0.004) were significantly higher in the low-CD163 expression group than in the high-CD163 expression group, respectively. Similarly, we also observed significantly improved 3-year PFS (49.8% vs. 11.0%, p< 0.001) and OS (77.4% vs. 45.0%, p< 0.001) rates in patients in the low-CD163/CD68 ratio group when compared with the high-CD163/CD68 ratio group. Multivariate analysis identified the density of CD163-positive cells as well as the ratio of CD163/CD68 as negative predictors for PFS and OS, respectively. Our results show that the infiltration of CD163-positive M2 macrophages as well as activation of macrophages towards the M2 phenotype may contribute to poor survival in advanced ovarian cancer.

Objectives:We aimed to determine the efficacy and toxicity of treating locally advanced cervical cancer (LACC) with a neoadjuvant chemotherapy (NAC) regimen combining docetaxel and cisplatin followed by radical surgery.Methods:We retrospectively reviewed the clinical records of patients with stage IB2 – IIB (tumor diameter ≥ 4 cm) disease admitted between January 2007 and July 2009 who, before radical hysterectomy and pelvic lymph node dissection, received two to three courses of an NAC regimen comprising docetaxel (75 mg/m2) and cisplatin (70 – 75 mg/m2).Results:Fifty-two patients with LACC received 109 cycles of NAC. The objective response rate was 86.5% (26.9% CR and 17.3% pathological CR). Stage IB2 disease had a more favorable response to NAC (95.7%, p 0.019). Deep stromal invasion and lymph-vascular space metastasis rates were significantly lower in NAC responders (p 0.033) than in nonresponders (p 0.012). Most side effects of NAC were mild or moderate. Log-rank test showed the 2-year overall survival and progression-free survival rates were 100 and 90.3% for NAC responders, compared with only 57.1% (p 0.000) and 68.6% for nonresponders (p 0.012), respectively.Conclusion:Neoadjuvant docetaxel combined with cisplatin yielded a high response rate with well tolerable toxicity for LACC and could decrease pathological risk factors in NAC responders.

Objective: Hepatitis B virus (HBV) reactivation is a well-known complication in cancer patients receiving cytotoxic chemotherapy, resulting in varying degrees of liver damage. The objective of this study was to investigate the efficacy of lamivudine for the prevention of HBV reactivation in non-Hodgkin's lymphoma (NHL) patients undergoing high-dose chemotherapy and autologous hematopoietic stem cell transplantation (AHSCT). Research design and methods: Thirty-two patients with NHL who were HBV surface antigen (HBsAg)-positive were enrolled in this pilot study. They were divided into two groups: 20 patients received prophylactic oral lamivudine 100 mg/day before, and until at least 6 months after transplantation. The historical control group comprised 12 patients who received high-dose chemotherapy and AHSCT without lamivudine. The incidence and severity of hepatitis due to HBV reactivation, as well as other adverse clinical outcomes, were compared between the two groups. Results: Most baseline clinical characteristics were similar in the two groups, except for HBV e-antigen (HBeAg)-positive status (85% in the lamivudine group vs 33.3% in the control group, p 0.006) and the type of AHSCT. There was a lower incidence of hepatitis due to HBV reactivation in the lamivudine group than in the control group (10 vs 50%, p 0.030), less severe hepatitis (0 vs 25%, p 0.009), and lower mortality (0 vs 25%, p 0.236). An HBV variant with tyrosine methionine aspartate aspartate (YMDD) mutation was detected in one patient in the lamivudine group (5%) after administration of lamivudine for 9 months. No significant adverse events were associated with the use of prophylactic lamivudine, and hematopoietic reconstitution was not affected by the intervention. Conclusions: Prophylactic lamivudine may reduce the incidence and severity of chemotherapy-related HBV reactivation and hepatitis-related mortality in HBsAg-positive NHL patients receiving high-dose chemotherapy and AHSCT. Additional randomized, multicenter trials are warranted.

Background/objective: We investigated the efficacy and safety of transdermal fentanyl for severe mucositis pain caused by chemotherapy. Methods: Thirty-two patients who had moderate to severe pain using the Numeric Rating Scale (NRS) were enrolled in this study. The analgesic effect, quality of life and side effects were evaluated after the administration of transdermal fentanyl. Results: The median NRS score was reduced from 6 (range 4 – 9) before treatment to 4 (range 0 – 9), 2.5 (range 0 – 8), 2 (range 0 – 8), 2 (range 0 – 6) and 0 (range 0 – 5) on days 3, 5, 7, 10 and 15, respectively, after treatment (p < 0.001). The patients' quality of life also improved significantly (p < 0.01). The side effects of treatment were mild, and disappeared within several days. Conclusions: Transdermal fentanyl is an effective, convenient and well-tolerated treatment for severe mucositis pain caused by chemotherapy that can improve patients' quality of life.

Background:Indolent B-cell lymphoma (iBCL) are clinically heterogeneous and accounts for 10-15% of all kind of subtypes in NHL in China. Although iBCL have a relatively good survival, majority of these lymphomas is considered incurable. The favorable activity and safety profile of rituximab monotherapy in the initial treatment of iBCL has been proven. Interferon alpha (IFN-α) has been proven to be effective in modulating immune responses and may enhance the clinical responses to rituximab in vitro and in vivo studies. Clinical combination of rituximab and IFN-α was associated with fewer early treatment failures compared to single agent rituximab. Peginterferon-α-2(peg-IFN-α2) has a longer half-life with less toxicity. It also is one of the options for the treatment of chronic hepatitis B virus (CHB) infection. Therefore, we hypothesized that peg-IFN-α2 may synergize with rituximab and would minimize or eliminate minimal residual disease (MRD). The purpose of this study is to evaluate the efficacy and safety for this combination in pts(pts) with treatment-naive iBCL.

Background

No relevant conflicts of interest to declare.

Lou: Antengene Therapeutics Ltd.: Current Employment. Fei: Antengene Therapeutics Ltd.: Current Employment. Wang: Antengene Therapeutics Ltd.: Current Employment. Lynch: Antengene Therapeutics Ltd.: Current Employment.