Pyroptosis is a form of programmed cell death characterized by the cleavage of gasdermin (GSDM) family proteins that form pores in the plasma membrane, cell rupture, and the release of pro-inflammatory cytokines. In this study, we performed immunohistochemistry for cleaved GSDMD, GSDME-N-terminal, and GSDMC in two different cohorts of diffuse large B-cell lymphoma (DLBCL), and analyzed their prognostic and immune impact. The results showed frequent cleaved GSDMD (GSDMD-N-terminal) expression. Only cytoplasmic GSDMD-N-terminal expression correlated with significantly better patient survival in two cohorts. In contrast, GSDME was mainly expressed in the vascular endothelium, correlated with significantly adverse prognostic effect. Correlating with the multiplex fluorescent immunohistochemistry (mfIHC) results, we found that cytoplasmic GSDMD-N-terminal expression was associated with increased CD38+ (activated) M1 macrophages in both cohorts, cognate interactions between live DLBCL cells and activated M1 macrophages (and T cells), and lower PD-1/PD-L1 expression in the analyzed cases. In contrast, T cell pyroptosis, lymphoma cell resistance to cell death, and phagocytosis by M2 macrophages were observed in cells with nuclear GSDMD-N-terminal expression. Bulk gene expression profiling and deconvolution analysis for patients with cytoplasmic GSDMD-N-terminal expression revealed downregulation of “Don’t eat me” signaling genes, upregulation of many RNA genes, decreased frequency of “Inflammatory” lymphoma microenvironment subtype, increased abundance of prognostically favorable cell states and ecotypes, and decreased abundance of T cell exhaustion state. In summary, this study showed distinct cellular and subcellular patterns of three gasdermin proteins and their associated immune response phenotypes and prognostic effects, with implications for novel therapeutic strategies for B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL), the most common type of lymphoma, arises from various pathogenic mechanisms including gene translocations and fusions. Detection of gene rearrangements using fluorescence in situ hybridization (FISH) is a standard practice for DLBCL diagnosis and guides treatment decisions. High-throughput chromosome conformation capture (Hi-C) DNA sequencing is a next-generation sequencing-based technology to identify genome-wide rearrangements using a single assay. In this study, Hi-C sequencing was performed using FFPE tissues from 159 patients with DLBCL, and identified 746 cancer genes at or proximal to the rearrangement breakpoints with a total of 1903 occurrences. Focusing on clinically important rearrangements, Hi-C detected 102 rearrangements of MYC, BCL2, and/or BCL6 in 92 patients and revealed the fusion partners, including 25 rearrangements missed by FISH. Causes of FISH negative results included FISH-cryptic breakpoints, complex or faint FISH signals, low percentage of FISH positivity, and issues related to tissue fixation. Moreover, in 20 patients (12.6%), Hi-C sequencing detected 22 rearrangements characteristic of other lymphoma types, including CCND1 rearrangements that could lead to reclassification as mantle cell lymphoma. Survival analysis for genome-wide rearrangements using machine learning models identified MYC, PD-L1, CCND1, BCL2, NTRK1/PRCC, RRAS, and FANCE rearrangements with significant prognostic effects in the DLBCL cohort. In conclusion, Hi-C sequencing detects gene rearrangements crucial for diagnosis in an unbiased and molecular manner and showed high sensitivity and specificity in our study. These advantages of Hi-C sequencing offer help to improve the workflow of clinical pathology laboratories, diagnostic precision, and treatment of large B-cell lymphoma.

Single-arm trials (SATs) are clinical studies without a parallel control group, serving as a vital alternative to randomized controlled trials (RCTs) in scenarios where traditional trial designs are impractical. These trials are particularly relevant in rare diseases, advanced malignancies, novel treatment modalities, and life-threatening conditions, where ethical concerns, logistical challenges, or small patient populations limit the feasibility of RCTs. SATs enable expedited evaluation of therapeutic interventions, often forming the foundation for regulatory approvals. This article explores the principles, applications, and methodological considerations of SATs. Their advantages include smaller sample size requirements, faster timelines, and regulatory acceptance by agencies such as the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA). Despite these benefits, SATs face challenges, such as potential biases due to the lack of a control group, limitations in endpoints, and reliance on historical controls that may compromise result validity. Best practices in SAT design are outlined, including refining scientific questions, defining eligibility criteria, selecting clinically meaningful endpoints, and employing robust statistical methods like Simon's two-stage design and Bayesian approaches.

The International Prognostic Index (IPI) remains widely used for risk stratification in diffuse large B-cell lymphoma (DLBCL). However, its predictive accuracy is suboptimal in the era of immunochemotherapy. Leveraging individual-level data from the phase III GOYA trial (NCT01287741), we developed and validated machine learning (ML) models integrating clinical, laboratory, imaging, and immunohistochemical variables to predict 1-, 2-, and 3-year overall survival (OS) in newly diagnosed DLBCL patients. We analyzed 1,166 patients with complete OS data from the GOYA trial (2011–2014), a global phase III study comparing G-CHOP versus R-CHOP in untreated DLBCL, accessed via the Vivli platform. OS (204 events) was defined as time from randomization to death from any cause. Baseline features included 15 variables eccompassing clinical factors (e.g., ECOG, age), laboratory markers (e.g., LDH, albumin, lymphocyte and monocyte counts), imaging-based tumor burden including bulky disease (maximum diameter >7.5 cm) and SPD (sum of the product of perpendicular diameters), and immunohistochemical markers (e.g., BCL2, COO). Patients were randomly split into training and test sets (70:30) stratified by OS status. Continuous variables were standardized. Missing values <1% were imputed using median/mode; COO (20.8%) and BCL2 (35.2%) were imputed using multiple imputation with missingness indicators. We trained Cox proportional hazards, random survival forest (RSF), and XGBoost models. Hyperparameters were tuned via 5-fold cross-validation for RSF and XGBoost. Model performance was assessed via 5-fold cross-validation (Cox/XGBoost) or out-of-bag estimation (RSF) in the training dataset, and evaluated using Harrell's concordance index (C-index) and time-dependent area under the ROC curve (AUC). Risk stratification was performed using the cumulative hazard function (CHF) predicted by the RSF model. 1000 bootstrap samples were created and used to calculate cutoff values for high, medium and low risk groups. Kaplan-Meier curve was created and log-rank test was applied to evaluate the goodness of risk stratification. In the test set, the RSF model achieved the best performance with AUCs of 0.78, 0.71, and 0.72 for 1-, 2-, and 3-year OS prediction (C-index: 0.71), followed by XGBoost (AUCs: 0.75, 0.70, 0.71; C-index: 0.69) and Cox (AUCs: 0.69, 0.67, 0.68; C-index: 0.66). All three models outperformed the classical IPI model (AUCs: 0.71, 0.67, 0.66; C-index: 0.65). SHAP and variable importance analyses consistently identified albumin, LDH, SPD, and age as the top predictors. RSF-based CHF stratified patients into low (<0.226), medium (0.226–0.330), and high (>0.330) risk groups, with distinct 36-month OS rates: 98.7%（95% Confidence Interval(CI):0.97-0.99）, 82.4%（95% CI:0.77-0.89）, and 54.3%（95% CI:0.48-0.61） (log-rank p<0.001). ML-based models, particularly RSF, improved OS prediction and risk stratification beyond IPI and Cox models in newly diagnosed DLBCL. Albumin, LDH, SPD, and age emerged as key prognostic variables. These findings support the integration of ML approaches in individualized treatment planning for DLBCL patients.

Objective: To compare the consistency of lymphoma multigene detection panels based on next-generation sequencing (NGS) with FISH detection of B-cell lymphoma gene rearrangement. Methods: From January 2019 to May 2023, fusion genes detected by lymphoma-related 413 genes that targeted capture sequencing of 489 B-cell lymphoma tissues embedded in paraffin were collected from Henan Cancer Hospital, and the results were compared with simultaneous FISH detection of four break/fusion genes: BCL2, BCL6, MYC, and CCND1. Consistency was defined as both methods yielding positive or negative results for the same sample. The relationship between fusion mutation abundance in NGS and the positivity rate of cells in FISH was also analyzed. Results: Kappa consistency analysis revealed high consistency between NGS and FISH in detecting the four B-cell lymphoma-related gene rearrangement (P<0.001 for all) ; however, the detection rates of positive individuals differed for the four genes. Compared with FISH, NGS demonstrated a higher detection rate for BCL2 rearrangement, a lower detection rate for BCL6 and MYC rearrangement, and a similar detection rate for CCND1 rearrangement. No correlation was found between fusion mutation abundance in NGS and the positivity rate of cells in FISH. Conclusions: NGS and FISH detection of B-cell lymphoma gene rearrangement demonstrate overall good consistency. NGS is superior to FISH in detecting BCL2 rearrangement, inferior in detecting MYC rearrangement, and comparable in detecting CCND1 rearrangement.

Conclusion Introduction：PCNSL is a diffuse large B cell lymphoma (DLBCL) occurring exclusively in the brain, spinal cord, cranial nerves, leptomeninges and/or eyes. Pathophysiology is incompletely understood, although a central role seems to comprise immunoglobulins binding to self-proteins expressed in the central nervous system (CNS) and alterations of genes involved in B cell receptor, Toll-like receptor and NF-κB signalling. Standard of care includes methotrexate-based polychemotherapy followed by age-tailored thiotepa-based conditioned autologous stem cell transplantation, whole-brain radiotherapy or singledrug maintenance。Lenalidomide, an immunomodulatory agent that penetrates the CNS, has shown promise in relapsed/refractory (R/R) aggressive NHL, with well-demonstrated singleagent activity and tolerability. We hypothesized that lenalidomide combined with immunochemotherapy(MTX-based regimen)might be a favorable option for PCNSL pts. Here, we present preliminary data from the phase 2 trial of lenalidomide combined with immunochemotherapy in PCNSL pts (NCT04737889). To investigate the efficacy of lenalidomide combined with immunochemotherapy in untreated PCNSL.The primary objective is 2-year progression free survival(PFS). The secondary objectives are objective response rate (ORR), incidence of grade 3/4 adverse event (AE), and overall survival (OS). aged 18-75 years untreated PCNSL and adequate organ function are being enrolled.Lenalidomide(25mg qd po,totally 10 days/cycle) plus R-MT(Rituximab-Methotrexate+Temozolomide) was administered in TN PCNSL. A totally of 6 cycles of treatment was planned for pts. Completed responders(CR) undergo autologous stem cell transplantation (ASCT) 、reduced dose whole brain radiotherapy or lenalidomide maintenance for 24 months, based on the patient's fitness and preference. RESULTS：From March 2019 to 18 April 2023, 24 pts have been enrolled . Their baseline characteristics are displayed in Table 1. By 30 May 2025, all pts had been evaluated for response. There were 19 CRs (79.2%), 3 PRs (12.5%) and 2 PDs(8.3%) . The median follow-up time was10 (1.2 - 51.4) months . One pt withdrew informed consent due to grade 3 renal toxicity , One died from non-tumor-related disease. Two year progression-free survival (PFS) and overall survival was 62% and 67%，respectively,the median PFS and OS not achieved. The most common adverse events were hematologic toxicities. Grade 3/4 AEs occurred in ≥20% pts were neutropenia, leukopenia .Grade 3/4 non-hematologic AEs occurred in ≥20% pts was hepatic injury. Lenalidomide combined with immunochemotherapy showed encouraging activity and acceptable tolerance in pts with TN PCNSL.The study is still ongoing and it is worth looking forward to updating the long-term survival data.

BACKGROUND:More and more novel anticancer drugs have been approved for patients with hematological malignancies in recent years, but HBV reactivation (HBV-R) data in this population is very scarce. This study aimed to evaluated HBV-R risk in patients with hematological malignancies receiving novel anticancer drugs. METHODS:HBV markers and serum HBV DNA levels of patients with hematological malignancies receiving novel anticancer drugs in a tertiary cancer hospital were retrospectively collected. HBV-R risk in the whole cohort and subgroups was described. The relevant literature was reviewed to make a pooled analysis. RESULTS:Of 845 patients receiving novel anticancer drugs, 258 (30.5%) were considered at risk for HBV-R. The median duration of exposure to novel drugs was 5.6 (0.1-67.6) months. The incidence of HBV-R was 2.1% in patients with past HBV infection without prophylactic antiviral treatment (PAT) and 1.2% in all patients at risk of HBV-R. In a pooled analysis of 11 studies with 464 patients, the incidence of HBV-R was 2.4% (95% CI: 1.3-4.2) in all at-risk patients receiving novel anticancer drugs and 0.6% (95% CI: 0.03-3.5) in patients with anticancer drugs plus PAT. The incidence of death due to HBV-R was 0.4% (95% CI: 0.1-1.6) in all at-risk patients and 18.2% (95% CI: 3.2-47.7) in patients with HBV-R. CONCLUSION:Most episodes of HBV-R are preventable, and most cases with HBV-R are manageable. We recommend that novel anticancer drugs should not be intentionally avoided when treating cancer patients with HBV infection.

Figure S3 shows the survival curve of patients treated by CHOP regimen.There was survival indifference between patients with distinct CACNA1C expression in the setting of CHOP treatment (p>0.05).

Extranodal NK/T-cell lymphoma (ENKTCL) is the most common subtype of T/NK-cell lymphoma in Asia and Latin America, but very rare in North American and Europe. Patient survival has improved significantly over the past two decades. However, standard treatment has not yet been established, although dozens of prospective trials have been conducted. To help understand how the treatment of ENKTCL has evolved in the past and what trends lie ahead, we have comprehensively reviewed the treatment of this aggressive malignancy, with a particular focus on neglected or unanswered issues, such as the optimal staging method, the best partner of asparaginase (Asp), the individualized administration of Asp, the preferred sequence of CT and RT and so on. Overall, the 5-year overall survival (OS) of patients with Ann Arbor stage I/II disease increased from < 50% in the early 20th century to > 80% in recent years, and the median OS of patients with Ann Arbor stage III/IV disease increased from < 1 year to more than 3 years. The improvement in patient survival is largely attributable to advances in radiation technology and the introduction of Asp and anti-PD-1/PD-L1 immunotherapy into practice. Radiotherapy is essential for patients with early-stage disease, while Asp-based chemotherapy (CT) and PD-1/PD-L1 inhibitors significantly improved the prognosis of patients with advanced-stage disease. ENKTCL management is trending toward simpler regimens, less toxicity, and higher efficacy. Novel drugs, such as manufactured T cells, monoclonal antibodies, and small molecule inhibitors, are being intensively investigated. Based on the fact that ENKTCL is highly resistant to cytotoxic drugs except Asp, and aggressive CT leads to higher toxicity rather than better outcomes, we recommend it is unnecessary to expend additional resources to compare different combinations of Asp with cytotoxic agents. Instead, more efforts should be made to optimize the use of Asp and immunotherapy to maximize efficacy and minimize toxicity, explore ways to overcome resistance to Asp and immunotherapy, identify novel treatment targets, and define subpopulations who may benefit more from specific treatments.

Introduction: Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma (NHL). Currently, R-CHOP (Rituximab-Cyclophosphamide, Epirubicin, Vincristine and Prednisone) is world-widely used in the first-line treatment for DLBCL, producing a long-term survival rate of approximately 60%. The unmet need is focused on high-risk DLBCL patients, having high International Prognostic Index (IPI) scores, non-germinal center-like B cell (non-GCB) origin, double expression of MYC and BCL2 protein, or TP53 aberrations. Lenalidomide is an active agent in the activated B cell-like (ABC) subtype of DLBCL by increasing interferon-stimulated gene transcription and activation of immunomodulatory mechanisms. At present, it has been approved for the treatment of multiple myeloma with good efficacy and safety. This is a prospective single arm, multi-center, phase II clinical trial and the goal of our trial is to assess the efficacy and safety of R-CHOP combined with lenalidomide in the first-line treatment for patients with high risk diffuse large B cell lymphoma. Methods: We did an investigator-initiated, open-label, phase 2 trial at the Affiliated Cancer Hospital of Zhengzhou University in China. Patients were eligible if they were aged over 18 years, had histologically confirmed DLBCL. The key inclusion criteria included untreated and medium to high /high risk DLBCL (International Prognostic Index (IPI) score 3-5, aaIPI score 2-3 or NCCN-IPI score≥ 4/ Immunohistochemical staining of double expression (BCL2 ≥ 50% and C-MYC ≥ 40%) or P53 protein mutation positive ≥ 50%). Participants in RL-CHOP cohort were given Lenalidomide orally 25 mg per day on days 1 through 10 of each cycle and delivered concomitantly with standard dose R-CHOP-21 chemotherapy. We also set another group treated with conventional R-CHOP-21 used as a matched contemporary cohort. The primary clinical endpoint was 2-year progression-free survival (PFS). The secondary efficacy endpoints were objective response rate (ORR), 2-year overall survival (OS) and safety. This trial is registered with ClinicalTrials.gov, number NCT04214626. Results: Between December 2019 and January 2023, 63 patients with untreated DLBCL enrolled and were evaluable in the investigator-initiated phase II study. The median age was 59 years (range: 25-76 years); 49.2% of patients were older than age 60 years. 46 of 63 patients (73.02%) had a ECOG score of 0-1; 43 of 63 patients (68.25%) had stage III-IV disease, and 33 of 63 patients (52.38%) had ≥2 extranodal localizations. The IPI score was high-intermediate and high in 73.02% (46/63) of patients. 51 of 63 patients (80.95%) were non-GCB subtype; 25 of 63 patients (39.68%) were double expressor. The TP53 protein was positive in 34.55% (19/55) of patients. In RL-CHOP cohort, the complete response rate was 80.95%, with overall response rate achieving 100%. The median follow-up time was 18.25 (3.73-42) months, median PFS and OS were not reached, and 2-year PFS and OS was 71.1% (+-6.7) and 87.4% (+-4.5), respectively. Comparing with historical matched contemporary cohort, the 2-year PFS and OS rates were improved for medium to high /high risk DLBCL. The most common adverse events of treatment were hematologic toxicities. Grade 3/4 AEs occurred in ≥20% patients were neutropenia, leukopenia, anemia, thrombocytopenia and decreased serum potassium, without bleeding complications. No grade 4 non-hematological adverse event was reported. Conclusion: RL-CHOP is effective and safe in patients with newly diagnosed DLBCL with high risk. Relevance of molecular biomarkers on RL-CHOP response warrants further investigation in DLBCL.

Background: Primary mediastinal B-cell lymphoma (PMBCL) is a rare aggressive B-cell lymphoma of thymic origin. Due to the low incidence rate of PMBCL, there is currently no internationally accepted standard first-line treatment regimen. Dose-adjusted (DA) EPOCH-R which is the more commonly used first-line therapy plan is not so effective because patients usually cannot tolerate it. The R-CHOP regimen is comparable to the R-DA-EPOCH for the first-line treatment of PMBCL in terms of survival and has a better safety profile (Bhatt, V.R. et al, Cancer Treat Rev 2015; Iwanicka el al., Curr Hematol Malig Rep 2014). Meanwhile, patients with PMBCL usually have alterations of 9p24.1, leading to overexpression of PDL-1/2. Previous studies have found that PD-1 monoclonal antibody shows good efficacy in recurrent and refractory PMBCL (Steidl et al., Blood 2011; Zinzani et al., Blood 2017). Tislelizumab, a humanized IgG4 antibody that binds PD-1 with high affinity, minimizes binding to Fcγ receptor 1 (FcγRI) on macrophages by the genetic engineering of Fc segment, abrogating antibody-dependent phagocytosis (ADCP)-induced T-cell clearance. The efficacy and safety of its combination with R-CHOP in previously untreated PMBCL is not yet clear. We speculate that the combination of both may be a new option for the first-line therapy for PMBCL patients with good efficacy and low toxicity. Methods: This is a single-arm, multi-center, phase II clinical study (ChiCTR2100044313). Patients aged 18 years or older with a diagnosis of PMBCL and previously untreated were eligible. Eligible patients received 6 cycles of Tislelizumab (200 mg D1), Rituximab (375 mg/m 2 D1), Cyclophosphamide (750 mg/m 2 D2), Pirarubicin (50 mg/m 2 D2), Vincristine (1.4 mg/m 2, maximum dose 2 mg, D2), Prednisone (100 mg/d D2-6), every 21 days for 1 cycle. Disease response assessments were performed by positron emission tomography and computed tomography (PET-CT) or enhanced CT every two cycles, meanwhile peripheral blood ctDNA was monitored, and treatment-related adverse effects were assessed and recorded. The primary endpoint was objective remission rate (ORR). The secondary endpoints included treatment safety, progression-free survival (PFS) and overall survival (OS), and the exploratory analyses of the correlation between PD-L1 expression in tumor tissues, tumor-associated macrophages (TAM) phenotype in tumor microenvironment and efficacy. Results: From June 2020 to June 2023, 12 patients were enrolled and 9 patients had evaluable efficacy with the median age of 34 years, 3 males and 6 females, all patients had large mediastinal mass at initial diagnosis. 7 patients had PD-L1 expression (VENTANA SP263) above 80% and 2 cases could not be further tested due to insufficient tissue specimens. The ORR was 100%, and the CR rate was 77.8% (7/9) after 6 cycles of treatment. The 5 th and 9 th patient reached PR after 6 cycles of treatment due to irregular hospitalization. And CR was achieved after 2 cycles of regular treatment for the 5 th patient. NGS from formalin-fixed paraffin-embedded (FFPE) and circulating tumor DNA (ctDNA) evaluation from blood were performed across all patients before treatment. 5 patients underwent end of treatment-ctDNA test. Median follow-up 15m (6.8m-26.3m), the third patient was lost to follow-up at 9m. The other patients who achieved CR are still at complete remission. Moreover, we found SOCS1, TNFAIP3 are the most frequently mutated genes in biopsies of PMBCL and only the 5th patient had RHOA mutation which is highly related to PMBCL. The PET-CT and ctDNA assessments were negative in three patients at the end of 6 cycles with 60% concordance, and the 5 th and 9 th patient achieved PR on PET-CT, but the ctDNA assessments were negative. The most common adverse events (AEs) were gastrointestinal reactions, 2 patients experienced grade IV myelosuppression and 1 patient had grade I hyperthyroidism. No treatment-related deaths occurred. Conclusion: Tislelizumab combined with R-CHOP for the treatment of previously untreated PMBCL had good efficacy and sustained response with low toxicity. Longer follow-up is required to access the survival benefit of this regimen. Figure 1: Disease Remission in the Included Patients

T淋巴母细胞性淋巴瘤（T-LBL）是一种高度侵袭性的血液恶性肿瘤，其特征是骨髓和外周血中浸润未成熟的T细胞，常侵犯纵隔，骨髓和淋巴结，预后差 [1]。异基因造血干细胞移植（allo-HSCT）可明显改善T-LBL患者的生存 [2]，但复发/难治性T-LBL（R/R T-LBL）患者的预后仍然很差 [3]。嵌合抗原受体T细胞（CAR-T）疗法作为一种新兴的治疗手段，近年来在复发/难治性血液系统恶性肿瘤患者中取得了令人鼓舞的疗效 [4,5,6]。我们采用allo-HSCT联合CD7 CAR-T细胞疗法治疗1例T-LBL获得满意疗效。

Background: Peripheral T-cell lymphoma (PTCL) is a highly heterogenous non-Hodgkin lymphoma with poor survival. Pts with relapsed/refractory PTCL (r/r PTCL) have extremely poor prognosis and limited treatment options. Conventional salvage treatments have a median progression-free survival (PFS) of only 3-4 months. Parsaclisib, a potent, highly-selective, next-generation PI3Kδ inhibitor has shown encouraging efficacy and favorable safety profile in B-cell malignancies. We developed a phase Ib/II study to evaluate the safety and efficacy of parsaclisib with HDAC inhibitor (HDACi) chidamide in r/r PTCL (NCT05083208). Here, we report the preliminary results of this study. Method: Eligible pts were ≤ 75 years old adults with histologically confirmed PTCL who received ≥ prior line of systemic therapy. Phase Ib dose-escalation study determined the maximum tolerated dose (MTD) of parsaclisib with chidamide using a 3 + 3 design. Parsaclisib was administered once daily at 3 dose levels (dose-level (DL) 1: 10 mg; DL2: 15 mg; DL3: 20mg) in the first 8 weeks followed by 2.5 mg QD in the subsequent treatment. Chidamide was administered at a fixed dose of 20 mg twice a week throughout the study. Once the MTD was established, pts were enrolled into phase 2 study to further characterize safety and efficacy. MTD of parsaclisib and objective response rate (ORR) were the primary endpoints; complete response rate (CRR), PFS, overall survival (OS) and tolerability were secondary endpoints. Prophylaxis for Pneumocystis jirovecii pneumonia (PJP) and cytomegalovirus (CMV) infection in the first 8 weeks were required. Results: From March 2022 to July 27, 2023 (date cut-off), 11 pts were recruited with a median age of 52 (39-74) years old. The median number of prior systemic therapies was 2 (1-5). Of 6 pts treated at DL1, 1 had dose-limiting toxicity (DLT) (grade 3 elevation of ALT/AST). No DLT was observed in 3 pts at DL2 and 2 at DL3. The DLT was resolved subsequently but the patient died from lymphoma progression. Treatment-emergent adverse events (TEAEs) were observed in all pts. The TEAEs were mainly hematologic toxicities and gastrointestinal reactions, most of which were grade 1/2. Grade 3/4 TEAEs were neutropenia (n=4), leukopenia (n=1), elevation of ALT/AST (n=1), and diarrhea (n=1) (Table 1). TEAE led to dose interruption in one patient. In 9 pts evaluable for responses (1 withdrew from this study and 1 was unevaluable), 5 (55.6%) pts achieved complete response (CR) and one (11.1%) partial response at the first efficacy assessment. In 7 pts previously exposed to chidamide, 4 pts achieved CR and 2 of them had a PFS > 16 months (Table 2 and Figure 1). Conclusion: Preliminary data demonstrated that selective PI3Kδ Inhibitor parsaclisib with HDACi chidamide was tolerable and produced promising responses in r/r PTCL, including patients previously exposed to chidamide. This trial is currently ongoing.

INTRODUCTION:With the expanding use of immune checkpoint inhibitors (ICIs) in patients with various types of cancers, many more patients are experiencing checkpoint inhibitor-related pneumonitis (CIP). After recovery from CIP, some patients are rechallenged with ICI therapy. The CIP will recur in a considerable proportion of rechallenged patients. When severe or recurrent CIP (rCIP) occurs, ICI therapy is usually terminated, resulting to treatment failure and tumour progression. The feasibility of multiple rechallenges with immunotherapy in patients with rCIP is unknow.CASE PRESENTATION:Two patients with refractory classical Hodgkin lymphoma (cHL) were treated with anti-programmed cell death protein 1 (PD-1) immunotherapy. The lymphoma responded well to the ICI therapy, but both patients experienced CIP. The immunotherapy was suspended and steroid was introduced to treated the CIP. When the CIP resolved, however, the lymphoma progressed.MANAGEMENT AND OUTCOME:The patients were rechallenged with anti-PD-1 immunotherapy in the absence of alternative treatment options. The lymphoma responded again, but the CIP recurred. The immunotherapy was suspended again and steroid was reintroduced. These episodes repeated multiple times. At the time of submission of this manuscript, the tumour in both patients has been controlled for more than 4 years, and the immunotherapy is still continuing.CONCLUSION:Multiple rechallenges with immunotherapy is feasible in selected patients with rCIP.

Background Hodgkin Lymphoma (HL) is a kind of malignant tumor of the lymph system, approximately 95% of which are classical Hodgkin's lymphoma (cHL). ABVD and BEACOPP regimens are commonly used first-line induction treatment regimens for cHL. Sequential radiotherapy for residual lesions or large masses is the current standard treatment after remission. However, disease relapse or drug resistance still occurs in approximately one third of patients, mainly in patients with advanced disease, including Ann Arbor stage III/IV, stage II with B symptoms, and large mediastinal mass or extranodal lesions. Studies have found that the PD-1/PD-L1 pathway plays an important role in the development of cHL disease. Blocking the signaling of the PD-1/PD-L1 pathway may relieve immunosuppression and promote the clearance of RS cells by the immune system. Camrelizumab, a humanized anti-PD-1 IgG4 monoclonal antibody, is independently developed in China. The goal of our trial is to assess the efficacy and safety of Camrelizumab combined with AVD (Epirubicin, Vincristine and Dacarbazine) in the first-line treatment for patients with advanced classical Hodgkin's lymphoma. Methods The patients received 6 cycles of Camrelizumab combined with AVD regimen as first-line therapy. The primary endpoint was objective response rate (ORR), including complete remission (CR) and partial remission (PR), and secondary endpoints were 2-year progression-free survival (PFS), overall survival (OS) and safety. Exploratory endpoints: efficacy and international prognostic score (IPS), hotspot driver gene mutations, characteristic expression (PDL1, BCL2, c-MYC, P53, CD10, BCL6, MUM1/IRF4, and EBER) of tumor cells (RS cells), and correlation of tumor microenvironment and cytokines. Results From September 15, 2019 to June 15, 2022, a total of 20 patients were enrolled, including 4 patients (20%) in stage II, 7 patients (35%) in stage III, and 9 patients (45%) in stage IV; 11 cases (55%) with B symptoms; 1 case (1/16) with IPS score of 0, 5 cases (5/16) with IPS score of 1, 6 cases (6/16) with IPS score of 2, and 2 cases (2/16) with IPS score of 3, and 2 cases (2/16) with IPS score of 4; EBER was positive in 8 cases (40%); lymphoma-related 93 gene detection was performed in 7 cases (35%). At present, 17 patients had completed all the treatments, and the final response of 15 patients had reached CR (88.2%) and 2 patients PR (11.8%). 2-year PFS has not been reached. The combination regimens were well tolerated. Among the 17 patients who had completed all treatments, the common adverse events of treatment were reactive cutaneous capillary endothelial proliferation (RCCEP) in 8 cases (47.1%), gastrointestinal reaction in 6 cases (35.3%), peripheral neuropathy in 4 cases (23.5%), hypothyroidism in 3 cases (17.6%), rash in 2 cases (11.8%), increased AST/ALT levels in 2 cases (11.8%), pneumonitis in 1 case (5.9%), and all of which were grade 1-2. 2 cases of liver function damage was grade 3 (11.8%). Conclusion Camrelizumab combined with AVD has a good effect in the first-line treatment for advanced classical Hodgkin lymphoma, with an objective response rate (ORR) of 100%, and the patients are well tolerated.

BACKGROUND:Extranodal NK/T-cell lymphoma (ENKTCL) is an Epstein-Barr virus (EBV)-related hematological malignancy. The presence of EBV-DNA in peripheral blood is a widely used ENKTCL tumor marker. However, there is no consensus on the preferred blood specimen type for EBV testing. Furthermore, discordance between EBV-based and imaging-based disease assessments is common, and how to interpret this discordance is important.METHOD:We retrospectively analyzed the data of ENKTCL patients in the Affiliated Cancer Hospital of Zhengzhou university and Sun Yat-sen University Cancer Center. All EBV-DNA and imaging-based disease assessment data were collected at diagnosis, during treatment, at the end of treatment, and during follow-up. We compared matched plasma EBV-DNA and peripheral blood mononuclear cell (PBMC) EBV-DNA and matched EBV-based and imaging-based assessments to uncover their clinical relevance.RESULT:A total of 450 patients with adequate data were included, of whom 278 had plasma EBV-DNA data, 250 had PBMC EBV-DNA data, and 78 had matched plasma and PBMC EBV-DNA data. No significant correlations were found between PBMC and plasma EBV-DNA and between PBMC EBV-DNA and imaging-based assessment, but patients with positive PBMC EBV-DNA at diagnosis or intermittently/persistently positive PBMC EBV-DNA during follow-up had poorer survival. In contrast, plasma EBV-DNA strongly correlated with lymphoma status. Detectable pre- and post-treatment plasma EBV-DNA was associated with significantly worse survival. Patients with early-stage disease who had detectable plasma EBV-DNA at the end of treatment shared similar survival to those with advanced-stage disease, even if their imaging-based assessments were negative. For disease relapse monitoring, 78 (55.7%) episodes of relapse were detected by both imaging and plasma EBV-DNA; 58 (41.4%) detected by plasma EBV-DNA earlier than imaging, with a median time of 9.3 (0.3 - 37.8) months; and only 4 (2.9%) detected by plasma EBV-DNA later than imaging. The sensitivities of plasma EBV-DNA, PET/CT, and CT/MRI were 97.1%, 76.8%, and 45.1%, respectively, and their specificities were 91.7%, 84.2%, and 96.7%, respectively. Analysis of EBV kinetic patterns in EBV+/imaging- episodes revealed that relapse occurred only in patients with intermittently/persistently positive plasma EBV-DNA. Persistent plasma EBV+ was also seen in patients after autologous hematopoietic stem cell transplantation. Occasional EBV+ was not associated with relapse.CONCLUSION:Plasma and PBMC EBV-DNA have different clinical relevance in ENKTCL patients. PBMC EBV-DNA does not correlate with imaging-based disease assessment. PBMC or even whole blood should not be used for response evaluation and relapse monitoring. However, PBMC EBV-DNA still has prognostic value. Plasma EBV-DNA is strongly related to tumor status and is not only a prognosticator at diagnosis and end of treatment, but also a sensitive marker in relapse monitoring compared to PET/CT and CT/MRI. The specificity of plasma EBV-DNA is relatively low, but when EBV-DNA kinetic patterns are considered, it can identify at-risk patients.

Background: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous hematologic malignancy with highly variable genetic abnormalities and clinical outcomes, highlighting the importance of individualized treatment. Previous studies showed that CD79B mutation was associated with higher risk of relapse and shorter survival after standard treatment (2020 ASH Abstract 2923), and both CD79B- or CD79A-mutant lymphoma cells were sensitive to BTKi in vitro (Nat Med. 2015;21:922-926.). Thus, we inferred that BTKi combined with immunochemotherapy might be a favorable option for pts with CD79A/CD79B-mutant DLBCL. Here, we present preliminary data from the phase 2 trial of Zanubrutinib combined with immunochemotherapy in pts with CD79A/CD79B-mutant DLBCL (NCT04668365). Aims: To investigate the efficacy of Zanubrutinib combined with immunochemotherapy in pts with CD79A/CD79B-mutant DLBCL. The primary objective is complete response rate (CRR). Methods: Pts aged 18-80 years with CD79A/CD79B-mutant DLBCL and adequate organ function are being enrolled. This study consisted of treatment naïve (TN) cohort and relapsed/refractory (R/R) cohort. Zanubrutinib (160 mg po bid) plus R-CHOP (ZR-CHOP) was administered in TN cohort, and Zanubrutinib (160 mg po bid) combined with investigator-determined conventional salvage chemotherapy (CSC, including ICE, DHAP, GDP, or GemOx, +/- rituximab) was administered in R/R cohort. A totally of 7 cycles of treatment was planned for TN patients. After 5 cycles of induction treatment, responders in R/R cohort undergo autologous stem cell transplantation (ASCT) or Zanubrutinib maintenance for 12 months, based on the patient's fitness and preference. Results: From July 2020 to 22 July 2022, 137 pts have been screened, including 103 TN pts and 34 R/R pts. CD79A/CD79B mutation was identified in 26 (25.2%) TN pts and in 14 (41.2%) R/R pts, of which 14 TN pts and 10 R/R pts agreed to participate in this trial. Their baseline characteristics are displayed in Table 1. By 30 July 2022, 12 TN pts and 9 R/R pts had been evaluated for response. There were 10 CRs (83.3%) and 2 PRs (16.7%) in the TN cohort; 5 CRs (55.6%), 2 PRs (22.2%), and 2 PDs (22.2%) in the R/R cohort. The median follow-up time was 6.4 (2.6 - 24.5) months for the TN cohort and 11.8 (1.4 - 14.9) months for the R/R cohort. One pt (5TN) died from non-tumor-related disease and no PD was observed in the TN cohort. In the R/R cohort, 3 pts experienced PD (all harbored TP53 mutations) and 2 of them (4R/R and 10R/R) died, another pt (8R/R) died from non-tumor-related disease. The most common adverse events in both cohorts were hematologic toxicities. Grade 3/4 AEs occurred in ≥20% pts were neutropenia, leukopenia, anemia, thrombocytopenia, and infection. Bleeding and cardiac events were not observed. Conclusion:CD79A/CD79B mutation was frequent in DLBCL patients, especially in R/R cases. Zanubrutinib combined with immunochemotherapy showed encouraging activity and acceptable tolerance in pts with CD79A/CD79B-mutant DLBCL. TP53 mutation seemed to be a detrimental factor. The study is still ongoing and it is worth looking forward to updating the long-term survival data. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Anthracycline-based chemotherapy resistance represents a major challenge in diffuse large B-cell lymphoma (DLBCL). MiRNA and gene expression profiles ( n = 47) were determined to uncover potential chemoresistance mechanisms and therapeutic approaches. An independent correlation between high expression of miRNA-363-3p and chemoresistance was observed and validated in a larger cohort ( n = 106). MiRNA-363-3p was shown to reduce doxorubicin-induced apoptosis and tumor shrinkage in in vitro and in vivo experiments by ectopic expression and CRISPR/Cas9-mediated knockout in DLBCL cell lines. DNA methylation was found to participate in transcriptional regulation of miRNA-363-3p. Further investigation revealed that dual specificity phosphatase 10 (DUSP10) is a target of miRNA-363-3p and its suppression promotes the phosphorylation of c-Jun N-terminal kinase (JNK). The miRNA-363-3p/DUSP10/JNK axis was predominantly associated with negative regulation of homologous recombination (HR) and DNA repair pathways. Ectopic expression of miRNA-363-3p more effectively repaired doxorubicin-induced double-strand break (DSB) while enhancing non-homologous end joining repair and reducing HR repair. Targeting JNK and poly (ADP-ribose) polymerase 1 significantly inhibited doxorubicin-induced DSB repair, increased doxorubicin-induced cell apoptosis and tumor shrinkage, and improved the survival of tumor-bearing mice. In conclusion, the miRNA-363-3p/DUSP10/JNK axis is a novel chemoresistance mechanism in DLBCL that may be reversed by targeted therapy.

We examined the effects of YM-31636 (2-(1H-imidazol-4-ylmethyl)-8H-indeno[1,2-d]thiazole monofumarate), a novel 5-HT3 receptor agonist, on gastrointestinal functions including visceral pain reflex in rats. Injection of YM-31636 increased the number of fecal pellets. This effect was completely inhibited by ramosetron, a 5-HT3 receptor antagonist. YM-31636 also increased the intracolonic pressure measured in both conscious and anesthetized rats. In isolated distal colon, YM-31636 increased the short-circuit current response. This effect was abolished by ramosetron. Both the maximal response and the potency of YM-31636 were weaker than those of other 5-HT3 receptor agonists. In two visceral pain reflex models, YM-31636 neither changed the magnitude of pressor response to colonic distension in anesthetized rats nor affected the visceromotor threshold to colorectal distension in conscious rats. In conclusion, YM-31636 facilitated defecation without increasing visceral pain. Consequently, 5-HT3 receptor agonists like YM-31636 would be promising in the treatment of chronic constipation.

Primary testicular lymphoma (PTL) is a rare malignancy of testis. Although the multimodality treatment (including orchiectomy, systemic chemotherapy, scrotal radiotherapy, and preventive central nervous system (CNS)-targeted treatment) is widely used to treat PTL, recurrence, especially CNS recurrence, occurred frequently. Patients with relapsed PTL have a dismal prognosis and limited treatment options. In this report, we described the case of a 63-year-old man with early-stage PTL. The patient received the multimodality treatment, but CNS relapse occurred 3 months following the front-line therapy. We gave him a combined chemo-free regimen treatment, including rituximab, ibrutinib, and lenalidomide (RIL), based on the tumor's gene mutation profile and the patient's preference. A complete response was achieved after the first cycle of treatment. Whole-brain radiotherapy was delivered as consolidative treatment following three more cycles of RIL. Thereafter, ibrutinib and lenalidomide continued as maintenance treatment. As of the submission of this manuscript, the response has lasted for more than 16 months. Based on the case, we believe chemo-free regimen RIL might be a favorable approach for PTL patients with CNS relapse, especially those frail elderly patients, when alternative treatments are not available.