Importance:Epigenetic dysregulation is associated with the pathogenesis and progression of diffuse large B-cell lymphoma (DLBCL). MYC/BCL2 double-expressor lymphoma (DEL), a distinct population of DLBCL defined by MYC and BCL2 coexpression, refers to poor prognosis after standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) immunochemotherapy. Tucidinostat (or chidamide), an oral, selective histone deacetylase inhibitor, has shown promising activity in DEL. Objective:To evaluate efficacy and safety of tucidinostat plus R-CHOP vs R-CHOP alone as first-line treatment for patients with DEL. Design, Setting, and Participants:This randomized, double-blind, placebo-controlled phase 3 trial enrolled patients from May 21, 2020, through July 25, 2022, with follow-up to June 26, 2025. The trial was conducted at 40 study centers in China; a total of 423 eligible patients were enrolled. Interventions:Patients were randomly assigned in a 1:1 ratio to receive oral tucidinostat (20 mg on days 1, 4, 8, and 11 of each 21-day cycle) or matching placebo, plus 6 cycles of R-CHOP. Patients with a complete response after combination therapy received either tucidinostat or placebo maintenance up to 24 weeks. Main Outcomes and Measures:The primary end point was event-free survival. Secondary end points included complete response rate, progression-free survival, disease-free survival, overall survival, and tolerability. Results:Among 423 patients randomized (median age, 63 years; 47.5% male), the median follow-up duration from randomization was 41.3 months. The tucidinostat group demonstrated a 28% lower risk of disease progression, relapse after complete response, death, or initiation of new therapy for residual disease compared with the placebo group (stratified hazard ratio, 0.72 [95% CI, 0.54-0.96]; P = .02), with a 2-year event-free survival rate of 60.3% vs 50.5%, respectively. The complete response rate was 73.0% vs 61.8% (difference, 11.1% [95% CI, 2.3%-20.0%]), respectively. Increased toxicity associated with treatment was observed in the tucidinostat group but generally manageable with supportive care. Conclusions and Relevance:Tucidinostat plus R-CHOP significantly improved event-free survival, with manageable toxicity in patients newly diagnosed with DEL. This trial is the first to demonstrate the benefit of an epigenetic modulator in DLBCL, offering a new first-line therapeutic approach dually targeting MYC and BCL2 oncoprotein for this high-risk population. Trial Registration:ClinicalTrials.gov Identifier: NCT04231448.

Background Hedgehog (HH) signaling is aberrantly activated in diffuse large B-cell lymphoma (DLBCL) and contributes to tumor proliferation and drug resistance. However, ligand-independent activation mechanisms, including gene mutations and epigenetic modifications, remain poorly defined. Methods We performed targeted sequencing of 475 lymphoma-related genes in 106 DLBCL patients and conducted genome-wide methylation profiling by circulating cell-free DNA reduced representation bisulfite sequencing (cfDNA-RBS). Promoter methylation and gene expression were validated by amplicon bisulfite sequencing (ampBS) and real-time quantitative PCR(RT-qPCR) in 35 DLBCL tissue samples. Functional effects of the hypomethylating agent azacitidine (AZA) on PTCH1 and downstream HH signaling in DLBCL were assessed in vitro . Results PTCH1 mutations were rare (2.8%) and not associated with adverse outcomes. Hypermethylation of the PTCH1 -T1 (targeting CpG156 island) was identified in DLBCL tissues and cell lines, correlating with reduced PTCH1 expression and increased HH pathway activity ( r = -0.469 and 0.531, respectively; both P < 0.01). AZA treatment reduced PTCH1 -T1 methylation, restored PTCH1 expression, suppressed GLI1 , and inhibited downstream nuclear factor kappa B (NF-κB) and protein kinase B (PKB/AKT) signaling. Conclusions Hypermethylation of PTCH1 promoter represents a key ligand-independent epigenetic mechanism driving HH pathway activation in DLBCL. These findings provide a rationale for targeting DNA methylation as a precision therapeutic strategy.

Complete remissions in subpopulations by assigned treatment group

Rocbrutinib is a fourth-generation Bruton’s tyrosine kinase (BTK) inhibitor that binds covalently to the wild type BTK and non-covalently to the cysteine 481 mutant variant. This phase I study evaluated the pharmacokinetics (PK), safety, and efficacy of rocbrutinib in Chinese patients with relapsed or refractory (R/R) non-germinal center B cell-like (non-GCB) diffuse large B cell lymphoma (DLBCL). Eligible participants were adults with non-GCB DLBCL and had received ≥ 2 prior lines of systemic therapy, including an anti-CD20 antibody-based regimen. Patients received rocbrutinib at 100, 150, 200 or 300 mg once daily (QD) as single agent till disease progression or unacceptable toxicity. Response was evaluated using computerized tomography (CT) and positron emission tomography (PET)-CT at the protocol-defined timepoints by the investigators. PK samples and adverse events were collected per protocol. A total of 45 patients were enrolled, of whom 44.4

Peripheral T-cell lymphoma (PTCL) remains a formidable challenge in clinical management. Histone deacetylase inhibitor chidamide has demonstrated its anti-tumor effects in real-world studies in relapsed or refractory PTCL. To evaluate the efficacy of real-world utilization of chidamide combined with chemotherapy for untreated PTCL and explore relative prognostic factors, a cohort of 151 PTCL patients treated with chidamide combined with chemotherapy as front-line treatment in our center were enrolled. The overall response rate (ORR) and complete remission rate (CRR) at the end of treatment were 81.5% and 67.5%. The 7-year overall survival (OS) rate and progression-free survival (PFS) rate were 67.6% and 49.7%, with a median follow-up period of 21 months, showing its satisfactory efficacy and survival advantage. Most of adverse events were transient and reversible. Furthermore, several baseline characteristics of patients were relevant to prognosis. The study identified gene mutations in TET2 (30.9%), STAT (22.7%), RHOA (17.5%), TP53 (14.4%), DNMT3A (12.4%), with TP53 and DNMT3A mutations correlating with worse clinical outcomes. The identification of gene mutations contributed to personalizing treatment strategies and predicting patient outcomes. This study raised the preliminary hypothesis that chidamide-containing front-line therapy might be promising for PTCL patients, which warranted further investigation.

Representativeness of Study Participants

Measurable residual disease (MRD) response analysis

QuestionDoes adding the histone deacetylase inhibitor tucidinostat to R-CHOP improve clinical outcomes in patients with newly diagnosed MYC/BCL2 double-expressor lymphoma?FindingsIn this randomized phase 3 clinical trial that included 423 patients, event-free survival was significantly improved with tucidinostat plus R-CHOP compared with placebo plus R-CHOP (hazard ratio, 0.72), with a generally manageable safety profile.MeaningThese findings support the use of an epigenetic modulator (tucidinostat) combined with R-CHOP as a first-line treatment for MYC/BCL2 double-expressor lymphoma, a biologically distinct entity of diffuse large B-cell lymphoma associated with poor prognosis after standard R-CHOP immunochemotherapy. ImportanceEpigenetic dysregulation is associated with the pathogenesis and progression of diffuse large B-cell lymphoma (DLBCL). MYC/BCL2 double-expressor lymphoma (DEL), a distinct population of DLBCL defined by MYC and BCL2 coexpression, refers to poor prognosis after standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) immunochemotherapy. Tucidinostat (or chidamide), an oral, selective histone deacetylase inhibitor, has shown promising activity in DEL.ObjectiveTo evaluate efficacy and safety of tucidinostat plus R-CHOP vs R-CHOP alone as first-line treatment for patients with DEL.Design, Setting, and ParticipantsThis randomized, double-blind, placebo-controlled phase 3 trial enrolled patients from May 21, 2020, through July 25, 2022, with follow-up to June 26, 2025. The trial was conducted at 40 study centers in China; a total of 423 eligible patients were enrolled.InterventionsPatients were randomly assigned in a 1:1 ratio to receive oral tucidinostat (20 mg on days 1, 4, 8, and 11 of each 21-day cycle) or matching placebo, plus 6 cycles of R-CHOP. Patients with a complete response after combination therapy received either tucidinostat or placebo maintenance up to 24 weeks.Main Outcomes and MeasuresThe primary end point was event-free survival. Secondary end points included complete response rate, progression-free survival, disease-free survival, overall survival, and tolerability.ResultsAmong 423 patients randomized (median age, 63 years; 47.5% male), the median follow-up duration from randomization was 41.3 months. The tucidinostat group demonstrated a 28% lower risk of disease progression, relapse after complete response, death, or initiation of new therapy for residual disease compared with the placebo group (stratified hazard ratio, 0.72 [95% CI, 0.54-0.96]; P = .02), with a 2-year event-free survival rate of 60.3% vs 50.5%, respectively. The complete response rate was 73.0% vs 61.8% (difference, 11.1% [95% CI, 2.3%-20.0%]), respectively. Increased toxicity associated with treatment was observed in the tucidinostat group but generally manageable with supportive care.Conclusions and RelevanceTucidinostat plus R-CHOP significantly improved event-free survival, with manageable toxicity in patients newly diagnosed with DEL. This trial is the first to demonstrate the benefit of an epigenetic modulator in DLBCL, offering a new first-line therapeutic approach dually targeting MYC and BCL2 oncoprotein for this high-risk population.Trial RegistrationClinicalTrials.gov Identifier: NCT04231448 This randomized clinical trial conducted in China evaluates the efficacy and safety of the histone deacetylase inhibitor tucidinostat plus R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) vs R-CHOP alone as first-line treatment for patients with MYC/BCL2 double-expressor lymphoma.

Hematologic and non-hematologic toxicity related to induction chemotherapy

Rocbrutinib is a fourth-generation Bruton’s tyrosine kinase (BTK) inhibitor with a unique dual covalent/non-covalent binding mechanism. Its efficacy and safety were evaluated in covalent BTK inhibitor-pretreated patients with mantle cell lymphoma in this phase 2 pivotal study. Patients received rocbrutinib until disease progression or unacceptable toxicities. The primary endpoint was overall response rate (ORR) assessed by independent review committee (IRC). Among 62 enrolled subjects, median age was 61 years (range, 37-79), and median number of prior therapies was 3 (range, 1-10). The IRC-assessed ORR was 63.9% (95% CI, 50.6-75.8), including 23.0% with complete response; Median duration of response was 16.46 months (95% CI, 8.25-not reached). Adverse events were primarily grade 1-2 hematologic events. Grade≥3 hemorrhage occurred in 3.2% of patients, and no atrial fibrillation/flutter cases were reported. Rocbrutinib achieved high response rate and durable response, with a favorable safety profile in this difficult-to-treat population. ClinicalTrials.gov registration: NCT05716087.

Abstract: Relmacabtagene autoleucel (relma-cel), an anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy, is approved in China for relapsed/refractory (R/R) large B-cell lymphoma and follicular lymphoma. This phase 2, open-label, single-arm, multicenter study evaluated its efficacy and safety in Chinese patients with heavily pretreated R/R mantle cell lymphoma (MCL). A total of 70 patients with R/R MCL who had received 1 to 9 previous therapies (including anthracycline or bendamustine chemotherapy, anti-CD20 antibodies, and Bruton tyrosine kinase [BTK] inhibitors) were enrolled. Of these, 59 received a single infusion of 100 × 106 CAR-positive T cells following leukapheresis. The primary end point was the objective response rate (ORR) at 3 months after infusion, assessed using the Lugano 2014 criteria. Secondary end points included the duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. At 3 months, the ORR was 71.19% (95% confidence interval [CI], 57.92-82.24) with a complete response rate of 59.32% (95% CI, 45.75-71.93). After a median follow-up of 13.3 months (95% CI, 9.04-18.69), the median DOR was 18.1 months, PFS was 15.5 months, and OS was 19.5 months. Grade 3 or higher treatment-emergent adverse events were common, including neutropenia (76.3%), leukopenia (69.5%), and lymphopenia (47.5%). Severe cytokine release syndrome and neurotoxicity occurred in 6.8% of patients each, and all cases resolved fully. No fatal events were reported. These findings demonstrate that relma-cel offers high response rates, durable remissions, and manageable safety in Chinese patients with R/R MCL. This trial was registered at www.clinicaltrials.gov as #NCT04718883.

Abstract Background: Patients with refractory or relapsed (R/R) diffuse large B-cell lymphoma (DLBCL) who had failed salvage therapy have an extremely poor prognosis. We previously investigated the efficacy of CD-R-GemOx, a dual epigenetic agent-primed immunochemotherapy regimen, consisting of chidamide, decitabine, rituximab, gemcitabine, and oxaliplatin, in this high-risk population. The findings showed promising outcomes with an overall response rate (ORR) of 78.6% and a complete response rate (CRR) of 42.9%. However, 92.7% of patients occurred grade III/IV hematological toxicity. This emphasizes the critical need to optimize the dual epigenetic immunochemotherapy approach to enhance patient outcomes while mitigating adverse effects. Aims:This study aims to evaluate the efficacy and safety of a modified dual epigenetic priming immunochemotherapy regimen, termed CAGM, consisting of chidamide, azacitidine, obinutuzumab, and mitoxantrone liposome, in R/R DLBCL patients who had failed salvage therapy. Methods:This ongoing, prospective, multicenter, open-label phase II study (NCT05823701) enrolled patients with R/R DLBCL who had failed salvage therapy. The study initiated with two cycles of induction therapy using CAGM, which includes Chidamide(20 mg orally on days 1, 4, 8, and 11 of each cycle), Azacitidine(100 mg subcutaneously on days 1-5 of each cycle), Obinutuzumab(1000 mg intravenously on day 4 of each cycle) and Liposomal Mitoxantrone(20 mg/m² intravenously on day 5 of each cycle). Following induction phase, patients who achieved complete remission (CR) or partial remission (PR) were considered for autologous stem cell transplantation (ASCT) or chimeric antigen receptor T-cell therapy (CAR-T), depending on their eligibility. For patients ineligible for ASCT/CAR-T, an additional four cycles of CAGM were administered. The primary endpoints were the ORR and CRR after two cycles of CAGM. Secondary endpoints included ORR and CRR after six cycles for patients ineligible for ASCT/CAR-T, 2-year overall survival (OS), 2-year progression-free survival (PFS), and safety profiles for all participants. Results: As of August 1, 2025, 26 patients had completed at least two cycles of CAGM and undergone efficacy assessments. The majority of these patients had non-GCB subtype diffuse large B-cell lymphoma (DLBCL) and were at advanced stages (III/IV). Over one-third had received three or more prior lines of therapy and were refractory to previous treatments before initiating CAGM. After two cycles of CAGM, 10 patients achieved complete response (CR), 10 achieved partial response (PR), and 6 experienced disease progression, leading to their withdrawal from the trial. The overall response rate (ORR) and complete response rate (CRR) after two cycles were 76.9% and 38.5%, respectively. Among the 20 responders, 6 patients received additional CAGM therapy, with an ORR of 83.3% and a CRR of 66.7% after 6 cycles of CAGM. Additionally, 4 patients underwent autologous stem cell transplantation (ASCT), 5 received CAR-T therapy, and 5 underwent sequential ASCT followed by CAR-T. Following consolidation therapy, the best ORR and CRR were 81.2% and 100%, respectively. At the time of analysis, 16 patients remained alive and all maintained CR. Four deaths were reported during follow-up, attributed to disease progression (2 cases), heart failure induced by severe hemolytic anemia (1 case), and severe COVID-19 infection (1 case). With a median follow-up of 28.5 months (range: 7.8-35.9 months), the 1-year overall survival (OS) and progression-free survival (PFS) rates were 80.2% and 56.7%, respectively, while the 2-year OS and PFS rates were 67.9% and 49.6%. The median OS was not reached, and the median PFS was 16.2 months. During CAGM induction, adverse events (AEs) were reported in 24 patients (92.3%). The most common AEs were hematological toxicities (88.5%), with 50.0% being grade III/IV. The most frequent non-hematological toxicities included elevated alanine aminotransferase/aspartate aminotransferase (19.2%), nausea (15.4%), mucositis (11.5%), fever (11.5%), pneumonia (3.8%), rash (3.8%), infusion-related reactions (3.8%) and COVID-19 infection (3.8%). Conclusions: This study demonstrates the favorable efficacy and significantly lower hematological toxicities of the CAGM regimen in R/R DLBCL patients, offering a promising therapeutic option for this challenging population.

Abstract Background: The prognosis for patients with peripheral T-cell lymphoma (PTCL) remains extremely poor, posing significant challenges in clinical management. With traditional anthracycline-based chemotherapy regimens such as CHOP (cyclophosphamide + doxorubicin + vincristine + prednisolone), approximately 70% of PTCL patients develop refractory or relapsed disease. Additionally, elderly, unfit, or frail patients often cannot tolerate chemotherapy, resulting in substantial unmet medical needs. Brentuximab vedotin (Bv), an antibody-drug conjugate (ADC) targeting CD30, has demonstrated superior efficacy compared to the traditional CHOP regimen when combined with chemotherapy in CD30-positive PTCL patients. Chidamide (C), the first selective histone deacetylase inhibitor (HDACi) independently developed in China, has shown favorable efficacy and safety profiles in both untreated and relapsed/refractory PTCL patients, whether used as monotherapy or in combination with chemotherapy. Given the mild toxicities of both agents and the proven synergistic effects between epigenetic and targeted therapies, the BvC (brentuximab vedotin plus chidamide) regimen is hypothesized to be effective in CD30-positive PTCL patients who are intolerant to chemotherapy. Aims:This study aims to evaluate the efficacy and safety of BvC regimen in CD30-positive PTCL patients who are unfit for chemotherapy. Methods:This is an ongoing, prospective, multicenter, open-label phase II study (NCT07074457) enrolling CD30-positive PTCL patients ineligible for conventional chemotherapy. Participants will undergo induction therapy with 3 cycles of the BvC regimen: brentuximab vedotin at 1.8 mg/kg on day 1, and chidamide at 20 mg twice weekly for 2 weeks, repeated every 3 weeks. Patients with disease progression (PD) or stable disease (SD) will be discontinued from the study. Those achieving complete remission (CR) or partial remission (PR) will receive 3 or 6 additional cycles of BvC consolidation therapy, respectively. Following consolidation, responding patients (CR/PR) will receive chidamide maintenance therapy (20 mg twice weekly for 2 weeks every 3 weeks) for at least 2 years. The primary endpoint is the complete response rate (CRR) after 3 cycles of BvC. Secondary endpoints include the objective response rate (ORR) after 3 cycles of BvC, 2-year overall survival (OS), 2-year progression-free survival (PFS), and safety profiles in all participants. Results: As of August 1, 2025, a total of 8 patients had been enrolled, comprising 6 males and 2 females, with a median age of 77 years (range: 74-86 years). The baseline characteristics of the enrolled patients were as follows: All (100%) patients had advanced-stage disease with an Eastern Cooperative Oncology Group (ECOG) performance status score of ≥2. Seven patients (87.5%) had elevated lactate dehydrogenase (LDH) levels, and four (50%) presented with extranodal involvement. All patients were classified as high-risk, including five (62.5%) with an International Prognostic Index (IPI) score of 4 and three (37.5%) with an IPI score of 5. Four patients completed at least 3 cycles of BvC therapy, among whom 3 achieved a response: 1 with complete response (CR) and 2 with partial response (PR). This yielded a complete response rate (CRR) of 25% and an overall response rate (ORR) of 75.0%. Adverse events (AEs) were reported in 6 patients (75%), with no cases of grade ≥3 AEs observed. The most common AEs included anemia (62.5%), thrombocytopenia (50%), nausea (37.5%), neutropenia (25%), elevated alanine aminotransferase/aspartate aminotransferase (25%) and elevated creatinine (12.5%). All toxicities were transient and reversible. Conclusions: This preliminary study demonstrates the favorable efficacy and significantly lower hematological toxicities of the BvC regimen in CD30-positive PTCL patients, offering a promising therapeutic option for this challenging population. Further updated clinical data will be shared as the study progresses.

Backgroud: Relapsed or refractory (R/R) indolent non-Hodgkin lymphomas (iNHLs) are incurable diseases. Based on the ZUMA-5 study, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, has been approved by the FDA for the treatment of adult patients with R/R follicular lymphoma (FL). Axi-cel was approved in China by the NMPA in June 2021 for the treatment of adult patients with R/R large B-cell lymphoma (LBCL). The efficacy and safety results of axi-cel for the treatment of R/R iNHLs including FL in the Chinese population have not yet been explored. Therefore, we conducted this single-arm, multi-center, phase 2 trial (ChiCTR2200058587) in China. AIMS: To assess the efficacy and safety of Axi-cel in R/R iNHLs in Chinese population. Methods: Patients were eligible if they were aged 18 years or older, with histologically confirmed iNHLs (FL or marginal zone lymphoma [MZL]), had relapsed or refractory disease, previously had two or more lines of therapy (including an anti-CD20 monoclonal antibody with an alkylating agent), and an Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1. The primary endpoint was best objective response rate (bORR) per Lugano classification. Secondary endpoints included complete remission (CR) rate, partial remission (PR) rate, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results: As of data cutoff (August 16, 2024), 31 patients were enrolled (FL: 30, MZL: 1) and 28 patients (FL: 27, MZL: 1) were evaluable for efficacy (1 FL patient receiving low-dose axi-cel was not included). The median age was 53 years (range 33–71). 92.9% had stage III-IV disease. Progression of disease within 2 years of frontline chemoimmunotherapy (POD24) occurred in 64.3% of patients. Patients had a median 3 prior lines of therapy (range 2–9); 60.7% patients were refractory to last therapy; 29.6% FL patients had higher FLIPI scores. Median follow-up was 12.16 mo (90% CI 9.53, 15.08). 27 (96.4% [95% CI 84.15, 99.82]) of 28 patients had a bORR as assessed by investigators, including 26 (96.3% [95% CI 83.60, 99.81]) of 27 patients with FL and 1 (100%) with MZL. 20 (71.4%) of 28 patients had a complete response as assessed by investigators, including 19 (70.4%) of 27 patients with FL and 1 (100%) with MZL. The median time to response (TTR) and time to complete response (TTCR) were 1.02 mo (IQR 0.95-1.05) and 1.03 mo (IQR 1.00-2.97), respectively. Pharmacokinetic results showed that after analyzing 29 subjects from all groups combined, the median Tmax of anti-CD19 CAR-T cells in peripheral blood was 11 days (range 6-14) post-infusion, and the median Cmax was 35.81 cells/ μ L (IQR 6.70-103.35). No new safety signals were observed in the Chinese population. Cytokine release syndrome(CRS) of any grade occurred in 21 patients (72.4%), with 2 patients (6.9%) experiencing grade ≥3. Neurological events(NE) of any grade occurred in 16 patients (55.2%), with 2 patients (6.9%) experiencing grade≥3. No grade 5 CRS or NE appeared. The most common grade ≥3 treatment-emergent adverse events (TEAEs) were decreased neutrophil count (86.2%), decreased white blood cell count (86.2%), and decreased lymphocyte count (17.2%). Summary/Conclusion: Axi-cel demonstrated deep responses in heavily pretreated Chinese patients with R/R iNHL; bORR was 96.4% with CR rate of 71.4%. Axi-cel had a generally manageable safety profile with a low incidence of grade ≥3 CRS or NE.

The advent of novel targeted and immunotherapeutic approaches, particularly Bruton's tyrosine kinase inhibitors (BTKis), have significantly improved survival outcomes in patients with mantle cell lymphoma (MCL), with acceptable safety profiles. However, therapeutic challenges (e.g. acquired resistance, intolerance, etc.) remain. Rocbrutinib is a highly selective, 4th-generation BTKi that integrates the advantages of covalent irreversible inhibition and non-covalent binding, and demonstrates superior pharmacokinetic profiles in humans. Previously, data have demonstrated that rocbrutinib induces high response rate and durable responses in heavily pre-treated patients with R/R MCL, particularly those with prior BTKi exposure (Yuqin Song et al. 2023 ASH). Here, we present updated data from the ongoing phase I trial LP-168-CN101 (NCT04993690) evaluating rocbrutinib in patients with BTKi naïve R/R MCL. Methods Patients aged 18–80 with R/R MCL who had received ≥1 line of therapies (including ≥1 line anti-CD20 antibody-based regimens) were treated with rocbrutinib monotherapy until disease progression. Adverse events (AEs) were graded per CTCAE v5.0, and efficacy was assessed per Lugano 2014 criteria. Results As of June 15, 2025, 28 BTKi-naïve R/R MCL patients were enrolled and received rocbrutinib 100 mg (n=4), 150 mg (n=23), or 200 mg (n=1) once daily (QD) treatment. The median age was 61 years (range: 40–77). Blastoid/pleomorphic variants accounted for 17.9% of cases, and 45.7% of patients were with intermediate- or high-risk per MCL international prognostic index (MIPI). The median number of prior lines of therapies was 1 (range: 1-3), with 14.3% of patients having undergone autologous stem cell transplantation. The most common treatment-related AEs (TRAEs, incidence≥20%) (any grade;≥grade 3) included decreased neutrophil count (46.4%; 7.1%), decreased platelet count (39.3%; 3.1%), increased blood creatinine (35.7%; 0), decreased white blood cell count (32.1%; 0), petechiae (32.1%; 0), anemia (28.6%; 0), and decreased lymphocyte count (21.4%; 0), most of which were grade 1. No atrial fibrillation,≥grade 3 hypertension or hemorrhage occurred. Dose interruption due to TRAEs occurred in 6 (21.4%) patients, but only 1 patient underwent dose reduction. No drug discontinuation or death due to TRAEs has occurred. Of 28 efficacy evaluable patients, the overall response rate (ORR) was 89.3%, with a complete response (CR) rate of 57.1%. After median follow-up of 21.2 (range: 0.9-43.1) months, PFS is not matured yet. The 18-month PFS rate was 74.3%. Conclusion Consistent with previously reported data in patients with post BTKi R/R MCL, rocbrutinib demonstrates a favorable safety profile and robust efficacy in patients with BTKi naïve R/R MCL, with high response rates, deep remissions, and durable responses.

Chimeric antigen receptor T-cell (CAR-T) therapy is gradually reshaping the treatment paradigm for patients with central nervous system lymphoma (CNSL). However, the duration of remission (DOR) has remained the major challenge in existing studies. This study aimed to provide real-world long-term follow-up data on CAR-T therapy in CNSL patients and primarily investigate the impact of maintenance therapy on prolonging DOR. This study evaluated the efficacy and safety of CAR-T therapy in 22 patients with CNSL, including 5 with primary CNSL and 17 with secondary CNSL (2025004, retrospectively registered). Maintenance therapy with programmed cell death protein-1 inhibitor (PD-1i) and Bruton’s tyrosine kinase inhibitor (BTKi) was initiated in responding patients, while subgroup analysis comparing maintenance versus non-maintenance was restricted to those who achieved complete remission after CAR-T therapy. The best overall remission rate was 90.9

Background: The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a transmembrane protein that is overexpressed in multiple cancers, including lymphomas. HDM2005 is an antibody-drug conjugate comprising a humanized IgG1 monoclonal antibody, a proteolytically cleavable linker, and the antimicrotubule cytotoxic agent monomethyl auristatin E (MMAE)，Preclinical studies have shown potent anti-tumor activity in various lymphomas and solid tumor models. Here, we report the clinical data in patients with relapsed or refractory B-NHL or cHL from the first in human study of HDM2005 (NCT06615193). Methods: Eligible patients aged ≥18 years with an Eastern Cooperative Oncology Group Performance Status of 0-2 and histological diagnosis of relapsed or refractory B-NHL (mantle cell lymphoma [MCL], diffuse large B-cell lymphoma [DLBCL]) or cHL that had failed ≥2 prior lines of therapies (r/r MCL patients must also fail prior BTK inhibitor and CD20 mAb containing treatments) were enrolled. HDM2005 was administered intravenously every 3 weeks. Phase 1a part commenced at 0.3 mg/kg with one patient and then switched to a bayesian optimal interval scheme at escalated doses 1.0, 1.8, 2.5, 2.75 mg/kg. Dose-limiting toxicity (DLT) for each cohort was evaluated during the first treatment cycle. The primary objectives are to assess the safety and tolerability, to determine the maximum tolerated dose (MTD) and recommended Phase II doses (RP2Ds). Objective responses in lymphomas were assessed by investigators according to the 2014 Lugano response criteria. Results: As of July 4, 2025, 29 patients were enrolled (n=1, 4, 10, 11 and 3 in the 0.3, 1.0, 1.8. 2.5, 2.75 mg/kg dose cohorts), including 17 pts with MCL, 8 pts with DLBCL, 4 pts with cHL. The median age was 60 years (range, 28-77); 21 (72.4%) patients were male; 9(31%) patients had an ECOG PS of 0 and most patients (21, 72.4%) had ≥3 lines of prior anti-tumor treatments. One DLT occurred in 1 patient with grade 3 gamma-glutamyltransferase increased in 2.75 mg/kg cohort. No drug related death occurred, no patient permanently discontinued due to treatment related AE. Treatment related adverse events (TRAEs) occurred in 25 (86.2%) patients; most commonly (≥20%) reported TRAEs of any grade were neutrophil count decrease (n=15, 51.7%), aspartate aminotransferase increased (n=11, 37.9%), alanine aminotransferase increased (n=9, 31%), gamma-glutamyltransferase increased (n=6, 20.7%) and alopecia (n=6, 20.7%). Grade ≥3 TRAEs occurred in 10 (34.5%) patients; the most common (≥5%) Grade ≥3 events were neutrophil count decrease (n=6, 20.7%). Peripheral neuropathy occurred in 4 patients (13.8%), all had severity of Grade 1 or 2. In efficacy evaluable patients, objective response rate (ORR) was 47.6% (10/21) across all dose levels, with 3 complete responses (CRs) and 7 partial responses (PRs). At 1.8 and 2.5mg/kg cohorts, ORR was 50% (6/12) in MCL patients, with 1 CR and 5 PRs; ORR was 100% (2/2) in cHL patients, both having CRs. Conclusion: HDM2005 was well tolerated and had promising albeit preliminary anti-tumor activity in patients with relapsed/refractory B-NHL or cHL. MTD not reached at dose of 2.75 mg/kg.