7073 Background: Mesutoclax (ICP-248) is a next-generation BCL2 inhibitor, and orelabrutinib is a marketed BTK inhibitor for CLL/SLL, MCL, and MZL. However, the clinical activity of their combination in these malignancies remains undefined. This analysis evaluated the combination of mesutoclax and orelabrutinib across B-cell malignancies. Methods: Patients with relapsed and refractory (R/R) MCL, MZL were enrolled in a phase 1 study (NCT05728658), and treatment-naive (TN) CLL/SLL were enrolled in a phase 2 study (NCT06378138). R/R MCL and MZL patients received continuous daily mesutoclax (125 mg) and orelabrutinib (150mg) from cycle 1 day 1 continuously until disease progression or unacceptable toxicity. For CLL/SLL patients, induction therapy with orelabrutinib (150 mg QD, Cycles 1-17) was administered first, followed by mesutoclax (100 mg or 125 mg QD, Cycles 3-14). The orelabrutinib treatment continued beyond cycle 17 if the uMRD (≤10-4) was not achieved. Mesutoclax was implemented with a ramp-up schedule in all patients to mitigate the risk of TLS. Results: As of 05 Jan 2026, 60 patients were enrolled and treated in the studies: 8 R/R MCL, 10 R/R MZL, and 42 TN CLL/SLL (mesutoclax 100 mg, n=21; 125 mg, n=21). In R/R patients, the median number of prior lines of therapy was 1 (1-4). 6 (33.3%) were refractory to the last line of therapy. For TN CLL/SLL, 76.2% (32/42) of patients had moderate or high TLS risk, and 14.3% (6/42) had TP53 mutation or del (17p). Among 5 MCL and 8 MZL patients who had at least one disease evaluation, the overall response rate (ORR) was 100%, with CRR of 100% and 50%, respectively. Five patients (38.5%) achieved peripheral blood (PB) uMRD. In the 21 CLL/SLL patients receiving mesutoclax 125 mg, the ORR was 100% and the CRR was 38.1%, and the peripheral blood uMRD rate at 36-week was 65%. The median time to CR was 3.7 months in R/R group and 7.1 months in TN group. The 12-month PFS rate was 100% in CLL/SLL, while data for MCL and MZL are immature due to short follow-up. As the safety data cutoff (31 Dec 2025), the combination of mesutoclax and orelabrutinib was well tolerated with a favorable safety profile, and no new safety signals were identified compared to either agent as monotherapy. Most TEAEs were grade 1-2, with no TEAEs leading to drug discontinuation or death reported. The most common grade ≥3 TEAEs include neutrophil count decreased (35%), platelet count decreased (11.7%). Notably, no grade ≥3 anemia was reported. No clinical or laboratory TLS occurred. Conclusions: Mesutoclax in combination with orelabrutinib demonstrated a tolerable safety profile across B cell malignancy subtypes (MCL, MZL, CLL/SLL). Significant 100% ORR and deep response were observed in patients receiving mesutoclax 125mg combined with orelabrutinib. This all oral, chemo-free regimen has the potential to establish a novel therapeutic option for B-NHLs. Clinical trial information: NCT05728658 .

Cell division cycle 20 homolog (CDC20), a critical substrate-recruiting subunit of the anaphase-promoting complex/cyclosome (APC/C), binds to APC/C to form the active APC/C-CDC20 complex, which regulates the degradation of key cell cycle substrates to ensure accurate and timely mitotic progression. Accumulating evidence demonstrates that CDC20 functions as an oncogenic factor, with its overexpression observed in various malignancies. Its dysregulation is closely associated with tumor initiation, progression, drug resistance, and poor clinical outcomes, underscoring its potential as a therapeutic target in anti-cancer strategies. In this review, we describe the biological functions of CDC20 in cancers, discuss its role and underlying mechanisms in solid tumors and hematological malignancies, and elucidate currently reported CDC20-targeted inhibitors along with their clinical benefits and challenges. By emphasizing the oncogenic significance of CDC20, we propose that the development of specific, safe, and potent CDC20 inhibitors could provide a promising therapeutic approach for cancer patients exhibiting CDC20 overexpression.

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.

We evaluated the effectiveness of adding anti-PD-1 antibody to P-GEMOX regimen in previously untreated advanced-stage natural killer/T-cell lymphoma (NKTCL) compared to P-GEMOX alone or with autologous stem cell transplantation (ASCT). 418 patients (135 and 283 in the immunochemotherapy and chemotherapy groups, respectively) were analyzed from 15 Chinese centers (2014-2023). The median follow-up was 40.7 months. The immunochemotherapy group had a higher objective response rate (ORR) (89.6% versus 77.0%), complete response (CR) rate (77.0% versus 50.5%), 3-year progression-free survival (PFS) rate (64.1% versus 40.7%), and 3-year overall survival (OS) rate (79.5% versus 60.8%) compared to the chemotherapy group. Grade 3-4 neutropenia was more common in the immunochemotherapy group (40.0% versus 20.8% in the chemotherapy group, p < 0.001). Grade 3-4 hematologic toxicities were prevalent during ASCT, whereas anti-PD-1 maintenance was well tolerated. Grade ≥3 non-hematologic adverse events during anti-PD-1 maintenance were rare. In propensity score-matched (PSM) analysis of patients achieving CR after induction (n = 41 per group), the 3-year disease-free survival (DFS) rate was 72.6% for immunochemotherapy plus anti-PD-1 maintenance versus 50.9% for chemotherapy plus ASCT (p = 0.032), and the 3-year OS rate was 91.5% versus 72.9% (p = 0.029). First-line anti-PD-1 antibody plus P-GEMOX followed by anti-PD-1 maintenance shows better response and survival over P-GEMOX chemotherapy alone and P-GEMOX with ASCT, while maintaining acceptable toxicity.

Cell-free DNA in blood originates from fragmented chromatin released by dying cells from both healthy and diseased tissues1,2. These fragments carry rich molecular modalities that can reveal pathological alterations in tissues of origin3-10. Here we develop cf-EpiTracing, a highly sensitive automated platform that profiles histone modifications in cell-free DNA from as little as 50 μl of human plasma. By integrating multimodal chromatin states with machine learning, cf-EpiTracing enables accurate deconvolution of cell types of origin. We generated 2,417 cf-EpiTracing profiles from plasma of 125 healthy individuals and 549 patients with inflammatory bowel disease, colorectal cancer, coronary heart disease or lymphoma. cf-EpiTracing enabled unbiased identification of primary diseased tissues and other organ involvement, stratification of B cell lymphoma subtypes with different genetic and epigenetic underpinnings, and detection of early-stage diseases or lesions. Surveying dynamics of epigenetic signatures uncovered disease transformation from follicular lymphoma to diffuse large B cell lymphoma. Further, cf-EpiTracing revealed genomic translocations and epigenetic alterations in patients with mantle cell lymphoma. Of note, our study leverages holistic epigenetic signatures, independently of knowledge of gene transcription, to accurately report recurrence risk and therapeutic response. Together, these findings establish cf-EpiTracing as an automated, non-invasive, epigenome-centric framework with broad applications in early diagnosis, molecular subtyping and prognostic prediction.

Abstract Patients with peripheral T cell lymphoma (PTCL) who achieved tumor response with first-line standard therapy were at high risk of disease relapse. We explored golidocitinib (150 mg once daily) as maintenance therapy for this group of patients (JACKPOT26, NCT06511869). This study included two cohorts: patients achieving a complete response (Cohort 1 (CR), N = 30) and a partial response (Cohort 2 (PR), N = 18) during induction stage. All enrolled patients were transplant ineligible or did not have a transplant plan. All dosed patients were included in the efficacy and safety analysis. In Cohort 1, the 24-month disease free survival (DFS) rate was 74.2% with golidocitinib treatment. In nodal subtypes (AITL, NOS, ALK- ALCL), the 24-month DFS rate was 62.7%. In Cohort 2, median progression free survival (PFS) was 17.4 months, and 24-month PFS rate was 48.6%. Nine out of 18 patients with initial PR achieved complete response, leading to a complete response rate of 50.0%, and median duration of response of 23.9 months. The most common ≥grade 3 treatment-related treatment-emergent adverse events (TRAEs) were hematological adverse events in nature, including neutrophil count decreased (47.9%), white blood cell count decreased (31.3%), lymphocyte count decreased (14.6%) and leukopenia (12.5%). The majority of these TRAEs were reversible and clinically manageable. TRAEs leading to treatment interruption and discontinuation occurred in 60.4% and 10% of patients, respectively. No TRAEs leading to fatal outcomes were reported. This study suggests the potential of golidocitinib as maintenance therapy for patients with PTCL.

Selinexor, a selective nuclear export inhibitor, blocks exportin-1 and reduces oncoprotein messenger RNA translation, and is approved for the treatment of relapsed/refractory multiple myeloma in combination with proteasome inhibitors, immunomodulators, anti-CD38 antibodies, etc. Nevertheless, selinexor presents limited monotherapy efficacy with an objective response rate of 29% and fails to completely overcome drug resistance. To improve the therapeutic outcome, this study investigated the combined treatment of selinexor and a CD73 inhibitor in a murine tumor model. The expression of CD73 in multiple tumor cell lines following selinexor treatment was first analyzed. In vivo experiments were performed on J558-inoculated BALB/c mice, which were divided into vehicle group, ATG-037 (CD73 inhibitor) monotherapy group, ATG-010 (selinexor) monotherapy group, and combination therapy group. Single-cell RNA sequencing (scRNA-seq) was utilized to characterize immune cell subtypes and tumor-immune crosstalk, and immunofluorescence staining was conducted on histological tumor samples. In addition, a co-culture model of CD8+ T cells and multiple myeloma cell lines was established to verify the synergistic anti-tumor effect and underlying mechanism of the combined regimen. The results demonstrated that selinexor treatment upregulated CD73 expression in the majority of tumors. The combination therapy remarkably suppressed tumor growth with an inhibition rate of 62%, which was superior to the monotherapy of ATG-037 (31%) and selinexor (43%). scRNA-seq analysis revealed that the combination treatment synergistically potentiates CD8+ T cell activation by enhancing the interaction between CD8+ T cells and Enpp1 cells via the CD80-CD28 signaling pathway, and the increased infiltration of CD8+ T cells in tumor tissues of the combination group was further validated by immunofluorescence staining. Co-culture experiments further confirmed that CD73 inhibition strengthens selinexor-mediated tumor cell killing by activating CD8+ T cells, as evidenced by significantly elevated levels of Granzyme B (P = 0.0252) and IFN-γ (P = 0.0067). In conclusion, CD73 inhibition enhances the anti-myeloma efficacy of selinexor by specifically activating CD8+ T cells and ultimately promoting the apoptosis of multiple myeloma cells.

This multicenter, randomized, controlled study was conducted to explore the safety and efficacy of low-dose baricitinib plus danazol for ITP patients who had failed corticosteroids and at least one recommended subsequent treatment. Participants were randomly assigned to receive baricitinib plus danazol (n = 108) or danazol alone (n = 108) by a central, interactive web-based system. Patients and caregivers were not blinded to group assignment. Efficacy assessments were performed in the intention-to-treat population by investigators blinded to group assignment. The primary endpoint was 6-month durable response. Forty-nine (45.4%) patients in the combination arm and 22 (20.4%) patients in the monotherapy arm achieved 6-month durable response (P < 0.001). The safety analysis set included patients who received at least one dose of study medication (n = 108 in the combination arm and n = 105 in the monotherapy arm). Fifty-two (48.1%) patients receiving baricitinib plus danazol and 47 (44.7%) patients receiving danazol alone reported at least one adverse event. Each arm reported two patients who developed an adverse event causing study discontinuation and one patient who developed a grade 3 or more severe adverse event. Low-dose baricitinib plus danazol might be a novel option for difficult-to-treat ITP. Funding: National Key Research and Development Program of China (No. 2023YFC2507800), National Natural Science Foundation of China (No. 82230004, No. 82430006, No. 82400157), Capital Health Development and Research of Special (No. 2022-1-4082), and Beijing Natural Science Foundation (No. 7242154 and No. 7232188). ClinicalTrials.gov identifier: NCT05852847.

This Phase I/II clinical trial (NCT04471064) evaluated the preliminary efficacy, safety, and pharmacokinetics of XY0206, a novel oral FMS-like tyrosine kinase 3 (FLT3) inhibitor, in patients with relapsed or refractory acute myeloid leukemia (R/R AML). From September 2020 to December 2022, this open-label, multicenter study enrolled patients aged ≥ 18 years with R/R AML. The trial included dose-escalation and dose-expansion phases, with six cohorts receiving XY0206 at doses ranging from 12.5 to 62.5 mg once daily or 25 mg twice daily. Of the 61 enrolled participants, 37 had FLT3 mutation-positive (FLT3mut+) AML. The overall response rate (ORR) was 34.4% in the entire cohort and 48.6% in FLT3mut+ patients. Among FLT3mut+ patients, the composite complete remission rate (CRc) was 45.9%, including a complete remission (CR) rate of 5.4% and a CR with partial hematologic recovery (CRh) rate of 13.5% and a CR with incomplete hematologic recovery (CRi) rate of 27.0%. In patients with FLT3 internal tandem duplication (FLT3-ITD) mutations, the ORR was 56.7%, with a CRc of 53.3% (CR: 6.7%; CRh: 16.7% ; CRi: 30.0%). The 37.5 mg dose cohort, identified as the target dose, was expanded exclusively for FLT3mut+ patients. XY0206 exhibited a favorable safety profile and demonstrated potent antileukemic activity, particularly in FLT3mut+ R/R AML patients, supporting its further clinical development. Trial Registration: CTR20201214 (CDE); ClinicalTrials.gov ID: NCT04471064.

Current staging systems for natural killer/T cell lymphoma (NKTCL) inadequately reflect its predominantly extranodal presentation and lack prognostic accuracy in the asparaginase era. This retrospective multicenter study analyzes 1,872 newly diagnosed NKTCL patients treated with asparaginase-based regimens or radiotherapy alone, from 15 institutions across China. For nasal-type NKTCL, skull base invasion (SBI) is identified as an independent adverse prognostic factor. We reclassify Ann Arbor stage I patients with SBI as stage II and stage II patients with SBI as stage III. For non-nasal-type NKTCL, we retain the Chinese Southwest Oncology Group and Asia Lymphoma Study Group (CA) system due to its superior prognostic discrimination. The revised system demonstrates improved outcome prediction, hazard discrimination, hazard consistency, and sample balance across training, internal, and external validation cohorts. Time-dependent receiver operating characteristic (ROC) analysis confirms superior predictive accuracy over existing systems. This proposal provides a refined prognostic framework to guide clinical decision-making and optimize patient selection for future trials.

Chimeric Antigen Receptor T-cell Immunotherapy represents a breakthrough in treating relapsed/refractory hematologic malignancies, yet immune-related adverse events, particularly hemophagocytic lymphohistiocytosis (HLH), also known as immune effector cell-associated HLH-like syndrome (IEC-HS), are rapid-progressing and life-threatening. This systematic review and meta-analysis searched PubMed, Embase, and Cochrane CENTRAL up to August 20, 2025. Nineteen studies were analyzed using a random-effects model, covering 2780 patients, 47 HLH cases, and 20 HLH-related deaths. The pooled incidence of HLH was 1.6% at a median follow-up of 12.9 months, with an associated HLH mortality of 0.7%. The incidence of HLH differed markedly by disease entity (p = 0.0008), highest in B-cell acute lymphoblastic leukemia (B-ALL: 6.9%). CAR T-cell product was also a significant determinant (p = 0.0036), with tisagenlecleucel (Tisa-cel) showing the highest incidence (4.3%). Subgroup analyses confirmed that Tisa-cel had a significantly higher HLH incidence than axicabtagene ciloleucel (Axi-cel) in large B-cell lymphoma (2.4% vs. 0.6%, p = 0.038), and ciltacabtagene autoleucel (Cilta-cel) had a higher incidence than idecabtagene vicleucel (Ide-cel) in multiple myeloma (2.6% vs. 0.7%, p = 0.022). Higher-grade cytokine release syndrome (CRS) was positively correlated with HLH incidence, particularly in MM. Overall HLH incidence was significantly positively correlated with mortality. In conclusion, HLH risk after CAR T-cell therapy is primarily driven by underlying disease type and specific CAR T-cell product, with additional contribution from severe CRS. Enhanced surveillance and early intervention are strongly recommended for high-risk groups, particularly B-ALL patients and recipients of Tisa-cel or Cilta-cel.

In this phase 2 TAI-SHAN9 study, we evaluated the safety and efficacy of birelentinib, a first-in-class oral dual inhibitor of LYN and BTK, in patients with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). A total of 58 patients were enrolled and received birelentinib at doses ranging from 25 to 75 mg once daily (QD). Antitumor efficacy was observed at 50 mg and above, among 42 efficacy-evaluable patients treated at 50 mg or 75 mg QD, overall objective response rate (ORR) was 47.6% (20/42) and complete response rate (CRR) was 31.0% (13/42). Responses were observed across GCB (ORR 58.3%) and non-GCB (ORR 44.8%) subtypes, as well as across the MCD-like, TP53Mut, and NOS molecular subtypes (each ORR 50.0%). At a median follow-up of 9.2 months for complete responders, the median DoR was not reached, with the longest ongoing CR exceeding 9.3 months. The grade ≥3 treatment-related adverse events included thrombocytopenia (20.7%), neutropenia (12.1%), and pneumonia (5.2%). No major bleeding, atrial fibrillation, or drug-related death was reported. These results suggest that birelentinib is a promising oral treatment for r/r DLBCL across molecular subtypes. Further clinical evaluation of LYN/BTK dual inhibition is warranted. Clinical trial information: ClinicalTrials.gov NCT06539195.

We retrospectively evaluated the efficacy and safety of zanubrutinib combined with age-adapted bendamustine and rituximab followed by zanubrutinib maintenance in 23 elderly patients with mantle cell lymphoma (MCL). Patients received six induction cycles of this regimen, followed by zanubrutinib maintenance for ≥2 years. After induction, the complete response rate was 73.9% and the overall response rate was 91.3%. The 24-month progression-free survival rate was 75.4% and the overall survival rate was 90.7%. Undetectable minimal residual disease (uMRD) was achieved in 88% of patients after induction and increased to 94% during maintenance. CD4 + T cell and NK cell counts declined to nadir post-induction but recovered by 12 months. Zanubrutinib combined with age-adapted bendamustine and rituximab, followed by zanubrutinib maintenance, is an active and feasible regimen for elderly patients with MCL, offering a potential treatment option in clinical practice.

Introduction Mantle cell lymphoma (MCL) constitutes an aggressive subtype of B-cell lymphoma and demonstrates significant clinical and biological heterogeneity. B symptoms are important clinical indicators in tumors. In the present study, we investigated the frequency and prognostic significance of B symptoms among different primary sites of MCL. Method We conducted an observational study of 2,025 MCL patients from the SEER database. We analyzed the frequency of B symptoms at different primary sites and evaluated their impact on prognosis. Results The highest incidence of B symptoms was observed in the small intestine (35.29%), and the lowest in the nasopharynx (6.67%). Among patients with primary lymph node involvement, the intrathoracic and abdominal lymph nodes showed the highest proportion of B symptoms (both 40%), while the head, face, and neck lymph nodes showed the lowest (9.3%). In patients with primary site involvement of lymph nodes or nasopharynx, those with B symptoms had a worse prognosis than those without B symptoms (P < 0.05). Similarly, patients with primary lesions involving multiple regional lymph nodes, lymph node not otherwise specified (NOS), or inguinal/leg lymph nodes exhibited worse prognosis when B symptoms were present (P < 0.05). Conclusion In summary, our study highlights the heterogeneity in both the frequency and prognostic significance of B symptoms across different primary sites in MCL patients.

Mantle cell lymphoma (MCL) is an uncommon and aggressive type of B-cell non-Hodgkin lymphoma, wherein TP53 mutations play a critical role. This study analyzed the effect of different TP53 mutations on the clinical characteristics and prognosis of patients with MCL. TP53 sequencing data and clinical and prognostic information were collected from 215 patients with MCL treated at Peking University Third Hospital between August 2017 and December 2022. Furthermore, descriptive and Cox regression analyses were also performed. Our findings revealed the association between TP53 mutations and higher Ki67 levels (p = 0.008), elevated combined MCL International Prognostic Index (MIPI-c; p = 0.032), blastoid/pleomorphic subtypes (p = 0.020) and ≥ 2 treatment lines (p = 0.026). Missense mutations (75.6

OBJECTIVES:Talquetamab (G-protein-coupled receptor class C group 5 member D [GPRC5D] × CD3 bispecific antibody) demonstrated antitumor activity in relapsed/recurrent multiple myeloma (RRMM) in the phase I/II MonumenTAL-1 study. We report the safety profile of talquetamab in Chinese patients from MonumenTAL-1, focusing on GPRC5D-associated on-target/off-tumor adverse events (AEs). METHODS:Adult Chinese patients with heavily pretreated RRMM and measurable disease received subcutaneous talquetamab 0.4 mg/kg once weekly (QW) or 0.8 mg/kg biweekly (Q2W). Incidence, time to onset, duration, and recovery status of GPRC5D-associated AEs were reported. Data cutoffs: 29 February 2024 (QW cohort); 26 August 2024 (Q2W cohort). RESULTS:A total of 41 adult Chinese patients were included in this study (QW cohort, n = 29; Q2W cohort n = 12). Median treatment duration was 7.7 months (QW cohort) and 7.1 months (Q2W cohort); median follow-up was 16.3 and 13.9 months, respectively. GPRC5D on-target/off-tumor AEs, predominantly grade 1-2 (one grade 3 non-rash skin toxicity; QW cohort), were most commonly oral AEs (dysgeusia, dry mouth), skin AEs (rash, non-rash skin toxicity), and nail disorders; 50%-100% resolved by data cutoff. AEs were managed with supportive therapies. Talquetamab dose modification was needed in one case (grade 2 weight decrease). DISCUSSION:The generally mild GPRC5D-associated AEs were well tolerated and consistent with the known safety profile of talquetamab. Supportive management of these AEs without need for dose modification enabled prolonged treatment. CONCLUSIONS:Education of patients with RRMM on potential GPRC5D-associated AEs before starting treatment, and timely management upon experience, may ensure optimum exposure and thus maximum benefit with talquetamab.

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.

OBJECTIVE:To investigate the efficacy and prognostic factors of autologous hematopoietic stem cell transplantation (ASCT) in the treatment of mantle cell lymphoma (MCL) in the real world. METHODS:The clinical data of 85 MCL patients who underwent ASCT in Peking University Third Hospital and other Chinese centers from January 2005 to December 2021 were retrospectively analyzed. The patients were treated with rituximab-based chemotherapy before transplantation, and the effects of clinical characteristics, treatment regimens and biological indicators on overall survival (OS) and progression-free survival (PFS) were observed. RESULTS:Among the 85 patients, there were 65 males and 20 females with a median age of 53 (34-68) years, 11 cases of blastic and pleomorphic type and 74 cases of classical type. According to Ann Arbor staging, 5 cases were in stage I-II and 80 cases were in stage III-IV. There were 18 cases with Ki-67≥50%, 29 cases with B symptoms, and 68 cases with external involvement. High-dose cytarabine was used in 56 patients, and 31 patients were in a relapsed/refractory state. With a median follow-up of 51 (12-202) months after ASCT, the estimated 5-year PFS rate was (68.4±6.0)%, and the estimated 5-year OS rate was (87.4±4.6) %. Multivariate Cox regression analysis showed that MIPI-c intermediate-high/high risk (HR=4.461, 95%CI : 1.822-10.918, P =0.001) and no maintenance treatment (HR=3.127, 95%CI : 1.398-6.991, P =0.005) were independent adverse prognostic factors for PFS, and relapsed and refractory state(HR=4.727, 95%CI : 1.005-22.234, P =0.049) were independent adverse prognostic factors for OS. CONCLUSION:ASCT consolidation therapy plays an important role in improving PFS and OS of MCL patients with young age and good general condition, especially for those with MIPI-c low/low-intermediate risk, receiving maintenance therapy with new drugs after ASCT, and non-relapsed/refractory state.

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.

Although targeting the ubiquitin-like PHD and RING finger domain-containing protein 1 (UHRF1) has shown promise in treating a number of diseases, its function in mantle cell lymphoma (MCL) and its regulatory connection to SOX11 are yet unknown. Our study showed that UHRF1 is markedly upregulated in MCL, and this overexpression is associated with a poorer overall survival rate in MCL patients. Furthermore, in clinical MCL specimens, UHRF1 showed a positive correlation with the expression of SOX11 and Ki-67. In vitro, UHRF1 knockdown induced apoptosis and caused G2/M-phase arrest while functionally suppressing MCL cell motility, invasion, and proliferation. In MCL xenograft models, UHRF1 silence significantly delayed tumor development, and pharmacological targeting UHRF1 with CM272 effectively inhibited MCL progression with a tolerable safety profile. Mechanistically, SOX11 drives the transcriptional activation of UHRF1 by directly binding to its promoter region. Our results reveal that the SOX11-UHRF1 regulatory axis is a critical modulator of tumor cell growth and proliferation and identify UHRF1 as a key oncogenic driver in MCL. Additionally, CM272’s antitumor effect was validated in preclinical MCL animal models while exhibiting an acceptable safety profile.