Orelabrutinib is a potent, irreversible, and highly-selective BTK inhibitor that has been approved for the treatment of relapsed/refractory chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL). This randomized, phase 3 study (ClinicalTrials.gov identifier: NCT04578613) compared orelabrutinib with chemoimmunotherapy in patients with treatment-naïve CLL/SLL. From February 20, 2021, to July 8, 2024, 192 eligible patients were randomly assigned (1:1) to receive either orelabrutinib (91 patients) or chlorambucil plus rituximab (101 patients), comprising the intention-to-treat population. At a median follow-up of 21.4 months (data cutoff, May 17, 2024), the primary endpoint of progression-free survival (PFS) per independent review committee (IRC) was not reached (NR; 95% CI, not estimable [NE]-NE) with orelabrutinib versus 19.4 months (95% CI, 16.6-NE) with chlorambucil plus rituximab (hazard ratio [HR], 0.32; 95% CI, 0.18-0.58; p < 0.0001; crossing the efficacy boundary). The IRC-assessed overall response rate (90.1% vs 79.2%; p = 0.041) and duration of response (HR, 0.30; 95% CI, 0.15-0.60; p = 0.0003) also favored orelabrutinib over chlorambucil plus rituximab. In the safety population, treatment-related adverse events occurred in 82 of 91 patients (90.1%) receiving orelabrutinib and 89 of 98 patients (90.8%) receiving chlorambucil plus rituximab, with 32 (35.2%) and 59 (60.2%) at grade 3 or worse, respectively. Orelabrutinib maintained or improved patient-reported outcomes compared with chemoimmunotherapy. In summary, orelabrutinib significantly improved PFS and response versus chemoimmunotherapy in patients with treatment-naïve CLL/SLL, with a manageable safety profile, supporting it as an effective alternative first-line option.

Introduction: Brentuximab vedotin (BV), a CD30-specific antibody-drug conjugate (ADC), is approved for the treatment of previously untreated advanced-stage and relapse/refractory(R/R) classical Hodgkin lymphoma (cHL). While clinical trials, including ECHELON-1 and SGN35-003, have demonstrated significantly improved outcomes with BV in both frontline and salvage treatment settings, data in Asian populations or real-world (RW) settings are limited. This study evaluated the safety profile and effectiveness of BV in Chinese adults with cHL, providing valuable insights into its real-world application. Methods: This is a subgroup analysis from a multicentre, prospective, observational RW study (BRAVE study; NCT04837222), which enrolled patients across 32 centers from June 7, 2021, to June 19, 2024. Eligible participants included patients (pts) aged ≥18 years, confirmed with CD30-positive cHL, who received BV-containing treatment regimens. The primary endpoint was serious adverse events (SAEs), and the secondary endpoints included adverse events (AEs), disease characteristics, BV dose intensity, objective response rate (ORR), complete response (CR), progressive-free survival (PFS), and overall survival (OS), etc. Results: A total of 512 patients with cHL were included, comprising 340 (66.4 %) newly diagnosed (ND) pts, and 172 (33.6%) R/R pts, with a median age of 35 years (range, 27–55), and with 19.4% classified as elderly pts (aged ≥60 years) ,and 24.9% in ND pts. The majority were males (N=287, 56.1%), and 5.1% had an ECOG performance status (PS) >2. Among ND patients, 122 (35.9%) and 205 (60.3%) were classified as Ann Arbor stage I-II and III-IV, with 118 (35.0%) pts exhibiting extranodal involvement and 37 (11.0%) having bone marrow infiltration. In the R/R group, 122 patients (70.9%) had stage III-IV disease, and 52.4% had experienced two or more relapses. AEs were observed in 344 patients (67.2 %), including 44 SAEs (8.6%), both lower than those reported in the ECHELON-1 trial (AEs, 99%; SAEs, 39%). Grade ≥3 AEs were observed in 123 patients (24.0%). Hematological SAEs were reported in 15 patients (2.4%). The most common non-hematological SAEs were infections (4.1%) and respiratory disorders (1.0%). Among elderly pts, the incidence of AEs was 70.4%, SAEs were 16.3%, and grade ≥3 AEs were 30.6%. Among ND patients, the median dose intensity was 1.19 (range, 1.03–1.28) mg/kg with a median number of 7.0 (range, 4.0–11.0) doses. More than 85% of pts received BV+AVD, while the remaining patients were treated with BV+PD-1 or BV monotherapy. The ORR and CRR were 86.9% and 59.9%, respectively. For elder pts, the ORR was 79.5% and CR was 45.5% ,while in patients aged <60 years, the ORR and CR were 88.5% and 63%, respectively. Patients with Ann Arbor stage I-II disease had an ORR of 86.7% and CR of 68.9%, while those with stage III-IV disease had an ORR of 87.7% and CR of 54.8%. T The 1-year OS rate was 100 in pts with Ann Arbor stage I-II disease and 97.9% in pts with stage III-IV disease. In the R/R group, the median dose intensity was 1.54 (range, 1.25–1.77) mg/kg with a median number of 5.0 (range, 2.0–7.0) doses. The most commonly used treatment regimen was BV + chemo, followed by BV + PD1 inhibitors. The ORR and CRR were 78.0% and 44.1%, respectively. No significant differences in ORR or CR were observed between BV+chemo (ORR:82%; CR,44%) and BV+PD1 (ORR, 80%; CR, 43.3%). The 1-year OS rate was 94.1 with a median follow-up of 10.7 (9.5–11.9) months. The 1-year OS rate was 82.8% in elderly patients, while the same was 96.6% for those aged <60 years. Conclusion: This is the largest real-world study of brentuximab vedotin in Asian patients with classical Hodgkin lymphoma. No new safety signals were identified relative to clinical trials. Outcomes with BV were similar across Arbor stages in newly diagnosed disease, yet efficacy remains suboptimal in elderly and RR populations, underscoring the need for optimizing BV-based therapeutic protocols.

BACKGROUND:Peripheral T-cell lymphoma (PTCL) represents a highly heterogeneous group of non-Hodgkin's lymphomas, often with aggressive biological behaviour. CD30 serves as a pivotal surface antigen in PTCL, however, its biological functions and therapeutic potential warrant further investigation. METHODS:We analysed 415 de novo patients with PTCL including 314 in the training cohort and 101 in the validation cohort across 11 medical centres in China. Genomic and transcriptomic profiles were examined by DNA- and RNA-sequencing in 355 and 169 patients, respectively. FINDINGS:In both cohorts, CD30+ PTCL presented significantly increased frequencies of SETD2, STAT3, and PTPRS mutations. Therefore, three molecular subtypes with distinct biological signatures were identified, including the HMA subtype characterised by dysregulation of histone methylation and acetylation, the JNE subtype by alterations in JAK-STAT, Notch signalling pathway, and EBV infection, and the PCT subtype by mutations in phosphorylation, chromatin remodelling, and T-cell receptor-major histocompatibility complex interaction, with extracellular matrix enrichment. Clinically, the JNE subtype demonstrated inferior progression-free survival (PFS) and overall survival (OS), as compared to the HMA and PCT subtypes. Brentuximab vedotin (BV)-containing treatment was associated with improved PFS and OS in the JNE and PCT subtypes. Furthermore, gene expression profile analysis demonstrated underlying vulnerabilities for the HMA, JNE, and PCT subtypes to epigenome-targeting agents, JAK or PI3K inhibitors, and PD-1 inhibitors, respectively. INTERPRETATION:The molecular subtypes of CD30+ PTCL demonstrated prognostic significance and varied sensitivity to BV treatment. Our findings further elucidated molecular regulatory networks of CD30+ PTCL, providing potential co-targeted approaches for genotype-guided precision medicine in PTCL. FUNDING:This study was supported by National Key R&D Program of China, National Natural Science Foundation of China, Clinical Research Plan of Shanghai Hospital Development Centre, Shanghai Clinical Research Centre for Cell Therapy, Shanghai Municipal Health Commission, and China Postdoctoral Science Foundation.

BACKGROUND:Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of aggressive non-Hodgkin's lymphoma with distinct clinical and molecular heterogeneity. DLBCL that arises in extranodal organs is particularly linked to poor prognosis. This study aimed to determine the clinical and molecular characteristics of extranodal involvement (ENI) in DLBCL and assess the actual survival status of the patients. METHODS:In this population-based cohort study, we investigated the clinical features of 5,023 patients newly diagnosed with DLBCL. Their clinical conditions, eligibility criteria, and sociodemographic details were recorded and analyzed. Gene panel sequencing was performed on 1,050 patients to discern molecular patterns according to ENI. RESULTS:The 2-year overall survival (OS) rate was 76.2% [95% confidence interval (CI), 74.0%-78.2%], and the 5-year OS rate was 67.9% (95% CI, 65.2%-70.4%). The primary treatment was immunochemotherapy with rituximab. Specific lymphoma involvement sites, especially the bones, bone marrow, and central nervous system, were identified as independent adverse prognostic factors. A high prevalence of non-germinal center B-cell (non-GCB) phenotype and myeloid differentiation primary response 88 (MYD88)/CD79B mutations were noted in lymphomas affecting the breasts, skin, uterus, and immune-privileged sites. Conversely, the thyroid and gastrointestinal tract showed a low occurrence of non-GCB phenotype. Remarkably, patients with multiple ENIs exhibited a high frequency of MYD88, tet methylcytosine dioxygenase 2 (TET2), CREB binding protein (CREBBP) mutations, increased MYD88L265P and CD79B mutation (MCD)-like subtypes, and poor prognosis. Genetic subtype-guided immunochemotherapy showed good efficacy in subgroup analyses after propensity score matching with 5-year OS and progression-free survival rates of 85.0% (95% CI, 80.6%-89.5%) and 72.1% (95% CI, 67.3%-76.7%). CONCLUSIONS:In the rituximab era, this large-scale retrospective analysis from Asia confirmed the poor prognosis of DLBCL with multiple ENIs and underscored the efficacy of genetic subtype-guided immunochemotherapy in treating extranodal DLBCL.

Birelentinib (DZD8586) is a LYN/BTK dual inhibitor designed to block both BTK-dependent and BTK-independent BCR signalling. In TAI-SHAN5 (NCT05824585) and TAI-SHAN8 (NCT06539182, CTR20240120) studies, patients who failed front line BTKi and/or BCL2i showed an overall response rate (ORR) of 84.2%. Similar responses were observed in patients with prior treatment of covalent BTKi, non-covalent BTKi as well as BTK degraders, with BTK C481X or “kinase-impaired” mutations (ASCO 2025). Here we report follow-up results of these studies. The data from TAI-SHAN5 and TAI-SHAN8 studies were pooled for the efficacy and safety analysis. Tumor response was assessed by investigators per iwCLL 2018 or Lugano 2014 criteria, as appropriate. All enrolled patients were included in safety analysis, and those patients enrolled by January 2025 were included in efficacy analysis to assess efficacy with long-term follow-up. As of July 7, 2025, a total of 65 patients with r/r CLL/SLL have been enrolled and received DZD8586 at doses ranging from 25 mg to 100 mg once daily (QD). At the recommended phase 3 dose (RP3D), 50 mg QD, 44 patients were enrolled. The median age was 62.5 years, 68% were male, and 64% had ECOG score of 1 or 2. The median number of prior therapies was 2 (range 1-5). Del(17p) and/or TP53 mutation was detected in 37% of the patients. Prior therapies included BTK inhibitor (71%, including 7% treated with non-covalent BTK inhibitor and 5% treated with BTK degrader), BCL-2 inhibitor (23%), and chemoimmunotherapy (41%). BTK mutations were detected in 55% of patients, including kinase proficient BTK mutation (55%) and kinase impaired BTK mutation (32%). In the efficacy analysis set at RP3D (N=19), 16 out of 19 patients achieved tumor response, with overall response rate (ORR) of 84.2%. Tumor response was observed in patients who received prior treatment with BTK inhibitors (ORR 82.4%, including non-covalent BTK inhibitors [2/2, ORR 100%]), Bcl-2 inhibitor (5/6, ORR 83%), and BTK degrader (1/2, ORR 50%). With median follow-up of 8.3 months, the estimated 12-month PFS rate was 61.9%. As of data cut-off date, the longest responder was on therapy for 12.1 months. DZD8586 was well tolerated across the doses investigated. No new safety signals were identified. At the RP3D, the most common ≥grade 3 drug-related TEAEs were neutropenia (22.7%). No febrile neutropenia was reported. No major bleeding or atrial fibrillation was reported. Nine percent of the patients had drug-related TEAEs leading to dose reduction. Only one patient discontinued treatment due to drug-related TEAE (cough). No drug-related TEAE related death was reported. DZD8586 showed encouraging anti-tumor activity with well tolerated and manageable safety profile in heavily pre-treated CLL/SLL patients, including patients with prior covalent BTKi, non-covalent BTKi, BTK degrader, and Bcl-2 inhibitor treatment. Durable tumor response was observed. The updated data will be presented at the meeting.

7010 Background: New therapies are needed for patients with relapsed or refractory (r/r) CLL/SLL following covalent and/or non-covalent BTK inhibitors. While early clinical data showed encouraging anti-tumor activities from BTK degraders in these patients, resistance mutations to both BTK inhibitors and degraders have already been reported. In addition, concerns with emerging clinical safety signals from these degraders may limit their longer-term clinical use. DZD8586 is a rationally designed LYN/BTK dual inhibitor with high selectivity against other TEC family members. Here we report results from ongoing phase 1/2 clinical studies of DZD8586 in r/r CLL/SLL patients with prior treatment of covalent and/or non-covalent BTK inhibitors as well as BTK degraders. Methods: The data from two clinical studies, TAI-SHAN5 (NCT05824585) and TAI-SHAN8 (NCT06539182, CTR20240120), were pooled for the safety and efficacy analysis in patients with CLL/SLL. Modulation of PD biomarkers was evaluated at doses tested. Tumor response was assessed by investigators per iwCLL 2018 or Lugano 2014 criteria as appropriate. Results: As of January 3, 2025, a total of 40 patients with r/r CLL/SLL have been enrolled and received DZD8586 at doses ranging from 25 mg to 100 mg once daily (QD). The median age was 64.5 years, 62.5% were male, and 60% had ECOG score of 1 or 2. A total of 30 patients were evaluable for efficacy analysis. The median number of prior therapies was 2 (range 1-8). Most common prior CLL/SLL therapies included BTK inhibitor (76.7%), and Bcl-2 inhibitor (43.3%). Patients previously treated by non-covalent BTK inhibitor (13.3%) and BTK degrader (13.3%) were also reported. Across all dose levels, 15 out of 30 patients achieved tumor response, with objective response rate (ORR) of 50%. At the recommended phase 2 dose (RP2D) of 50 mg QD, 9 out of 14 patients achieved tumor response, with ORR of 64.3%. Efficacy was observed in patients with prior BTK inhibitor treatment (ORR 52.2%), and Bcl-2 inhibitor treatment (ORR 46.2%). Seventy five percent patients who received prior BTK degrader treatment achieved partial response. As of the data cut-off date, the longest responder was on therapy for 12.1 months. Deepening response was observed with longer treatment time. DZD8586 was well tolerated across the doses investigated. At the RP2D, the most common ≥grade 3 TEAEs were neutropenia (15%) and pneumonia (10%). No major bleeding or atrial fibrillation was reported. No grade 4/5 AEs reported. Conclusions: DZD8586 showed encouraging anti-tumor activity with a well tolerated and manageable safety profile in heavily pre-treated CLL/SLL patients, including patients with prior covalent BTKi, non-covalent BTKi, BTK degrader and Bcl-2 inhibitor treatment. PK/PD results confirmed dose/exposure-dependent pathway inhibition by DZD8586. The updated data will be presented at the meeting. Clinical trial information: NCT06539182 , NCT05824585 .

Abstract Introduction: BCL2 inhibition is an established CLL/SLL therapeutic strategy, and combination with Bruton tyrosine kinase inhibition (BTKi) achieves therapeutic synergy. Mesutoclax (ICP-248) is highly selective and potent BCL2 inhibitor with improved pharmokinetical profile and metabolic stability. Orelabrutinib is a marketed second-generation BTKi with best kinase selectivity and good efficacy and safety in CLL/SLL. Herein, we present updated results of two ongoing studies of mesutoclax alone or combined with orelabrutinib in patients with treatment-naive (TN) or relapsed/refractory (R/R) CLL/SLL (NCT06378138; NCT05728658). Methods: Patients with TN CLL/SLL were randomized 1:1 with stratification, by age and TP53/del (17p) status, to receive mesutoclax (100 mg or 125mg once daily [cycles 3-14]) after two cycles orelabrutinib (150mg once daily [cycles 1-17]) lead in. Patients with R/R CLL/SLL received mesutoclax monotherapy until disease progression or unacceptable toxicity. Mesutoclax was administrated with a 5-week ramp-up schedule to the target dose to mitigate risk of tumor lysis syndrome (TLS). TN CLL/SLL can be continuously treated with orelabrutinib if stopping rules (undetectable MRD [uMRD; ≤10-4] at cycle 17) are not reached. Results: Between Apr 2023 and Sep 2024, 66 patients were enrolled: 42 patients were TN (mesutoclax 100 mg, n=21; 125 mg, n=21) and 24 patients were R/R. The median age for TN and R/R CLL/SLL were 59.5 y and 61.7 y, respectively. At baseline, 76.2% (32/42) of TN CLL/SLL patients had moderate or high TLS risk, while 70.8% of R/R CLL/SLL patients were refractory disease, among which 41.7% of patients were previously treated with BTKi. The median prior therapeutic line was 2 (range 1-7). Mesutoclax is well tolerated with good safety profile. No dose-limiting toxicities (DLTs) observed up to 150 mg QD, and maximum tolerated dose (MTD) not reached. As of Jul 21, 2025, all patients were still on treatment. Most treatment emergent adverse events (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, white blood cell count decreased and platelet count decreased. After 2 cycles of orelabrutinib lead in, 100% TN patients with high TLS risk were effectively debulked to moderate or low risk, and no clinical or laboratory TLS occurred. In TN CLL/SLL, the overall response rate (ORR) was 100% and the complete remission rate (CRR) was 28.6% at 125 mg. At week 36 of the combination therapy, the peripheral blood (PB) uMRD rate was 65% (13/20) at 125 mg. The median time to CR was 7.1 mo (range, 3.5-9.4 mo), the median time to uMRD was 5.8 mo (range, 5.5-11.3 mo). The ORR was 100% and CRR was 27.8% in R/R CLL/SLL patients at 125 mg. In 10 R/R CLL/SLL patients who failed prior BTKi treatment, the ORR was 100% and CRR was 30.0%, PB uMRD rate was 20.0%. 12-mo progression-free survival (PFS) rate was 100%. Conclusions: Mesutoclax monotherapy or in combination with orelabrutinib demonstrated a tolerable safety profile across all dose levels tested. Substantial efficacy and deep remission were observed in both TN CLL/SLL patients receiving mesutoclax 125mg combined with orelabrutinib and R/R CLL/SLL treated with mesutoclax alone.

7038 Background: BCL2, a critical protein regulator of the apoptotic pathway, highly expressed in various malignancies, including B-cell non-Hodgkin lymphomas (B-NHLs). The only approved BCL2 inhibitor, Venetoclax, has been approved for the treatment of chronic lymphocytic leukemia/small cell lymphoma (CLL/SLL) or acute myeloid leukemia (AML). However, hematologic toxicities and tumor lysis syndrome (TLS) remain as safety challenges in clinical practice. ICP-248 was developed as a potent and highly selective BCL2 inhibitor. Preclinical studies have demonstrated favorable pharmacokinetics profile and excellent safety profile. Methods: ICP-CL-01201 is an ongoing phase I study (NCT05728658) including dose escalation and dose expansion parts. Safety and tolerability of ICP-248 was evaluated from target doses of 50 mg to 200 mg. Patients receive oral treatment every day until disease progression or intolerable toxicities. Eligible patients include those aged 18-80 years, diagnosed with CLL/SLL and B-NHLs who are in relapsed or refractory disease. Key exclusion criteria include CNS involvement, resistance to BCL2 inhibitors and clinically significant cardiovascular disease. Efficacy was evaluated according to the Lugano 2014 or iwCLL 2018 criteria. Results: As of 12 Dec 2024, 55 patients were enrolled in the study: 18 in dose escalation and 37 in dose expansion. 24 patients were CLL/SLL, 26 patients were mantle cell lymphoma (MCL), 5 patients were other B-NHLs. The median age was 65 years, and 72.7% of patients were refractory disease and 56.4% of the patients were previously treated with BTK inhibitors. The median prior therapeutic line was 2 (1-8). ICP-248 was well tolerated through all dose levels, with no dose-limiting toxicities (DLTs) observed, and maximum tolerated dose (MTD) not reached. Toxicity leading to drug discontinuation and death was not observed. Most of TEAEs were in grade 1-2. The most frequent TEAEs were hematologic AEs including neutropenia, leukopenia, and thrombocytopenia. Serious adverse events (SAEs) were reported in 16.4% patients. As cutoff date, 20 CLL/SLL and 19 MCL patients treated with ICP-248 dose ≥100 mg had at least one response assessment: ORR was 80% and CRR was 15% in r/r CLL/SLL patients, while those for r/r MCL patients were 78.9% and 42.1% respectively. uMRD was reported in 10% CLL/SLL and 15.8% MCL patients. In 10 patients with previous BTK inhibitor refractory MCL patients (2 blastoid or pleomorphic subtype and median 3.5 prior treatment lines), the ORR was 80% and CRR was 30%; in 11 patients with previous BTK inhibitor failure CLL/SLL, the ORR was 81.8% and CRR was 18.2%. Conclusions: The preliminary results of ICP-248 monotherapy suggests a well-tolerated safety profile and an exciting efficacy with dose-dependent effect in BTK failed, heavily treated, relapsed or refractory B-cell malignancies. Clinical trial information: NCT05728658 .

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.

BackgroundRelevant studies have demonstrated the poor treatment outcomes and prognosis for double-expressor diffuse large B cell lymphoma (DE-DLBCL) in the rituximab era. Zanubrutinib plus R-CHOP (rituximab, cyclophosphamide, doxorubicin/liposomal doxorubicin, vincristine, prednisone; ZR-CHOP) has shown efficacy in untreated non-GCB DLBCL patients with extranodal involvement. However, its efficacy in newly diagnosed DE-DLBCL remains uncertain.ObjectiveThis retrospective study sought to assess the efficacy and safety of ZR-CHOP in comparison to R-CHOP in treatment-naïve patients with DE-DLBCL.MethodThis study assessed 78 patients with newly diagnosed DE-DLBCL who were admitted between June 2017 and January 2024. Among them, 55 patients received the R-CHOP regimen, while 23 patients were treated with the ZR-CHOP regimen. The clinical characteristics were well balanced between the two groups.ResultsThe complete response rates (CRR) were higher in the ZR-CHOP group than the R-CHOP group, regardless of whether patients completed 4 or 6 treatment cycles (P= 0.019; P= 0.025). ORR in the ZR-CHOP group showed a higher trend than that in the R-CHOP group (P= 0.624; P= 0.219). The median follow-up period was 23.3 months, and the predicted median progression free survival (PFS) in the R-CHOP group was 22.8 months, whereas the median PFS in the ZR-CHOP group was not reached. The 1-, 2-, and 3-year PFS rates in the ZR-CHOP group showed a beneficial trend compared with the R-CHOP group, but there was no statistical difference (P= 0.072). However, the PFS of the ZR-CHOP group was longer than that of the R-CHOP group in patients with Ki67 index >75% (P= 0.034) and p53 expression >50% (P= 0.0033). The predicted median overall survival (OS) in the ZR-CHOP and R-CHOP groups were not reached. The 1-, 2- and 3-year OS rates were not significantly different between the two groups (P= 0.29). The most common adverse event in both groups was hematotoxicity, but there was no significant difference in the incidence of all adverse events between the two groups.ConclusionFirst-line treatment with the ZR-CHOP regimen improved CRR in the untreated patients with DE-DLBCL and prolonged PFS in the Ki67 index >75% subgroup and the p53 expression >50% subgroup.

Objective: Mucosa-associated lymphoid tissue (MALT) lymphoma represents a distinct subtype among marginal zone lymphomas (MZL). The stomach is the most frequently involved site in MALT lymphoma, but the disease can occur in mucosa-associated lymphoid tissue of all organs, including the orbit, lung, and salivary glands. Current clinical studies indicate BTK inhibitors exhibit promising efficacy in MZL. As a novel BTK inhibitor, Orelabrutinib reduces adverse reactions associated with off-target effects and improves patient tolerance. Nevertheless, clinical data on Orelabrutinib combined with Anti-CD20 monoclonal antibody for treating MALT lymphoma remains insufficient. Therefore, this study aims to evaluate the effectiveness and safety of the Orelabrutinib combined with Anti-CD20 monoclonal antibody regimen in treating MALT lymphoma through a single-center retrospective analysis. Methods: Clinical data of MALT lymphoma patients diagnosed and treated with the Orelabrutinib combined with Anti-CD20 monoclonal antibody regimen at Union Hospital, Tongji Medical College, Huazhong University of Science and Technology between June 2023 and April 2025 were retrospectively analyzed. Treatment efficacy was assessed based on PET-CT/CT imaging or gastrointestinal endoscopy results before and after medication. Primary endpoints included: objective response rate (ORR), complete response rate (CR), progression-free survival (PFS), overall survival (OS), and incidence of adverse events. Results: Baseline Characteristics By April 2025, this study enrolled 12 evaluable MALT lymphoma patients, comprising 4 males and 8 females. The median age was 61 years (range 30-73). Among them, 25% (3/12) had Ann Arbor stage III-IV disease, with 1 case presenting bone marrow involvement. Primary sites included gastric (n=4) and non-gastric (n=8), with non-gastric subtypes comprising pulmonary MALT lymphoma (n=4), orbital MALT lymphoma (n=2), parotid MALT lymphoma (n=1), and colonic MALT lymphoma (n=1). According to MALT-IPI stratification, 8 cases (66.7%) were low-risk and 4 cases (33.3%) were intermediate-low risk. Ten treatment-naïve MALT lymphoma patients received the Orelabrutinib combined with Anti-CD20 monoclonal antibody regimen as first-line treatment. One treatment-naïve patient received it as second-line therapy due to prior chemotherapy intolerance, while one refractory patient received this regimen as second-line treatment. Efficacy and safety The ORR for the entire cohort was 100%, with a CR rate of 75% (9/12). The gastric MALT lymphoma subgroup comprised 4 patients with a median follow-up of 11 months. All patients received first-line treatment, achieving a CR rate of 75% (3/4). The non-gastric MALT lymphoma subgroup included 8 patients with a median follow-up of 13 months, attaining a CR rate of 87.5% (7/8). All four pulmonary MALT lymphoma patients achieved a 100% CR rate. Among them: one patient was assessed as PR after 4 cycles of R-miniCDOP regimen but switched to Orelabrutinib combined with Anti-CD20 monoclonal antibody regimen due to chemotherapy intolerance, subsequently achieving CR after 4 cycles; another patient showed progressive disease after 2 cycles of R-CDOP regimen but attained CR after switching to 4 cycles of Orelabrutinib combined with Anti-CD20 monoclonal antibody regimen. Both orbital MALT lymphoma patients achieved 100% CR. The single colonic MALT lymphoma patient reached 100% CR. One parotid MALT lymphoma patient was preliminarily assessed as PR after 2 treatment cycles. No disease progression, relapse, or death occurred among all patients; therefore, OS and PFS were not evaluated. Hematological adverse events were observed in 25% (3/12) of cases, including two grade 1 leukopenia events and one grade 2 thrombocytopenia event. No non-hematological adverse events were reported. Conclusion: Despite the limited sample size in this retrospective study, the results indicate that the Orelabrutinib combined with Anti-CD20 monoclonal antibody regimen demonstrates favorable safety and efficacy in MALT lymphoma patients, providing an effective and safe treatment option for this population.

Background: Venetoclax is the only approved BCL2 inhibitor for treating chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and acute myeloid leukemia (AML). However, the single agent efficacy in mantle cell lymphoma (MCL), remains unsatisfactory. Mesutoclax is a novel BCL2 inhibitor and preliminary clinical results have showed its promising efficacy and safety in B-NHLs. Methods: ICP-CL-01201 (NCT05728658) and ICP-CL-01202 (NCT06351527) are two ongoing phase I studies of Mesutoclax for the treatment of Chinese and Caucasian patients with B-cell malignancies, respectively. Both studies contain dose escalation and dose expansion parts. Eligible patients include relapsed and refractory (r/r) MCL, CLL/SLL and other B-NHLs. Safety and tolerability were assessed across all dose levels, from 50 mg to 150 mg. Oral treatment was administered once daily until disease progression or intolerable toxicities. Key exclusion criteria comprise CNS involvement, prior resistance to BCL2 inhibitors, and significant cardiovascular conditions. Efficacy of MCL and other B-NHLs patients was evaluated according to the Lugano 2014 criteria. Herein, we report the pooled analysis of efficacy and safety in mantle cell MCL patients treated with Mesutoclax across these two studies. Results: As of 10Jul 2025, 43 MCL patients were enrolled in ICP-CL-01201 study and treated with Mesutoclax monotherapy. The median age was 66 years (range 30-79). Of the patients, 32 (74.4%) were previously treated with and refractory to BTK inhibitors, and 35 (81.4%) were refractory to the last line of therapy. The median prior therapeutic line was 2 (range 1-8). Mesutoclax was well tolerated through all dose levels, with no dose-limiting toxicities (DLTs) observed, and maximum tolerated dose (MTD) not reached. One patient experienced dose reduction due to TEAE. Toxicity leading to drug discontinuation was not reported. Most of the TEAEs were in grade 1-2. The most frequent (≥10%) ≥grade3 TEAEs were neutrophil count decreased (18.6%), white blood cell count decreased (16.3%), and platelet count decreased (14.0%). Noteworthily​, there is no reported ≥grade3 anemia, which is a common toxicity of BCL2 inhibitors, in this study (72 patients with monotherapy in total). Serious adverse events (SAEs) were reported in 10 (23.3%) patients. Treatment-related SAE reported in ≥2 patients were pneumonia (14.0%), neutrophil count decreased (4.7%), platelet count decreased (4.7%), and herpes zoster (4.7%). As of cutoff date, 32 MCL patients treated with Mesutoclax monotherapy in 125 mg dose level (recommended phase 2 dose) had at least one disease assessment. In total, ORR was 87.5% and CRR was 46.9%. Notably, in 25 MCL patients who were BTK inhibitor refractory (2 blastoid or pleomorphic subtype and median 2 [1-8] prior treatment lines), highly encouraging efficacy was achieved following Mesutoclax treatment: an ORR of 84.0%, CRR of 36.0%, and a median PFS of 8.3 months (95% CI 5.5, NA). mDOR was not reached, and the 6 months DOR rate was 74.5%. Conclusion: The clinical data from Mesutoclax monotherapy demonstrate low toxicity and potential best in class efficacy in MCL patients, particularly in heavily treated patients with BTK inhibitors refractory disease. These findings support further development of Mesutoclax to address the unmet need in r/r MCL patients who failed previous BTK inhibitors.

Rocbrutinib, a highly selective, 4th-generation Bruton's tyrosine kinase (BTK) inhibitor, uniquely takes advantages of both covalent irreversible inhibition for wide-type BTK and non-covalent binding for C481-mutant variants. Here, we present the safety and efficacy results from the ongoing phase I trial (LP-168-CN101; NCT04993690) of rocbrutinib in Chinese patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Eligible patients aged 18–80 with a confirmed diagnosis of CLL/SLL were treated with rocbrutinib monotherapy until disease progression or intolerable toxicity. Adverse events (AEs) were graded per CTCAE v5.0, and response was evaluated per 2018 iwCLL criteria. As of April 15, 2025, 41 (untreated (1L), n=12; relapsed/refractory (R/R) BTKi-naïve, n=17; R/R post-BTKi, n=12) CLL/SLL patients were enrolled and treated with rocbrutinib (100 mg ,n=1; 150 mg, n=28; 200 mg, n=10; 300mg, n=2) once daily. The median age was 60 (range, 35-79) years. Of the patients with evaluable samples, 26.9% (7/26) with del(17p), 42.9% (12/28) with TP53 mutation, 63.0% (17/27) with unmutated IGHV and 44.0% (11/25) with complex karyotype. Of the 29 R/R CLL/SLL patients, the median number of prior therapies was 2 (range, 1-5), including prior covalent BTKis (34.5%), BCL2 inhibitors (BCL-2i, 24.1%), and noncovalent BTKis (6.9%). In R/R post-BTKi CLL/SLL patients, most (91.7%) discontinued prior BTKi due to disease progression; 41.6% had prior BCL-2i ; 6/9 (66.7%) carried BTK mutations, including BTKC481S, BTKC481Y/R and BTKL528W. The most common treatment-related AEs (TRAEs, incidence≥20%)(any grade;≥grade 3) included decreased neutrophil count (41.5%; 19.5%), anemia (36.6%; 2.4%), decreased platelet count (29.3%; 2.4%), hyperuricemia (26.8%; 0) and rash (22.0%; 0), most of which were grade 1. No ≥grade 3 atrial fibrillation, hypertension or hemorrhage occurred. Dose interruption due to TRAEs occurred in 8 (19.5%) patients, however, only 1 (2.4%) patient underwent dose reduction. No drug discontinuation or death due to TRAEs has occurred. In 1L patients (n=12), the overall response rate (ORR, partial response with lymphocytosis or better) was 91.7%. The ORR and complete remission (CR)/CR with incomplete marrow recovery (CRi) rates in R/R BTKi-naïve patients (n=17) were 100% and 17.6%, respectively. In R/R post-BTKi patients, rocbrutinib monotherapy achieved 75% ORR including16.7% CR/CRi. In BTKi and BCL-2i double refractory population (n=5), ORR and CR/CRi rates were 80.0% and 40.0%, respectively; 3 patients are still in remission while the other 2 patients both had durable response of more than 17 months. 2 patients with BTKL528W mutation achieved PR and are still on treatment (DOR: 8.1 and 14.0 months). After median follow-up of 7.4 months, all 12 1L patients remained on treatment. In the R/R BTKi naive population (median follow-up 15.8 months), the estimated 12-month PFS rate as 94.1% (95% CI: 65.0-99.1); In the R/R post-BTKi population (median follow-up 15.5 months), the estimated 12-month PFS rate as 83.3% (95% CI: 48.2-95.6). Rocbrutinib has a favorable safety profile and shows durable responses in patients with CLL/SLL, including those with prior BTK inhibitor exposure and/or with covalent and noncovalent BTKi-resistant mutations.

Objective:​​ To investigate the clinicopathological characteristics, genomic mutational profiles, prognostic determinants, survival outcomes, and current diagnostic/therapeutic landscape of thyroid diffuse large B-cell lymphoma (TDLBCL), distinguishing primary from secondary subtypes. Methods:​​​ A multi-center retrospective analysis was conducted on 190 TDLBCL patients (123 primary, 67 secondary) treated across 22 Chinese institutions between November 2003 and November 2024. Clinicopathological data, treatment modalities, and survival outcomes were analyzed. Targeted sequencing of 55 lymphoma-associated genes was performed on 49 tumor samples to characterize mutational patterns. Results:​​​ Primary TDLBCL patients exhibited significantly higher proportions (P<0.05) of the following favorable features compared to secondary cases: ECOG performance status ≤1(P=0.005), Ann Arbor stage I–II(P< 0.001), ≤1 extranodal involvement site(P< 0.001), normal lactate dehydrogenase (LDH) (P< 0.001), combined surgical resection and chemotherapy(P< 0.001), concurrent Hashimoto's thyroiditis (HT) (P=0.005), neck mass as initial presentation(P< 0.001), localized compressive symptoms(P< 0.001), absence of B symptoms(P=0.002), thyroid dysfunction(P=0.021), and maximum tumor diameter <6 cm(P=0.018). Among 175 evaluable patients, primary TDLBCL (91.0%，101/111) achieved superior objective response rates (ORR) versus secondary disease (73.4%，47/64) (P=0.002). For 108 patients receiving first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)-based therapy, primary TDLBCL demonstrated significantly improved 5-year progression-free survival (PFS) (66.9% vs. 52.4%; P=0.018).Prognostic Factors:​​Univariate analysis of R-CHOP-treated patients identified extranodal involvement ≥2 sites(HR=2.185, 95%CI 1.011‒4.720), ECOG performance status ≥2(HR=2.378, 95%CI 1.039‒5.441), Ann Arbor stage III–IV(HR=2.262, 95%CI 1.046‒4.891), and elevated LDH (HR=2.690, 95%CI 1.178‒6.142) as significant adverse prognostic factors for progression-free survival (PFS), while maximum tumor diameter ≥6 cm (HR=5.788, 95%CI 1.436‒23.338) and double-expressor (DE) (HR=5.585, 95%CI 1.001‒31.150)（P=0.05） subtype detrimentally impacted overall survival (OS) (P<0.05); Multivariate analysis: Elevated LDH independently predicted inferior progression-free survival (HR = 2.690, 95% CI: 1.178–6.142, P = 0.019), while maximum tumor diameter emerged as an independent predictor for overall survival (model χ² = 8.587, P = 0.014), with tumors <6 cm conferring significantly reduced mortality risk (HR = 0.348, 95% CI: 0.159–0.759, P = 0.008). furthermore, genomic profiling revealed recurrent mutations in TP53 (30.6%), TET2 (30.6%), and KMT2D (26.5%), with TET2 mutational frequency differing significantly between primary and secondary TDLBCL subtypes (P=0.032), though none of these mutations demonstrated a statistically significant association with survival outcomes. Conclusion:​​ Primary TDLBCL demonstrates superior survival outcomes and enhanced response to first-line therapy compared to secondary TDLBCL. Adverse prognostic factors significantly impacting patient survival include Ann Arbor stage III–IV, elevated serum LDH, extranodal involvement ≥2 sites, maximum tumor diameter ≥6 cm, and the DE phenotype.Serum LDH levels and tumor diameter serve as ​independent predictors​ for PFS and OS, respectively, underscoring their critical role in prognostication.Genomic profiling identified TET2, TP53, and KMT2D as the most recurrently mutated genes in TDLBCL; however, none of these genetic alterations exhibited a statistically significant association with prognosis.

Introduction BCL-2 inhibitors play an important role in the treatment of CLL/SLL. Although venetoclax monotherapy is approved (ex-China) to treat pts with CLL/SLL who have a 17p deletion [del(17p)] (Davids MS et al, Clin Lym Mye Leuk. 2017), there is no effective treatment available for pts with CLL/SLL that has failed prior BTKi therapies, especially those who previously received CD20-based immunochemotherapy (ICT) or had high-risk (HR) factors. This issue remains a highly unmet medical need in China. Methods In this pivotal phase 2 study (APG2575CC201; NCT05147467), eligible pts with R/R CLL/SLL met dual criteria: (A) documented progression on ≥ 1 prior BTKi, and (B) either previous ICT failure or had HR factors (e.g., del(17p)/TP53 mutation, unmutated IGHV, chromosomal complex karyotype [CK]). Pts were treated with daily oral doses of lisaftoclax (a novel investigational BCL-2 inhibitor) using a rapid 5-day ramp-up from 20 to 600 mg (target dose), in repeated 28-day cycles, until disease progression or unacceptable toxicity. The primary end point was objective response rate (ORR). Efficacy was assessed by the investigators and by an independent review committee (IRC) based on hematology, imaging examinations, and bone marrow (BM) examinations, in accordance with the NCI-WG-CLL criteria and the 2014 Lugano criteria for NHL, including complete response (CR), CR with incomplete marrow recovery (CRi), and partial response (PR). Secondary endpoints included progression-free survival (PFS), duration of response (DOR), overall survival (OS), minimal residual disease (MRD), and adverse events (AEs). Results As of July 25, 2025, 77 pts had been enrolled, and the last enrolled pt completed ≥18 cycles of treatment. The median follow-up was 22.01 months (mo.); median age was 63 years; 59.7% were male; and 31.2% had an ECOG PS of 2. Sixty-eight pts (88.3%) were diagnosed with CLL, 66 (85.7%) had Binet stage B/C, and 45 (58.4%) had Rai stage II-IV. Nine pts (11.7%) had SLL with Rai stage III/IV. Thirty-five pts (45.5%) had disease that had relapsed or was refractory or intolerant to both BTKis and ICT. The remaining 42 pts (54.5%) disease that had previously failed on BTKis and had HR factors. Thirty pts (39.0%) had del(17p) and/or TP53 mutations; 33 (42.9%) had CK; 21 (27.3%) had high CK (abnormal chromosome number ≥ 5); and 41 (53.2%) had unmutated IGHV. Among the 33 pts with CK, 21 cases (63.6%) also had del(17p) or TP53 mutation. Among 72 evaluable pts, the ORR was 62.5% (per IRC), and 58.3% (per investigators). The median PFS (mPFS) was 23.89 mo.; median time-to-response (TTR) was 3.68 mo.; and median DOR was 18.53 mo. Median OS was not reached. Almost all pts were resistant to prior BTKis (and not BTKi intolerant); 14 (18.2%) pts experienced rotation between different BTKis, and only 5 achieved PR. Univariate analysis showed that mPFS of pts with del(17p)/TP53 mutation plus CK was 11.2 months vs 29.6 months in pts without del(17p)/TP53 mutation or CK. In pts with high CK versus those without high CK, the mPFS was 12.9 months vs 29.6 months, respectively. These two groups accounted for nearly 30% of the total population, which is much higher than observed in historical studies and represents true BTKi failure and a pt population with very HR refractory disease. In 55 MRD-evaluable pts, 12 cases (21.8%) were MRD-negative. Of 11 evaluable cases with BM MRD, 6 (54.5%) were MRD-negative. In 11 cases where peripheral blood and BM MRD could be evaluated, 6 cases (54.5%) were MRD-negative. Of note, because study enrollment occurred during the COVID-19 epidemic, many pts were unable to adhere to treatment and achieve satisfactory efficacy due to COVID-19 infections. Fifty-five (74%) pts experienced grade ≥ 3 TEAEs during treatment; frequent TEAEs (≥ 10%) included decreased neutrophil (28.6%) and platelet (23.4%) counts; anemia (15.6%), and infectious pneumonia (11.7%). Forty (53.2%) pts experienced grade ≥ 3 AEs related to the study drug (TRAEs), including decreased neutrophil (27.3%), decreased platelet (16.9%), and white blood cell (7.8%) counts; anemia (9.1%), and infectious pneumonitis (3.9%). No tumor lysis syndrome was reported, and no lisaftoclax-related deaths occurred. Conclusion In this study, we show that lisaftoclax monotherapy achieved significant ORR and long-lasting PFS with an acceptable safety profile in pts with heavily-treated R/R CLL/SLL refractory to BTKis.

Objective To evaluate the efficacy and safety of polatuzumab vedotin (Pola)–based regimens in newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients, with a focus on the performance of the Pola-R-CHP regimen in different subtypes and high-risk populations. Methods We retrospectively analyzed the clinical data of 42 newly diagnosed DLBCL patients treated with Pola-based regimens at our center between January 2023 and May 2025. Treatment regimens included Pola-R-CHP (rituximab, cyclophosphamide, doxorubicin, prednisone) in 30 patients, Pola-miniCHP in 4 patients, Pola-ZR (zanubrutinib, rituximab) in 6 patients, and other regimens in 2 patients. Baseline clinical characteristics, overall response rate (ORR), complete response (CR) rate, subgroup outcomes, survival, and adverse events were collected. Response assessment was based on whole-body PET-CT or contrast-enhanced CT, and adverse events were graded according to CTCAE version 5.0. Results Among 42 patients, 47.6% were male and 52.4% female, with a median age of 61 years (range, 18–81). Non-GCB subtype accounted for 73.8%, double-expressor lymphoma (DEL) for 28.6%, extranodal involvement for 90.5%, and IPI score 3–5 for 61.9%. Median follow-up was 182 days (range, 57–731). The ORR for all Pola-based regimens was 90.5%, with a CR rate of 71.4%, partial response (PR) rate of 19.1%, and progressive disease (PD) rate of 9.5%. Estimated 1-year overall survival (OS) and progression-free survival (PFS) rates were 92.9% and 88.1%, respectively. No statistically significant differences in ORR or CR rates were observed among clinical subgroups. By regimen, Pola-R-CHP achieved an ORR of 93.3% and CR rate of 76.7%; Pola-miniCHP, 100.0% and 50.0%; and Pola-ZR, 83.3% and 66.7%, respectively. Combined analysis of Pola-miniCHP and Pola-ZR (mainly for elderly, frail, or chemotherapy-intolerant patients) yielded an ORR of 90.0% and CR rate of 60.0%. In the Pola-R-CHP cohort (n=30), ORR was 93.3%, CR 76.7%, PR 16.7%, and PD 6.7%. DEL vs. non-DEL patients had ORRs of 85.7% and 95.7%, and CR rates of 71.4% and 78.3%, respectively. IPI 0–2 vs. 3–5 had ORRs of 100.0% and 88.2%, and CR rates of 84.6% and 70.6%. Patients with <2 vs. ≥2 extranodal sites had ORRs of 100.0% and 88.2%, and CR rates of 92.3% and 64.7%. Estimated 1-year OS and PFS were 94.4% and 89.4%, respectively. The most common hematologic toxicities were anemia (grade 1–2, 59.5%; grade 3–4, 9.5%), neutropenia (16.7%; 21.4%), and leukopenia (33.3%; 21.4%). The most common non-hematologic toxicity was pneumonia (26.2%). In the Pola-R-CHP group, anemia occurred in 53.3% (grade 1–2) and 10.0% (grade 3–4); leukopenia in 23.3% and 23.3%; neutropenia in 10.0% and 13.3%; and pneumonia in 23.3%. Conclusion In real-world practice, Pola-based regimens demonstrated high response rates and favorable tolerability in newly diagnosed DLBCL patients. Pola-R-CHP, as the predominant frontline regimen, showed consistent efficacy and manageable safety in high-risk subgroups including non-GCB, DEL, high IPI scores, and multiple extranodal involvement. Dose-reduced chemoimmunotherapy (Pola-miniCHP) and chemo-light regimens (Pola-ZR) provided reasonable efficacy in elderly or frail patients, warranting further evaluation in larger cohorts. Keywords polatuzumab vedotin; diffuse large B-cell lymphoma; newly diagnosed; efficacy; safety

The multi-center randomized phase III NHL-004 study compared etoposide, dexamethasone and pegaspargase (ESA) versus the methotrexate, etoposide, dexamethasone and pegaspargase (MESA) regimen, combined with sandwiched radiotherapy, in newly diagnosed early-stage nasal natural killer / T-cell lymphoma (NKTCL). Here we report the long-term outcomes (median follow-up, 64 months) and biomarker analysis. A total of 256 eligible patients aged 14-70 years were randomly assigned (1:1) to the ESA or the MESA arm. The 5-year progression-free survival (PFS) rates were 80.3% and 74.9% in the ESA and MESA arms (hazard ratio [HR]=0.78 [95% CI: 0.46-1.33], P=0.371), and the 5-year overall survival (OS) rates were 85.1% and 80.9% (HR=0.74 [95% CI: 0.40-1.37], P=0.332), respectively. No new safety signals related to treatments were observed. Interim plasma Epstein-Barr virus (EBV) DNA positivity and stable disease / progressive disease response were independent predictors of inferior PFS and OS. No prognostic significance was observed according to molecular subtypes. Interim EBV DNA positivity correlated with up-regulated chromatin remodeling alterations, immune escape-related genes, and decreased infiltrating monocytes / M1 macrophages. With low toxicity, non-intravenous administration, and an outpatient design, ESA with sandwiched radiotherapy achieved long-term durable response in patients with newly diagnosed early-stage NKTCL. Dynamic monitoring of plasma EBV DNA provided a clinical rationale for future mechanism-based therapy in NKTCL.

Zanu, a potent, specific next-generation BTK inhibitor with a favorable safety profile, is approved in over 70 countries globally for the treatment of multiple B-cell malignancies. Pts with R/R DLBCL face a poor prognosis, and the CD79B mutation is an unfavorable prognostic factor for survival, especially following immunochemotherapy. Zanu has demonstrated modest antitumor activity in R/R non-germinal center B-cell (GCB) DLBCL in clinical trials, and retrospective biomarker analyses have indicated that pts with mutated CD79Bshow an enhanced response to zanutreatment(Yang et al Blood Adv 2022; Liu et al Leuk Lymphoma 2024). Currently, there is no established standard of care for CD79B-mutated R/R DLBCL, highlighting an unmet clinical need. Thus, this study assessed antitumor activity and related biomarkers of zanu for CD79B-mutated R/R DLBCL. In this phase 2 trial (NCT05068440), pts with centrally confirmed CD79B-mutated R/R DLBCL who were ineligible for high-dose therapy/stem cell transplant and had received ≥1 prior line of systemic therapy were enrolled across 20 sites in China. Treatment included zanu 160 mg BID po continuously in 28-day cycles until disease progression, unacceptable toxicity, loss to follow-up, or end of the study. Evaluations occurred at baseline, then every 12 weeks for 24 months [mo], and then every 24 weeks thereafter. Primary endpoint was overall response rate (ORR) per 2014 Lugano criteria. Secondary endpoints included complete response (CR) rate, duration of response (DOR), time to response (TTR), progression-free survival (PFS), overall survival (OS), and safety per NCI-CTCAE v5.0. Immunohistochemistry (IHC) DLBCL subtyping data were collected from local sites. For pts without local IHC data, central laboratory staining of CD10, BCL-6, and MUM1 with FFPE tissue specimens were used to classify phenotypes using the Han's Algorithm. Molecular profiling was conducted in biomarker-evaluable pts using DNA (custom Oncolym-413 panel [Gene+]) and RNA sequencing data. Between August 2021 and March 2025, a total of 65 pts were enrolled. All pts were Asian; 52.3% (n=34) of pts were male. Median age was 66 years (range: 42-92 years), 86.2% had non-GCB DLBCL, 63.1% had relapsed disease, 81.5% had Ann Arbor stage III/IV disease, and 84.6% had Eastern Cooperative Oncology Group performance status of ≤1. Median number of prior therapies was 1. All pts were included in the safety and efficacy analysis set. With a median follow-up of 13.9 mo (range: 0.5-36.4 mo), the ORR was 46.2%, CR was 29.2%, and PR was 16.9%. In responders, the median DOR was 22.7 mo (2.8-NE). Median TTR was 2.8 mo. Median PFS and OS were 4.3 mo (95% CI 2.7-5.5) and 18.1 mo (95% CI 11.4-NE), respectively. Pts with non-GCB DLBCL achieved encouraging response rates (ORR 51.8%). Zanu demonstrated a tolerable and manageable safety profile consistent with the established safety profile. The reported incidence of grade ≥3 treatment-related treatment-emergent adverse events (TRAEs) was 16 pts (24.6%). The most frequently reported TRAEs of grade ≥3 were pneumonia (6.2%), decreased neutrophil count (6.2%), decreased platelet count (3.1%), anemia (3.1%), and decreased lymphocyte count (3.1%). With a median exposure time to zanu of 4.0 mo (range: 0.3-36.4 mo), no atrial fibrillation or flutter, hypertension, opportunistic infections, second primary malignancies, or tumor lysis syndrome events were reported. Retrospective biomarker analyses demonstrated that 32/64 pts with low levels of ctDNA (<275.898 hGE/mL) at baseline had favorable clinical outcomes including higher response rates (ORR 62.5% vs 28.1%; P<.0001) and longer PFS (P<.01). Further, pts who achieved CR had a high rate of undetectable ctDNA at first response following zanu treatment (17/18; 94.4%). Pts with co-occurring CD79B and MYD88L265P mutations demonstrated better ORR and CR compared with pts without (ORR 14/23 vs 15/41, P=.070; CR 10/23 vs 8/41, P<.05). Acquired BTK and PLCG2 mutations were observed in 17/34 pts who progressed following zanu treatment.Conclusion: Zanu demonstrated encouraging antitumor activity and a tolerable safety profile in pretreated CD79B-mutated R/R DLBCL. Retrospective biomarker analyses demonstrated improved zanu response in pts with non-GCB subtype, low baseline ctDNA levels, or co-occurring CD79B and MYD88L265P mutations. These data suggest zanu may provide clinical benefit for these pts with limited therapeutic options.

High-dose chemotherapy combined with autologous hematopoietic stem cell transplantation (auto-HSCT) is a well-established consolidation treatment for lymphoma and multiple myeloma, reducing relapse risk and improving survival. Effective mobilization of peripheral blood stem cells (PBSC), measured by the collection of an adequate number of CD34+ cells, is critical for successful auto-HSCT. Mecapegfilgrastim, a novel pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF), offers a stable structure, low immunogenicity and extended half-life. Despite its growing use in PBSC mobilization for hematological malignancies, data on its efficacy in different dosing regimens remain scarce. This study evaluates the efficacy and safety of single-dose versus split-dose mecapegfilgrastim combined with high-dose etoposide for PBSC mobilization in patients with lymphoma and multiple myeloma. In this prospective, randomized, controlled, single-center clinical trial, 57 patients (25 with lymphoma, 32 with multiple myeloma) undergoing autologous PBSC mobilization were recruited between July 2021 and March 2024. Participants were randomized into two groups based on the mecapegfilgrastim administration pattern: a split-dose group (n=30) receiving 6 mg on days 3 and 7, and a single-dose group (n=27) receiving 12 mg on day 3. All the patients received etoposide (1.6 g/m² over 10 hours) on day 1. Apheresis was performed based on the peripheral blood CD34+ cell count (≥10 cells/μL) or a risk-benefit assessment. Primary endpoint was the rate of successful mobilization (≥2×10⁶ CD34+ cells/kg). Baseline characteristics, including age, sex, Eastern Cooperative Oncology Group (ECOG) status, underlying disease, previous chemotherapy cycles, and prior exposure to lenalidomide, bendamustine, and radiotherapy, were comparable between the two groups. The median day for the first collection was day 8 (range 8-10) in both groups. The split-dose group achieved a significantly higher optimal mobilization rate (≥5×10⁶ CD34+ cells/kg) of the first collection compared with the single-dose group (56.7% vs. 25.9%, P=0.019), though there was no significant difference in the success mobilization rate (70.0% vs. 66.7%, P=0.787). After two collections, the differences in mobilization rates were not statistically significant: optimal mobilization (70.0% vs. 59.3%, P=0.396) and successful mobilization (76.7% vs. 77.8%, P=0.920). Overall, the split-dose regimen showed a trend towards greater efficiency, but the differences were not statistically significant (successful mobilization: 90.0% vs. 81.5%, P=0.355; optimal mobilization: 76.7% vs. 70.4%, P=0.590). The number of apheresis procedures required for successful mobilization was 1 (range 1-4) in the split-dose group and 1 (range 1-3) in the single-dose group, while for optimal mobilization, the split-dose group required 1 (range 1-3) and the single-dose group required 2 (range 1-3). Median days to hematopoietic reconstitution post-transplantation did not differ significantly (neutrophil: 10 vs. 9.5 days, P=0.689; platelet: 11 vs. 12 days, P=0.632). The incidence of treatment-emergent adverse events (TEAEs) was comparable between groups. Common grade 3 or higher TEAEs included thrombocytopenia (86.7% in the split-dose group vs. 100% in the single-dose group), neutropenia (96.7% vs. 96.3%), anemia (36.7% vs. 22.2%), and febrile neutropenia (20.0% vs. 14.8%). No treatment-related serious adverse events were reported in either group. In conclusion, both single-dose and split-dose regimens of mecapegfilgrastim combined with etoposide are effective and safe for PBSC mobilization in lymphoma and multiple myeloma patients. The split-dose regimen demonstrated a superior optimal mobilization rate at the first collection, suggesting that it may offer a more efficient mobilization approach. The combination of mecapegfilgrastim and high-dose etoposide represents a promising strategy for PBSC mobilization, which merits further investigation.

Background Peripheral T-cell lymphoma (PTCL) is a heterogeneous disease with dismal outcomes. We conducted an open-label, phase 2 nonrandomised, externally controlled study to evaluate the efficacy i cacy and safety of targeted agents plus CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) (CHOPX) for PTCL in the front-line setting. Methods Eligible patients were >= 18 years of age and newly diagnosed PTCL. Patients in the CHOPX group received standard CHOP at Cycle 1. Specific fi c targeted agents were added from Cycle 2, decitabine if TP53 mut , azacytidine if TET2/KMT2Dmut, mut , tucidinostat if CREBBP/EP300mut, mut , and lenalidomide if without mutations above. Patients in the CHOP group received CHOP for 6 cycles. The primary endpoint was the complete response rate (CRR) at the end of treatment (EOT). Secondary endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. The study was registered with ClinicalTrials.gov, NCT04480099. Findings Between July 29, 2020, and Sep 22, 2022, 96 patients were enrolled and included for efficacy fi cacy and safety analysis with 48 in each group. The study met its primary endpoint. CRR at EOT in the CHOPX group was superior to the CHOP group (64.6% vs. 33.3%, OR 0.27, 95%CI 0.12-0.64; - 0.64; p = 0.004). At a median follow-up of 24.3 months (IQR 12.0-26.7), - 26.7), improved median PFS was observed in the CHOPX group (25.5 vs. 9.0 months; HR 0.57, 95%CI 0.34-0.98; - 0.98; p = 0.041). The median OS was similar between two groups (not reached vs. 30.9 months; HR 0.55, 95%CI 0.28-1.10; - 1.10; p = 0.088). The most common grade 3-4 - 4 hematological and non-hematological adverse events in the CHOPX group were neutropenia (31, 65%) and infection (5, 10%). Interpretation Targeted agents combined with CHOP demonstrated effective and safe as fi rst-line treatment in PTCL. Biomarker-driven therapeutic strategy is feasible and may lead to promising efficacy fi cacy specifically fi cally toward molecular features in PTCL. Funding This study was supported by the National Key Research and Development Program (2022YFC2502600) and the General Program of the Shanghai Municipal Health Commission (202040400). Copyright (c) 2024 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Health 2024;50: Published https://doi.org/10. 1016/j.lanwpc.2024. 101160