PURPOSE:Patients with newly diagnosed multiple myeloma (NDMM) who are ineligible for or not proceeding to autologous stem-cell transplantation (ASCT)-often because of age or frailty-have limited opportunities to receive multiple effective lines of therapy, underscoring the need for novel frontline strategies. METHODS:In this phase II, open-label, single-arm trial (ClinicalTrials.gov identifier: NCT05860036), patients received 3-4 cycles of protocol-allowed induction, followed by B-cell maturation antigen (BCMA) CAR-T infusion, and subsequent consolidation and lenalidomide maintenance. The primary end point was the rate of minimal residual disease (MRD) negativity (10-5) at Month three postinfusion. RESULTS:Between April 4, 2023, and December 26, 2024, 43 patients were screened, 40 were enrolled, and 36 received infusion (median age, 68 years [46-75]). In the infused cohort, the MRD negativity rate at Month three postinfusion was 100% (36 of 36; 95% CI, 90.3 to 100.0). With a median follow-up of 15.8 months postinfusion (range, 4.3-26.0), no MRD recurrence was observed. The complete response rate (CRR) increased from 33.3% (12 of 36; 95% CI, 18.6 to 51.0) preinfusion to 69.4% (25 of 36; 95% CI, 51.9 to 83.7) at Month 3% and 94.4% (34 of 36; 95% CI, 81.3 to 99.3) at last follow-up. The most common grade 3 to 4 adverse events were transient cytopenia, including lymphopenia (100%), neutropenia (88.9%), leukopenia (80.6%), thrombocytopenia (19.4%), and anemia (8.3%). Cytokine release syndrome occurred in 52.8% of patients (all grade 1 to 2), immune effector cell-associated neurotoxicity in 5.6% (all grade 1), and infections in 30.6% (grade ≥3 in 19.4%). No deaths or disease progressions occurred by cutoff. CONCLUSION:Frontline BCMA CAR-T therapy induces deep, rapid, and durable remissions with a manageable safety profile in the NDMM population ineligible for or not proceeding to ASCT. These findings support its investigation as a potentially practice-changing strategy for this population.

7078 Background: GT719 is an off-the-shelf CAR-NKT therapy derived from umbilical cord blood hematopoietic stem cells and genetically engineered to co-express an anti-CD19 CAR, an invariant natural killer T (NKT)-specific TCR, and secreted interleukin-15 (IL-15). This design enables CD19-targeted tumor killing, avoids risk of graft-versus-host disease (GVHD), and enhanced cellular expansion, persistence, and immune function through IL-15 signaling. We report clinical data from 7 adults with relapsed or refractory (R/R) CD19-positive B-cell hematologic malignancies enrolled in two open-label, single-arm studies (NCT06948981, NCT07131254) evaluating the safety and preliminary efficacy. Methods: The primary endpoint was safety, including treatment-emergent adverse events (TEAEs), graded per CTCAE v5.0. Secondary endpoints included 3-month overall response rate (ORR), best overall response (BOR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Efficacy was assessed using Lugano 2014 criteria and the 2024 Chinese guidelines for adult acute lymphoblastic leukemia. Results: As of December 31, 2025, 7 patients were treated (median age 51 years; median two prior therapies), including 3 with B-ALL and 4 with B-NHL. Following FC lymphodepletion, all patients received a single GT719 infusion (5×10⁷ to 1×10⁹ viable cells). Most adverse events (AEs) were Grade 1-2. Grade ≥3 AEs were limited to lymphodepletion-related cytopenia and resolved or improved to Grade ≤2 within 14 days, excluding disease-related cytopenia. One patient experienced Grade 1 cytokine release syndrome that resolved within 1 day. No ICANS, neurotoxicity, or GVHD, severe infections, or serious TEAEs were observed. Efficacy was evaluable in all patients across B-ALL, follicular lymphoma (FL, grade 3a), and diffuse large B-cell lymphoma (DLBCL). The 3-month ORR was 50% (3/6), with all responders achieving CR; one patient was excluded due to insufficient follow-up. The disease control rate (DCR) was 71.4% (5/7). Two of 3 FL patients achieved CR, while one had a PR and remained under follow-up. One of three B-ALL patients achieved stringent complete remission, maintained through 24 weeks of relapse-free follow-up. CAR transgene analysis demonstrated robust in vivo expansion, with peak levels occurring between Days 7-10 in B-ALL and within two months in FL. GT719 persistence was observed for up to six months post-infusion. Conclusions: GT719 demonstrated a favorable safety profile and encouraging antitumor activity in adults with R/R CD19-positive B-cell malignancies. The absence of severe GT719-related toxicities and evidence of durable cellular persistence support further clinical investigation of this off-the-shelf CAR-NKT therapy. Clinical trial information: NCT06948981 , NCT07131254 . Research Sponsor: Grit Biotechnology.

Relapse and treatment resistance remain critical obstacles in the clinical management of angioimmunoblastic T-cell lymphoma (AITL), limiting the success of current therapeutic strategies. Therefore, a comprehensive characterization of the tumor microenvironment (TME) in AITL is essential to enhance treatment efficacy. This study analyzed samples from 68 patients with AITL, stratified into three molecular subtypes based on immunoglobulin (IG) gene rearrangement and flow cytometry results. Utilizing single-cell RNA sequencing, the TME was profiled across subtypes A, B, and C, sampling multiple disease sites including the bone marrow, lymph nodes, and peripheral blood. Our findings revealed subtype-specific variations in cellular composition and transcriptional programs within the TME. Unlike other subtypes, subtype C was associated with a pronounced immunosuppressive environment at diagnosis and relapse. Additionally, it exhibited an enhanced response to Epstein–Barr virus infection, consistent with upregulated CD70 expression at relapse. Through the analysis of cellular communication networks, CD70, programmed cell death 1 (PDCD1), and inducible T cell costimulator (ICOS) were identified as promising immunotherapeutic targets in AITL. Finally, we delineated distinct cellular proportions and gene expression signatures characteristic of each subtype, providing a foundation for the development of tailored therapeutic interventions for patients with AITL.

Abstract Mantle cell lymphoma (MCL) is a biologically heterogeneous B-cell malignancy. Although genomics and transcriptomics have delineated parts of the MCL disease spectrum, proteomics remains largely unexplored. Here, we conducted a comprehensive proteogenomic analysis integrating genomics, transcriptomics, and proteomics on peripheral blood samples from 27 patients with MCL and 4 healthy donors to investigate the translational and posttranslational dimensions of MCL. Our study identified 1296 downregulated and 468 upregulated proteins in MCL cells. The splicing pathways were significantly upregulated at both the mRNA and protein levels, suggesting a critical role for aberrant RNA splicing in MCL pathogenesis. Integration of proteomic data with genetic aberrations revealed immunoglobulin heavy chain variable mutational status and CCND1 mutation are associated with distinctive transcriptomic and proteomic profiles, which correspond to significant differences in clinical outcomes. A multiomics molecular stratification model incorporating proteomic data showed superior predictive power for patient survival compared with single-omics models (concordance index, 0.83 vs 0.74). This study provides, to our knowledge, the first comprehensive proteogenomic profile of MCL, offering novel insights into its molecular mechanisms and clinical behavior. The identification of molecular subtypes and prognostic protein signatures underscores the potential of proteomics to guide precision medicine strategies for MCL.

Abstract Background: Adoptive cell therapy, particularly CAR-T therapy, has transformed the treatment of hematologic malignancies, but autologous products remain limited by high cost, long manufacturing, and insufficient functional T cells in heavily pretreated patients. These challenges underscore the need for off-the-shelf allogeneic approaches. Invariant natural killer T (iNKT) cells are an attractive cell platform because they recognize lipid antigens via the non-polymorphic CD1d molecule, avoiding graft-versus-host disease (GvHD). CAR-engineered iNKT cells also provide multimodal tumor killing, tumor microenvironment modulation, enhanced infiltration, and natural bone marrow homing. However, their scarcity in peripheral blood poses manufacturing challenges. To address this, we developed GT719, an allogeneic anti-CD19 CAR-iNKT therapy generated through in vitro differentiation of cord blood-derived CD34+ hematopoietic stem cells. Rational CAR design and optimized manufacturing enable scalable production capable of treating thousands of patients per batch. Extensive preclinical studies show that GT719 eliminates malignant B cells through coordinated CAR-, invariant TCR-, and NK receptor-mediated cytotoxicity and selectively depletes immunosuppressive macrophages and myeloid-derived suppressor cells. Study Design and Methods: Based on promising preclinical results, a first-in-human investigator-initiated clinical trial (NCT06948981) has been launched to evaluate the safety, toxicity, dose-limiting toxicities (DLTs), and recommended treatment dose of GT719 for patients with relapsed or refractory CD19-positive B cell malignancies, including both B cell non-Hodgkin lymphoma (B-NHL) and B cell acute lymphoblastic leukemia (B-ALL). This open-label Trial in Progress begins with two single-patient acceleration cohorts testing doses of 5× 107 and 1 × 108 cells per patient, followed by a classical 3+3 dose-escalation design testing doses of 5 × 108 and 1 × 109 cells per patient. Enrolled patients undergo a standard lymphodepletion regimen consisting of cyclophosphamide and fludarabine from Day -5 to Day -2, consistent with protocols used for autologous CAR-T therapies. GT719 is administered intravenously on Day 0, and the primary safety observation window for DLTs extends from Day 1 to Day 28. Adverse events are assessed for incidence and severity according to CTCAE version 5.0. Although the trial is ongoing, we anticipate presenting preliminary safety and efficacy data for GT719 at the meeting. Clinical trial registration number: NCT06948981 Citation Format: Dehui Zou, Wei Liu, Yan Yu, Huimin Liu, Yi Wang, Sisi Feng, Xiaona Xu, He Zhang, Ershao Zhang, Jiang Li, Jingman Wang, Jing Hao, Ning Wang, Huipin Zheng, Yin Cheng, Jun Cui, Jingwei Sun, Yarong Liu. Stem cell-derived allogeneic anti-CD19 CAR-iNKT cell therapy GT719 for relapsed/refractory B cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3725.

Waldenström macroglobulinemia (WM) is a rare indolent B-cell lymphoma with marked clinical and molecular heterogeneity. Clinical risk models, including IPSSWM, rIPSSWM, and MSSWM, were developed prior to the widespread use of Bruton tyrosine kinase inhibitors (BTKi), and their performance in the BTKi era remains uncertain. In addition, the prognostic impact of various genomic alterations is controversial. We retrospectively analyzed 453 symptomatic WM patients, including 203 who received non-BTKi therapy and 250 who received BTKi-based therapy. All three models significantly stratified prognosis in the non-BTKi cohort, with rIPSSWM showing the highest predictive accuracy, but none effectively predicted survival in BTKi-treated patients. Notably, among patients receiving first-line BTKi-based therapy, high-risk patients by any model achieved survival outcomes comparable to those of lower-risk patients, suggesting that upfront BTKi can overcome the adverse impact of high-risk clinical features. At the molecular level, MYD88 mutation was significantly associated with favorable outcomes exclusively in patients treated with first-line BTKi-based therapy, while CXCR4 and TP53 mutations predicted significantly inferior prognosis in both BTKi-based and non-BTKi cohorts. Our findings indicate that although clinical risk models remain relevant for patients receiving non-BTKi therapy, molecular features, especially MYD88, CXCR4, and TP53 mutations, provide superior prognostic insights for patients with BTKi-based regimens.

Approximately 5%-10% of patients with chronic lymphocytic leukemia (CLL) develop autoimmune hemolytic anemia (AIHA). However, its pathogenesis and prognostic significance remain heterogeneous and incompletely defined. This study investigated the clinical and molecular features of CLL-associated AIHA and aimed to clarify its prognostic impact. We retrospectively analyzed baseline characteristics, first-line treatments, and survival outcomes in 1,404 patients with CLL. The incidence of AIHA was 10.4%, with 69.2% of cases classified as warm-antibody AIHA (wAIHA). CLL patients with AIHA were characterized by male predominance, advanced disease stage, IGHV4-34 usage, and other adverse biological features. Among the tested genes, DNMT3A mutations were more frequent in patients with AIHA, while MYD88 mutations were enriched in cold-antibody AIHA (cAIHA). Although AIHA conferred a significantly adverse prognostic impact on CLL outcomes, this effect was markedly attenuated with targeted therapies. Unmutated IGHV status predicted inferior outcomes in the overall CLL cohort, but not among patients with AIHA. Our findings underscore the importance of routine AIHA screening in high-risk CLL and support consideration of targeted therapies to mitigate the adverse impact of AIHA on long-term survival.

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

Utilization of novel Bruton tyrosine kinase inhibitors (BTKi) has become common for treating CLL/SLL patients, yet limited evidence exists on the clinical characteristics and outcomes following BTKi therapy discontinuation in China. This multicenter retrospective study analyzed 37 CLL/SLL patients in China who discontinued BTKi therapy. The mean age at discontinuation was 62.67 years, with the majority being male (67.57%). Most patients (62.16%) were relapsed/refractory (R/R) CLL/SLL patients prior to BTKi treatment, and 37.84% were treatment-naïve patients. Treatment-naïve patients were significantly younger than R/R patients (56.93 vs. 66.16 years, p = 0.005). Discontinuation reasons included resistance (48.65%), intolerance (32.43%), and other factors (18.92%). The most frequently used regimen among the post-BTKi first subsequent therapies was the anti-CD20 antibody combination therapy (52.90%). The overall disease control rate during BTKi treatment was 78.13%. The median progression-free survival (PFS) for BTKi therapy was 19.09 months, 19.09 months for treatment-naïve patients, and 14.39 months for R/R patients. The minimum median PFS was observed in patients with resistance (7.86 months). After BTKi discontinuation, median PFS was shorter: 8.87 months for first subsequent therapy and 5.32 months for second subsequent therapy. No significant difference was observed in overall survival. These findings illustrate the impact of prior treatment and discontinuation reasons on subsequent outcomes.

Background: CD19 CAR-T cells have changed the treatment landscape for relapsed/refractory non-Hodgkin lymphoma (R/R NHL) offering a potential curative-intent strategy. Axicabtagene ciloleucel (axi-cel), an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, has demonstrated consistent efficacy in Chinese R/R NHL patients, with lower rates of neurotoxicity (NE) of any grade and ≥grade 3. Although increased risk of relapse and mortality was reported in elderly patients with R/R NHL, subgroup analysis of ZUMA-1 study showed durable response and manageable toxicity with axi-cel in R/R LBCL patients aged ≥65. Real-world data analyses from the Center for International Blood and Marrow Transplantation Research (CIBMTR) indicate that axi-cel is associated with a better prognosis compared to conventional chemoimmunotherapy in elderly patients. Here, we report a subgroup analysis comparing outcomes between patients ≥65 and <65 years of age from a Chinese real-world study (ChiCTR2100047990). Methods: Patients with R/R NHL and ≥2 lines of prior therapy were treated with commercial axi-cel at 20 Chinese centers. Axi-cel was administered at a target dose of 2×10⁶ CAR-T cells/kg. The primary endpoint was overall survival (OS). Best objective response rate (bORR), best complete response (CR) rate, and progression-free survival (PFS) were assessed. Adverse events (AEs) were graded according to NCI-CTCAE 5.0. Adverse events of special interest (AESI) included cytokine release syndrome (CRS) and neurological events (NEs). The present analysis was based on 3-month follow-up data from all patients who had completed their scheduled assessments by the data cut-off date (May 31, 2024). Results: This analysis included 160 participants stratified by age (≥65: n=51; <65: n=109), with a median follow-up of 17.6 months. Baseline characteristics, aside from age, were largely similar between patients aged ≥65 and those aged <65. Notably, the aged ≥65 subgroup demonstrated higher proportions of ECOG performance status ≥2 (37.3% vs 22.9%) and International Prognostic Index (IPI) scores 3-5 (74.5% vs 38.5%) compared with the aged <65 subgroup, consistent with the age-dependent weighting in these scoring systems. Hepatic (15.7% vs 5.5%) and renal (68.6% vs 17.4%) impairment rates were higher in the aged ≥65 subgroup. Fewer patients in aged ≥65 subgroup experienced autologous stem cell transplantation (ASCT) than those in aged <65 subgroup (39.2% vs 52.3%). Following axi-cel treatment, the aged ≥65 subgroup demonstrated a higher bORR (86.3% vs. 80.7%) and a higher CR rate (78.4% vs. 60.6%) compared to the aged <65 subgroup. The 9-month PFS rate was higher in the aged ≥65 subgroup than aged <65 subgroup (66.7% vs. 59.4%). The median overall survival (OS) was not reached. The proportion of patients who experienced grade ≥3 axi-cel-related adverse events was comparable between the two groups (92.2% vs 93.6%). Grade ≥3 NEs were infrequent in both groups and occurred at similar rates (3.9% vs. 2.7%). However, the incidence of grade ≥3 CRS was higher in the aged ≥65 subgroup (23.5% vs. 11.1%). Conclusion: In this subgroup analysis of the real-world study, axi-cel demonstrated effectiveness and tolerability in patients with R/R NHL, both in those younger than than 65 years and those aged 65 years or older. Notably, patients aged ≥65 exhibited numerically higher CR rates and improved PFS compared to younger patients (aged <65), with a manageable safety profile. These findings further support the broader use of axi-cel in older patients with R/R NHL. Clinical trial Registry: ChiCTR2100047990.

Objective: ALK-positive anaplastic large cell lymphoma (ALK+ ALCL) is a rare T-cell lymphoma. Anthracycline-based combination chemotherapy is the first-line treatment with a high remission rate, but the necessity of hematopoietic stem cell transplantation (HSCT) for consolidation remains inconclusive. This study aims to summarize the clinical characteristics of ALK+ ALCL and explore prognostic factors and treatment efficacy. Methods: A retrospective analysis was conducted on 52 ALK+ ALCL patients treated at the Institute of Hematology, Chinese Academy of Medical Sciences from May 2011 to November 2024. All patients had completed at least one line of chemotherapy with or without HSCT. Clinical characteristics, treatment outcomes, and prognostic factors were analyzed. Results: The median age of onset was 25.5 years (range: 11-64), with a male-to-female ratio of 2.3:1. At initial diagnosis, 81.1% (42/52) of patients were in advanced stages (III-IV), 55.8% (29/52) presented with B symptoms, and 28.8% (15/52) had elevated LDH levels. Extranodal involvement was observed in 59.6% (31/52) of patients, with 40.4% (21/52) having ≥2 extranodal sites involved. The International Prognostic Index (IPI) score was intermediate-high/high (3-5) in 21.2% (11/52) of patients. The median number of first-line treatment cycles was 6 (range: 2-8). First-line regimens included EPOCH (44.2%, 23/52), EPOCH (25%, 13/52), BV+CHP (21.2%, 11/52), and CHOP (9.6%, 5/52). With a median follow-up of 45.7 months, the complete remission (CR) rate for first-line treatment was 75% (39/52), and the overall response rate (ORR) was 90.4% (47/52). The 5-year overall survival (OS) rate was 91%, and the 5-year progression-free survival (PFS) rate was 67%. Primary refractory disease (n=5) and early relapse within 3 months of CR (n=6) were identified as significant prognostic factors for OS (P=0.039). Among these 11 patients, one who did not undergo transplantation had an OS of only 9.3 months, while the remaining 10 patients who achieved CR/PR with subsequent treatments and underwent HSCT had 8 survivors and 2 deaths due to relapse. In the chemotherapy-only group (n=30), IPI scores of 3-5 were significant prognostic factors for both OS and PFS (P=0.016; P=0.011). Among the 11 patients with IPI scores of 3-5, 4 received chemotherapy only (1 death, 1 sustained CR, 1 sustained PR, 1 lost to follow-up after progression), while 7 underwent chemotherapy followed by HSCT (6 survivors, 1 lost to follow-up within one year post-transplantation). The sustained CR rates for intermediate-high/high-risk patients treated with chemotherapy alone versus chemotherapy plus HSCT were 25% and 71.43%, respectively (P=0.24), with 5-year OS rates of 75% and 100% (P=0.19). CR rates for first-line regimens were 72.6% for EPOCH/EPOCH, 81.2% for BV+CHP, and 100% for CHOP. The corresponding ORRs were 88.8%, 90.9%, and 100%. The 5-year OS rates were 89%, 100%, and 100% (P=0.6).It was noting that the 5-year PFS rates were 74%, 40%, and 30% ( P=0.03). Conclusion: ALK+ ALCL predominantly affects males under 30 years of age, with most patients presenting at advanced stages. Pathological features include CD30 and EMA positivity. The disease shows high chemosensitivity, with EPOCH/EPOCH regimens demonstrating superior remission maintenance compared to other regimens. Overall survival is favorable, but primary refractory disease/early relapse within 3 months, and IPI scores ≥3-5 are poor prognostic factors. These patients may benefit from sequential HSCT following chemotherapy.

Three CD19-directed CAR T-cell therapies - axicabtagene ciloleucel (axi-cel), lisocabtagene maraleucel (liso-cel), and tisagenlecleucel (tisa-cel) - are FDA-approved for relapsed/refractory large B-cell lymphoma (R/R LBCL) following ≥2 prior lines of therapy or early relapse within 12 months of first-line treatment. Clinical studies have shown ORRs of 52-83% (CR 40-58%) in ≥3rd-line and 46-86% (CR 28-66%) in 2nd-line settings, with median PFS of 2.9-6.8 months (≥3rd-line) and 14.7 months (2nd-line, ZUMA-7 trial), respectively. In China, axi-cel and relma-cel (a CD19 CAR-T therapy developed based on liso-cel's technology but with a modified manufacturing process) have been approved for R/R LBCL. Previous studies suggested that combining CAR T-cell therapy with high-dose therapy/autologous stem cell transplantation (HDT/ASCT) may improve response rates and survival in R/R LBCL (Cao et al., 2021; Liu et al., 2024). However, these studies utilized investigational or compassionate-use CAR-T products. In this study, we report single-center outcomes from combining commercial CAR-T products (axi-cel and relma-cel) with HDT/ASCT for R/R LBCL. Methods We retrospectively analyzed patients with R/R LBCL or transformed LBCL who received combination therapy of commercial CAR T-cell therapy (axi-cel or relma-cel) and HDT/ASCT from January 2022 to December 2024 at the Institute of Hematology & Blood Diseases Hospital. The conditioning regimen was determined by treating physicians, with CAR T-cell infusion administered on days +2, +3, or +4 following autologous stem cell reinfusion. This study was approved by the Institutional Review Board/Ethics Committee of the Blood Diseases Hospital, Chinese Academy of Medical Sciences. Results A total of 15 patients received the combination therapy and were included in this study. Pathological classification identified 14 patients (93.3%) with de novo DLBCL and 1 patient (6.7%) with transformed follicular lymphoma. The median age was 52 years (range: 31-61), with 9 male patients (60.0%). Most patients (93.3%) had advanced-stage disease, including 4 (26.7%) with central nervous system involvement. The median lines of prior therapy was 2 (range, 1-3). At the time of leukapheresis, 8 patients (53.3%) exhibited refractory disease to their last-line therapy, 4 patients (26.7%) had achieved responses (3 PR, 1 CR), and 3 patients (20.0%) presented with relapsed disease. Following leukapheresis, thirteen patients (86.7%) underwent bridging therapy during CAR T-cell manufacturing. After combination HDT/ASCT with CAR T-cell therapy (axi-cel [n=6] or relma-cel [n=9]), the ORR was 93.3% (CR: 80.0%, PR: 13.3%). With a median follow-up duration of 25.1 months (data cutoff: July 26, 2025), the estimated 2-year progression-free survival and overall survival rates were 65.2% and 78.0%, respectively. Ten patients (66.7%) experienced cytokine release syndrome (all grade 1-2), while immune effector cell-associated neurotoxicity syndrome occurred in 3 patients (20.0%; grade 2 in 1 patient, grade 4 in 2 patients). No treatment-related mortality or unexpected toxicities were observed. Conclusions The combination of axi-cel/relma-cel with HDT/ASCT demonstrates promising efficacy and acceptable safety in patients with R/R LBCL, representing a viable therapeutic option for transplantation-eligible candidates.

Background and Significance:Adoptive cell therapy, particularly CAR-T therapy, has transformed cancer treatment, showing remarkable efficacy in hematologic malignancies. FDA-approved CAR-T products targeting CD19 and BCMA offer hope not only to cancer patients but also those with autoimmune diseases and viral infections. However, autologous CAR-T approaches are limited by high cost, lengthy manufacturing, and inadequate T cells in heavily pretreated patients, spurring interest in off-the-shelf allogeneic CAR-T therapies with broader accessibility and lower cost. Invariant natural killer T (iNKT) cells are promising candidates for allogeneic cell therapy due to their unique biology. They recognize lipid antigens via CD1d, a non-polymorphic MHC I-like molecule, enabling them to avoid inducing graft-versus-host disease (GvHD). CAR-engineered iNKT cells offer several advantages over conventional CAR-T cells: multi-modal tumor killing, modulation of the tumor microenvironment, improved infiltration, and bone marrow homing. However, their rarity in peripheral blood (0.001%–1%) presents a major obstacle for clinical use. To overcome this, we developed GT719, a novel anti-CD19 CAR-iNKT cell therapy derived from in vitro differentiation of cord blood CD34+ hematopoietic stem cells. Rational CAR design and optimized manufacturing enable large-scale production, potentially treating thousands of patients per batch. Preclinical studies demonstrate GT719 targets malignant B cells via multiple mechanisms: CAR-driven cytotoxicity, invariant TCR activity, NK receptor signaling, and selective depletion of tumor-associated macrophages and myeloid-derived suppressor cells. These findings support clinical evaluation of GT719. Study Design and Methods:This is a single-center, single-arm, open-label pilot trial conducted at the Chinese Academy of Medical Sciences Hematology Hospital in Tianjin, China (ClinicalTrials.gov: NCT06948981). The study population includes adults (≥18 years) with relapsed/refractory CD19-positive B cell malignancies, including B cell non-Hodgkin lymphoma (B-NHL) and B cell acute lymphoblastic leukemia (B-ALL). Key Inclusion Criteria: Relapsed/refractory CD19+ B-ALL (≥5% marrow blasts), Ph+ ALL resistant/intolerant to ≥2 TKIs (excluding T315I mutation), or B-NHL (aggressive/indolent) unresponsive to prior therapies. Key Exclusion Criteria: History or active CNS/testicular leukemia/lymphoma, recent HSCT, prior CD19 CAR-T/NK therapy. Treatment: This is a classical 3+3 dose-escalation design evaluating doses of 5 × 10⁸ and 1 × 10⁹ cells per patient. Lymphodepletion with cyclophosphamide and fludarabine is administered from Day –5 to Day –2. GT719 is infused on Day 0. The DLT evaluation window is from Day 1 to Day 28. AEs are graded using CTCAE v5.0. Endpoints: 1) Primary: Incidence and severity of DLTs and AEs within 28 days post-infusion; 2) Secondary: 3-month ORR, best overall response (BOR), progression-free survival (PFS), overall survival (OS), time to peak expansion, peak level AUC, and GT719 persistence; 3) Exploratory: Changes in peripheral immune cell populations and cytokine profiles over time. Statistics: Up to 24 patients will be enrolled. DLTs and ORR will be summarized with 95% confidence intervals (CI) via the Clopper-Pearson method. Duration of response (DOR), PFS, and OS will be analyzed using the Kaplan-Meier method. Summary: This first-in-human investigator-initiated trial evaluates the safety, DLTs, and recommended dose of GT719 for patients with CD19+ B cell malignancies. Preliminary safety data will be presented at the meeting.

ABSTRACT:Monoclonal gammopathy (MG) in chronic lymphocytic leukemia (CLL) portends heterogeneous outcomes, yet its molecular drivers and therapeutic implications remain undefined. In this retrospective analysis of 2075 patients with CLL (1999-2024), MG was detected in 18.47% cases, with immunoglobulin M (IgM) (8.18%), IgG (8.09%), light-chain (1.14%), and IgA (1.06%) subtypes demonstrating divergent clinicogenomic profiles. Patients with IgA-MG were older at diagnosis, whereas those with IgG-MG had a younger age and a higher frequency of mutated immunoglobulin heavy-chain variable (IGHV). In contrast, IgM-MG was associated with unmutated IGHV, elevated lactate dehydrogenase and β2-microglobulin levels, higher frequencies of TP53 aberrations, and enrichment of MYD88, BIRC3, and DDX3X mutations. IgG-MG was associated with shorter time-to-first treatment (TTFT) only, whereas IgM-MG correlated with significantly inferior TTFT, progression-free survival, and overall survival. Subgroup analyses revealed that the adverse prognostic impact of MG was pronounced in IGHV-mutated CLL but attenuated in unmutated cases. Prognostic discrimination by the CLL-International Prognostic Index (CLL-IPI) remained robust regardless of MG status. Notably, patients with IgM-MG did not experience significant survival benefit from targeted therapy compared with conventional regimens. These findings demonstrate that MG subtypes, particularly IgM-MG, define biologically and clinically distinct subsets of CLL. Given the limited efficacy of Bruton tyrosine kinase inhibitors in IgM-MG, immunofixation-based MG profiling may inform risk-adapted treatment strategies and personalized therapy selection.

Background:Although the overall survival of multiple myeloma (MM) has improved significantly, patients with ultra-high-risk features (UHR-MM) had dismal outcomes. New therapies to address this unmet medical need are warranted. Equecabtagene autoleucel (eque-cel) has been approved for patients who have received at least three previous lines of therapy by the Chinese National Medical Products Administration. With good efficacy and safety profile in these patients, eque-cel is being explored in early relapse or newly diagnosed UHR-MM patients, Hereby, we report the primary real world data of eque-cel followed ASCT in UHR-MM patients. Methods:We conducted a retrospective chart review on UHR-MM patients who received eque-cel followed ASCT. UHR-MM are defined as: 1) Genetic ultra-high risk: del(17p)≥60%; or ≥2 high-risk cytogenetic abnormalities including TP53 mutation, del(17p)/P53 deletion, t(4;14), t(14;16), t(14;20), 1q21 gain/ amplification; 2) Primary refractory: Results:From August 2023 to April 2025, 12 UHR-MM patients completed ASCT followed by eque-cel infusion. Six patients received melphalan, five received bendamustine combining melphalan and one patient received fludarabine combining melphalan conditioning. Peripheral stem cell was administrated at (2.3-5.5) × 106 cells/kg, and eque-cel was administrated at 1 × 106 cells/kg for all 12 patients. The median age was 53 years (range: 36-67) and 11 (91.7%) were male. Eight patients (72.7%) had genetic ultra-high risk features, one patients (8.3%) were early progression, and two patients (16.7%) had primary PCL history. Two (16.7%) patients had extramedullary disease. With median 2 (range: 1-4) previous line of therapy, the median disease course is 10.5 months before ASCT. Eleven (91.7%) patients had received daratumumab based triplet or quadruplet therapy. All patients received bridging and 11 received maintenance therapy. Two patients, who had received eque-cel infusion within the preceding 6 months but did not achieve a complete response (CR), subsequently underwent consolidation therapy with eque-cel followed ASCT. With a median follow-up of 196 days (from ASCT date), seven patients (58.3%) experienced grade 1 and three patients (25.0%) experienced grade 2 CRS and fully recovered. Four patients were treated with glucocorticoids. No ICANS event was reported. As expected, AEs are dominated by hematological toxicities. All 12 patients achieved hematopoietic reconstitution within 1 months after ASCT, with a median time of 15 days for ANC reconstitution (≥0.5×109/L) and 11.5 days for PLT reconstitution (≥20×109/L) post ASCT. By July 1st, 2025, the ORR was 100%, with all 12 patients reached CR. All patients are MRD negative. Two patients received first eque-cel 3 month before ASCT, which achieved both VGPR. After ASCT and second eque-cel infusion, achieved sCR and MRD negative status on day 23 and day 190 post-ASCT, respectively. The early progression patient relapsed at 55 days post ASCT, all the other patients are keeping their response and under follow-up. The median DOR, PFS and OS were not reached by cutoff date. Robust CAR T-cell expansion was observed, with a median Tmax of 11 days (range 7~21). The median Cmax was 665.04 cells/μL. The pharmacokinetic profile is similar to that of eque-cel in R/RMM patients. Conclusion:Eque-cel followed ASCT demonstrated promising deep and durable response and was well tolerated in UHR-MM patients. CRS events are slight, hematopoietic reconstruction rate was 100%. We are looking forward to more patients gaining long-term benefit from this new treatment.

Polatuzumab vedotin (Pola), an anti-CD79b monoclonal antibody-drug conjugate, has been approved for first-line treatment of diffuse large B-cell lymphoma (DLBCL) based on results from the POLARIX phase III trial. This study demonstrated that Pola-R-CHP significantly improved progression-free survival (PFS) compared to R-CHOP in patients with LBCL and IPI scores of 2-5 (Tilly et al., 2022). Meanwhile, R-DA-EPOCH has shown superior PFS to R-CHOP in DLBCL patients with IPI 3-5 (Bartlett et al., 2019) and is the preferred regimen for primary mediastinal large B-cell lymphoma (PMBCL) or high-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements. However, the safety and efficacy of incorporating Pola into modified R-EDCH (with vincristine omission and dexamethasone substitution) remains unknown. To investigate this novel combination, we conducted a prospective phase 2 study evaluating R-EDCH plus Pola in high-risk aggressive non-Hodgkin's lymphoma or PMBCL. Methods This study enrolled patients aged 18-65 years with newly diagnosed aggressive B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma not otherwise specified (HGBL-NOS), and high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH). Non-PMBCL DLBCL patients were required to have high-risk disease, defined as an International Prognostic Index (IPI) score ≥3 or age-adjusted IPI (aaIPI) score ≥2. All participants received six 21-day cycles of Pola-R-EDCH, consisting of polatuzumab vedotin (1.8 mg/kg IV, day 1), rituximab (375 mg/m² IV, day 0), etoposide (50 mg/m²/day continuous IV infusion, days 1-4), liposomal doxorubicin (30-40 mg/m² IV, day 1), cyclophosphamide (750 mg/m² IV, day 5), and dexamethasone (30 mg IV, days 1-5). The study protocol was approved by the Institutional Review Board/Ethics Committee of Blood Diseases Hospital, Chinese Academy of Medical Sciences. Results From July 2023 to April 2025, 16 patients were included in the study, with a median age of 41.5 years (range: 18-63 years). Among them, 4 patients (25%) were diagnosed with PMBCL, while the remaining 12 patients (75%) had DLBCL. Key clinical characteristics showed that 81.3% of patients had non-GCB subtype, 75% had elevated LDH levels, 37.5% presented with extranodal involvement, and 25% were classified as double-expressor lymphoma. Cytogenetic and molecular analysis revealed TP53 depletion/mutation in 5 patients (31.3%), CDKN2A depletion in 5 patients (31.3%), and concurrent TP53 and CDKN2A abnormalities in 3 patients (18.8%). No MYC rearrangements were detected in any patient. As of July 26, 2025, all 16 patients had undergone at least one efficacy evaluation. The best overall response rate was 100%, with a complete response rate of 81.3%. After a median follow-up of 10.1 months, disease progression occurred in 4 patients. Three of these progressing patients (75%) harbored TP53 depletion/mutation, and 2 (50%) had both TP53 depletion/mutation and CDKN2A depletion. The estimated 1-year progression-free survival (PFS) rate was 62.5%, while the 1-year overall survival (OS) rate was 87.5%.Treatment-related adverse events included grade ≥3 neutropenia in 15 patients (93.8%) and grade ≥3 thrombocytopenia in 5 patients (31.3%). Febrile neutropenia was reported in 43.8% of cases. Peripheral neuropathy occurred in 50% of patients, all of which were grade 1 or 2. Conclusions The Pola-R-EDCH regimen demonstrated high response rates in patients with PMBCL or high-risk LBCL. The addition of polatuzumab vedotin did not result in unexpected toxicities. Patients with TP53 abnormalities, with or without CDKN2A depletion, showed an increased risk of disease progression.