e19045 Background: Mantle cell lymphoma (MCL) is characterized by Bruton tyrosine kinase (BTK)-signaling which activates the B-cell receptor (BCR) signaling cascade. Although BTK-inhibitors are effective therapy, acquired resistance is common. Proteolysis-targeting chimera molecules (PROTACs) facilitating BTK-degradation (BTK-PROTAC) are a potential therapy. Methods: We designed 24 BTK-PROTACs and screened their activity against MCL cell lines through half maximal inhibitory concentration (IC50) assays and BTK-degradation efficiency. Effects of BTK-PROTAC on differentially expressed genes and on activation of the BCR-signaling cascade were studied by RNA-seq and molecular experiments. BTK variant cells were developed to assess the ability of BTK-PROTAC to reverse acquired BTK-inhibitor resistance in vitro assays and in mouse models. Results: Amongst BTK-PROTACs we synthesized C23 had the strongest ability to degrade BTK and inhibit proliferation of several MCL cell lines. C23 induced cell apoptosis and suppressed cancer growth by activating the ubiquitin-proteasome pathway thereby inhibiting the BCR-signaling cascade including NF-κB- and PI3K-AKT-mTOR-signaling. C23 degraded BTK inhibiting growth of BTK C481S and BTK L528W variant cells and suppressed growth of MCL cells in mouse xenograft models with BTK C481S and BTK L528W variants. Conclusions: The C23 BTK-PROTAC inhibits MCL cells with BTK variants resistant to BTK-inhibitors in vitro and in vivo models. BTK-PROTAC C23 is a potential therapy of BTK-inhibitor resistant MCL.

261 Background: Mantle cell lymphoma (MCL) is characterized by Bruton tyrosine kinase (BTK)-signaling which activates the B-cell receptor (BCR) signaling cascade. Although BTK-inhibitors are effective therapy, acquired resistance is common. Proteolysis-targeting chimera molecules (PROTACs) facilitating BTK-degradation (BTK-PROTAC) are a potential therapy. Methods: We designed 24 BTK-PROTACs and screened their activity against MCL cell lines through half maximal inhibitory concentration (IC50) assays and BTK-degradation efficiency. Effects of BTK-PROTAC on differentially expressed genes and on activation of the BCR-signaling cascade were studied by RNA-seq and molecular experiments. BTK variant cells were developed to assess the ability of BTK-PROTAC to reverse acquired BTK-inhibitor resistance in vitro assays and in mouse models. Results: Amongst BTK-PROTACs we synthesized C23 had the strongest ability to degrade BTK and inhibit proliferation of several MCL cell lines. C23 induced cell apoptosis and suppressed cancer growth by activating the ubiquitin-proteasome pathway thereby inhibiting the BCR-signaling cascade including NF-κB- and PI3K-AKT-mTOR-signaling. C23 degraded BTK inhibiting growth of BTK C481S and BTK L528W variant cells and suppressed growth of MCL cells in mouse xenograft models with BTK C481S and BTK L528W variants. Conclusions: The C23 BTK-PROTAC inhibits MCL cells with BTK variants resistant to BTK-inhibitors in vitro and in vivo models. BTK-PROTAC C23 is a potential therapy of BTK-inhibitor resistant MCL.

PURPOSECombined-modality therapy (CMT) improves survival in patients with early-stage extranodal natural killer-/T-cell lymphoma (ENKTCL) compared with radiotherapy (RT) alone. However, the effect is inadequate for low-risk patients as defined by nomogram-revised risk index (NRI). As such, it remains unclear whether the survival benefits outweigh the additional costs.MATERIALS AND METHODSA Markov model was constructed to compare CMT versus RT alone for patients with early-stage ENKTCL, according to five risk groups defined by NRI model. Transition probabilities, effectiveness, and cost data were derived from the China Lymphoma Collaborative Group cohort, while health utility data were estimated from adverse effects. Life-years, costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios were calculated from the perspective of Chinese payers. Evaluations for customized countries or settings can be accomplished using a web-based tool.RESULTSOver the 6-year horizon, CMT increased life-years by 5.47, 5.19, 4.82, 4.62, and 4.49 years at $517,472 US dollars (USD)/QALY, $22,871 USD/QALY, $7,865 USD/QALY, $4,598 USD/QALY, and $2,278 USD/QALY for the low-risk (NRI = 0), intermediate-low-risk (NRI = 1), intermediate-high-risk (NRI = 2), high-risk (NRI = 3), and very high-risk (NRI = 4) groups, respectively. The probabilities of cost-effectiveness at a willingness-to-pay threshold of $5,208 USD/QALY were 0.00%, 0.01%, 7.40%, 72.07%, and 99.10% for each risk group. Over the lifetime horizon, all risk groups, except for low-risk group, had a probability of over 90% of being cost-effective. Estimates were varied according to country settings, integrated through a web-based customized analysis.CONCLUSIONCMT is unlikely to be cost-effective for low-risk patients but highly likely to be cost-effective for high-risk and very high-risk patients. As for intermediate-low or intermediate-high-risk patients, the cost-effectiveness of CMT varies depending on the time horizon and willingness-to-pay threshold.

Abstract Background: Histological transformation of follicular lymphoma (tFL) represents an aggressive subtype characterized by a complex and immunosuppressive tumor immune microenvironment (TIME). Therefore, it is urgent to investigate the characteristics of TIME and develop more effective immunotherapy strategies for tFL patients. Methods: Using single-cell RNA sequencing, a high-resolution landscape of the entire TIME ecosystem of follicular lymphoma (FL) and tFL patients is depicted. Findings were validated by multiplex immunofluorescence (mIF) staining, in vitro assays, and a mouse model. Results: Compared to FL patients, tFL patients exhibited a higher proportion of exhausted CD8+T cells expressing checkpoint receptors such as LAG3, CTLA4, PD-1, and HAVCR2. Notably, Galectin-3 expression was acquired by tumor cells after transformation, leading to enhanced Galectin-3–LAG3 interactions with CD8⁺T cells, as confirmed by mIF staining. In co-culture experiments, Galectin-3-overexpressing tumor cells impaired CD8⁺ T cell proliferation and cytotoxicity, inducing an exhausted phenotype. Treatment with the Galectin-3 inhibitor GB1107 rescued T cell function. Similar T cell dysfunction and GB1107 response were observed in Galectin-3-overexpressing mouse xenograft model. Additionally, we identified an accumulation of MDSC-like monocytes and M2-like macrophages in tFL patients, further contributing to immune suppression. Conclusion: Galectin-3 drives T cell exhaustion and reshapes the immune microenvironment in tFL patients, promoting immune evasion and disease progression. Targeting Galectin-3 may represent a promising immunotherapeutic strategy for tFL patients.

The phase III AUGMENT trial (ClinicalTrials.gov identifier: NCT01938001) demonstrated improved efficacy for lenalidomide plus rituximab (R2) versus rituximab with placebo (R-placebo) in patients with relapsed or refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). Here, we present the long-term follow-up results and prespecified subgroup analyses of patients with follicular lymphoma (FL), including those 70 years and older. Patients with R/R grade 1 to 3a iNHL were randomly assigned 1:1 to receive R2 or R-placebo. In this long-term follow-up report, progression-free survival (PFS) was assessed per the investigator. Secondary end points included overall survival (OS) and safety. Of the 358 randomly assigned patients (intent-to-treat [ITT] population), 295 had FL (≥70 years, n = 66). At long-term follow-up (median, 65.9 months), in the ITT iNHL population, PFS (hazard ratio [HR], 0.50 [95% CI, 0.38 to 0.66]) and OS (HR, 0.59 [95% CI, 0.37 to 0.95]) were improved with R2 versus R-placebo. Safety findings were consistent with the primary analysis. Improved long-term efficacy with R2 versus R-placebo and manageable safety with R2 were observed in patients with FL, including those 70 years and older. With a follow-up of >5 years, data from the AUGMENT trial continue to support the use of R2 as a standard of care for patients with R/R iNHL.

7055 Background: Histological transformation of follicular lymphoma (tFL) represents an aggressive subtype characterized by a complex and immunosuppressive tumor immune microenvironment (TIME). Therefore, it is urgent to investigate the characteristics of TIME and develop more effective immunotherapy strategies for tFL patients. Methods: Using single-cell RNA sequencing, a high-resolution landscape of the entire TIME ecosystem of follicular lymphoma (FL) and tFL patients is depicted. Findings were validated by multiplex immunofluorescence (mIF) staining, in vitro assays, and a mouse model. Results: Compared to FL patients, tFL patients exhibited a higher proportion of exhausted CD8+T cells expressing checkpoint receptors such as LAG3, CTLA4, PD-1, and HAVCR2. Notably, Galectin-3 expression was acquired by tumor cells after transformation, leading to enhanced Galectin-3–LAG3 interactions with CD8⁺ T cells, as confirmed by mIF staining. In co-culture experiments, Galectin-3-overexpressing tumor cells impaired CD8⁺ T cell proliferation and cytotoxicity, inducing an exhausted phenotype. Treatment with the Galectin-3 inhibitor GB1107 rescued T cell function. Similar T cell dysfunction and GB1107 response were observed in Galectin-3-overexpressing mouse xenograft model. Additionally, we identified an accumulation of MDSC-like monocytes and M2-like macrophages in tFL patients, further contributing to immune suppression. Conclusions: Galectin-3 drives T cell exhaustion and reshapes the immune microenvironment in tFL patients, promoting immune evasion and disease progression. Targeting Galectin-3 may represent a promising immunotherapeutic strategy for tFL patients.

Hepatitis B virus (HBV) infections are associated with an increased risk of B-cell lymphomas, including follicular lymphoma (FL). Chronic HBV infection and shifts in infection status following treatment can influence lymphomagenesis and immune reprogramming, potentially affecting clinical outcomes. Using the CosMx Spatial Molecular Imaging, after integrated with dynamic HBV infection states and duration of overt infection, this refines four recurrent patterns, especially memory B cell-like malignant cells (MBLM) subtype (PTPRCAP + ) that is traced with atypical features and latent indolence, and virus protein transport-related follicular dendritic cell (FDC) which shows interplay with MBLM. Except for virus-induced immune exhaustion, distinct contributions to POD24 occurrence from malignant cells and immunosuppressive cell communities under distinct HBV infection states are discerned such as through CCL21/CCR7 signaling pathway. Taken together, our spatial multicellular dynamics reveal an increased prevalence of MBLM and variable FDC phenotypes which is associated with POD24 occurrence in HBV-related FL tumors.

Abstract Background: Epidemiologic and other studies have identified environmental, occupational, and genetic risk factors for lymphoid and myeloid malignancies, but most studies have been conducted in Western populations. Investigations in populations with differing exposure patterns, distributions of disease subtypes, and genetic architecture are needed to fully understand hematopoietic tumor etiology. Methods: We conducted a large, multicenter, hospital-based case-control study of lymphoid and myeloid neoplasms in East Asia (AsiaLymph), including 5,671 lymphoid cases, 1,879 myeloid cases, and 3,858 controls. Participants completed a computer-assisted personal interview and provided biospecimens. Cases underwent central pathology review and were coded into the WHO Classification. Herein, we describe the study methods in detail and report association results for education, body mass index, and family history. Results: Greater BMI at age 20 but not at age 40 was associated with odds of total lymphoid neoplasm (per 5 kg/m2 increase: OR [95% CI]: 1.18 [1.09-1.27]), total myeloid neoplasm (OR [95% CI]: 1.17 [1.05-1.29]), and several subtypes. Greater educational attainment was associated with increased odds of total lymphoid neoplasm (for college vs. less than primary education: OR [95% CI]: 1.41 [1.21-1.65]) but not myeloid neoplasm (OR [95% CI]: 1.17 [0.95-1.45]; p-heterogeneity=0.02). There were also positive associations between family history of hematologic cancer in first degree relatives and odds of lymphoid neoplasm (OR [95% CI]: 1.53 [1.15-2.03]) and myeloid neoplasm (OR [95% CI]: 1.65 [1.11-2.44]) and specific subtypes. None of the evaluated risk factors were associated with NK/T-cell lymphoma, which supports a distinct etiology for this subtype. Conclusion: The AsiaLymph Study is one of the largest molecular epidemiology studies of both lymphoid and myeloid neoplasms with standardized World Health Organization classification of histopathologic subtypes and will serve as a valuable resource for etiologic investigations into risk factors for these malignancies. Citation Format: Qing Lan, Lauren M. Hurwitz, John K. Chan, Tai Hing Lam, Kexin Chen, Yok Lam Kwong, Xu Caigang, Brian CH Chiu, Raymond Liang, Ip Dennis, Wei Hu, Bryan Bassig, Mark Purdue, Jun Xu, Sarah Locke, Sophia S. Wang, James R. Cerhan, Sonja Berndt, Jonathan N. Hofmann, Jianxin Shi, Kai Yu, Shahinaz Gadalla, Lisa J. McReynolds, Rena Jones, Hongji Dai, Zhangyan Lyu, Lugui Qiu, Wei Liu, Huilai Zhang, Xianhuo Wang, Lindsay M. Morton, Stephen Chanock, Martha Linet, Melissa C. Friesen, Roel Vermeulen, Nathaniel Rothman. A multi-center hospital-based case-control study of lymphoid and myeloid neoplasms (AsiaLymph): Study design and initial findings for education, body mass index, and family history [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 5051.

Background: Cancer-treatment-induced-thrombocytopenia (CTIT) increases bleeding risk and disrupts cancer treatment, while many anticancer agents also cause cardiotoxicity. Recombinant-human-thrombopoietin (rhTPO) is well-established for platelet recovery, with preclinical evidence suggesting cardioprotective potential. This study aims to evaluate efficacy and safety of prophylactic rhTPO in patients at dual-risk for CTIT and cardiac injury. Methods: In this multicenter, open-label, randomized-controlled-trial, eligible patients were randomized (2:1) to prophylactic subcutaneous rhTPO (300 U/kg daily for 5 days, initiated 3 days before anticancer therapy) or conventional management. Primary endpoint was the proportion of patients maintaining platelet counts ≥75×109/L without rescue therapy by the end of cycle 2. Secondary endpoints included severe hematologic toxicities and cardiac assessments. The trial is registered on ClinicalTrials.gov (NCT05411705). Findings: Between June 2022 and November 2024, 165 patients were randomized to rhTPO group (n=112) or control group (n=53). Significantly more prophylactic rhTPO-treated patients achieved primary endpoint than the controls (62·5% vs. 22·6%, P<0·001). The rhTPO group also had lower incidences of severe thrombocytopenia (25·0% vs. 41·5%; P=0·032), neutropenia (0·9% vs. 9·4%; P=0·006), and anemia (6·3% vs. 24·5%; P<0·001), alongside reduced rescue therapy (29·5% vs. 77·4%; P<0·001) and platelet transfusion (1·8% vs. 9·4%; P=0·023). Cardiac assessments revealed lower rate of abnormal BNP/NT-proBNP elevation (31·3% vs. 49·1%; P=0·028), favorable left atrial remodeling, and a significantly attenuated heart rate increase at Day-90 in rhTPO group. Safety profiles were comparable between groups, with no rhTPO-related thromboembolic events. Interpretation: Prophylactic rhTPO effectively prevents CTIT, reduces severe hematologic toxicity, and exhibits favorable cardiac effects in high-risk patients, supporting its use in those at dual-risk for thrombocytopenia and cardiotoxicity.

e19044 Background: Despite the efficacy of chemoimmunotherapy in untreated mantle cell lymphoma (MCL), long-term outcomes and toxicities remain concerns. The POLARIS study evaluates orelabrutinib, lenalidomide, and rituximab (OLR) as a chemotherapy-free regimen to improve response and survival with early BTK inhibition. Methods: In this multicenter, open-label phase II study, untreated MCL pts received six 28-day cycles of induction therapy with orelabrutinib (150 mg once daily) plus LR, followed by OLR maintenance for up to 18 cycles. The primary endpoint was complete response rate (CRR) at the end of the 6-cycle induction therapy (EOIT). Results: As of February 20, 2025, 29 patients were enrolled (male 89.7%; median age 62 y); most had Ki-67 ≥ 30% (55.2%), Ann Arbor III–IV (82.8%), or bulky disease (58.6%). All completed six OLR induction cycles, 22 continued maintenance, and 3 (10.3%) remained on study at cutoff. At EOIT, CRR and ORR were 69% (95% CI 49.2–84.7%) and 96.6% (95% CI 82.2–99.9%), respectively. Best responses were CR in 26 (89.7%) and PR in 3 (10.3%) for a 100% best ORR. Median time to response was 3.0 months, and duration of response was not reached (NR). After a median follow-up of 29.6 months, four progression or death events occurred, with median PFS and OS both NR. ctDNA positivity after six cycles was 32.1% (9/28). CCND1 was the most frequent baseline mutation, and TP53 mutations correlated significantly with PFS. Grade 3–4 treatment-related AEs occurred in 24 (82.8%), mainly neutropenia (65.5%). Conclusions: The OLR regimen provided an encouraging clinical and molecular response and favorable safety in untreated MCL, potentially representing a highly active and less toxic chemotherapy-free option. More data will be reported from this study. Clinical trial information: NCT05076097 . Clinical characteristics of patients. Characteristics Total patients (n=29) Age, years-median (range) 62 (49-74) <70≥70 27 (93.1)2 (6.9) SexMaleFemale 26 (89.7)3 (10.3) ECOG performance status 0-1 28 (96.6) 2 1 (3.4) MIPI-C score Low risk 10 (34.5) Low-intermediate risk 13 (44.8) Intermediate-high risk 5 (17.2) High risk 1 (3.4) Ann Arbor stage II 5 (17.2) III-IV 24 (82.8) Ki67 index <30% 13 (44.8) ≥30% 16 (55.2) BM involvement Yes NoBulky mass (>5 cm) 12 (41.4)17 (58.6) Yes NoGastrointestinal involvement Yes No 17 (58.6)12 (41.4)5 (17.2)24 (82.8) ctDNA MRD*PositiveNegativeMissing 25 (86.2)3 (10.3)1 (3.4) TP53 Wild typeMutantLeukocyte count(10 9 /L)-median (IQR) 24 (82.8)5 (17.2)6.1 (4.3-8.4) Unless otherwise specified, data were expressed as n (%). *ctDNA was detected in 28 patients with available baseline plasma samples. MRD-negativity was defined as the absence of detectable somatic mutations of ctDNA. ECOG, Eastern Cooperative Oncology Group; MIPI, Mantle Cell Lymphoma International Prognostic Index; MRD, minimal residual disease; IQR, interquartile range.

7007 Background: At the primary analysis, Mosun-Pola demonstrated superior efficacy versus R-GemOx, with infrequent cytokine release syndrome (CRS) events and manageable safety in patients (pts) with R/R LBCL in the Phase 3 SUNMO trial (NCT05171647; Budde et al. 2025). We report updated efficacy and safety, including in the 2L setting. Methods: Pts with R/R LBCL ineligible for autologous stem-cell transplant (ASCT) were randomized 2:1 to Mosun (subcutaneous)-Pola or R-GemOx. Dual primary endpoints were IRC-assessed progression-free survival (PFS) and objective response rate (ORR); secondary endpoints included complete response (CR) rate, duration of response (DOR), duration of CR (DOCR), and safety. Overall survival (OS) was not assessed as the data cut-off was prior to the pre-defined final OS analysis. Results: At data cut-off (August 8, 2025), 138 and 70 pts were assigned to Mosun-Pola or R-GemOx, respectively. Overall, 91 pts had 1 prior line of therapy (LOT; 2L; Mosun-Pola, n=61; R-GemOx, n=30) and 117 had ≥2 prior LOT (3L+; Mosun-Pola, n=77; R-GemOx, n=40). With a median follow-up of 28.3 months (mos), Mosun-Pola continued to demonstrate superior PFS benefits over R-GemOx (HR, 0.41; 95% CI: 0.28–0.60; Table). ORRs with Mosun-Pola were 70.3% vs 40.0% with R-GemOx. The observed PFS benefit of Mosun-Pola over R-GemOx was similar in 2L (HR, 0.38; 95% CI: 0.22–0.67) and 3L+ (HR, 0.48; 95% CI: 0.29–0.81) subgroups. With Mosun-Pola vs R-GemOx in 2L, the 2-year PFS rates were 40.3% vs 20.1%, and the 2-year DOCR estimates were 60.8% vs 37.5%, respectively. Median DOCR was not reached with Mosun-Pola in 2L and 3L+ subgroups. ORRs with Mosun-Pola vs R-GemOx were 75.4% vs 36.7% in 2L pts, and 66.2% vs 42.5% in 3L+ pts, respectively. The safety profile was unchanged since the primary analysis. Grade (Gr) ≥2 CRS occurred in 4% of Mosun-Pola-treated pts and no ICANS events occurred. The safety profile was consistent in 2L pts: Gr 2 CRS occurred in 3% of Mosun-Pola-treated pts, with no Gr ≥3 CRS events. Conclusions: Mosun-Pola continues to show notable efficacy with manageable safety in pts with ASCT-ineligible R/R LBCL, particularly in the 2L setting. Clinical trial information: NCT05171647 . Mos (95% CI), unless stated Mosun-Pola (n=138) R-GemOx (n=70) 2L Mosun-Pola (n=61) 2L R-GemOx (n=30) 3L+ Mosun-Pola (n=77) 3L+ R-GemOx (n=40) Median PFS 11.6 (5.6–17.6) 3.8 (2.9–4.1) 17.6 (5.6–NE) 3.6 (2.1–5.3) 8.6 (4.0–16.2) 3.9 (2.1–5.6) Median DOR 18.8 (11.5–NE) 6.0 (3.7–23.9) 18.8 (11.3–NE) 6.0 (3.9–NE) 21.5 (9.5–NE) 5.4 (2.3–18.3) CR, % (95% CI) 51.4 (42.8–60.0) 24.3 (14.8–36.0) 60.7 (47.3–72.9) 20.0 (7.7–38.6) 44.2 (32.8–55.9) 27.5 (14.6–43.9) Median DOCR NE 18.3 (3.9–NE) NE (15.6–NE) 21.4 (3.9–NE) NE (21.5–NE) 7.5 (2.3–NE) NE, not estimable.

Relapsed or refractory CNS lymphoma (R/R CNSL) has limited treatment options. This multicenter retrospective study enrolled 84 consecutive R/R CNSL patients (median age 59 years; 53 PCNSL, 31 SCNSL) to evaluate efficacy and safety profiles of glofitamab therapy. With a median of 2.5 prior lines of therapy, the objective response rates (ORR) and complete response rates (CRR) for PCNSL were 88% (CRR 59%) with glofitamab monotherapy (n=32) and 100% (CRR 81%) with combination therapy (n=21), respectively; for SCNSL, ORR and CRR were 88% (CRR 75%) with glofitamab monotherapy (n=8) and 91% (CRR 65%) with combination therapy (n=23). At 14.7 months follow-up, median progression-free survival was 19.5 months for PCNSL and 13.5 months for SCNSL. Cytokine release syndrome occurred in 40% (all grade 1-2) of patients, and ICANS in 8%. Glofitamab-based therapy demonstrated substantial activity with manageable toxicity in this study, offering a promising treatment paradigm for R/R CNSL patients.

Extranodal involvement (ENI) is incorporated into routine risk assessment for diffuse large B-cell lymphoma (DLBCL), but treating ENI as a single binary adverse feature may conceal clinically relevant heterogeneity in extranodal burden, anatomical distribution, treatment feasibility, and immune-molecular context. We evaluated ENI as a burden- and site-aware phenotype rather than as a uniform descriptor. We retrospectively studied 710 adults with newly diagnosed DLBCL treated with first-line immunochemotherapy between June 2011 and December 2024. Outcomes were analyzed according to ENI status, number of extranodal sites, and involved organs. Targeted sequencing was available in 176 tumors, and RNA sequencing was performed in 107 quality-controlled tumor samples. Clinical models were interpreted as adjustment models because ENI burden overlaps with established risk factors; site-specific and molecular analyses were prespecified as exploratory and were interpreted with attention to available-case denominators, treatment heterogeneity, sparse subgroups, and multiplicity. ENI was associated with inferior overall survival (OS) and progression-free survival (PFS) in unadjusted analyses. Multisite ENI was enriched for adverse baseline features, including advanced Ann Arbor stage, elevated lactate dehydrogenase (LDH), higher International Prognostic Index (IPI), and impaired performance status. After multivariable adjustment, the independent prognostic contribution of ENI burden was attenuated, indicating substantial clinical overlap with systemic disease burden and host fitness. Several anatomical sites showed candidate adverse signals, but rare-site estimates were limited by small subgroup sizes, wide confidence intervals, and multiple testing. Targeted sequencing and RNA-seq suggested heterogeneous genomic and immune-transcriptional patterns across ENI categories; these results should be regarded as hypothesis-generating because of tissue availability, tumor-only sequencing in many cases, modest molecular sample sizes, and lack of orthogonal immune validation. ENI in DLBCL is best interpreted as a clinically heterogeneous disease descriptor rather than a single uniform prognostic category. ENI burden and anatomical distribution provide useful descriptive and prognostic context, but they should be interpreted alongside established clinical risk, treatment intensity, censoring patterns, tissue-sampling constraints, and molecular ascertainment limitations. Exploratory genomic and immune-transcriptional correlates identified in this study require prospective multicenter validation with harmonized staging, treatment-intensity annotation, matched-normal sequencing, and spatial or cellular immune profiling before ENI-informed biological or therapeutic stratification can be applied clinically. Study design, ENI boundary definitions, statistical safeguards, and multi-omics integration

Outcomes in older patients with Hodgkin lymphoma (HL) are compromised by the interplay of patient frailty and disease aggressiveness; however, current stratification tools, including the International Prognostic Score (IPS) and Comprehensive Geriatric Assessment (CGA), lack sufficient prognostic discrimination in the older HL population. We developed and validated a prognostic model integrating metabolic tumor burden and geriatric assessment. In this retrospective study across 14 centers in China between 2006 and 2024, we enrolled 306 patients aged ≥ 60 years with histologically confirmed HL. Patients were randomly partitioned into training (n = 250) and validation (n = 56) cohorts. Among the 306 patients, 98 deaths and 130 progression events were recorded during follow-up. We analyzed 21 candidate variables. The least absolute shrinkage and selection operator (LASSO) analysis and multivariable Cox regression identified five independent predictors for 5-year overall survival (OS): age > 73 years, baseline 18F-FDG PET/CT-derived total lesion glycolysis (TLG) > 200, hemoglobin ≤ 101 g/L, activities of daily living (ADL) dependence, and lymphocyte-depleted classical Hodgkin lymphoma (LDCHL). A weighted Geriatric Risk Score stratified patients into low-, intermediate-, and high-risk groups. In the validation cohort, the Geriatric Risk Score showed higher discriminatory accuracy than the CGA for both OS (C-index, 0.770 [95% CI, 0.674-0.867] vs. 0.671 [0.581-0.762]) and PFS (0.761 [0.668-0.853] vs. 0.635 [0.535-0.735]). Among advanced-stage (Ann Arbor stage III-IV) patients, it also outperformed the IPS-7 and IPS-3. By integrating metabolic tumor burden and geriatric assessment, the Geriatric Risk Score improves risk stratification over existing tools in older patients with HL.

Diffuse large B-cell lymphoma (DLBCL) poses a challenge in hematology given its varied symptoms, and the complex interplay between disease and treatment effects on health-related quality of life (HRQoL). The phase 3 POLARIX study demonstrated superior progression-free survival and a similar safety profile with polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) vs R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in patients with previously untreated DLBCL. Here, we evaluate HRQoL through patient-reported outcome (PRO) instruments to fully characterize the patient experience in the POLARIX study. Changes from baseline in HRQoL, lymphoma symptoms, and gastrointestinal (GI) symptoms were assessed, as well as incidence and severity of common symptoms by PROs vs clinician-reported adverse events (AEs). Baseline characteristics of PRO-evaluable patients (N = 874) were consistent. Comparison between PROs and clinician-reported AEs revealed a notable discordance; patients generally reported a higher incidence of symptoms than clinicians, emphasizing the need for patient-centric tools to accurately capture the patient experience. Both treatments exhibited rapid and sustained improvements in HRQoL and lymphoma symptoms, with the most substantial improvements seen in global health status/QoL, lymphoma symptoms, fatigue, role, emotional, and social functioning. GI symptoms (diarrhea, constipation, nausea, and vomiting) were generally similar between treatment arms and returned to baseline levels after treatment completion. These HRQoL data underscore the complementarity of PROs, as an adjunct to clinician-reported AEs, in evaluating the efficacy and tolerability of new treatments, including Pola-R-CHP, which may represent a new benchmark for patient-reported HRQoL in previously untreated DLBCL. This trial was registered at www.clinicaltrials.gov as NCT03274492.

ABSTRACT:Patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) typically have a poor prognosis. In preclinical studies, lenalidomide and a Bruton tyrosine kinase (BTK) inhibitor demonstrated synergistic antitumor effects. Zanubrutinib, a next-generation BTK inhibitor, has greater selectivity to minimize off-target binding. BGB-3111-110 was a phase 1 multicenter dose-escalation/-expansion study. Patients with R/R DLBCL received zanubrutinib 160 mg twice daily plus lenalidomide (15, 20, or 25 mg once daily) until progression or unacceptable toxicity. Primary end points were safety, recommended phase 2 dose (RP2D), and overall response rate (ORR; Lugano 2014 criteria). Sixty-six patients were enrolled and treated. Patients had a median of 2 previous therapies, 83% had stage III/IV disease, and ∼67% had non-geminal center B-cell-like or activated B-cell-like DLBCL. No dose-limiting toxicities occurred; the lenalidomide RP2D was 25 mg once daily when combined with zanubrutinib 160 mg twice daily. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 74%; the most common (>20%) grade ≥3 TEAEs were decreased neutrophil count (58%) and decreased white blood cell count (29%). TEAEs led to 7 treatment discontinuations (11%) and 2 deaths (3%). At the RP2D, ORR and complete response rate were 58% and 42%, respectively; median time to response was 2.8 months. Median duration of response was 14.9 months. Median progression-free survival was 5.5 months (95% confidence interval [CI], 2.9-11.1); the 12-month event-free rate was 34% (95% CI, 21-48). Zanubrutinib plus lenalidomide demonstrated acceptable tolerability and antitumor activity in patients with R/R DLBCL. This trial was registered at www.clinicaltrials.gov as NCT04436107.

The tumor suppressor gene TP53 is the most frequently mutated gene in human cancers and has been a popular area of research in the field of oncology. The p53 protein, encoded by the TP53 gene, not only binds to many targeted genes but also regulates apoptosis, autophagy, cell cycle arrest, metabolism, senescence and the tumor immune microenvironment to suppress tumorigenesis. In recent years, an increasing number of new functions of p53 have been discovered, and p53-mediated tumor suppressor functions have been greatly expanded. Mutations in TP53 not only abolish its ability to suppress tumorigenesis but also confer carcinogenic properties to p53-mutant cells. Because of the prevalence of p53 dysfunction in various disease types, p53 has long been considered an attractive target for new anticancer drugs. However, drugs targeting p53 are still under investigation in early clinical trials and have not been approved for clinical use. This finding is consistent with the speculation that p53 is widely regarded as “undruggable.” Surprisingly, several novel therapeutic approaches targeting p53, including MDM2/4 antagonists, compounds that target specific p53 mutants or restore the wild-type function of the mutated p53 protein, p53-based genetic therapies and p53-based tumor immunotherapy, have been developed in recent years. Here, we present a review of the structure, inactivation, and roles of p53 in diseases. In addition, this review discusses the efforts to target diseases associated with p53 dysfunction and the challenges encountered in the clinical development of these approaches.