Real‑World Effectiveness of Zanubrutinib Plus Salvage Chemotherapy in Relapsed or Refractory Double‑Expressor DLBCL

Real‑World Effectiveness of Zanubrutinib Plus Salvage Chemotherapy in Relapsed or Refractory Double‑Expressor DLBCL | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Real‑World Effectiveness of Zanubrutinib Plus Salvage Chemotherapy in Relapsed or Refractory Double‑Expressor DLBCL jinbo lu, yujie zhang, xuan ye, jingru shi, qiuyan lin, ran li, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8652982/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 15 Apr, 2026 Read the published version in Annals of Hematology → Version 1 posted 8 You are reading this latest preprint version Abstract Purpose To evaluate the efficacy and safety of the Bruton tyrosine kinase (BTK) inhibitor zanubrutinib in combination with salvage chemotherapy in patients with relapsed or refractory double-expressor diffuse large B-cell lymphoma (R/R DE-DLBCL). Methods We performed a retrospective analysis of 35 patients with R/R DE-DLBCL treated at two hematology centers from June 2021 to June 2024. All patients received zanubrutinib combined with one of several salvage regimens, including zR-MINE, zR-DHAP, zR-GemOx, or zR2. Endpoints included objective response rate (ORR), complete response rate (CRR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs). Results The median age was 60 years, and 91.4% of patients had the non-germinal center B-cell (non-GCB) subtype. At the end of therapy, the ORR and CRR were 45.7% (16/35) and 42.9% (15/35), respectively. After a median follow-up of 33.0 months, median PFS and OS were 8.0 and 12.0 months, respectively. Relapsed patients achieved a significantly higher CRR than refractory patients (56.5% vs. 16.7%, p = 0.034). On multivariate analysis, longer duration of response to prior therapy was an independent protective factor for OS (HR 0.88, 95% CI 0.77–0.99; p = 0.041). Grade 3–4 hematologic AEs were mainly neutropenia (42.8%) and thrombocytopenia (14.3%). Pulmonary infection was the most common non-hematologic AE (34.3%), and overall toxicity was manageable. Conclusion Zanubrutinib combined with salvage chemotherapy demonstrates clinically meaningful activity with a manageable safety profile in patients with R/R DE-DLBCL and may represent a therapeutic option for this high-risk population. Zanubrutinib BTK inhibitor Double-expressor diffuse large B-cell lymphoma Relapsed/refractory Salvage therapy Figures Figure 1 Figure 2 Introduction Diffuse large B-cell lymphoma (DLBCL) is a biologically heterogeneous malignancy with particularly poor outcomes in the relapsed or refractory (R/R) setting. In the SCHOLAR-1 study, a large international retrospective analysis of 635 patients with R/R DLBCL, conventional salvage chemotherapy achieved an ORR of only 26% and a CRR of 7%, with a median overall survival (OS) of 6.3 months[ 1 ]. These limited outcomes leave many patients ineligible for autologous hematopoietic stem-cell transplantation (auto-HSCT). Even among those who undergo transplantation, the 3-year OS generally remains below 30%[ 2 ], highlighting a critical unmet clinical need. Double-expressor lymphoma (DE-DLBCL), defined by concurrent overexpression of MYC and BCL-2 proteins, represents an aggressive DLBCL subtype characterized by chemoresistance and poor prognosis[ 3 , 4 ]. Biologically, many DE-DLBCL tumors arise from post-germinal center B cells and depend on sustained B-cell receptor (BCR) signaling, providing a strong rationale for targeting Bruton’s tyrosine kinase (BTK)[ 5 ]. Although the first-generation BTK inhibitor ibrutinib is clinically approved, it has demonstrated only modest activity in R/R DLBCL, with an ORR of 23%[ 6 ], underscoring the need for more effective therapies. Zanubrutinib, a next-generation BTK inhibitor, offers improved selectivity and pharmacokinetics, resulting in enhanced efficacy and a favorable safety profile across B-cell malignancies[ 7 ]. By potently inhibiting BCR signaling, zanubrutinib may sensitize malignant B cells to chemotherapy. We therefore hypothesized that combining zanubrutinib with salvage chemotherapy could overcome treatment resistance in R/R DE-DLBCL. However, real‑world evidence on the use of zanubrutinib combined with salvage chemotherapy in R/R DE‑DLBCL remains scarce. To bridge this knowledge gap, we conducted a retrospective analysis of R/R DE-DLBCL patients who were treated with this combination regimen. This study evaluated the antitumor activity, safety, and survival outcomes to inform clinical decision‑making for this high‑risk population. Materials and methods Patients This retrospective study included patients with R/R DE-DLBCL treated at two hematology centers—the First Affiliated Hospital of Nanjing Medical University and First People’s Hospital of Yancheng—from June 2021 to June 2024. All patients received zanubrutinib in combination with salvage chemotherapy. Clinicopathologic characteristics and follow-up information were obtained from electronic medical records and supplemented by telephone interviews when needed. Eligible patients were required to be ≥ 18 years of age, have histologically confirmed DE-DLBCL with immunohistochemical overexpression of MYC (≥ 40%) and BCL-2 (≥ 50%), and have relapsed or refractory disease after at least one prior line of therapy. Refractory disease was defined as progressive disease (PD) or stable disease (SD) as the best response to chemotherapy, or relapse within 12 months of the last treatment. Primary refractory disease was defined as failure to achieve complete or partial response to first-line therapy, or relapse within 3 months of response. Exclusion criteria included central nervous system involvement, double-hit or high-grade B-cell lymphoma, EBV-positive DLBCL, or prior exposure to BTK inhibitors. Only patients with complete clinical and follow-up data were included in the final analysis.. The final follow‑up date was August 31, 2025. The study was approved by an ethics committee and adhered to the principles of the Helsinki Declaration for Good Clinical Practice and its subsequent amendments(ethical approval: 2025-SR-121). Owing to the retrospective design, the requirement for written informed consent was waived. Treatment All patients received zanubrutinib 160 mg orally twice daily, administered continuously in 21-day cycles and combined with a physician-selected salvage chemotherapy regimen. Chemotherapy combinations included R-MINE (rituximab, ifosfamide, etoposide, mitoxantrone), R-ICE (rituximab, ifosfamide, carboplatin, etoposide), R-GDP (rituximab, gemcitabine, dexamethasone, cisplatin), R-DHAP (rituximab, dexamethasone, cytarabine, cisplatin), and R-GemOx (rituximab, oxaliplatin, gemcitabine). A non-chemotherapy regimen, R2 (rituximab plus lenalidomide), was also used. Patients eligible for transplantation who achieved a response were recommended to undergo autologous hematopoietic stem-cell transplantation (auto-HSCT) as consolidation therapy. Study Assessments Treatment response was assessed according to the Lugano 2014 criteria, including complete response (CR), partial response (PR), stable disease, and progressive disease. Response evaluation included ^18F-FDG PET/CT at mid-treatment and at the end of induction, followed by contrast-enhanced CT every 3 months for 2 years. Follow-up information was obtained from medical records and telephone interviews through August 31, 2025. The primary endpoint was objective response rate (ORR), defined as the proportion of patients achieving CR or PR. Secondary endpoints included progression-free survival (PFS) and OS. PFS was defined as the time from initiation of combination therapy to disease progression, relapse, death from any cause, or last follow-up. OS was defined as the time from initiation of therapy to death from any cause or last follow-up. Adverse events (AEs) were recorded and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Statistical analysis Statistical analyses were performed using GraphPad Prism 10 and RStudio version 4.3.2. Continuous variables were summarized as medians with ranges, and categorical variables as frequencies and percentages. Group comparisons for categorical variables were conducted using the χ² test or Fisher’s exact test, as appropriate. Survival curves were generated using the Kaplan–Meier method and compared with the log-rank test. Prognostic factors were evaluated using univariate and multivariate Cox proportional hazards models. Two-sided p values < 0.05 were considered statistically significant. Results Patients’ characteristics A total of 35 patients with R/R DE-DLBCL treated with zanubrutinib plus salvage chemotherapy were included. The cohort comprised 18 men (51.4%) and 17 women (48.6%), with a median age of 60 years (range, 22–82); 51.4% (n = 18) were aged ≥ 60 years. The non-GCB subtype predominated (91.4%, n = 32), and most patients (77.1%, n = 27) had Ann Arbor stage III–IV disease. High-risk features were frequent: 48.6% (n = 17) had an IPI score of 3–5, 62.9% (n = 22) had a Ki-67 index ≥ 80%, and 40.0% (n = 14) presented with B symptoms. All patients had received at least one prior systemic therapy; 22 (62.9%) had relapsed disease and 13 (37.1%) had refractory disease. The median number of prior treatment lines was 1 (range, 1–3), and 31.4% (n = 11) had received ≥ 2 lines. Most patients (94.3%, n = 33) had previously been treated with R-CHOP or an R-CHOP–like regimen. Four patients had undergone autologous stem-cell transplantation, and two had received CD19-directed CAR-T therapy. Efficacy Patients received one of several zanubrutinib-based regimens: zR-MINE (n = 8, 22.9%), zR-DHAP (n = 8, 22.9%), zR-GemOx (n = 6, 17.1%), zR-GDP (n = 2, 5.7%), zR-ICE (n = 2, 5.7%), or the oral regimen zR₂ (n = 9, 25.7%). Treatment courses are summarized in Fig. 1 . The median treatment duration was 8.0 months (range, 3.0–32.0). The best observed overall response rate and complete response rate during treatment were 68.6% (95% CI, 50.7–83.2) and 54.3% (95% CI, 36.6–71.2), respectively. At interim assessment, the ORR was 68.6% (24/35), including 19 complete responses (54.3%) and 5 partial responses (14.3%); 11 patients (31.4%) had progressive disease. After completion of induction therapy, the final ORR was 45.7% (16/35; 95% CI, 28.8–63.4), and the CR rate was 42.9% (15/35; 95% CI, 26.3–60.6). Overall, 19 patients (54.3%) experienced disease progression, including four who initially achieved CR at interim assessment but subsequently relapsed. Among responders, four patients proceeded to autologous stem-cell transplantation and two received subsequent CD19-directed CAR-T therapy. As of August 30, 2025, five patients (14.3%) remained on zanubrutinib maintenance. Treatment discontinuation was primarily due to disease progression (n = 19, 54.3%) or death (n = 4, 11.4%). Subgroup analyses were performed to evaluate the association between baseline characteristics and treatment response at the end of induction therapy (Table 1 ). Pretreatment disease status emerged as a key determinant of response depth. Patients with relapsed disease achieved a significantly higher complete response rate than those with refractory disease (56.5% vs. 16.7%, p = 0.034), with a non-significant trend toward a higher ORR (56.5% vs. 25.0%, p = 0.152). Other baseline variables, including age, IPI score, Ann Arbor stage, cell of origin, number of prior treatment lines, and salvage regimen, were not significantly associated with response. Table 1 Subgroup analysis of treatment response in 35 patients with relapsed or refractory double-expressor diffuse large B-cell lymphoma [n (%)] Characteristics and Treatment Selection CRR p value ORR p value Age 0.315 0.505 ≥ 60 years 6/18 (33.3) 7/18 (38.9) 0.999 0.738 0–2 8/18 (44.4) 9/18 (50.0) 3–5 7/17 (41.2) 7/17 (41.2) Ann Arbor Stage > 0.999 > 0.999 I ~ II 3/8 (37.5) 4/8 (50.0) III ~ V 12/27 (44.4) 12/27 (44.4) Cell of origin (Hans) 0.564 0.582 GCB 2/3 (66.7) 2/3 (66.7) non-GCB 13/32 (40.6) 14/32 (43.8) Disease status pre-treatment 0.034 0.152 Refractory 2/12 (16.7) 3/12 (25.0) Relapsed 13/23 (56.5) 13/23 (56.5) Number of prior lines of therapy > 0.999 > 0.999 1 10/24 (41.7) 11/24 (45.8) ≥ 2 5/11 (45.5) 5/11 (45.5) Treatment Regimen 0.758 0.843 zR-MINE 3/8 (37.5) 3/8 (37.5) zR-DHAP 3/8 (37.5) 3/8 (37.5) zR-GemOx 3/6 (50.0) 3/6 (50.0) zR-GDP 1/2 (50.0) 1/2 (50.0) zR-ICE 2/2 (100.0) 2/2 (100.0) zR2 3/9 (33.3) 4/9 (44.4) As of August 31, 2025, with a median follow-up of 33.0 months (range, 2.0–49.0), 23 patients (65.7%) had experienced disease progression or death. One elderly patient died from multifocal cerebral infarction three months after treatment despite achieving a complete response. Sixteen patients died within 12 months following disease progression, one patient died two years after progression, and three patients died from SARS-CoV-2 infection despite best responses of partial or complete remission. All deaths were considered unrelated to zanubrutinib. Median progression-free survival was 8.0 months (95% CI, 6.0 months to not reached), and median overall survival was 12.0 months (95% CI, 9.0 months to not reached). The 1- and 2-year PFS rate were both 40.1% (95% CI, 26.4–60.8), and the 1- and 2-year OS rates were 48.6% (95% CI, 34.5–68.3) and 42.7% (95% CI, 29.0–62.7), respectively. Kaplan–Meier survival curves are shown in Figs. 2 a and 2 b. In univariate analysis for overall survival, age ≥ 60 years was associated with inferior OS (HR 2.72, 95% CI, 1.09–6.78; p = 0.032), which was confirmed by Kaplan–Meier analysis (log-rank p = 0.021; Fig. 2 d). Longer duration of response to prior therapy was associated with a trend toward improved OS (HR 0.92, 95% CI, 0.82–1.02; p = 0.100). On multivariate analysis, duration of response to prior therapy remained an independent protective factor for OS (HR 0.88, 95% CI, 0.77–0.99; p = 0.041), whereas age was no longer independently associated with survival. Sex, Ann Arbor stage, and IPI score were not significantly associated with OS. The detailed results of the univariate and multivariate analyses for OS are summarized in Table 2 . No independent prognostic factors for PFS were identified in multivariate analysis. In univariate analysis, elevated baseline LDH showed a trend toward shorter PFS (HR, 2.08; 95% CI, 0.86–5.00; p = 0.103). Consistently, Kaplan–Meier analysis demonstrated significantly inferior PFS in patients with elevated LDH (p = 0.047; Fig. 2 c). Table 2 Univariate and multivariate analysis for OS. Univariate Cox Multivariate Cox Variable HR (95%CI) P value HR (95%CI) P value Gender 1.23 (0.52 ~ 2.90) 0.640 Age (< 60; ≥60), years 2.72 (1.09 ~ 6.78) 0.032 2.24 (0.82 ~ 6.07) 0.114 Ann Arbor stage (I ~ II; III ~ IV) 0.87 (0.32 ~ 2.38) 0.783 IPI risk group (0 ~ 2; 3 ~ 5) 0.91 (0.39 ~ 2.14) 0.825 Cell of origin (Hans) non-GCB; GCB 0.55 (0.13 ~ 2.40) 0.428 Bsymptom (yes; no) 1.17 (0.49 ~ 2.78) 0.724 Ecog score (0 ~ 1; ≥2) 1.19 (0.46 ~ 3.06) 0.726 Bone marrow involvement (yes; no) 0.69 (0.16 ~ 2.97) 0.620 Serum LDH (normal; rise) 1.91 (0.80 ~ 4.57) 0.146 1.48 (0.60 ~ 3.62) 0.395 B2MG 0.95 (0.54 ~ 1.69) 0.871 WBC 0.91 (0.77 ~ 1.08) 0.293 HB 1.01 (0.97 ~ 1.04) 0.673 PLT 1.00 (0.99 ~ 1.00) 0.064 1.00 (0.99 ~ 1.00) 0.054 Ki67 index 1.01 (0.97 ~ 1.05) 0.706 Early treatment (1 line; ≥2 line) 0.95 (0.38 ~ 2.37) 0.920 DOR 0.92 (0.82 ~ 1.02) 0.100 0.88 (0.77 ~ 0.99) 0.041 HR: Hazard Ratio, CI: Confidence Interval,DOR: Response duration to previous treatment Safety Treatment was generally well tolerated. The most common grade 3–4 hematologic adverse events were neutropenia (42.8%) and thrombocytopenia (14.3%). Febrile neutropenia occurred in 17.1% of patients, and 5.7% required platelet transfusion. The most frequent non-hematologic adverse events were pulmonary infection (34.3%) and fatigue (25.7%), followed by nausea or vomiting (11.4%) and rash (8.6%). One case of grade 3 hematochezia and one grade 3 thrombotic event were observed and successfully managed with supportive care. No cases of atrial fibrillation, opportunistic infection, tumor lysis syndrome, or treatment-related death were reported. Discussion Patients with R/R DLBCL generally have a poor prognosis. In a large real-world analysis by Fuji et al., the median OS after conventional salvage therapy was only 1.10 years, with a 3-year OS rate of 30.7%[ 8 ]. Within this already high-risk population, the DE subtype represents an even more adverse subgroup; retrospective studies report a median OS of less than 6 months in R/R DE-DLBCL[ 9 ], underscoring the urgent need for more effective therapies. This unmet need is further highlighted by the finding that even intensive chemotherapy regimens like DA-EPOCH-R failed to improve outcomes for patients with DE, despite showing benefit in other DLBCL subgroups[ 10 ]. In our study, zanubrutinib combined with salvage chemotherapy achieved a median OS of 12.0 months and a CR rate of 42.9%, with the best CR rate reaching 54.3%, representing a clinically meaningful improvement. These findings are consistent with the synergistic activity reported by Wang et al.[ 11 ] and further support the rationale for BTK-based combination strategies in this ultra-high-risk setting. Real-world data from the REAL-DREND study showed that salvage chemotherapy alone achieved an ORR of 30% and a CR rate of 9%, with a median OS of 5.9 months in R/R DLBCL[ 12 ]. Consistent with this, historical data at our center for patients receiving conventional salvage chemotherapy reported a CR rate of only 27.3%[ 13 ]. BTK inhibitor monotherapy has demonstrated limited activity; in a phase II study of zanubrutinib monotherapy in R/R non-GCB DLBCL, the ORR and CR rate were 29.3% and 17.1%, respectively, with modest PFS and OS outcomes[ 14 ]. Patients with the DE phenotype typically respond even more poorly, reinforcing the rationale for mechanism-driven combination strategies. Several early-phase studies have demonstrated the potential of BTK inhibitor–based combinations in R/R DLBCL, including the DE subtype. For example, ibrutinib plus R-ICE achieved an ORR of 90% and a CR rate of 55%[ 15 ], while ibrutinib combined with bendamustine-rituximab or lenalidomide-rituximab also showed encouraging activity[ 16 , 17 ]. Although outcomes vary across regimens, these studies collectively suggest that BTK inhibitor–based combinations can overcome the limitations of monotherapy. The efficacy observed in our study (ORR 45.7%, CR 42.9%, median OS 12.0 months) compares favorably with these prior findings, particularly given the high-risk DE-DLBCL population. A recent real-world study by He et al. further supports these results, reporting an ORR of 57.1% and a median PFS of 6.0 months with zanubrutinib-based combinations in transplant-ineligible R/R DLBCL[ 18 ]. Together, these data position zanubrutinib-based combinations as a promising therapeutic option. Mechanistically, the aggressiveness of DE-DLBCL is driven by MYC and BCL-2 overexpression and sustained activation of the B-cell receptor (BCR) signaling pathway. Zanubrutinib, a highly selective BTK inhibitor, effectively suppresses downstream survival and proliferation signals, promoting apoptosis in malignant B cells[ 19 , 20 ]. This targeted inhibition may sensitize DE-DLBCL cells to chemotherapy, while salvage chemotherapy provides direct cytotoxicity—together contributing to the high CR rate observed in our study. Beyond this synergistic mechanism, appropriate patient selection is critical. Prior studies, including those by He et al., have identified CD79B and MYD88 mutations as strong predictors of response to zanubrutinib-based therapy, with mutation-positive patients achieving markedly higher ORR and longer PFS[ 18 ]. Although our study did not include genomic profiling, these findings underscore the importance of incorporating molecular biomarkers into future prospective studies to refine patient selection and optimize therapeutic benefit. Subgroup analysis identified pretreatment disease status as the primary determinant of response depth. Relapsed patients achieved significantly higher CR rates than those with primary refractory disease (56.5% vs. 16.7%, p = 0.034), with a similar trend observed for ORR. This finding is consistent with the known biology of primary refractory disease, which is typically more aggressive and less responsive to therapy. Other clinical characteristics—including age, IPI score, Ann Arbor stage, cell of origin, number of prior therapies, and regimen type—were not significantly associated with response. Notably, most patients in our cohort (68.6%) had received only one prior line of therapy, and efficacy was similar regardless of treatment intensity. The relatively high proportion of relapsed and lightly pretreated patients may partly explain the favorable outcomes observed. These results suggest that the benefit of zanubrutinib-based combinations is not restricted to specific clinical subgroups and may be maximized when introduced early, particularly at first relapse or before the development of broad chemoresistance. Multivariate analysis demonstrated that duration of response to prior therapy was an independent predictor of overall survival, suggesting that patients with more durable prior responses derive greater benefit from this combination. A longer prior response may reflect preserved chemosensitivity and less complex clonal evolution, enabling more sustained disease control with combination therapy. These findings further support the potential value of earlier intervention, before the development of broad treatment resistance. In contrast, traditional clinical prognostic factors were not independently associated with survival, raising the possibility that zanubrutinib-based combinations may partially mitigate baseline risk heterogeneity. This hypothesis warrants confirmation in larger, prospective studies. These results prompt reconsideration of the traditional classification framework for R/R DE-DLBCL. Consistent with prior studies in R/R DLBCL[ 21 ], we observed no significant differences in CR or ORR between GCB and non-GCB subtypes, suggesting that cell-of-origin may have limited prognostic relevance in the relapsed/refractory setting—particularly within the DE subtype. Instead, disease biology in these patients is likely driven by shared molecular abnormalities, including aberrant BCR signaling and MYC/BCL-2 overexpression. Given the substantial molecular heterogeneity of DLBCL, therapeutic strategies targeting core pathogenic pathways, such as BCR signaling, may be more clinically meaningful than traditional cell-of-origin–based classification. Safety is a critical consideration when evaluating combination regimens. Hematologic toxicities were the most common, with neutropenia (42.8%) and thrombocytopenia (14.3%) occurring at expected frequencies; no treatment-related deaths or severe infections were observed, consistent with appropriate supportive care in routine clinical practice. Non-hematologic toxicities—including nausea, vomiting, and fatigue—were consistent with conventional chemotherapy and were generally manageable. Although pneumonia occurred in 34.3% of patients, most cases were associated with disease progression rather than treatment toxicity. Notably, no zanubrutinib-specific adverse events such as atrial fibrillation or major bleeding were observed, consistent with its improved BTK selectivity[ 22 , 23 ]. Overall, the regimen demonstrated a manageable safety profile and good tolerability. This study has several limitations. First, it was a two-center retrospective study, and the sample size was relatively small, which may introduce selection bias. Second, the use of heterogeneous salvage chemotherapy regimens—reflecting real-world practice—may have contributed to variability in treatment outcomes. Third, the lack of molecular profiling limited our ability to elucidate the mechanistic basis of synergy and to identify predictive biomarkers. Finally, although CAR-T cell therapy is an established option for R/R LBCL, the retrospective design precluded direct comparison with this modality. Future prospective, controlled studies are needed to validate our findings, refine patient selection, and determine the optimal timing and sequencing of zanubrutinib-based therapy in relation to CAR T and other emerging treatments. In conclusion, zanubrutinib combined with salvage chemotherapy demonstrated encouraging efficacy and acceptable tolerability in patients with R/R DE-DLBCL. These findings support its potential role as a salvage option for this high-risk population. Larger, prospective studies incorporating molecular profiling are warranted to optimize combination strategies and to identify the patients most likely to benefit. Declarations Competing interests The authors declare no competing interests. Funding This work was supported by Natural Science Foundation of Jiangsu Province [BK20232039]; National Natural Science Foundation of China [82470186]; Jiangsu Province Hospital Clinical Diagnosis and Treatment Technology Innovation Open Bidding and Leader Selecting Project [JBGS202404]. Author Contribution J. L performed the research and wrote the paper. Y.Z, X.Y analyzed the data. J.S, Q.L, X.D collected patients’ data and managed the database. R.L, J.W, L.C, H.L, Y.X critically edited the manuscript.H.S, S.W and L.F designed the research study, oversaw the research and critically reviewed the manuscript. All authors gave final approval for the manuscript. Data Availability The study was implemented in accordance with local regulations, the principles of the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice guidelines. The study protocol and all amendments were approved by institutional review boards and independent ethics committees. 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Blood Adv 6(6):1629–1636. https://doi.org/10.1182/bloodadvances.2020003698 Sauter CS, Matasar MJ, Schoder H, Devlin SM, Drullinsky P, Gerecitano J, Kumar A, Noy A, Palomba ML, Portlock CS et al (2018) A phase 1 study of ibrutinib in combination with R-ICE in patients with relapsed or primary refractory DLBCL. Blood 131(16):1805–1808. https://doi.org/10.1182/blood-2017-08-802561 Zhang Y, Li Y, Zhuang Z, Wang W, Wei C, Zhao D, Zhou D, Zhang W (2021) Preliminary evaluation of zanubrutinib-containing regimens in DLBCL and the cerebrospinal fluid distribution of zanubrutinib: a 13-case series. Front Oncol 11:760405. https://doi.org/10.3389/fonc.2021.760405 Goy A, Ramchandren R, Ghosh N, Munoz J, Morgan DS, Dang NH, Knapp M, Delioukina M, Kingsley E, Ping J et al (2019) Ibrutinib plus lenalidomide and rituximab has promising activity in relapsed/refractory non-germinal center B-cell-like DLBCL. Blood 134(13):1024–1036. https://doi.org/10.1182/blood.2018891598 He S, Sun J, Zhong D, Rong C, Liao C, Tan X (2025) Zanubrutinib plus salvage chemotherapy in patients with refractory/relapsed diffuse large B-cell lymphoma non-candidate for autologous stem cell transplantation: a retrospective study. Ann Hematol 104(10):5181–5190. https://doi.org/10.1007/s00277-025-06673-8 Muñoz J, Wang Y, Jain P, Wang M (2022) Zanubrutinib in lymphoproliferative disorders: a comprehensive review. Ther Adv Hematol 13:20406207221093980. https://doi.org/10.1177/20406207221093980 Brown JR, Eichhorst B, Hillmen P, Jurczak W, Kaźmierczak M, Lamanna N, O'Brien SM, Tam CS, Qiu L, Zhou K et al (2023) Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. N Engl J Med 388(4):319–332. 10.1056/NEJMoa2211582 Desai SH, Mwangi R, Smith AN, Maurer MJ, Farooq U, King RL, Cerhan JR, Feldman AL, Habermann TM, Thompson CA et al (2023) Cell of origin is not associated with outcomes of relapsed or refractory diffuse large B cell lymphoma. Hematol Oncol 41(1):39–49. https://doi.org/10.1002/hon.3098 Guo Y, Liu Y, Hu N, Yu D, Zhou C, Shi G, Zhang B, Wei M, Liu J, Luo et al (2019) Discovery of Zanubrutinib (BGB-3111), a Novel, Potent, and Selective Covalent Inhibitor of Bruton’s Tyrosine Kinase. J Med Chem 62(17):7923–7940. https://doi.org/10.1021/acs.jmedchem.9b00687 Tam CS, Opat S, D'Sa S, Jurczak W, Lee HP, Cull G, Owen RG, Marlton P, Wahlin BE, Sanz RG et al (2020) A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study. Blood 136(18):2038–2050. 10.1182/blood.2020006844 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 15 Apr, 2026 Read the published version in Annals of Hematology → Version 1 posted Editorial decision: Revision requested 16 Feb, 2026 Reviews received at journal 16 Feb, 2026 Reviewers agreed at journal 11 Feb, 2026 Reviewers agreed at journal 10 Feb, 2026 Reviewers invited by journal 08 Feb, 2026 Editor assigned by journal 06 Feb, 2026 Submission checks completed at journal 06 Feb, 2026 First submitted to journal 20 Jan, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8652982","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":589666566,"identity":"27069bbf-d300-419a-973b-8a89fea32f77","order_by":0,"name":"jinbo lu","email":"","orcid":"","institution":"Jiangsu Province Hospital","correspondingAuthor":false,"prefix":"","firstName":"jinbo","middleName":"","lastName":"lu","suffix":""},{"id":589666567,"identity":"9725aca2-d463-44cd-99d7-9e9b70577c49","order_by":1,"name":"yujie zhang","email":"","orcid":"","institution":"Jiangsu Province 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21:07:56","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8652982/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8652982/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00277-026-06974-6","type":"published","date":"2026-04-15T15:59:07+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":102746699,"identity":"05669c67-b57c-49a6-bf89-e602b86fdfa2","added_by":"auto","created_at":"2026-02-16 08:59:21","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":433124,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTreatment course and response dynamics in 35 patients with R/R DE-DLBCL receiving zanubrutinib plus salvage chemotherapy\u003c/strong\u003e Each horizontal bar represents an individual patient. The bar length corresponds to treatment duration. Bar color intensity represents the Ann Arbor stage at study enrollment, with darker shades indicating more advanced disease (Stage I-II: light blue; Stage III-IV: dark blue). Key clinical events are marked as follows: complete response (CR), partial response (PR), progressive disease (PD), autologous stem cell transplantation (Auto-HSCT), chimeric antigen receptor T-cell therapy (CAR-T therapy), death, and ongoing zanubrutinib treatment (BTKi continued).\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8652982/v1/aab9a0ca8a6522b150a35a2e.jpeg"},{"id":102747272,"identity":"bc0ad002-4276-49dc-a38d-5594bb002a09","added_by":"auto","created_at":"2026-02-16 09:04:22","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":386243,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eEfficacy outcomes and prognostic analysis of zanubrutinib treatment. (a) \u003c/strong\u003eKaplan-Meier curve for PFS. \u003cstrong\u003e(b) \u003c/strong\u003eKaplan-Meier curve for OS. \u003cstrong\u003e(c) \u003c/strong\u003ePFS according to baseline LDH level (\u003cem\u003ep\u003c/em\u003e = 0.047 by log-rank test). \u003cstrong\u003e(d) \u003c/strong\u003eOS stratified by age group (\u003cem\u003ep\u003c/em\u003e = 0.021 by log-rank test).\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8652982/v1/ba438383bae28893032afd61.jpeg"},{"id":107351499,"identity":"ab7b3e42-8fe7-4040-a4e7-590dec4b6f21","added_by":"auto","created_at":"2026-04-20 16:11:13","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1257993,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8652982/v1/282603bc-50e0-4fec-b1ad-4bb1a3bec93d.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Real‑World Effectiveness of Zanubrutinib Plus Salvage Chemotherapy in Relapsed or Refractory Double‑Expressor DLBCL","fulltext":[{"header":"Introduction","content":"\u003cp\u003eDiffuse large B-cell lymphoma (DLBCL) is a biologically heterogeneous malignancy with particularly poor outcomes in the relapsed or refractory (R/R) setting. In the SCHOLAR-1 study, a large international retrospective analysis of 635 patients with R/R DLBCL, conventional salvage chemotherapy achieved an ORR of only 26% and a CRR of 7%, with a median overall survival (OS) of 6.3 months[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. These limited outcomes leave many patients ineligible for autologous hematopoietic stem-cell transplantation (auto-HSCT). Even among those who undergo transplantation, the 3-year OS generally remains below 30%[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], highlighting a critical unmet clinical need.\u003c/p\u003e \u003cp\u003eDouble-expressor lymphoma (DE-DLBCL), defined by concurrent overexpression of MYC and BCL-2 proteins, represents an aggressive DLBCL subtype characterized by chemoresistance and poor prognosis[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Biologically, many DE-DLBCL tumors arise from post-germinal center B cells and depend on sustained B-cell receptor (BCR) signaling, providing a strong rationale for targeting Bruton\u0026rsquo;s tyrosine kinase (BTK)[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Although the first-generation BTK inhibitor ibrutinib is clinically approved, it has demonstrated only modest activity in R/R DLBCL, with an ORR of 23%[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], underscoring the need for more effective therapies. Zanubrutinib, a next-generation BTK inhibitor, offers improved selectivity and pharmacokinetics, resulting in enhanced efficacy and a favorable safety profile across B-cell malignancies[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. By potently inhibiting BCR signaling, zanubrutinib may sensitize malignant B cells to chemotherapy. We therefore hypothesized that combining zanubrutinib with salvage chemotherapy could overcome treatment resistance in R/R DE-DLBCL.\u003c/p\u003e \u003cp\u003eHowever, real‑world evidence on the use of zanubrutinib combined with salvage chemotherapy in R/R DE‑DLBCL remains scarce. To bridge this knowledge gap, we conducted a retrospective analysis of R/R DE-DLBCL patients who were treated with this combination regimen. This study evaluated the antitumor activity, safety, and survival outcomes to inform clinical decision‑making for this high‑risk population.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eThis retrospective study included patients with R/R DE-DLBCL treated at two hematology centers\u0026mdash;the First Affiliated Hospital of Nanjing Medical University and First People\u0026rsquo;s Hospital of Yancheng\u0026mdash;from June 2021 to June 2024. All patients received zanubrutinib in combination with salvage chemotherapy. Clinicopathologic characteristics and follow-up information were obtained from electronic medical records and supplemented by telephone interviews when needed.\u003c/p\u003e \u003cp\u003eEligible patients were required to be \u0026ge;\u0026thinsp;18 years of age, have histologically confirmed DE-DLBCL with immunohistochemical overexpression of MYC (\u0026ge;\u0026thinsp;40%) and BCL-2 (\u0026ge;\u0026thinsp;50%), and have relapsed or refractory disease after at least one prior line of therapy. Refractory disease was defined as progressive disease (PD) or stable disease (SD) as the best response to chemotherapy, or relapse within 12 months of the last treatment. Primary refractory disease was defined as failure to achieve complete or partial response to first-line therapy, or relapse within 3 months of response. Exclusion criteria included central nervous system involvement, double-hit or high-grade B-cell lymphoma, EBV-positive DLBCL, or prior exposure to BTK inhibitors.\u003c/p\u003e \u003cp\u003eOnly patients with complete clinical and follow-up data were included in the final analysis.. The final follow‑up date was August 31, 2025. The study was approved by an ethics committee and adhered to the principles of the Helsinki Declaration for Good Clinical Practice and its subsequent amendments(ethical approval: 2025-SR-121). Owing to the retrospective design, the requirement for written informed consent was waived.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eTreatment\u003c/h3\u003e\n\u003cp\u003eAll patients received zanubrutinib 160 mg orally twice daily, administered continuously in 21-day cycles and combined with a physician-selected salvage chemotherapy regimen. Chemotherapy combinations included R-MINE (rituximab, ifosfamide, etoposide, mitoxantrone), R-ICE (rituximab, ifosfamide, carboplatin, etoposide), R-GDP (rituximab, gemcitabine, dexamethasone, cisplatin), R-DHAP (rituximab, dexamethasone, cytarabine, cisplatin), and R-GemOx (rituximab, oxaliplatin, gemcitabine). A non-chemotherapy regimen, R2 (rituximab plus lenalidomide), was also used. Patients eligible for transplantation who achieved a response were recommended to undergo autologous hematopoietic stem-cell transplantation (auto-HSCT) as consolidation therapy.\u003c/p\u003e\n\u003ch3\u003eStudy Assessments\u003c/h3\u003e\n\u003cp\u003eTreatment response was assessed according to the Lugano 2014 criteria, including complete response (CR), partial response (PR), stable disease, and progressive disease. Response evaluation included ^18F-FDG PET/CT at mid-treatment and at the end of induction, followed by contrast-enhanced CT every 3 months for 2 years. Follow-up information was obtained from medical records and telephone interviews through August 31, 2025.\u003c/p\u003e \u003cp\u003eThe primary endpoint was objective response rate (ORR), defined as the proportion of patients achieving CR or PR. Secondary endpoints included progression-free survival (PFS) and OS. PFS was defined as the time from initiation of combination therapy to disease progression, relapse, death from any cause, or last follow-up. OS was defined as the time from initiation of therapy to death from any cause or last follow-up. Adverse events (AEs) were recorded and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eStatistical analyses were performed using GraphPad Prism 10 and RStudio version 4.3.2. Continuous variables were summarized as medians with ranges, and categorical variables as frequencies and percentages. Group comparisons for categorical variables were conducted using the χ\u0026sup2; test or Fisher\u0026rsquo;s exact test, as appropriate. Survival curves were generated using the Kaplan\u0026ndash;Meier method and compared with the log-rank test. Prognostic factors were evaluated using univariate and multivariate Cox proportional hazards models. Two-sided p values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u0026rsquo; characteristics\u003c/h2\u003e \u003cp\u003eA total of 35 patients with R/R DE-DLBCL treated with zanubrutinib plus salvage chemotherapy were included. The cohort comprised 18 men (51.4%) and 17 women (48.6%), with a median age of 60 years (range, 22\u0026ndash;82); 51.4% (n\u0026thinsp;=\u0026thinsp;18) were aged\u0026thinsp;\u0026ge;\u0026thinsp;60 years. The non-GCB subtype predominated (91.4%, n\u0026thinsp;=\u0026thinsp;32), and most patients (77.1%, n\u0026thinsp;=\u0026thinsp;27) had Ann Arbor stage III\u0026ndash;IV disease. High-risk features were frequent: 48.6% (n\u0026thinsp;=\u0026thinsp;17) had an IPI score of 3\u0026ndash;5, 62.9% (n\u0026thinsp;=\u0026thinsp;22) had a Ki-67 index\u0026thinsp;\u0026ge;\u0026thinsp;80%, and 40.0% (n\u0026thinsp;=\u0026thinsp;14) presented with B symptoms.\u003c/p\u003e \u003cp\u003eAll patients had received at least one prior systemic therapy; 22 (62.9%) had relapsed disease and 13 (37.1%) had refractory disease. The median number of prior treatment lines was 1 (range, 1\u0026ndash;3), and 31.4% (n\u0026thinsp;=\u0026thinsp;11) had received\u0026thinsp;\u0026ge;\u0026thinsp;2 lines. Most patients (94.3%, n\u0026thinsp;=\u0026thinsp;33) had previously been treated with R-CHOP or an R-CHOP\u0026ndash;like regimen. Four patients had undergone autologous stem-cell transplantation, and two had received CD19-directed CAR-T therapy.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEfficacy\u003c/h3\u003e\n\u003cp\u003ePatients received one of several zanubrutinib-based regimens: zR-MINE (n\u0026thinsp;=\u0026thinsp;8, 22.9%), zR-DHAP (n\u0026thinsp;=\u0026thinsp;8, 22.9%), zR-GemOx (n\u0026thinsp;=\u0026thinsp;6, 17.1%), zR-GDP (n\u0026thinsp;=\u0026thinsp;2, 5.7%), zR-ICE (n\u0026thinsp;=\u0026thinsp;2, 5.7%), or the oral regimen zR₂ (n\u0026thinsp;=\u0026thinsp;9, 25.7%). Treatment courses are summarized in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The median treatment duration was 8.0 months (range, 3.0\u0026ndash;32.0). The best observed overall response rate and complete response rate during treatment were 68.6% (95% CI, 50.7\u0026ndash;83.2) and 54.3% (95% CI, 36.6\u0026ndash;71.2), respectively. At interim assessment, the ORR was 68.6% (24/35), including 19 complete responses (54.3%) and 5 partial responses (14.3%); 11 patients (31.4%) had progressive disease. After completion of induction therapy, the final ORR was 45.7% (16/35; 95% CI, 28.8\u0026ndash;63.4), and the CR rate was 42.9% (15/35; 95% CI, 26.3\u0026ndash;60.6). Overall, 19 patients (54.3%) experienced disease progression, including four who initially achieved CR at interim assessment but subsequently relapsed. Among responders, four patients proceeded to autologous stem-cell transplantation and two received subsequent CD19-directed CAR-T therapy. As of August 30, 2025, five patients (14.3%) remained on zanubrutinib maintenance. Treatment discontinuation was primarily due to disease progression (n\u0026thinsp;=\u0026thinsp;19, 54.3%) or death (n\u0026thinsp;=\u0026thinsp;4, 11.4%).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eSubgroup analyses were performed to evaluate the association between baseline characteristics and treatment response at the end of induction therapy (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Pretreatment disease status emerged as a key determinant of response depth. Patients with relapsed disease achieved a significantly higher complete response rate than those with refractory disease (56.5% vs. 16.7%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.034), with a non-significant trend toward a higher ORR (56.5% vs. 25.0%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.152). Other baseline variables, including age, IPI score, Ann Arbor stage, cell of origin, number of prior treatment lines, and salvage regimen, were not significantly associated with response.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSubgroup analysis of treatment response in 35 patients with relapsed or refractory double-expressor diffuse large B-cell lymphoma [n (%)]\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics and Treatment Selection\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCRR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eORR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003ep\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.315\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.505\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;60 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6/18 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7/18 (38.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;60 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9/17 (52.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9/17 (52.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIPI Score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.738\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u0026ndash;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8/18 (44.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9/18 (50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u0026ndash;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7/17 (41.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7/17 (41.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnn Arbor Stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eI\u0026thinsp;~\u0026thinsp;II\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3/8 (37.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4/8 (50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIII\u0026thinsp;~\u0026thinsp;V\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12/27 (44.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12/27 (44.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCell of origin (Hans)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.564\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.582\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGCB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2/3 (66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2/3 (66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003enon-GCB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13/32 (40.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e14/32 (43.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease status pre-treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.034\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.152\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRefractory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2/12 (16.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3/12 (25.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRelapsed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13/23 (56.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e13/23 (56.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of prior lines of therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.999\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10/24 (41.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e11/24 (45.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5/11 (45.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5/11 (45.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment Regimen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.758\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.843\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ezR-MINE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3/8 (37.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3/8 (37.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ezR-DHAP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3/8 (37.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3/8 (37.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ezR-GemOx\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3/6 (50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3/6 (50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ezR-GDP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1/2 (50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1/2 (50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ezR-ICE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2/2 (100.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2/2 (100.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ezR2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3/9 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4/9 (44.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAs of August 31, 2025, with a median follow-up of 33.0 months (range, 2.0\u0026ndash;49.0), 23 patients (65.7%) had experienced disease progression or death. One elderly patient died from multifocal cerebral infarction three months after treatment despite achieving a complete response. Sixteen patients died within 12 months following disease progression, one patient died two years after progression, and three patients died from SARS-CoV-2 infection despite best responses of partial or complete remission. All deaths were considered unrelated to zanubrutinib. Median progression-free survival was 8.0 months (95% CI, 6.0 months to not reached), and median overall survival was 12.0 months (95% CI, 9.0 months to not reached). The 1- and 2-year PFS rate were both 40.1% (95% CI, 26.4\u0026ndash;60.8), and the 1- and 2-year OS rates were 48.6% (95% CI, 34.5\u0026ndash;68.3) and 42.7% (95% CI, 29.0\u0026ndash;62.7), respectively. Kaplan\u0026ndash;Meier survival curves are shown in Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb.\u003c/p\u003e \u003cp\u003eIn univariate analysis for overall survival, age\u0026thinsp;\u0026ge;\u0026thinsp;60 years was associated with inferior OS (HR 2.72, 95% CI, 1.09\u0026ndash;6.78; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.032), which was confirmed by Kaplan\u0026ndash;Meier analysis (log-rank \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.021; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ed). Longer duration of response to prior therapy was associated with a trend toward improved OS (HR 0.92, 95% CI, 0.82\u0026ndash;1.02; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.100). On multivariate analysis, duration of response to prior therapy remained an independent protective factor for OS (HR 0.88, 95% CI, 0.77\u0026ndash;0.99; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.041), whereas age was no longer independently associated with survival. Sex, Ann Arbor stage, and IPI score were not significantly associated with OS. The detailed results of the univariate and multivariate analyses for OS are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eNo independent prognostic factors for PFS were identified in multivariate analysis. In univariate analysis, elevated baseline LDH showed a trend toward shorter PFS (HR, 2.08; 95% CI, 0.86\u0026ndash;5.00; p\u0026thinsp;=\u0026thinsp;0.103). Consistently, Kaplan\u0026ndash;Meier analysis demonstrated significantly inferior PFS in patients with elevated LDH (p\u0026thinsp;=\u0026thinsp;0.047; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariate and multivariate analysis for OS.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eUnivariate Cox\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eMultivariate Cox\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR (95%CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHR (95%CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.23 (0.52\u0026thinsp;~\u0026thinsp;2.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.640\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (\u0026lt;\u0026thinsp;60; \u0026ge;60), years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.72 (1.09\u0026thinsp;~\u0026thinsp;6.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.032\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.24 (0.82\u0026thinsp;~\u0026thinsp;6.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.114\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnn Arbor stage (I\u0026thinsp;~\u0026thinsp;II; III\u0026thinsp;~\u0026thinsp;IV)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.87 (0.32\u0026thinsp;~\u0026thinsp;2.38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.783\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIPI risk group (0\u0026thinsp;~\u0026thinsp;2; 3\u0026thinsp;~\u0026thinsp;5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.91 (0.39\u0026thinsp;~\u0026thinsp;2.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.825\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCell of origin (Hans) non-GCB; GCB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.55 (0.13\u0026thinsp;~\u0026thinsp;2.40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.428\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBsymptom (yes; no)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.17 (0.49\u0026thinsp;~\u0026thinsp;2.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.724\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEcog score (0\u0026thinsp;~\u0026thinsp;1; \u0026ge;2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.19 (0.46\u0026thinsp;~\u0026thinsp;3.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.726\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBone marrow involvement (yes; no)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.69 (0.16\u0026thinsp;~\u0026thinsp;2.97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.620\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum LDH (normal; rise)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.91 (0.80\u0026thinsp;~\u0026thinsp;4.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.146\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.48 (0.60\u0026thinsp;~\u0026thinsp;3.62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.395\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eB2MG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.95 (0.54\u0026thinsp;~\u0026thinsp;1.69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.871\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWBC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.91 (0.77\u0026thinsp;~\u0026thinsp;1.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.293\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.01 (0.97\u0026thinsp;~\u0026thinsp;1.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.673\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePLT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.00 (0.99\u0026thinsp;~\u0026thinsp;1.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.064\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.00 (0.99\u0026thinsp;~\u0026thinsp;1.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.054\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKi67 index\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.01 (0.97\u0026thinsp;~\u0026thinsp;1.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.706\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEarly treatment (1 line; \u0026ge;2 line)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.95 (0.38\u0026thinsp;~\u0026thinsp;2.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.920\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDOR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.92 (0.82\u0026thinsp;~\u0026thinsp;1.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.88 (0.77\u0026thinsp;~\u0026thinsp;0.99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.041\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eHR: Hazard Ratio, CI: Confidence Interval,DOR: Response duration to previous treatment\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eSafety\u003c/h3\u003e\n\u003cp\u003eTreatment was generally well tolerated. The most common grade 3\u0026ndash;4 hematologic adverse events were neutropenia (42.8%) and thrombocytopenia (14.3%). Febrile neutropenia occurred in 17.1% of patients, and 5.7% required platelet transfusion. The most frequent non-hematologic adverse events were pulmonary infection (34.3%) and fatigue (25.7%), followed by nausea or vomiting (11.4%) and rash (8.6%). One case of grade 3 hematochezia and one grade 3 thrombotic event were observed and successfully managed with supportive care. No cases of atrial fibrillation, opportunistic infection, tumor lysis syndrome, or treatment-related death were reported.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003ePatients with R/R DLBCL generally have a poor prognosis. In a large real-world analysis by Fuji et al., the median OS after conventional salvage therapy was only 1.10 years, with a 3-year OS rate of 30.7%[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Within this already high-risk population, the DE subtype represents an even more adverse subgroup; retrospective studies report a median OS of less than 6 months in R/R DE-DLBCL[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], underscoring the urgent need for more effective therapies. This unmet need is further highlighted by the finding that even intensive chemotherapy regimens like DA-EPOCH-R failed to improve outcomes for patients with DE, despite showing benefit in other DLBCL subgroups[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. In our study, zanubrutinib combined with salvage chemotherapy achieved a median OS of 12.0 months and a CR rate of 42.9%, with the best CR rate reaching 54.3%, representing a clinically meaningful improvement. These findings are consistent with the synergistic activity reported by Wang et al.[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] and further support the rationale for BTK-based combination strategies in this ultra-high-risk setting.\u003c/p\u003e \u003cp\u003eReal-world data from the REAL-DREND study showed that salvage chemotherapy alone achieved an ORR of 30% and a CR rate of 9%, with a median OS of 5.9 months in R/R DLBCL[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Consistent with this, historical data at our center for patients receiving conventional salvage chemotherapy reported a CR rate of only 27.3%[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. BTK inhibitor monotherapy has demonstrated limited activity; in a phase II study of zanubrutinib monotherapy in R/R non-GCB DLBCL, the ORR and CR rate were 29.3% and 17.1%, respectively, with modest PFS and OS outcomes[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Patients with the DE phenotype typically respond even more poorly, reinforcing the rationale for mechanism-driven combination strategies. Several early-phase studies have demonstrated the potential of BTK inhibitor\u0026ndash;based combinations in R/R DLBCL, including the DE subtype. For example, ibrutinib plus R-ICE achieved an ORR of 90% and a CR rate of 55%[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], while ibrutinib combined with bendamustine-rituximab or lenalidomide-rituximab also showed encouraging activity[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Although outcomes vary across regimens, these studies collectively suggest that BTK inhibitor\u0026ndash;based combinations can overcome the limitations of monotherapy. The efficacy observed in our study (ORR 45.7%, CR 42.9%, median OS 12.0 months) compares favorably with these prior findings, particularly given the high-risk DE-DLBCL population. A recent real-world study by He et al. further supports these results, reporting an ORR of 57.1% and a median PFS of 6.0 months with zanubrutinib-based combinations in transplant-ineligible R/R DLBCL[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Together, these data position zanubrutinib-based combinations as a promising therapeutic option.\u003c/p\u003e \u003cp\u003eMechanistically, the aggressiveness of DE-DLBCL is driven by MYC and BCL-2 overexpression and sustained activation of the B-cell receptor (BCR) signaling pathway. Zanubrutinib, a highly selective BTK inhibitor, effectively suppresses downstream survival and proliferation signals, promoting apoptosis in malignant B cells[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. This targeted inhibition may sensitize DE-DLBCL cells to chemotherapy, while salvage chemotherapy provides direct cytotoxicity\u0026mdash;together contributing to the high CR rate observed in our study. Beyond this synergistic mechanism, appropriate patient selection is critical. Prior studies, including those by He et al., have identified CD79B and MYD88 mutations as strong predictors of response to zanubrutinib-based therapy, with mutation-positive patients achieving markedly higher ORR and longer PFS[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Although our study did not include genomic profiling, these findings underscore the importance of incorporating molecular biomarkers into future prospective studies to refine patient selection and optimize therapeutic benefit.\u003c/p\u003e \u003cp\u003eSubgroup analysis identified pretreatment disease status as the primary determinant of response depth. Relapsed patients achieved significantly higher CR rates than those with primary refractory disease (56.5% vs. 16.7%, p\u0026thinsp;=\u0026thinsp;0.034), with a similar trend observed for ORR. This finding is consistent with the known biology of primary refractory disease, which is typically more aggressive and less responsive to therapy. Other clinical characteristics\u0026mdash;including age, IPI score, Ann Arbor stage, cell of origin, number of prior therapies, and regimen type\u0026mdash;were not significantly associated with response. Notably, most patients in our cohort (68.6%) had received only one prior line of therapy, and efficacy was similar regardless of treatment intensity. The relatively high proportion of relapsed and lightly pretreated patients may partly explain the favorable outcomes observed. These results suggest that the benefit of zanubrutinib-based combinations is not restricted to specific clinical subgroups and may be maximized when introduced early, particularly at first relapse or before the development of broad chemoresistance.\u003c/p\u003e \u003cp\u003eMultivariate analysis demonstrated that duration of response to prior therapy was an independent predictor of overall survival, suggesting that patients with more durable prior responses derive greater benefit from this combination. A longer prior response may reflect preserved chemosensitivity and less complex clonal evolution, enabling more sustained disease control with combination therapy. These findings further support the potential value of earlier intervention, before the development of broad treatment resistance. In contrast, traditional clinical prognostic factors were not independently associated with survival, raising the possibility that zanubrutinib-based combinations may partially mitigate baseline risk heterogeneity. This hypothesis warrants confirmation in larger, prospective studies.\u003c/p\u003e \u003cp\u003eThese results prompt reconsideration of the traditional classification framework for R/R DE-DLBCL. Consistent with prior studies in R/R DLBCL[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], we observed no significant differences in CR or ORR between GCB and non-GCB subtypes, suggesting that cell-of-origin may have limited prognostic relevance in the relapsed/refractory setting\u0026mdash;particularly within the DE subtype. Instead, disease biology in these patients is likely driven by shared molecular abnormalities, including aberrant BCR signaling and MYC/BCL-2 overexpression. Given the substantial molecular heterogeneity of DLBCL, therapeutic strategies targeting core pathogenic pathways, such as BCR signaling, may be more clinically meaningful than traditional cell-of-origin\u0026ndash;based classification.\u003c/p\u003e\u003cp\u003eSafety is a critical consideration when evaluating combination regimens. Hematologic toxicities were the most common, with neutropenia (42.8%) and thrombocytopenia (14.3%) occurring at expected frequencies; no treatment-related deaths or severe infections were observed, consistent with appropriate supportive care in routine clinical practice. Non-hematologic toxicities\u0026mdash;including nausea, vomiting, and fatigue\u0026mdash;were consistent with conventional chemotherapy and were generally manageable. Although pneumonia occurred in 34.3% of patients, most cases were associated with disease progression rather than treatment toxicity. Notably, no zanubrutinib-specific adverse events such as atrial fibrillation or major bleeding were observed, consistent with its improved BTK selectivity[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Overall, the regimen demonstrated a manageable safety profile and good tolerability.\u003c/p\u003e \u003cp\u003eThis study has several limitations. First, it was a two-center retrospective study, and the sample size was relatively small, which may introduce selection bias. Second, the use of heterogeneous salvage chemotherapy regimens\u0026mdash;reflecting real-world practice\u0026mdash;may have contributed to variability in treatment outcomes. Third, the lack of molecular profiling limited our ability to elucidate the mechanistic basis of synergy and to identify predictive biomarkers. Finally, although CAR-T cell therapy is an established option for R/R LBCL, the retrospective design precluded direct comparison with this modality. Future prospective, controlled studies are needed to validate our findings, refine patient selection, and determine the optimal timing and sequencing of zanubrutinib-based therapy in relation to CAR T and other emerging treatments.\u003c/p\u003e \u003cp\u003eIn conclusion, zanubrutinib combined with salvage chemotherapy demonstrated encouraging efficacy and acceptable tolerability in patients with R/R DE-DLBCL. These findings support its potential role as a salvage option for this high-risk population. Larger, prospective studies incorporating molecular profiling are warranted to optimize combination strategies and to identify the patients most likely to benefit.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003cstrong\u003eCompeting interests\u003c/strong\u003e \u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis work was supported by Natural Science Foundation of Jiangsu Province [BK20232039]; National Natural Science Foundation of China [82470186]; Jiangsu Province Hospital Clinical Diagnosis and Treatment Technology Innovation Open Bidding and Leader Selecting Project [JBGS202404].\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eJ. L performed the research and wrote the paper. Y.Z, X.Y analyzed the data. J.S, Q.L, X.D collected patients\u0026rsquo; data and managed the database. R.L, J.W, L.C, H.L, Y.X critically edited the manuscript.H.S, S.W and L.F designed the research study, oversaw the research and critically reviewed the manuscript. All authors gave final approval for the manuscript.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003e The study was implemented in accordance with local regulations, the principles of the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice guidelines. The study protocol and all amendments were approved by institutional review boards and independent ethics committees. All patients provided written informed consent.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCrump M, Neelapu SS, Farooq U, Van Den Neste E, Kuruvilla J, Westin J, Link BK, Hay A, Cerhan JR, Zhu L et al (2017) Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. 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Blood 136(18):2038\u0026ndash;2050. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1182/blood.2020006844\u003c/span\u003e\u003cspan address=\"10.1182/blood.2020006844\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Zanubrutinib, BTK inhibitor, Double-expressor diffuse large B-cell lymphoma, Relapsed/refractory, Salvage therapy","lastPublishedDoi":"10.21203/rs.3.rs-8652982/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8652982/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eTo evaluate the efficacy and safety of the Bruton tyrosine kinase (BTK) inhibitor zanubrutinib in combination with salvage chemotherapy in patients with relapsed or refractory double-expressor diffuse large B-cell lymphoma (R/R DE-DLBCL).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe performed a retrospective analysis of 35 patients with R/R DE-DLBCL treated at two hematology centers from June 2021 to June 2024. All patients received zanubrutinib combined with one of several salvage regimens, including zR-MINE, zR-DHAP, zR-GemOx, or zR2. Endpoints included objective response rate (ORR), complete response rate (CRR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe median age was 60 years, and 91.4% of patients had the non-germinal center B-cell (non-GCB) subtype. At the end of therapy, the ORR and CRR were 45.7% (16/35) and 42.9% (15/35), respectively. After a median follow-up of 33.0 months, median PFS and OS were 8.0 and 12.0 months, respectively. Relapsed patients achieved a significantly higher CRR than refractory patients (56.5% vs. 16.7%, p\u0026thinsp;=\u0026thinsp;0.034). On multivariate analysis, longer duration of response to prior therapy was an independent protective factor for OS (HR 0.88, 95% CI 0.77\u0026ndash;0.99; p\u0026thinsp;=\u0026thinsp;0.041). Grade 3\u0026ndash;4 hematologic AEs were mainly neutropenia (42.8%) and thrombocytopenia (14.3%). Pulmonary infection was the most common non-hematologic AE (34.3%), and overall toxicity was manageable.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eZanubrutinib combined with salvage chemotherapy demonstrates clinically meaningful activity with a manageable safety profile in patients with R/R DE-DLBCL and may represent a therapeutic option for this high-risk population.\u003c/p\u003e","manuscriptTitle":"Real‑World Effectiveness of Zanubrutinib Plus Salvage Chemotherapy in Relapsed or Refractory Double‑Expressor DLBCL","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-12 17:59:28","doi":"10.21203/rs.3.rs-8652982/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-02-16T11:16:21+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-16T10:00:03+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"129221876169982842648131824340641156178","date":"2026-02-11T13:45:55+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"41831608495843747823540123010094562118","date":"2026-02-10T15:57:53+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-08T14:52:29+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-06T15:46:11+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-06T15:43:14+00:00","index":"","fulltext":""},{"type":"submitted","content":"Annals of Hematology","date":"2026-01-20T20:33:45+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"d3a31eb2-5ea8-4f62-93f3-46824cbb94fc","owner":[],"postedDate":"February 12th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-04-20T16:08:48+00:00","versionOfRecord":{"articleIdentity":"rs-8652982","link":"https://doi.org/10.1007/s00277-026-06974-6","journal":{"identity":"annals-of-hematology","isVorOnly":false,"title":"Annals of Hematology"},"publishedOn":"2026-04-15 15:59:07","publishedOnDateReadable":"April 15th, 2026"},"versionCreatedAt":"2026-02-12 17:59:28","video":"","vorDoi":"10.1007/s00277-026-06974-6","vorDoiUrl":"https://doi.org/10.1007/s00277-026-06974-6","workflowStages":[]},"version":"v1","identity":"rs-8652982","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8652982","identity":"rs-8652982","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}