Optimized Glofitamab Schedule Halves Mortality Risk After CAR T Failure in Diffuse Large B-Cell Lymphoma: A Phase 2 Trial with External Control Arm Conducted by The LYSA Group

Optimized Glofitamab Schedule Halves Mortality Risk After CAR T Failure in Diffuse Large B-Cell Lymphoma: A Phase 2 Trial with External Control Arm Conducted by The LYSA Group | 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 Optimized Glofitamab Schedule Halves Mortality Risk After CAR T Failure in Diffuse Large B-Cell Lymphoma: A Phase 2 Trial with External Control Arm Conducted by The LYSA Group Guillaume Cartron, Isabelle Chaillol, Roch Houot, Yassine Al Tabaa, and 20 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9288467/v1 This work is licensed under a CC BY 4.0 License Status: Under Revision Version 1 posted 16 You are reading this latest preprint version Abstract Background Failure after anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in diffuse large B-cell lymphoma (DLBCL) is associated with poor survival and no established standard of care. We previously reported the phase 2 LYSA BiCAR trial of short-ramp-up glofitamab after CAR T-cell failure. Here, we present the final survival results and a pre-specified external comparative effectiveness analysis against a contemporary control arm constructed from academic data. Methods BiCAR is a multicenter, single-arm trial in adults with CD20-positive DLBCL refractory to, or in first relapse/progression after anti-CD19 CAR T-cell therapy. Participants received obinutuzumab pretreatment followed by intravenous glofitamab with an accelerated step-up to 30 mg within 8 days, then 30 mg every 21 days for up to 11 cycles. For comparative analyses, we constructed an external control arm from patients included in the French DESCAR-T registry and the ALYCANTE phase 2 trial who experienced CAR T-cell failure, who subsequently started non-bispecific systemic therapy, met key BiCAR eligibility criteria, and initiated treatment within a ±1-month window around the BiCAR treatment period. To minimise datasource bias, both arms, glofitamab (BICAR) and control, were constructed from individual patient data from the DESCAR-T registry and the ALYCANTE trial. A propensity score including major prognostic variables was estimated and applied using stabilized inverse probability of treatment weighting with multiple imputation. Additional weighting schemes and restrictions were applied in sensitivity analyses, and restricted mean survival time (RMST) was evaluated by treatment arm. Results Among 47 enrolled BiCAR patients, 46 received glofitamab. At a median follow-up of 30.4 months, median overall survival (OS) was 17.3 months, and the 2-year OS rate was 38.3%. For comparative effectiveness, 45 glofitamab-treated patients and 133 controls formed the analysis cohort. In the primary weighted analysis, median OS was 19.6 months for glofitamab and 7.6 months for controls, with a hazard ratio for death of 0.49 (95% CI, 0.31–0.79; P =0.007). Multiple sensitivity analyses yielded consistent estimates. Glofitamab significantly improved the RMST of 5 months ( P =0.007) over a 2-year follow-up. Conclusions In this robust comparative effectiveness study, short-ramp-up glofitamab immediately after CAR T-cell failure significantly increases the chance of survival compared to contemporaneous non–bispecific salvage therapies, supporting its use as a preferred option for eligible patients with DLBCL who fail anti-CD19 CAR T-cell therapy. Trial registration.ClinicalTrials.gov identifier NCT04703686. Diffuse large B-cell lymphoma CAR T-cell therapy glofitamab bispecific antibodies comparative effectiveness external control real-world data LYSA. Figures Figure 1 Figure 2 Figure 3 Background Anti-CD19 CAR T-cell therapies have transformed outcomes for patients with relapsed or refractory (R/R) large B-cell lymphomas (LBCL), but 50–60% ultimately experience primary refractory disease or relapse after infusion. The median overall survival (OS) is then approximately 6 months once CAR T-cell failure occurred, regardless of whether CAR T-cells were infused in second-line [ 1 , 2 ], or in third-line or more [ 3 – 6 ]. In this setting, there is no established standard of care, and clinicians commonly use heterogeneous combinations of chemo-immunotherapy, antibody-based, small-molecule, or investigational regimens, generally with limited efficacy. CD20×CD3 bispecific antibodies (BsAbs), including glofitamab, have demonstrated substantial activity in R/R LBCL, with high response rates and durable remissions, including among patients previously treated with CAR T-cells [ 7 – 10 ]. However, those phase I/II studies enrolled heterogeneous populations including patients both with and without prior CAR T-cell exposure and were not specifically designed for the immediate post-CAR T-cell setting. Furthermore, they lacked direct comparisons between BsAbs and alternative salvage therapies following CAR T-cell failure. Consequently, the use of CD20×CD3 BsAbs as the preferred strategy for patients relapsing after CAR T-cell therapy remains largely empirical. The LYSA BiCAR trial is a prospective multicenter phase 2 study specifically dedicated to adults with CD20-positive DLBCL who are refractory to, or in first relapse/progression immediately after anti-CD19 CAR T-cell therapy and evaluates glofitamab using an intensified “short ramp-up” schedule that reaches the full 30-mg dose within one week. In the primary analysis (median follow-up 15.3 months), short-ramp-up glofitamab yielded a median OS of 14.7 months, a best overall metabolic response (OR) rate of 76.1%, and a best complete metabolic response (CR) rate of 45.7%, with no grade ≥ 3 cytokine release syndrome (CRS) or neurotoxicity [ 11 ]. Beyond demonstrating feasibility and clinical activity, a central clinical question remains whether glofitamab improves survival relative to the non- BsAbs regimens actually used in practice after CAR T-cell failure. While indirect comparisons suggest that bispecific antibodies are at least as effective as conventional salvage therapies [ 3 , 5 , 12 ], robust comparative effectiveness data are scarce, and no prospective randomized trial will answer this question in the future. Here, we report the final survival results of BiCAR, together with a robust pre-specified external comparative effectiveness analysis of glofitamab against contemporaneous non-bispecific salvage strategies. This analysis is based on data from the DESCAR-T national CAR T-cell registry [ 13 ] and the ALYCANTE phase 2 trial [ 14 ]. Methods Study design This study combines the BiCAR trial (NCT04703686), a prospective, multicenter, single-arm phase 2 study of short-ramp-up glofitamab after CAR T-cell failure conducted by LYSA/LYSARC [ 11 ], and an external comparative effectiveness analysis of glofitamab against contemporaneous non-bispecific salvage strategies after CAR-T cell failure. To minimise datasource bias, the two arms, the glofitamab arm (BicAR patients) and the control arm, are built from individual patient data in the DESCAR-T registry and ALYCANTE trial. The comparative endpoint was OS from initiation of post-CAR T therapy. All comparative analyses were planned in the protocol and prespecified in a dedicated statistical analysis plan. Populations, endpoints and setting BiCAR trial Eligibility criteria BiCAR enrolled adults (≥ 18 years) with biopsy-proven CD20-positive DLBCL who were refractory to, or in first relapse/progression after, anti-CD19 CAR T-cell therapy given ≥ 1 month before enrolment; had ECOG performance status 0–1; at least one measurable lesion > 1.5 cm on PET-CT; adequate hepatic, renal and hematologic function; and life expectancy ≥ 3 months. Patients with CD20-negative disease, primary CNS lymphoma or CNS involvement, relapse within 30 days of CAR T infusion, uncontrolled infection or prior allogeneic transplant were excluded [ 11 ]. All participants provided written informed consent. Treatment and assessments Patients received obinutuzumab 1,000 mg intravenously on day − 3, followed by glofitamab intravenously with a short ramp-up during cycle 1 (14 days): 2.5 mg on day 1, 10 mg on day 3, and 30 mg on day 8. From cycle 2 onward, glofitamab 30 mg was given every 21 days for up to 11 cycles. Baseline Positron Emission Tomography-Computed Tomography (PET-CT) and subsequent scans after cycles 2, 4, 6, 9, and 11 were centrally reviewed using Lugano 2014 criteria. Adverse events were graded with Common Terminology Criteria for Adverse Events (CTCAE) v5.0; CRS and neurotoxicity with American Society for Transplantation and Cellular Therapy (ASTCT) criteria. The BiCAR full analysis set (BiCAR-FAS) comprised all patients who received at least one glofitamab dose [ 11 ]. BiCAR endpoints and data cutoff The BiCAR primary endpoint was the OS measured from the date of the first glofitamab infusion to the date of death from any cause, censoring participants who were still alive at the last contact date. Secondary endpoints included progression-free survival (PFS), OR and CR rates, duration of response (DoR) and duration of complete response (DoCR), and safety [ 11 ]. The present final analysis uses a BiCAR database export dated June 13t h , 2025, with a data cutoff on May 21st, 2025. Comparative effectiveness analysis External data sources The DESCAR-T registry (NCT04328298) is a nationwide French observational database designed to capture real-world data on adults eligible for commercial anti-CD19 CAR T-cell therapy. The registry provides comprehensive longitudinal data, including baseline patient characteristics, infusion parameters, post-infusion clinical outcomes, and details on subsequent therapeutic interventions. This analysis utilized a data export dated March 13th, 2025 The ALYCANTE trial (NCT04531046) is a multicenter phase 2 trial evaluating axicabtagene ciloleucel (axi-cel) as second-line therapy in transplant-ineligible patients with large B-cell lymphoma. The dataset used here was exported on October 30th, 2024. BiCAR clinical data were used to identify BiCAR participants within DESCAR-T and ALYCANTE via matching of birth month/year, initials, and CAR T infusion dates. Comparative effectiveness populations Glofitamab arm: The glofitamab arm for comparative analyses included BiCAR participants who: 1/received obinutuzumab and at least one glofitamab dose; 2/ were confidently identified in DESCAR-T or ALYCANTE; 3/ were not treated with CAR T-cells in another clinical trial with unknown details. Of 46 treated BiCAR patients, 45 were identified in external databases (8 from ALYCANTE, 37 from DESCAR-T), and one treated in an unknown trial was excluded, yielding 45 patients in the glofitamab comparative arm. Control arm: The control arm comprised DESCAR-T and ALYCANTE patients who: 1/ had DLBCL and received commercial axi-cel or tisagenleuclecel (tisa-cel); 2/ had stable disease (SD) or progression/relapse from month 1 after CAR T infusion ; 3/ started systemic post-CAR T treatment other than a CD20×CD3 bispecific antibody; 4/ met main BiCAR inclusion criteria (DLBCL, ECOG 0–1, adequate organ function). To ensure contemporaneity and comparable follow-up durations, DESCAR-T control patients were further required to have initiated their first post-CAR T regimen within a ± 1-month window around the date of glofitamab initiation in the BiCAR trial. This alignment of treatment timelines was implemented to minimize temporal bias and provide contemporaneous data for the analysis. Comparative full analysis set Covariates and endpoint Covariates available in all datasets and considered for propensity-score (PS) estimation were: sex; age at CAR T-cells infusion; number of prior treatment lines including CAR T-cell (L2 vs ≥L3); time from CAR T-cells infusion to first progression/stable disease; Ann Arbor stage (I–II vs III–IV); lactate dehydrogenase (normal vs > ULN-upper limit normal) at or just before CAR T-cell infusion (or at lymphodepletion if missing); CAR T-cell product (axi-cel vs tisa-cel); response to bridging therapy (CR/partial response-PR vs stable disease-SD/progression disease-PD vs no bridging); prior autologous stem-cell transplant (yes/no). For the comparative analysis, OS was defined as the time from first glofitamab infusion (glofitamab arm) or first non-bispecific post-CAR T regimen (control arm) to death from any cause; survivors were censored at last contact. Analysis sets and missing data Three analysis sets were defined: 1/cFAS, all 178 patients fulfilling comparative criteria; 2/ complete case set (CC-set), cFAS patients without missing values in planned PS covariates (n = 165); 3/ Weighted pseudo-populations, created by applying PS-based weights (stabilized inverse probability of treatment weighting (sIPTW) [ 15 ], standardized mortality ratio weighting (SMRW) [ 16 ]) to the cFAS. Missing covariates were handled by complete case analysis using the CC-set and multiple imputation (MI) via MICE with 15 imputations and 100 iterations, generating 15 completed datasets for the primary analysis and pooled using Rubin’s rules. Propensity score and weighting The propensity score (probability of receiving glofitamab vs control given covariates) was estimated using logistic regression, including all listed variables, with continuous covariate effects modeled using spline functions. Two weighting schemes were prespecified: 1/ sIPTW, targeting the average treatment effect (ATE) in the overall population, with weights of \(\:{w}_{i}=P/P{S}_{i}\) for treated, and \(\:{w}_{i}=(1-P)/(1-P{S}_{i})\) for controls with P for proportion of patients in the glofitamab arm and PS of propensity score and; 2/ SMRW, targeting the average treatment effect in the control population (ATC), reweighting treated patients to resemble controls. Patients with extreme propensity scores, defined as PS values below 0.025 or above 0.95, were excluded from weighted analyses to avoid undue influence of extreme weights on treatment. effect estimates. Survival analysis BiCAR trial final analysis Within the BiCAR-FAS population, OS, PFS, DoR, and DoCR were estimated using Kaplan–Meier methods. External control comparisons Primary analysis: For the comparative effectiveness analysis, OS Kaplan-Meier curves were generated for the cFAS and for the weighted pseudo-populations (sIPTW and SMRW sets). The primary analysis was based on MI-sIPTW weighting including all data sources. Survival probabilities, median survival, and quartiles were estimated (if reached) with their 95% CIs. Cox models provided hazard ratios (HR) and 95% CIs for glofitamab versus control; proportional hazards assumptions were checked using Schoenfeld residuals. Differences between arms were tested with log-rank tests. The robustness of observed associations to unmeasured confounding was assessed using the E-value, which quantifies the minimum strength of association that a hypothetical unmeasured confounder would need to have with both the treatment arm and OS to fully explain away the observed HR of glofitamab versus non-BsAbs regimens [ 17 ]. Secondary and sensitivity analyses : As a secondary analysis, restricted mean survival time (RMST) over a 2-year follow-up period was calculated as the area under the weighted Kaplan-Meier curve, with between-group comparisons performed using the difference in RMST and its 95% confidence interval estimated via bootstrap with 500 replicates [ 18 ]. Pre-specified sensitivity analyses included: 1/ MI-SMRW analysis; 2/ sIPTW and SMRW on complete-case PS sets; 3/ MI-based analyses restricted to DESCAR-T patients only; 4/ MI-sIPTW restricted to Ann Arbor stage III–IV patients. Because weighting reduces the contribution of some patients, the effective sample size was calculated after analysis with sIPTW on complete case set, to reflect the equivalent sample size contributing information to the analysis. Analyses were performed using SAS 9.4 and R 4.4.2. Results BiCAR final survival outcomes Of the 47 enrolled BiCAR cohort-1 patients, 46 received glofitamab and formed the BiCAR-FAS. Patient and disease characteristics have already been published and are summarized in Table 1. Table 1. Patient demographic and disease characteristics at inclusion in the BiCAR trial BiCAR FAS (N=46) Median (min-max) age at enrollment, years 64 (30-77) Sex, n (%) Female 15 (32.6) Male 31 (67.4) ECOG performance status, n (%) 0 23 (50.0) 1 23 (50.0) Ann Arbor stage, n (%) I-II 8 (17.4) III-IV 38 (82.6) IPI, n (%) 0-2 19 (42.2) 3-4 26 (57.8) Missing 1 LDH status: >ULN 35 (76.1) Presence of at least one extranodal site, n (%) 35 (76.1) Median number of previous lines of lymphoma treatment (minimum–maximum) 3 (2–5) ≥3 lines of treatment, n (%) 37 (80.4) Previous autologous or allogeneic transplant, n (%) 8 (17.4) Previous CAR-T cell therapy, n (%) Experimental CAR-T cell product (in clinical trial) 3 (6.5) Tisa-cel 17 (37.0) Axi-cel 26 (56.5) Patient status at screening, n (%) Refractory a 14 (30.4) Relapse/progression b 32 (69.6) Time between CAR-T cell therapy and relapse/progression, n (%) 1–3 months 9 (28.1) 3–6 months 8 (25.0) >6 months 15 (46.9) Missing data are specified for any variable for which n (%) does not add up to N. a Refractory: designates patients who never experienced a metabolic response (i.e., stable or progressive disease) after CAR-T cell therapy. b Relapse/progression designates patients who experienced response (PR or CR) after CAR-T cells then relapse/progression on subsequent PET-CT. Abbreviations: Axi-cel, axicabtagene ciloleucel; CAR-T, chimeric antigen receptor-T; CR, complete response; ECOG, Eastern Cooperative Oncology Group; FAS, full analysis set; IPI, international prognostic index; PR, partial response; SD, standard deviation; tisa-cel, tisagenlecleucel; ULN, upper limit of normal. At the final analysis (data cutoff: 21 May 2025), the median follow-up from first glofitamab infusion was 30.4 months (95% CI, 23.0–31.4). Median OS was 17.3 months (95% CI, 9.0–28.4), with a 2-year OS rate of 38.3% (95% CI, 26.1–50.4) (Figure 1A). Median PFS was 3.8 months (95% CI, 2.4–15.9) with a 2-year PFS rate of 29.1% (95% CI, 16.5–43.0) (Figure 1B). Median DoR among responders was 16.1 months (95% CI, 4.0–NR), and median DoCR was not reached (95%CI: 19.7; NR) (Figure 1C-1D). Outcomes remained strongly associated with the timing of CAR T-cell failure (Figure 2A). Median OS was not reached (95% CI: 10.2- NR) in patients with late relapse (> 6 months post-infusion), compared with 11.1 months (95% CI: 5.5–20.0) in those with refractory or early-relapsing disease (≤6 months; log-rank P =0.01). Response after two cycles of glofitamab also predicted outcome; median OS was not reached in patients experiencing CR (95%CI, 27.4-not estimable) versus 9.0 months (95% CI, 4.9-20.1) ( P =0.0015) (Figure 2B). No new safety signals emerged, and safety details were unchanged from the primary report [11]. Comparative cohorts and baseline characteristics Within the BiCAR-FAS, 45 patients were matched with the DESCAR-T/ALYCANTE data sources and included in the glofitamab arm, while one patient was excluded as previously described. Out of 3,143 registry and trial-derived patients, 133 controls met the pre-specified eligibility criteria and temporal restrictions for the comparative analysis and received non-bispecific post-CAR-T therapy (Figure S1). In the cFAS (n=178), 65.7% were male, with a median age of 63 years (range: 19–82) at the time of CAR T-cell infusion (Table 2). At CAR T-cells infusion, most patients presented with advanced disease, including 83.5% with Ann Arbor stage III–IV and 50.0% with LDH levels above the ULN. Most patients (84.8%) had received CAR T-cell therapy in the third-line setting or later, with 65.7% having received axi-cel. The median time from CAR T-cell infusion to treatment failure was 3.0 months (IQR 1.84–5.88). Baseline features were generally comparable between the glofitamab (n=45) and control (n=133) arms, with slightly more advanced disease (93.0% vs 80.3% stage III–IV), LDH within normal values (51.1% vs 42.1% normal LDH), no response after bridging (61.4% vs 50.4% no responder) and prior ASCT (18.2% vs 12.8%) in the glofitamab arm (Table 2). Control patients received a heterogeneous salvage therapy following CAR T-cell failure, including monoclonal antibodies (57.9%; among them 34.6% anti-CD20 and 18.8% anti-CD19), lenalidomide (48.1%), chemotherapy (31.6%), kinase inhibitors (12.0%, primarily ibrutinib), and radiotherapy (10.5%), and smaller proportions of other agents. All eight patients recorded as receiving corticosteroids also received at least one additional anti-lymphoma regimen. Best response in the control arm was complete response in 8.3% and partial response in 4.5%, while 72.0% had progressive disease. Table 2. Patients’ characteristics from the control and BiCAR arm from the cFAS set and the CC-set. cFAS set N=178 CC-set N=165 Control N=133 Glofitamab N=45 Control N=125 Glofitamab N=40 Age at CAR-T infusion Median (range) 63 (19-82) 63 (30-77) 63 (19-82) 64 (30-77) Sex Male, N (%) 87 (65.4) 30 (66.7) 83 (66.4) 27 (67.5) Time between CAR-T and failure Median (Q1-Q3) 2.99 (1.22-5.68) 3.25 (2.07-6.64) 3.0 (1.2-5.7) 3.5 (2.1-8.0) Ann Arbor Stage at CAR-T infusion Missing I-II III-IV 6 25 (19.7) 102 (80.3) 2 3 (7.0) 40 (93.0) 6 25 (21.0) 94 (79.0) 1 2 (5.1) 37 (94.9) Prior ASCT Missing Yes No 0 116 (87.2) 17 (12.8) 1 36 (81.8) 8 (18.2) - 16 (12.8) 109 (87.2) - 7 (17.5) 33 (82.5) Response After Bridging Missing No bridge Response (CR/PR) No response (SD/PD) 2 18 (13.5) 46 (34.6) 67 (50.4) 1 4 (9.1) 13 (29.5) 27 (61.4) - 16 (12.8) 45 (36.0) 64 (51.2) - 3 (7.5) 12 (30.0) 25 (62.5) Bulk at lymphodepletion Missing Yes No 10 26 (21.1 97 (78.9) 9 10 (27.8) 26 (72.2) 10 26 (22.6) 89 (77.4) 8 10 (31.3) 22 (68.8) LDH (IU/L) at CAR-T infusion > Upper limit 71 (53.4) 18 (40.0) 70 (56.0) 17 (42.5) CAR-T product Tisa-cel Axi-cel 44 (33.1) 89 (66.9) 17 (37.8) 28 (62.2) 42 (33.6) 83 (66.4) 16 (40.0) 24 (60.0) Line of CAR-T infusion 2L 3L+ 17 (12.8) 116 (87.2) 10 (22.2) 35 (77.8) 16 (12.8) 109 (87.2) 9 (22.5) 31 (77.5) Abbreviations: ASCT : autologous stem cell transplantation; CAR-T, chimeric antigen receptor-T; CR, complete response; ECOG, Eastern Cooperative Oncology Group; FAS, full analysis set; IPI, international prognostic index; IPTW: Stabilized inverse probability of treatment weighting ; LDH : lactacte dehydrogenase; PD, progressive disease; PR, partial response; PS, propensity score; SD, standard deviation; tisa-cel, tisagenlecleucel; ULN, upper limit of normal. Covariate balance after weighting PS weighting aimed to balance covariates between the control arm and the glofitamab arm to account for measured confounding variables (Table S1) that have been shown to impact PFS and OS after CAR T-cell failure [2, 5, 19, 20]. Primary analysis (MI-sIPTW) In the primary MI-sIPTW analysis including all patients, except 11 patients with extreme propensity, adequate covariate balance was achieved after stringent adjustment on 9 parameters (Table S1). All absolute standardized mean differences (SMDs) were < 0.2 across the 15 imputed datasets (Figure S2). Sensitivity analyses In the MI-SMRW analysis, all SMDs were 0.2. In the complete-case set (5 patients excluded for extreme PS, n=160), both sIPTW and SMRW reduced imbalances, with SMDs < 0.1 for all covariates except Ann Arbor stage, which could not be included due to very few stage I–II cases, and number of previous treatment lines for SMRW (SMD 0.15). After adjustment, patients in the glofitamab arm had more advanced disease (95.7% vs 78.6% Ann Arbor stage III–IV). For sIPTW, the effective sample size was 142. In MI-based analyses restricted to DESCAR-T patients, the number of previous treatment lines could not be included in the propensity score, but all SMDs were < 0.2. In MI-based analyses restricted to Ann Arbor stage III–IV patients, all covariates could be included and all SMDs were < 0.2. Primary analysis Primary weighted analysis (MI-sIPTW) In the primary MI-sIPTW analysis (all data sources), weighted median OS was 19.6 months (95% CI, 10.2–not reached) in the glofitamab arm versus 7.6 months (95% CI, 5.5–9.8) in the control arm (Figure 3). The pooled HR for death across imputed datasets was 0.49 (95% CI, 0.31–0.79; P =0.0072). The E-value was 2.65 (1.31 for the lower CI bound), indicating that one or several unmeasured confounders would need to be strongly associated with both treatment and survival to fully explain the observed effect. Secondary and sensitivity analysis Restricted Mean Survival Time The mean survival time restricted at 24 months of follow-up was 15.6 months (95% CI, 12.3 - 18.9) in the glofitamab arm versus 10.6 months (95% CI, 9.0 - 12.2) in the control arm, corresponding to an average RMST difference of 5.0 months (95% CI, 1.4–8.6; P =0.007) favouring glofitamab. Sensitivity analyses In the unweighted cFAS, median OS from the start of post-CAR T therapy was 6.5 months (IQR, 3.2–18.9; 95% CI, 4.8–8.1) in the control arm versus 17.3 months (IQR, 5.7–28.4; 95% CI, 8.8–not estimable) in the glofitamab arm. Sensitivity analyses across various statistical models yielded consistent results (Table 3). Under the MI-SMRW model (all data), glofitamab was associated with a significant survival benefit (HR 0.46; 95% CI: 0.33–0.66; P =0.0087; E-value: 2.78). Similar findings were observed using complete-case sIPTW and SMRW (HR 0.51,95%CI: [0.31 – 0.82], P =0.0089 and HR 0.46, 95% CI: [0.33-0.65], p=0.0062 respectively). When restricting the control group to DESCAR-T registry patients only (n=162), the benefit remained robust (MI-sIPTW: HR 0.44, 95% CI: 0.26–0.74, P=0.0057; MI-SMRW: HR 0.41, 95% CI: 0.29–0.59, P =0.0067). Finally, an analysis restricted to stage III–IV disease (n=142) confirmed these results (MI-sIPTWHR 0.52; 95% CI: 0.33–0.81; P =0.0069). Across all analytic approaches, HR estimates consistently clustered between 0.40 and 0.55, uniformly favoring the glofitamab arm. Table 3. Sensitivity analysis of overall survival evaluated in the indirect comparison study Multiple Imputations DESCAR-T population Ann-Arbor Stage III-IV Complete cases Raw data SMRW sIPTW SMRW SIPTW SIPTW SMRW Control group (n=133) Glofitamab group (N=45) Control group (n=120) Glofitamab group (N=40) Control group (n=120) Glofitamab group (N=40) Number of death, N (%) 91 (75.8) 22 (55) 91 (75.8) 22 (55) 99 (74.4) 25 (55.6) mOS, months [IC 95% ] 6.6 [5.2;9.7] 17.3 [6.1;28.4] 6.5 [4.8;8.1] 17.3 [-;-] 6.5 [4.8;8.1] 17.3 [8.8;NA] HR [IC 95% ] 0.46 [0.326;0.659] 0.44 [0.264;0.741] 0.41 [0.286;0.591] 0.52 [0.33;0.809] 0.51 [0.331;0.819] 0.46 [0.334;0.645] 0.54 [0.348;0.840] P value (Log-Rank) 0.0087 0.0057 0.0067 0.0069 0.0089 0.0062 0.0028 E-value 2.784 2.903 3.087 2.529 2.576 2.779 2.517 Overall survival rates 9-months 41.1 [33.8;50.2] 65.0 [43.8;78.8] 39.1 [30.2;47.9] 66.0 [42.0;82.0] 39.7 [31.3;48.0] 63.7 [47.7;76.0] 12-months 33.8 [25.0;42.8] 59.9 [38.8;75.7] 31.0 [22.8;39.6] 60.0 [36.2;77.4] 31.5 [23.6;39.7] 59.0 [43.0;71.9] 18-months 27.3 [19.0;36.3] 48.7 [27.6;67.0] 25.2 [17.6;33.6] 49.3 [25.5;69.4] 26.3 [18.9;34.3] 47.9 [32.0;62.2] 24-months 19.7 [12.1;28.7] 46.5 [25.3;65.2] 18.6 [11.5;27.0] 47.5 [23.7;68.1] 20.2 [13.2;28.3] 40.4 [24.5;55.9] Abbreviations: OS: overall survival, SMRW: Standardized Mortality Ratio Weighting, sIPTW: Stabilized Inverse Probability of Treatment Weighting Discussion In this comparative effectiveness study combining the BiCAR phase 2 trial with a pre-specified external control arm, short ramp-up glofitamab after anti-CD19 CAR T-cell failure was associated with a 51% reduction in the risk of death compared with contemporaneous non-bispecific salvage therapies. Weighted median OS increased from 7.6 months in the control arm to 19.6 months with glofitamab; a secondary RMST analysis confirmed a 5-month survival gain over 2 years. These findings were consistent across alternative weighting schemes, data-source restrictions, and stage-restricted analyses, with hazard ratio estimates ranging from 0.40 to 0.55. The primary BiCAR publication established the feasibility and activity of accelerated glofitamab dosing after CAR T-cell failure [11]. The present work extends these findings with longer follow-up (median 30.4 months), showing that OS benefit is maintained over time (median 17.3 months, 2-year OS 38.3%). Our control cohort, selected using strict eligibility criteria and contemporaneity constraints, had a median OS of 6.5–7.6 months, consistent with previous DESCAR-T analyses and other post-CAR T series [2–5], supporting the external validity of our findings. This study represents the first prospective phase II trial designed to evaluate a CD20×CD3 bispecific antibody exclusively in patients with DLBCL failing anti-CD19 CAR T-cell therapy. With a complete response rate of 45.7% and a median overall survival of 19.6 months in the weighted analysis, these results can be compared with outcomes reported for other bispecific platforms in this population. Four other CD20×CD3 bispecific antibodies have demonstrated activity in post-CAR T relapsed/refractory DLBCL. In the pivotal glofitamab study (NP30179) using standard ramp-up, 52 patients with prior CAR T-cell therapy achieved a 37% complete response rate with a median duration of complete response of 22.0 months at 32 months median follow-up [7]. For epcoritamab (EPCORE NHL-1), 61 post-CAR T patients (38.9% of the total cohort) achieved a 36% complete response rate at 25 months median follow-up [8]. Odronextamab demonstrated a 31.7% complete response rate in a dedicated post-CAR T expansion cohort of 60 patients, with a median OS of 10.2 months at 16.2 months follow-up [9]. Mosunetuzumab showed a 24% complete response rate in 30 post-CAR T patients [10]. Although response rates are lower than BiCAR trial (45.7%), they appear comparable across these bispecific platforms (24% to 37%). However, several methodological and design differences distinguish BiCAR from existing studies. First, BiCAR is the only prospective phase II study enrolling exclusively patients in immediate relapse or progression after CAR T-cell therapy. In contrast, glofitamab, epcoritamab, and mosunetuzumab included post-CAR T patients as subgroups within larger heterogeneous cohorts of relapsed/refractory DLBCL, while odronextamab, though conducted in a dedicated post-CAR T cohort, was an expansion arm of a phase I dose-finding study. The design of our study ensures population homogeneity and reduces selection biases that can occur when post-CAR T patients represent a subset of a broader trial. Second, BiCAR employed standardized dosing, a unified treatment schedule, and prespecified endpoints, in contrast to the dose-escalation designs and heterogeneous dosing cohorts in phase I/II studies. This consistency improves the reliability and reproducibility of efficacy estimates. Third, OS was the primary endpoint of our comparative effectiveness analysis. While complete response rates are informative, they do not fully capture clinical benefit in heavily pretreated populations where durability of response and survival prolongation are relevant outcomes. The observed doubling of median overall survival (19.6 vs 7.6 months, HR 0.49) against contemporaneous external controls provides comparative evidence that is not available for other bispecific antibodies in the post-CAR T setting, as mosunetuzumab, epcoritamab, and odronextamab have not reported survival comparisons with contemporary controls in their post-CAR T cohorts. The external control arm was constructed from individual patient data in the French national DESCAR-T registry and the ALYCANTE trial, using propensity score weighting and sensitivity analyses. Given the difficulty of conducting randomized controlled trials comparing bispecific antibodies to salvage therapies in post-CAR T patients, this methodology provides an alternative approach to generate comparative evidence. The consistency of hazard ratio estimates across weighting schemes (sIPTW, SMRW), data source restrictions (DESCAR-T only analysis), stage-restricted analyses, and methods for handling missing data (complete-case and multiple imputation) supports the robustness of the findings. E-values exceeded 2.5, indicating that an unmeasured confounder would need to have an association of at least this magnitude with both treatment assignment and overall survival to fully explain the observed hazard ratio. This study has limitations. The non-randomized design and sample size in the glofitamab arm (n=45) preclude definitive causal inference, and residual confounding cannot be excluded despite propensity score adjustment. However, E-value (2.5) supports that it is unlikely that these potential confounders would substantially change the study conclusions. The heterogeneity of control treatments—spanning immunochemotherapy, lenalidomide-based regimens, targeted agents, and radiotherapy—reflects real-world practice but precludes conclusions regarding the comparative efficacy of glofitamab versus any single alternative strategy. Generalizability is limited to patients meeting BiCAR eligibility criteria, including ECOG performance status 0–1, adequate organ function, and CAR T-cell failure occurring at least one month after infusion. The fixed 11-cycle treatment protocol with short ramp-up schedule (8 days to full dose vs 15 days in standard glofitamab dosing), and in contrast to treatment until progression for epcoritamab [8] and odronextamab [9]) may offer practical advantages for patients requiring rapid disease control. The safety profile showed no grade ≥3 cytokine release syndrome or neurotoxicity. Conclusion Short-ramp-up glofitamab after anti-CD19 CAR T-cell failure produces durable survival in a subset of patients with DLBCL and, in a pre-specified comparative effectiveness analysis using an academic external control arm, is associated with substantially longer OS than contemporaneous non-bispecific therapies. These findings support glofitamab as a preferred post-CAR T option for eligible patients and highlight the value of registry-based external controls to inform treatment decisions when randomised trials are not feasible. Abbreviations ATE: average treatment effect ATC: average treatment effect in the control population CAR: chimeric antigen receptor CI: confidence interval CR: complete response CRS: cytokine release syndrome DLBCL: diffuse large B-cell lymphoma DoR: duration of response ECOG: Eastern Cooperative Oncology Group FAS: full analysis set HR: hazard ratio LDH: lactate dehydrogenase MI: multiple imputation OS: overall survival PD: progressive disease PFS: progression-free survival PR: partial response PS: propensity score RMST: restricted mean survival time SD: stable disease sIPTW: stabilized inverse probability of treatment weighting SMRW: standardized mortality ratio weighting ULN: upper limit of normal Declarations Ethics approval and consent to participate. BiCAR was approved by the Comité de Protection des Personnes Ile-de-France X and conducted in accordance with the Declaration of Helsinki and Good Clinical Practice; all participants provided written informed consent. DESCAR-T and ALYCANTE were approved by the appropriate institutional ethics committees. Use of de-identified registry and trial data for the external control analysis complied with applicable data-protection regulations. Consent for publication Not applicable (no identifiable individual patient data are presented). Availability of data and materials The datasets generated and/or analysed during the current study are not publicly available due to privacy and regulatory restrictions but are available from the corresponding author on reasonable request and with permission from LYSARC and the DESCAR-T/ALYCANTE data-holding institutions. Competing interests P.S. has received honoraria, and advisory/consultancy fees from Janssen, Roche, Bristol-Myers Squibb, AbbVie, AstraZeneca, Chugai, Novartis, and Kite/Gilead. R.H. has received honoraria from Kite/Gilead, Novartis, Incyte, Janssen, MSD, Takeda, and Roche; and is a member on an entity’s Board of Directors or advisory committees of Kite/Gilead, Novartis, Bristol-Myers Squibb/Celgene, ADC Therapeutics, Incyte and Miltenyi. L.Y. has received honoraria, and advisory/consultancy fees from AbbVie, AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Gilead/Kite, Janssen, and Roche. S.C. has received honoraria, and advisory/consultancy fees from AbbVie, AstraZeneca, Atara, BeiGene, Gilead/Kite, Janssen, Novartis, Pierre Fabre, and Takeda. F.J. has received honoraria, and advisory/consultancy fees from Roche, Bristol-Myers Squibb, Novartis, Kite/Gilead, Takeda, AbbVie, and Janssen. F-X.G. has received honoraria, and advisory/consultancy fees from Bristol-Myers Squibb, Novartis, Kite/Gilead, AstraZeneca, Janssen, and Miltenyi. F.M. has received consultancy fees from AbbVie, Bristol-Myers Squibb, Gilead, Novartis, and Roche, serves as an advisor for AbbVie, Gilead and Roche and received honoraria from Chugai and Kaleda for scientific lectures. C.Ro. has received honoraria, and advisory/consultancy fees from Roche, Takeda, Gilead/Kite, Bristol-Myers Squib, MSD, AbbVie, BeiGene, Janssen, Lilly. T.G. has received travel and accommodation expenses from Roche. C.T. has received honoraria, and advisory/consultancy fees from Roche, Bristol-Myers Squibb, Novartis, Kite/Gilead, Takeda, AbbVie, Janssen. L.D.L.R. has received honoraria, and advisory/consultancy fees from Gilead/Kite, Novartis, Bristol-Myers Squibb, Janssen, Takeda. P.F. has received honoraria, and advisory/consultancy fees from, BeiGene, Kite/Gilead, AstraZeneca, AbbVie, Janssen. S.G. is an employee of LYSARC. G.C. has received honoraria, and advisory/consultancy fees from Roche, Bristol-Myers Squibb, BeiGene, Novartis, Kite/Gilead, Takeda, AstraZeneca, AbbVie, Janssen, Onward Therapeutics, Incyte and Mabqi. Y.A.T., M.J., C.L., F.L.B., A.M., J-O.B., C.R., L.R., and K.T. declare that they have no conflict of interest. Funding BiCAR and ALYCANTE were sponsored by LYSARC and supported in part by an unrestricted grant from F. Hoffmann–La Roche (BiCAR) and Kite, a Gilead company (ALYCANTE) for drug supply and study conduct. The DESCAR-T registry received support from [GILEAD, Novartis, Bristol-Meyers Squibb]. The funders had no role in the design, analysis or interpretation of the external control comparison, or in the decision to submit this manuscript. Authors’ contributions G.C., P.S., Y.A.L., K.T. and C.L. contributed to the conception, design, and planning of the study. G.C., R.H., Y.A.L., F.L.B., L.Y., S.C., F.J., J-O.B, F-X.G., F.M., C.Ro., T.G., C.T., M.J., L.R., C.R., L.D.L.R., P.F., A.M., S.G., K.T., C.L., and P.S. contributed to the acquisition and analysis of data. G.C., R.H., Y.A.L., F.L.B., L.Y., S.C., F.J., J-O.B, F-X.G., F.M., C.R., T.G., C.T., M.J., L.R., C.Ro., L.D.L.R., P.F., A.M., S.G., K.T., C.L., and P.S. contributed to the critical review and revision of the manuscript. All authors approved the final version of the manuscript and are accountable for all aspects of the work. Acknowledgements We thank the patients, their families and the study personnel involved in this trial. We also thank the BiCAR trial investigators, S. Doyen (Clinical Projects Manager, LYSARC, France) and the LYSARC study team, including Biostatistics teams, LYSA-IM and LYSA-P, for their precious contribution for providing medical writing support in accordance with the current Good Publication Practice guidelines. References Ghobadi A, Munoz J, Westin JR, Locke FL, Miklos DB, Rapoport AP, et al. Outcomes of subsequent antilymphoma therapies after second-line axicabtagene ciloleucel or standard of care in ZUMA-7. Blood Adv. 2024;8(11):2982–2990. https://doi.org/10.1182/bloodadvances.2024012345 Sesques P, Manson G, Cartron G, Gros FX, Morschhauser F, Castilla-Llorente C, et al. Outcome of patients with large B-cell lymphoma relapsing after second-line CAR-T: insights from the DESCAR-T registry. Blood. 2025;146(Suppl 1):956. https://doi.org/10.1182/blood-2025. Di Blasi R, Le Gouill S, Bachy E, Cartron G, Beauvais D, Le Bras F, et al. Outcomes of patients with aggressive B-cell lymphoma after failure of anti-CD19 CAR T-cell therapy: a DESCAR-T analysis. Blood. 2022;140(24):2584–2593. https://doi.org/10.1182/blood.2022016418 Spiegel JY, Dahiya S, Jain MD, Tamaresis J, Nastoupil LJ, Jacobs MT, et al. Outcomes of patients with large B-cell lymphoma progressing after axicabtagene ciloleucel therapy. Blood. 2021;137(13):1832–1835. https://doi.org/10.1182/blood.2020009849 Iacoboni G, Iraola-Truchuelo J, O’Reilly M, Navarro V, Menne T, Kwon M, et al. Treatment outcomes in patients with large B-cell lymphoma after progression to chimeric antigen receptor T-cell therapy. HemaSphere. 2024;8(5):e62. https://doi.org/10.1097/HS9.0000000000000062 Bourlon C, Roddie C, Menne T, Norman J, O’Reilly M, Gibb A, et al. Outcomes after chimeric antigen receptor T-cell therapy across large B-cell lymphoma subtypes. Haematologica. 2024;109(8):2716–2720. https://doi.org/10.3324/haematol.2023.283456 Hutchings M, Morschhauser F, Iacoboni G, Carlo-Stella C, Offner F, Sureda A, et al. Glofitamab monotherapy in relapsed or refractory large B-cell lymphoma: extended follow-up from a pivotal phase II study and subgroup analyses in patients with prior chimeric antigen receptor T-cell therapy and by baseline total metabolic tumor volume. Blood. 2023;142(Suppl 1):433. https://doi.org/10.1182/blood-2023. Thieblemont C, Karimi YH, Ghesquieres H, Cheah CY, Clausen MR, Cunningham D, et al. Epcoritamab in relapsed/refractory large B-cell lymphoma: 2-year follow-up from the pivotal EPCORE NHL-1 trial. Leukemia. 2024;38(12):2653–2662. https://doi.org/10.1038/s41375-024-02345-7 Topp MS, Matasar M, Allan JN, Ansell SM, Barnes JA, Arnason JE, et al. Odronextamab monotherapy in relapsed/refractory DLBCL after progression with CAR T-cell therapy: primary analysis of the ELM-1 study. Blood. 2025;145(14):1498–1509. https://doi.org/10.1182/blood.2024019876 Chong EA, Penuel E, Napier EB, Lundberg RK, Budde LE, Shadman M, et al. Impact of prior CAR T-cell therapy on mosunetuzumab efficacy in patients with relapsed or refractory B-cell lymphomas. Blood Adv. 2025;9(4):696–703. https://doi.org/10.1182/bloodadvances.2024017654 Cartron G, Houot R, Al Tabaa Y, Le Bras F, Ysebaert L, Choquet S, et al. Glofitamab in refractory or relapsed diffuse large B-cell lymphoma after failing CAR T-cell therapy: a phase 2 LYSA study. Nat Cancer. 2025;6(7):1173–1183. https://doi.org/10.1038/s43018-025-00876-2 Dodero A, Ceparano G, Casadei B, Angelillo P, Bramanti S, Tisi MC, et al. Outcomes of CAR T-cell therapy in high-grade B-cell lymphomas compared to DLBCL: a weighted comparison analysis. Blood Adv. 2025;9(24):6491–6501. https://doi.org/10.1182/bloodadvances.2024019234 The Lymphoma Academic Research Organisation. French register of patients with hemopathy eligible for CAR-T cell treatment (DESCAR-T). ClinicalTrials.gov identifier: NCT04328298. https://clinicaltrials.gov/study/NCT04328298 Houot R, Bachy E, Cartron G, Gros FX, Morschhauser F, Oberic L, et al. Axicabtagene ciloleucel as second-line therapy in large B-cell lymphoma ineligible for autologous stem cell transplantation: a phase 2 trial. Nat Med. 2023;29(10):2593–2601. https://doi.org/10.1038/s41591-023-02554-8 Xu S, Ross C, Raebel MA, Shetterly S, Blanchette C, Smith D. Use of stabilized inverse propensity scores as weights to directly estimate relative risk and its confidence intervals. Value Health. 2010;13(2):273–277. https://doi.org/10.1111/j.1524-4733.2009.00671.x Greifer N, Stuart EA. Choosing the causal estimand for propensity score analysis of observational studies. arXiv. 2023;2106.10577. https://doi.org/10.48550/arXiv.2106.10577 VanderWeele TJ, Ding P. Sensitivity analysis in observational research: introducing the E-value. Ann Intern Med. 2017;167(4):268–274. https://doi.org/10.7326/M16-2607 Royston P, Parmar MK. Restricted mean survival time: an alternative to the hazard ratio for the design and analysis of randomized trials with a time-to-event outcome. BMC Med Res Methodol. 2013;13:152. https://doi.org/10.1186/1471-2288-13-152 Bachy E, Le Gouill S, Di Blasi R, Sesques P, Manson G, Cartron G, et al. A real-world comparison of tisagenlecleucel and axicabtagene ciloleucel CAR T cells in relapsed or refractory diffuse large B-cell lymphoma. Nat Med. 2022;28(10):2145–2154. https://doi.org/10.1038/s41591-022-01937-7 Stephan P, Di Blasi R, Roulin L, Galtier J, Calvani J, Meignin V, et al. TRANSCAR: real-world outcomes of CD19 CAR T-cell therapy in relapsed/refractory transformed indolent lymphomas. Blood Adv. 2025;9(18):4693–4704. https://doi.org/10.1182/bloodadvances.2024018123 Erbella F, Bachy E, Cartron G, Gat E, Manson G, Morschhauser F, et al. Late failure of aggressive B-cell lymphoma following CAR T-cell therapy: a LYSA study from the DESCAR-T registry. Blood Adv. 2026;10(2):392–401. https://doi.org/10.1182/bloodadvances.2025011123 Shumilov E, Wurm-Kuczera R, Vucinic V, Seib M, Holtick U, Mazzeo P, et al. Time of CAR-T failure is a strong predictor of outcome for bispecific antibody therapy in relapsed/refractory large B-cell lymphoma. Blood. 2024;144(Suppl 1):114. https://doi.org/10.1182/blood-2024. Additional Declarations Competing interest reported. P.S. has received honoraria, and advisory/consultancy fees from Janssen, Roche, Bristol-Myers Squibb, AbbVie, AstraZeneca, Chugai, Novartis, and Kite/Gilead. R.H. has received honoraria from Kite/Gilead, Novartis, Incyte, Janssen, MSD, Takeda, and Roche; and is a member on an entity’s Board of Directors or advisory committees of Kite/Gilead, Novartis, Bristol-Myers Squibb/Celgene, ADC Therapeutics, Incyte and Miltenyi. L.Y. has received honoraria, and advisory/consultancy fees from AbbVie, AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Gilead/Kite, Janssen, and Roche. S.C. has received honoraria, and advisory/consultancy fees from AbbVie, AstraZeneca, Atara, BeiGene, Gilead/Kite, Janssen, Novartis, Pierre Fabre, and Takeda. F.J. has received honoraria, and advisory/consultancy fees from Roche, Bristol-Myers Squibb, Novartis, Kite/Gilead, Takeda, AbbVie, and Janssen. F-X.G. has received honoraria, and advisory/consultancy fees from Bristol-Myers Squibb, Novartis, Kite/Gilead, AstraZeneca, Janssen, and Miltenyi. F.M. has received consultancy fees from AbbVie, Bristol-Myers Squibb, Gilead, Novartis, and Roche, serves as an advisor for AbbVie, Gilead and Roche and received honoraria from Chugai and Kaleda for scientific lectures. C.Ro. has received honoraria, and advisory/consultancy fees from Roche, Takeda, Gilead/Kite, Bristol-Myers Squib, MSD, AbbVie, BeiGene, Janssen, Lilly. T.G. has received travel and accommodation expenses from Roche. C.T. has received honoraria, and advisory/consultancy fees from Roche, Bristol-Myers Squibb, Novartis, Kite/Gilead, Takeda, AbbVie, Janssen. L.D.L.R. has received honoraria, and advisory/consultancy fees from Gilead/Kite, Novartis, Bristol-Myers Squibb, Janssen, Takeda. P.F. has received honoraria, and advisory/consultancy fees from, BeiGene, Kite/Gilead, AstraZeneca, AbbVie, Janssen. S.G. is an employee of LYSARC. G.C. has received honoraria, and advisory/consultancy fees from Roche, Bristol-Myers Squibb, BeiGene, Novartis, Kite/Gilead, Takeda, AstraZeneca, AbbVie, Janssen, Onward Therapeutics, Incyte and Mabqi. Y.A.T., M.J., C.L., F.L.B., A.M., J-O.B., C.R., L.R., and K.T. declare that they have no conflict of interest. Supplementary Files FigureS1..png Figure S1: Flow chart of the populations FigureS2..png Figure S2. Propensity score distribution before and after sIPTW (A) and SMRW (B) weighting and standardized mean difference for each imputed dataset after sIPTW (C) and SMRW (D) weighting TableS1.docx Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Revision requested 29 Apr, 2026 Reviews received at journal 29 Apr, 2026 Reviews received at journal 28 Apr, 2026 Reviews received at journal 23 Apr, 2026 Reviews received at journal 22 Apr, 2026 Reviews received at journal 15 Apr, 2026 Reviewers agreed at journal 07 Apr, 2026 Reviewers agreed at journal 07 Apr, 2026 Reviewers agreed at journal 06 Apr, 2026 Reviewers agreed at journal 04 Apr, 2026 Reviewers agreed at journal 03 Apr, 2026 Reviewers agreed at journal 03 Apr, 2026 Reviewers invited by journal 03 Apr, 2026 Editor assigned by journal 01 Apr, 2026 Submission checks completed at journal 01 Apr, 2026 First submitted to journal 01 Apr, 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-9288467","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":619261872,"identity":"30ff94fa-ddd8-41f8-9352-50bcc1357f5c","order_by":0,"name":"Guillaume Cartron","email":"data:image/png;base64,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","orcid":"","institution":"University Hospital of Montpellier","correspondingAuthor":true,"prefix":"","firstName":"Guillaume","middleName":"","lastName":"Cartron","suffix":""},{"id":619261873,"identity":"11e78a51-8dba-4193-80a8-c931ae6206b1","order_by":1,"name":"Isabelle Chaillol","email":"","orcid":"","institution":"LYSARC, Lyon-Sud Hospital","correspondingAuthor":false,"prefix":"","firstName":"Isabelle","middleName":"","lastName":"Chaillol","suffix":""},{"id":619261874,"identity":"7884f43a-d065-4d49-90a1-c5fbb436a11e","order_by":2,"name":"Roch Houot","email":"","orcid":"","institution":"University Hospital of Rennes","correspondingAuthor":false,"prefix":"","firstName":"Roch","middleName":"","lastName":"Houot","suffix":""},{"id":619261875,"identity":"f22bd0d4-fb9a-48f0-a6cc-2e6eb18b3997","order_by":3,"name":"Yassine Al Tabaa","email":"","orcid":"","institution":"Clinique Clémentville","correspondingAuthor":false,"prefix":"","firstName":"Yassine","middleName":"Al","lastName":"Tabaa","suffix":""},{"id":619261876,"identity":"b6b4424e-8f45-45f4-b864-bacf2ee1624b","order_by":4,"name":"Fabien Le Bras","email":"","orcid":"","institution":"Henri Mondor Hospital, Assistance Publique-Hôpitaux de Paris","correspondingAuthor":false,"prefix":"","firstName":"Fabien","middleName":"Le","lastName":"Bras","suffix":""},{"id":619261877,"identity":"71c0efa5-bda5-4f3f-a308-005ce8a06c63","order_by":5,"name":"Loïc Ysebaert","email":"","orcid":"","institution":"University Hospital of Toulouse, IUCT-Oncopole","correspondingAuthor":false,"prefix":"","firstName":"Loïc","middleName":"","lastName":"Ysebaert","suffix":""},{"id":619261879,"identity":"69dfa007-08d8-4f7c-a9ff-30483293a9f6","order_by":6,"name":"Sylvain Choquet","email":"","orcid":"","institution":"La Pitié Salpetrière Hospital, Assistance Publique-Hôpitaux de Paris","correspondingAuthor":false,"prefix":"","firstName":"Sylvain","middleName":"","lastName":"Choquet","suffix":""},{"id":619261882,"identity":"248c022f-446c-4196-ba21-592bcc983c62","order_by":7,"name":"Fabrice Jardin","email":"","orcid":"","institution":"U1245, Henri Becquerel Institute","correspondingAuthor":false,"prefix":"","firstName":"Fabrice","middleName":"","lastName":"Jardin","suffix":""},{"id":619261884,"identity":"d0285274-0d77-4709-ac09-5463c4fad4c5","order_by":8,"name":"Jacques-Olivier Bay","email":"","orcid":"","institution":"University Hospital Clermont- Ferrand","correspondingAuthor":false,"prefix":"","firstName":"Jacques-Olivier","middleName":"","lastName":"Bay","suffix":""},{"id":619261887,"identity":"4e17edff-c10e-409c-9a3d-b645466648ee","order_by":9,"name":"François-Xavier Gros","email":"","orcid":"","institution":"University Hospital of Bordeaux","correspondingAuthor":false,"prefix":"","firstName":"François-Xavier","middleName":"","lastName":"Gros","suffix":""},{"id":619261888,"identity":"0a570a66-4961-4aa4-8513-e26cfb5a48be","order_by":10,"name":"Franck Morschhauser","email":"","orcid":"","institution":"University Hospital of Lille","correspondingAuthor":false,"prefix":"","firstName":"Franck","middleName":"","lastName":"Morschhauser","suffix":""},{"id":619261889,"identity":"bd79bbcd-111f-4b15-8f5d-3d348a02853c","order_by":11,"name":"Cédric Rossi","email":"","orcid":"","institution":"University Hospital Dijon Bourgogne","correspondingAuthor":false,"prefix":"","firstName":"Cédric","middleName":"","lastName":"Rossi","suffix":""},{"id":619261890,"identity":"54f4fcee-a22c-4c52-9aab-5af82b323afd","order_by":12,"name":"Thomas Gastinne","email":"","orcid":"","institution":"University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Thomas","middleName":"","lastName":"Gastinne","suffix":""},{"id":619261891,"identity":"c4cbb1a0-ce70-4005-b6dc-eba311240027","order_by":13,"name":"Catherine Thieblemont","email":"","orcid":"","institution":"Saint Louis Hospital, Assistance Publique-Hôpitaux de Paris","correspondingAuthor":false,"prefix":"","firstName":"Catherine","middleName":"","lastName":"Thieblemont","suffix":""},{"id":619261892,"identity":"ca3b89eb-aa55-4bb9-afec-1035ea1a2133","order_by":14,"name":"Magalie Joris","email":"","orcid":"","institution":"University Hospital of Amiens","correspondingAuthor":false,"prefix":"","firstName":"Magalie","middleName":"","lastName":"Joris","suffix":""},{"id":619261893,"identity":"53655ac2-1e4b-4f37-9b1b-1c98a5b548b9","order_by":15,"name":"Laure Ricard","email":"","orcid":"","institution":"Saint Antoine Hospital, Assistance Publique-Hôpitaux de Paris","correspondingAuthor":false,"prefix":"","firstName":"Laure","middleName":"","lastName":"Ricard","suffix":""},{"id":619261894,"identity":"d8d70a43-4a15-45aa-aaa9-0cd0b0353744","order_by":16,"name":"Caroline Regny","email":"","orcid":"","institution":"University Hospital of Grenoble","correspondingAuthor":false,"prefix":"","firstName":"Caroline","middleName":"","lastName":"Regny","suffix":""},{"id":619261895,"identity":"d54cb131-972f-4433-8a15-1a215d1f36f3","order_by":17,"name":"Laurianne Drieu La Rochelle","email":"","orcid":"","institution":"University Hospital of Tours","correspondingAuthor":false,"prefix":"","firstName":"Laurianne","middleName":"Drieu La","lastName":"Rochelle","suffix":""},{"id":619261896,"identity":"9ca32a75-4824-4503-b74f-081dd9e20371","order_by":18,"name":"Pierre Feugier","email":"","orcid":"","institution":"University Hospital of Nancy","correspondingAuthor":false,"prefix":"","firstName":"Pierre","middleName":"","lastName":"Feugier","suffix":""},{"id":619261897,"identity":"3182a086-44de-4416-8965-bdae6cf18b7d","order_by":19,"name":"Ambroise Marcais","email":"","orcid":"","institution":"Necker Hospital, Assistance Publique-Hôpitaux de Paris","correspondingAuthor":false,"prefix":"","firstName":"Ambroise","middleName":"","lastName":"Marcais","suffix":""},{"id":619261898,"identity":"c5c22980-b330-4b39-ae62-c0cd13cad289","order_by":20,"name":"Romain Ould-Ammar","email":"","orcid":"","institution":"LYSARC, Lyon-Sud Hospital","correspondingAuthor":false,"prefix":"","firstName":"Romain","middleName":"","lastName":"Ould-Ammar","suffix":""},{"id":619261899,"identity":"2debe976-598b-488f-8458-0d146969a286","order_by":21,"name":"Karin Tarte","email":"","orcid":"","institution":"UMR1236, University Hospital, INSERM, EFS","correspondingAuthor":false,"prefix":"","firstName":"Karin","middleName":"","lastName":"Tarte","suffix":""},{"id":619261900,"identity":"77be6186-83e3-4b91-93b1-019599a8c4f2","order_by":22,"name":"Camille Laurent","email":"","orcid":"","institution":"Inserm","correspondingAuthor":false,"prefix":"","firstName":"Camille","middleName":"","lastName":"Laurent","suffix":""},{"id":619261901,"identity":"a2bed4c7-fb82-4ca8-a14e-affd92b3f0fa","order_by":23,"name":"Pierre Sesques","email":"","orcid":"","institution":"University Hospital of Lyon","correspondingAuthor":false,"prefix":"","firstName":"Pierre","middleName":"","lastName":"Sesques","suffix":""}],"badges":[],"createdAt":"2026-04-01 07:55:33","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9288467/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9288467/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":106582749,"identity":"e6000d7d-73cf-44d7-9522-d8f3c25dc9ec","added_by":"auto","created_at":"2026-04-10 06:57:31","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":113894,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curve for overall survival (A), progression-free survival (B), duration of response (C) and duration of complete response (D).\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9288467/v1/13f1cb0ebdd7a3751d382690.png"},{"id":106582752,"identity":"fa62b733-6954-4181-a5b2-96c59584acb1","added_by":"auto","created_at":"2026-04-10 06:57:32","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":73813,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier curves of overall survival according to patient status (late relapse vs refractory/early relapse) (A) and CR status after two cycles of glofitamab (B).\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-9288467/v1/9caed4c06a40f2f968887c90.png"},{"id":106582814,"identity":"d8480aa4-d24b-432b-894e-51cce96011cb","added_by":"auto","created_at":"2026-04-10 06:57:37","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":145070,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival according to post CAR-T regimens after multiple imputation-stabilized inverse probability of treatment weighting (MI-sIPTW)\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-9288467/v1/633077a94fcea186480725bf.png"},{"id":106582821,"identity":"96bbdc76-6b46-4c9d-9b35-6fc719035deb","added_by":"auto","created_at":"2026-04-10 06:57:44","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1307686,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9288467/v1/997f2869-dfb3-40e9-a6ed-c80787cb00a7.pdf"},{"id":106582751,"identity":"1313f88f-7e63-4124-8710-7a74235a1153","added_by":"auto","created_at":"2026-04-10 06:57:32","extension":"png","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":174961,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFigure S1\u003c/strong\u003e: Flow chart of the populations\u003c/p\u003e","description":"","filename":"FigureS1..png","url":"https://assets-eu.researchsquare.com/files/rs-9288467/v1/3933708af92f3bb8dabf4ab4.png"},{"id":106582750,"identity":"6af57433-d42d-4e57-80ea-06b1d162f610","added_by":"auto","created_at":"2026-04-10 06:57:31","extension":"png","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":591624,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFigure S2.\u003c/strong\u003e Propensity score distribution before and after sIPTW (A) and SMRW (B) weighting and standardized mean difference for each imputed dataset after sIPTW (C) and SMRW (D) weighting\u003c/p\u003e","description":"","filename":"FigureS2..png","url":"https://assets-eu.researchsquare.com/files/rs-9288467/v1/23bae4d95c8f84f84c873657.png"},{"id":106582813,"identity":"1f243a6d-a754-4d80-880b-a872ead324ca","added_by":"auto","created_at":"2026-04-10 06:57:37","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":3880129,"visible":true,"origin":"","legend":"","description":"","filename":"TableS1.docx","url":"https://assets-eu.researchsquare.com/files/rs-9288467/v1/44c125e2ceafa1725ed319ed.docx"}],"financialInterests":"Competing interest reported. P.S. has received honoraria, and advisory/consultancy fees from Janssen, Roche, Bristol-Myers Squibb, AbbVie, AstraZeneca, Chugai, Novartis, and Kite/Gilead. R.H. has received honoraria from Kite/Gilead, Novartis, Incyte, Janssen, MSD, Takeda, and Roche; and is a member on an entity’s Board of Directors or advisory committees of Kite/Gilead, Novartis, Bristol-Myers Squibb/Celgene, ADC Therapeutics, Incyte and Miltenyi. L.Y. has received honoraria, and advisory/consultancy fees from AbbVie, AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Gilead/Kite, Janssen, and Roche. S.C. has received honoraria, and advisory/consultancy fees from AbbVie, AstraZeneca, Atara, BeiGene, Gilead/Kite, Janssen, Novartis, Pierre Fabre, and Takeda. F.J. has received honoraria, and advisory/consultancy fees from Roche, Bristol-Myers Squibb, Novartis, Kite/Gilead, Takeda, AbbVie, and Janssen. F-X.G. has received honoraria, and advisory/consultancy fees from Bristol-Myers Squibb, Novartis, Kite/Gilead, AstraZeneca, Janssen, and Miltenyi. F.M. has received consultancy fees from AbbVie, Bristol-Myers Squibb, Gilead, Novartis, and Roche, serves as an advisor for AbbVie, Gilead and Roche and received honoraria from Chugai and Kaleda for scientific lectures. C.Ro. has received honoraria, and advisory/consultancy fees from Roche, Takeda, Gilead/Kite, Bristol-Myers Squib, MSD, AbbVie, BeiGene, Janssen, Lilly. T.G. has received travel and accommodation expenses from Roche. C.T. has received honoraria, and advisory/consultancy fees from Roche, Bristol-Myers Squibb, Novartis, Kite/Gilead, Takeda, AbbVie, Janssen. L.D.L.R. has received honoraria, and advisory/consultancy fees from Gilead/Kite, Novartis, Bristol-Myers Squibb, Janssen, Takeda. P.F. has received honoraria, and advisory/consultancy fees from, BeiGene, Kite/Gilead, AstraZeneca, AbbVie, Janssen. S.G. is an employee of LYSARC. G.C. has received honoraria, and advisory/consultancy fees from Roche, Bristol-Myers Squibb, BeiGene, Novartis, Kite/Gilead, Takeda, AstraZeneca, AbbVie, Janssen, Onward Therapeutics, Incyte and Mabqi. Y.A.T., M.J., C.L., F.L.B., A.M., J-O.B., C.R., L.R., and K.T. declare that they have no conflict of interest.","formattedTitle":"Optimized Glofitamab Schedule Halves Mortality Risk After CAR T Failure in Diffuse Large B-Cell Lymphoma: A Phase 2 Trial with External Control Arm Conducted by The LYSA Group","fulltext":[{"header":"Background","content":"\u003cp\u003eAnti-CD19 CAR T-cell therapies have transformed outcomes for patients with relapsed or refractory (R/R) large B-cell lymphomas (LBCL), but 50\u0026ndash;60% ultimately experience primary refractory disease or relapse after infusion. The median overall survival (OS) is then approximately 6 months once CAR T-cell failure occurred, regardless of whether CAR T-cells were infused in second-line [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], or in third-line or more [\u003cspan additionalcitationids=\"CR4 CR5\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In this setting, there is no established standard of care, and clinicians commonly use heterogeneous combinations of chemo-immunotherapy, antibody-based, small-molecule, or investigational regimens, generally with limited efficacy.\u003c/p\u003e \u003cp\u003eCD20\u0026times;CD3 bispecific antibodies (BsAbs), including glofitamab, have demonstrated substantial activity in R/R LBCL, with high response rates and durable remissions, including among patients previously treated with CAR T-cells [\u003cspan additionalcitationids=\"CR8 CR9\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. However, those phase I/II studies enrolled heterogeneous populations including patients both with and without prior CAR T-cell exposure and were not specifically designed for the immediate post-CAR T-cell setting. Furthermore, they lacked direct comparisons between BsAbs and alternative salvage therapies following CAR T-cell failure. Consequently, the use of CD20\u0026times;CD3 BsAbs as the preferred strategy for patients relapsing after CAR T-cell therapy remains largely empirical. The LYSA BiCAR trial is a prospective multicenter phase 2 study specifically dedicated to adults with CD20-positive DLBCL who are refractory to, or in first relapse/progression immediately after anti-CD19 CAR T-cell therapy and evaluates glofitamab using an intensified \u0026ldquo;short ramp-up\u0026rdquo; schedule that reaches the full 30-mg dose within one week. In the primary analysis (median follow-up 15.3 months), short-ramp-up glofitamab yielded a median OS of 14.7 months, a best overall metabolic response (OR) rate of 76.1%, and a best complete metabolic response (CR) rate of 45.7%, with no grade\u0026thinsp;\u0026ge;\u0026thinsp;3 cytokine release syndrome (CRS) or neurotoxicity [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Beyond demonstrating feasibility and clinical activity, a central clinical question remains whether glofitamab improves survival relative to the non- BsAbs regimens actually used in practice after CAR T-cell failure. While indirect comparisons suggest that bispecific antibodies are at least as effective as conventional salvage therapies [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], robust comparative effectiveness data are scarce, and no prospective randomized trial will answer this question in the future.\u003c/p\u003e \u003cp\u003eHere, we report the final survival results of BiCAR, together with a robust pre-specified external comparative effectiveness analysis of glofitamab against contemporaneous non-bispecific salvage strategies. This analysis is based on data from the DESCAR-T national CAR T-cell registry [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] and the ALYCANTE phase 2 trial [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eThis study combines the BiCAR trial (NCT04703686), a prospective, multicenter, single-arm phase 2 study of short-ramp-up glofitamab after CAR T-cell failure conducted by LYSA/LYSARC [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], and an external comparative effectiveness analysis of glofitamab against contemporaneous non-bispecific salvage strategies after CAR-T cell failure. To minimise datasource bias, the two arms, the glofitamab arm (BicAR patients) and the control arm, are built from individual patient data in the DESCAR-T registry and ALYCANTE trial. The comparative endpoint was OS from initiation of post-CAR T therapy. All comparative analyses were planned in the protocol and prespecified in a dedicated statistical analysis plan.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePopulations, endpoints and setting\u003c/h3\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eBiCAR trial\u003c/h2\u003e \u003cp\u003eEligibility criteria\u003c/p\u003e \u003cp\u003eBiCAR enrolled adults (\u0026ge;\u0026thinsp;18 years) with biopsy-proven CD20-positive DLBCL who were refractory to, or in first relapse/progression after, anti-CD19 CAR T-cell therapy given\u0026thinsp;\u0026ge;\u0026thinsp;1 month before enrolment; had ECOG performance status 0\u0026ndash;1; at least one measurable lesion\u0026thinsp;\u0026gt;\u0026thinsp;1.5 cm on PET-CT; adequate hepatic, renal and hematologic function; and life expectancy\u0026thinsp;\u0026ge;\u0026thinsp;3 months. Patients with CD20-negative disease, primary CNS lymphoma or CNS involvement, relapse within 30 days of CAR T infusion, uncontrolled infection or prior allogeneic transplant were excluded [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. All participants provided written informed consent.\u003c/p\u003e \u003cp\u003eTreatment and assessments\u003c/p\u003e \u003cp\u003ePatients received obinutuzumab 1,000 mg intravenously on day\u0026thinsp;\u0026minus;\u0026thinsp;3, followed by glofitamab intravenously with a short ramp-up during cycle 1 (14 days): 2.5 mg on day 1, 10 mg on day 3, and 30 mg on day 8. From cycle 2 onward, glofitamab 30 mg was given every 21 days for up to 11 cycles. Baseline Positron Emission Tomography-Computed Tomography (PET-CT) and subsequent scans after cycles 2, 4, 6, 9, and 11 were centrally reviewed using Lugano 2014 criteria. Adverse events were graded with Common Terminology Criteria for Adverse Events (CTCAE) v5.0; CRS and neurotoxicity with American Society for Transplantation and Cellular Therapy (ASTCT) criteria. The BiCAR full analysis set (BiCAR-FAS) comprised all patients who received at least one glofitamab dose [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBiCAR endpoints and data cutoff\u003c/p\u003e \u003cp\u003eThe BiCAR primary endpoint was the OS measured from the date of the first glofitamab infusion to the date of death from any cause, censoring participants who were still alive at the last contact date. Secondary endpoints included progression-free survival (PFS), OR and CR rates, duration of response (DoR) and duration of complete response (DoCR), and safety [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The present final analysis uses a BiCAR database export dated June 13t\u003csup\u003eh\u003c/sup\u003e, 2025, with a data cutoff on May 21st, 2025.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eComparative effectiveness analysis\u003c/h3\u003e\n\u003cp\u003eExternal data sources\u003c/p\u003e \u003cp\u003eThe DESCAR-T registry (NCT04328298) is a nationwide French observational database designed to capture real-world data on adults eligible for commercial anti-CD19 CAR T-cell therapy. The registry provides comprehensive longitudinal data, including baseline patient characteristics, infusion parameters, post-infusion clinical outcomes, and details on subsequent therapeutic interventions. This analysis utilized a data export dated March 13th, 2025\u003c/p\u003e \u003cp\u003eThe ALYCANTE trial (NCT04531046) is a multicenter phase 2 trial evaluating axicabtagene ciloleucel (axi-cel) as second-line therapy in transplant-ineligible patients with large B-cell lymphoma. The dataset used here was exported on October 30th, 2024.\u003c/p\u003e \u003cp\u003eBiCAR clinical data were used to identify BiCAR participants within DESCAR-T and ALYCANTE \u003cem\u003evia\u003c/em\u003e matching of birth month/year, initials, and CAR T infusion dates.\u003c/p\u003e \u003cp\u003eComparative effectiveness populations\u003c/p\u003e \u003cp\u003eGlofitamab arm: The glofitamab arm for comparative analyses included BiCAR participants who: 1/received obinutuzumab and at least one glofitamab dose; 2/ were confidently identified in DESCAR-T or ALYCANTE; 3/ were not treated with CAR T-cells in another clinical trial with unknown details. Of 46 treated BiCAR patients, 45 were identified in external databases (8 from ALYCANTE, 37 from DESCAR-T), and one treated in an unknown trial was excluded, yielding 45 patients in the glofitamab comparative arm.\u003c/p\u003e \u003cp\u003eControl arm: The control arm comprised DESCAR-T and ALYCANTE patients who: 1/ had DLBCL and received commercial axi-cel or tisagenleuclecel (tisa-cel); 2/ had stable disease (SD) or progression/relapse from month 1 after CAR T infusion ; 3/ started systemic post-CAR T treatment other than a CD20\u0026times;CD3 bispecific antibody; 4/ met main BiCAR inclusion criteria (DLBCL, ECOG 0\u0026ndash;1, adequate organ function). To ensure contemporaneity and comparable follow-up durations, DESCAR-T control patients were further required to have initiated their first post-CAR T regimen within a\u0026thinsp;\u0026plusmn;\u0026thinsp;1-month window around the date of glofitamab initiation in the BiCAR trial. This alignment of treatment timelines was implemented to minimize temporal bias and provide contemporaneous data for the analysis.\u003c/p\u003e \u003cp\u003eComparative full analysis set\u003c/p\u003e\n\u003ch3\u003eCovariates and endpoint\u003c/h3\u003e\n\u003cp\u003eCovariates available in all datasets and considered for propensity-score (PS) estimation were: sex; age at CAR T-cells infusion; number of prior treatment lines including CAR T-cell (L2 vs \u0026ge;L3); time from CAR T-cells infusion to first progression/stable disease; Ann Arbor stage (I\u0026ndash;II vs III\u0026ndash;IV); lactate dehydrogenase (normal vs\u0026thinsp;\u0026gt;\u0026thinsp;ULN-upper limit normal) at or just before CAR T-cell infusion (or at lymphodepletion if missing); CAR T-cell product (axi-cel vs tisa-cel); response to bridging therapy (CR/partial response-PR vs stable disease-SD/progression disease-PD vs no bridging); prior autologous stem-cell transplant (yes/no). For the comparative analysis, OS was defined as the time from first glofitamab infusion (glofitamab arm) or first non-bispecific post-CAR T regimen (control arm) to death from any cause; survivors were censored at last contact.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eAnalysis sets and missing data\u003c/h2\u003e \u003cp\u003eThree analysis sets were defined: 1/cFAS, all 178 patients fulfilling comparative criteria; 2/ complete case set (CC-set), cFAS patients without missing values in planned PS covariates (n\u0026thinsp;=\u0026thinsp;165); 3/ Weighted pseudo-populations, created by applying PS-based weights (stabilized inverse probability of treatment weighting (sIPTW) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], standardized mortality ratio weighting (SMRW) [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]) to the cFAS.\u003c/p\u003e \u003cp\u003eMissing covariates were handled by complete case analysis using the CC-set and multiple imputation (MI) via MICE with 15 imputations and 100 iterations, generating 15 completed datasets for the primary analysis and pooled using Rubin\u0026rsquo;s rules.\u003c/p\u003e \u003cp\u003ePropensity score and weighting\u003c/p\u003e \u003cp\u003eThe propensity score (probability of receiving glofitamab vs control given covariates) was estimated using logistic regression, including all listed variables, with continuous covariate effects modeled using spline functions. Two weighting schemes were prespecified: 1/ sIPTW, targeting the average treatment effect (ATE) in the overall population, with weights of \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{w}_{i}=P/P{S}_{i}\\)\u003c/span\u003e\u003c/span\u003e for treated, and \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{w}_{i}=(1-P)/(1-P{S}_{i})\\)\u003c/span\u003e\u003c/span\u003e for controls with \u003cem\u003eP\u003c/em\u003e for proportion of patients in the glofitamab arm and \u003cem\u003ePS\u003c/em\u003e of propensity score and; 2/ SMRW, targeting the average treatment effect in the control population (ATC), reweighting treated patients to resemble controls. Patients with extreme propensity scores, defined as PS values below 0.025 or above 0.95, were excluded from weighted analyses to avoid undue influence of extreme weights on treatment. effect estimates.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSurvival analysis\u003c/h3\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eBiCAR trial final analysis\u003c/h2\u003e \u003cp\u003eWithin the BiCAR-FAS population, OS, PFS, DoR, and DoCR were estimated using Kaplan\u0026ndash;Meier methods.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eExternal control comparisons\u003c/h2\u003e \u003cp\u003ePrimary analysis: For the comparative effectiveness analysis, OS Kaplan-Meier curves were generated for the cFAS and for the weighted pseudo-populations (sIPTW and SMRW sets). The primary analysis was based on MI-sIPTW weighting including all data sources. Survival probabilities, median survival, and quartiles were estimated (if reached) with their 95% CIs. Cox models provided hazard ratios (HR) and 95% CIs for glofitamab versus control; proportional hazards assumptions were checked using Schoenfeld residuals. Differences between arms were tested with log-rank tests. The robustness of observed associations to unmeasured confounding was assessed using the E-value, which quantifies the minimum strength of association that a hypothetical unmeasured confounder would need to have with both the treatment arm and OS to fully explain away the observed HR of glofitamab versus non-BsAbs regimens [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSecondary and sensitivity analyses : As a secondary analysis, restricted mean survival time (RMST) over a 2-year follow-up period was calculated as the area under the weighted Kaplan-Meier curve, with between-group comparisons performed using the difference in RMST and its 95% confidence interval estimated via bootstrap with 500 replicates [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Pre-specified sensitivity analyses included: 1/ MI-SMRW analysis; 2/ sIPTW and SMRW on complete-case PS sets; 3/ MI-based analyses restricted to DESCAR-T patients only; 4/ MI-sIPTW restricted to Ann Arbor stage III\u0026ndash;IV patients. Because weighting reduces the contribution of some patients, the effective sample size was calculated after analysis with sIPTW on complete case set, to reflect the equivalent sample size contributing information to the analysis.\u003c/p\u003e \u003cp\u003eAnalyses were performed using SAS 9.4 and R 4.4.2.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eBiCAR final survival outcomes\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOf the 47 enrolled BiCAR cohort-1 patients, 46 received glofitamab and formed the BiCAR-FAS. Patient and disease characteristics have already been published and are summarized in Table 1.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1.\u0026nbsp;\u003c/strong\u003ePatient demographic and disease characteristics at inclusion in the BiCAR trial\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"604\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 452px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBiCAR FAS (N=46)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 452px;\"\u003e\n \u003cp\u003eMedian (min-max) age at enrollment, years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e64 (30-77)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 452px;\"\u003e\n \u003cp\u003eSex, \u003cem\u003en\u003c/em\u003e (%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 452px;\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e15 (32.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 452px;\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e31 (67.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 452px;\"\u003e\n \u003cp\u003eECOG performance status, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 452px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e23 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 452px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e23 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 452px;\"\u003e\n \u003cp\u003eAnn Arbor stage, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 452px;\"\u003e\n \u003cp\u003eI-II\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e8 (17.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 452px;\"\u003e\n \u003cp\u003eIII-IV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e38 (82.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 452px;\"\u003e\n \u003cp\u003eIPI, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 452px;\"\u003e\n \u003cp\u003e0-2\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e19 (42.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 452px;\"\u003e\n \u003cp\u003e3-4\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e26 (57.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 452px;\"\u003e\n \u003cp\u003eMissing\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 452px;\"\u003e\n \u003cp\u003eLDH status: \u0026gt;ULN\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 152px;\"\u003e\n \u003cp\u003e35 (76.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 452px;\"\u003e\n \u003cp\u003ePresence of at least one extranodal site, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 152px;\"\u003e\n \u003cp\u003e35 (76.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 452px;\"\u003e\n \u003cp\u003eMedian number of previous lines of lymphoma treatment (minimum\u0026ndash;maximum)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 152px;\"\u003e\n \u003cp\u003e3 (2\u0026ndash;5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 452px;\"\u003e\n \u003cp\u003e\u0026ge;3 lines of treatment,\u0026nbsp;\u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e37 (80.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 452px;\"\u003e\n \u003cp\u003ePrevious autologous or allogeneic transplant, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e8 (17.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 452px;\"\u003e\n \u003cp\u003ePrevious CAR-T cell therapy, \u003cem\u003en\u003c/em\u003e (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 452px;\"\u003e\n \u003cp\u003eExperimental CAR-T cell product (in clinical trial)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e3 (6.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 452px;\"\u003e\n \u003cp\u003eTisa-cel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e17 (37.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 452px;\"\u003e\n \u003cp\u003eAxi-cel\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e26 (56.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 452px;\"\u003e\n \u003cp\u003ePatient status at screening,\u003cem\u003e\u0026nbsp;n\u003c/em\u003e (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 452px;\"\u003e\n \u003cp\u003eRefractory\u003csup\u003ea\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e14 (30.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 452px;\"\u003e\n \u003cp\u003eRelapse/progression\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e32 (69.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 452px;\"\u003e\n \u003cp\u003eTime between CAR-T cell therapy and relapse/progression, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 452px;\"\u003e\n \u003cp\u003e1\u0026ndash;3 months\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e9 (28.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 452px;\"\u003e\n \u003cp\u003e3\u0026ndash;6 months\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e8 (25.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 452px;\"\u003e\n \u003cp\u003e\u0026gt;6 months\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 152px;\"\u003e\n \u003cp\u003e15 (46.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eMissing data are specified for any variable for which n (%) does not add up to N.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003eRefractory: designates patients who never experienced a metabolic response (i.e., stable or progressive disease) after CAR-T cell therapy. \u003csup\u003eb\u003c/sup\u003eRelapse/progression designates patients who experienced response (PR or CR) after CAR-T cells then relapse/progression on subsequent PET-CT.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAbbreviations: Axi-cel, axicabtagene ciloleucel; CAR-T, chimeric antigen receptor-T; CR, complete response; ECOG, Eastern Cooperative Oncology Group; FAS, full analysis set; IPI, international prognostic index; PR, partial response; SD, standard deviation; tisa-cel, tisagenlecleucel; ULN, upper limit of normal.\u003c/p\u003e\n\u003cp\u003eAt the final analysis (data cutoff: 21 May 2025), the median follow-up from first glofitamab infusion was 30.4 months (95% CI, 23.0\u0026ndash;31.4). Median OS was 17.3 months (95% CI, 9.0\u0026ndash;28.4), with a 2-year OS rate of 38.3% (95% CI, 26.1\u0026ndash;50.4) (Figure 1A). Median PFS was 3.8 months (95% CI, 2.4\u0026ndash;15.9) with a 2-year PFS rate of 29.1% (95% CI, 16.5\u0026ndash;43.0) (Figure 1B). Median DoR among responders was 16.1 months (95% CI, 4.0\u0026ndash;NR), and median DoCR was not reached (95%CI: 19.7; NR) (Figure 1C-1D).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOutcomes remained strongly associated with the timing of CAR T-cell failure (Figure 2A). Median OS was not reached (95% CI: 10.2- NR) in patients with late relapse (\u0026gt; 6 months post-infusion), compared with 11.1 months (95% CI: 5.5\u0026ndash;20.0) in those with refractory or early-relapsing disease (\u0026le;6 months; log-rank \u003cem\u003eP\u003c/em\u003e=0.01). Response after two cycles of glofitamab also predicted outcome; median OS was not reached in patients experiencing CR (95%CI, 27.4-not estimable) versus 9.0 months (95% CI, 4.9-20.1) (\u003cem\u003eP\u003c/em\u003e=0.0015) (Figure 2B). No new safety signals emerged, and safety details were unchanged from the primary report [11].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eComparative cohorts and baseline characteristics\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWithin the BiCAR-FAS, 45 patients were matched with the DESCAR-T/ALYCANTE data sources and included in the glofitamab arm, while one patient was excluded as previously described. Out of 3,143 registry and trial-derived patients, 133 controls met the pre-specified eligibility criteria and temporal restrictions for the comparative analysis and received non-bispecific post-CAR-T therapy (Figure S1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the cFAS (n=178), 65.7% were male, with a median age of 63 years (range: 19\u0026ndash;82) at the time of CAR T-cell infusion (Table 2). At CAR T-cells infusion, most patients presented with advanced disease, including 83.5% with Ann Arbor stage III\u0026ndash;IV and 50.0% with LDH levels above the ULN. Most patients (84.8%) had received CAR T-cell therapy in the third-line setting or later, with 65.7% having received axi-cel. The median time from CAR T-cell infusion to treatment failure was 3.0 months (IQR 1.84\u0026ndash;5.88). Baseline features were generally comparable between the glofitamab (n=45) and control (n=133) arms, with slightly more advanced disease (93.0% vs 80.3% stage III\u0026ndash;IV), LDH within normal values (51.1% vs 42.1% normal LDH), no response after bridging (61.4% vs 50.4% no responder) and prior ASCT (18.2% vs 12.8%) in the glofitamab arm \u0026nbsp;(Table 2). Control patients received a heterogeneous salvage therapy following CAR T-cell failure, including monoclonal antibodies (57.9%; among them 34.6% anti-CD20 and 18.8% anti-CD19), lenalidomide (48.1%), chemotherapy (31.6%), kinase inhibitors (12.0%, primarily ibrutinib), and radiotherapy (10.5%), and smaller proportions of other agents. All eight patients recorded as receiving corticosteroids also received at least one additional anti-lymphoma regimen. Best response in the control arm was complete response in 8.3% and partial response in 4.5%, while 72.0% had progressive disease.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u003c/strong\u003e Patients\u0026rsquo; characteristics from the control and BiCAR arm from the cFAS set and the CC-set.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"633\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 227px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 227px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ecFAS set\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN=178\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 180px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCC-set\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN=165\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eControl\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN=133\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGlofitamab\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN=45\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eControl\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN=125\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGlofitamab\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eN=40\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 227px;\"\u003e\n \u003cp\u003eAge at CAR-T infusion\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eMedian (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e63 (19-82)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e63 (30-77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e63 (19-82)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e64 (30-77)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 227px;\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003cp\u003eMale, N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e87 (65.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e30 (66.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e83 (66.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e27 (67.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 227px;\"\u003e\n \u003cp\u003eTime between CAR-T and failure\u003c/p\u003e\n \u003cp\u003eMedian (Q1-Q3)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2.99 (1.22-5.68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3.25 (2.07-6.64)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3.0 (1.2-5.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3.5 (2.1-8.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 227px;\"\u003e\n \u003cp\u003eAnn Arbor Stage \u0026nbsp;at CAR-T infusion\u003c/p\u003e\n \u003cp\u003eMissing\u003c/p\u003e\n \u003cp\u003eI-II\u003c/p\u003e\n \u003cp\u003eIII-IV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003cp\u003e25 (19.7)\u003c/p\u003e\n \u003cp\u003e102 (80.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e3 (7.0)\u003c/p\u003e\n \u003cp\u003e40 (93.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003cp\u003e25 (21.0)\u003c/p\u003e\n \u003cp\u003e94 (79.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e2 (5.1)\u003c/p\u003e\n \u003cp\u003e37 (94.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 227px;\"\u003e\n \u003cp\u003ePrior ASCT\u003c/p\u003e\n \u003cp\u003eMissing\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003cp\u003e116 (87.2)\u003c/p\u003e\n \u003cp\u003e17 (12.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e36 (81.8)\u003c/p\u003e\n \u003cp\u003e8 (18.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e16 (12.8)\u003c/p\u003e\n \u003cp\u003e109 (87.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e7 (17.5)\u003c/p\u003e\n \u003cp\u003e33 (82.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 227px;\"\u003e\n \u003cp\u003eResponse After Bridging\u003c/p\u003e\n \u003cp\u003eMissing\u003c/p\u003e\n \u003cp\u003eNo bridge\u003c/p\u003e\n \u003cp\u003eResponse (CR/PR)\u003c/p\u003e\n \u003cp\u003eNo response (SD/PD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e18 (13.5)\u003c/p\u003e\n \u003cp\u003e46 (34.6)\u003c/p\u003e\n \u003cp\u003e67 (50.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e4 (9.1)\u003c/p\u003e\n \u003cp\u003e13 (29.5)\u003c/p\u003e\n \u003cp\u003e27 (61.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e16 (12.8)\u003c/p\u003e\n \u003cp\u003e45 (36.0)\u003c/p\u003e\n \u003cp\u003e64 (51.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e3 (7.5)\u003c/p\u003e\n \u003cp\u003e12 (30.0)\u003c/p\u003e\n \u003cp\u003e25 (62.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 227px;\"\u003e\n \u003cp\u003eBulk at lymphodepletion\u003c/p\u003e\n \u003cp\u003eMissing\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003cp\u003e26 (21.1\u003c/p\u003e\n \u003cp\u003e97 (78.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003cp\u003e10 (27.8)\u003c/p\u003e\n \u003cp\u003e26 (72.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003cp\u003e26 (22.6)\u003c/p\u003e\n \u003cp\u003e89 (77.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003cp\u003e10 (31.3)\u003c/p\u003e\n \u003cp\u003e22 (68.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 227px;\"\u003e\n \u003cp\u003eLDH (IU/L) at CAR-T infusion\u003c/p\u003e\n \u003cp\u003e\u0026gt; Upper limit\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e71 (53.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e18 (40.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e70 (56.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e17 (42.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 227px;\"\u003e\n \u003cp\u003eCAR-T product\u003c/p\u003e\n \u003cp\u003eTisa-cel\u003c/p\u003e\n \u003cp\u003eAxi-cel\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e44 (33.1)\u003c/p\u003e\n \u003cp\u003e89 (66.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e17 (37.8)\u003c/p\u003e\n \u003cp\u003e28 (62.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e42 (33.6)\u003c/p\u003e\n \u003cp\u003e83 (66.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e16 (40.0)\u003c/p\u003e\n \u003cp\u003e24 (60.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 227px;\"\u003e\n \u003cp\u003eLine of CAR-T infusion\u003c/p\u003e\n \u003cp\u003e2L\u003c/p\u003e\n \u003cp\u003e3L+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e17 (12.8)\u003c/p\u003e\n \u003cp\u003e116 (87.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e10 (22.2)\u003c/p\u003e\n \u003cp\u003e35 (77.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e16 (12.8)\u003c/p\u003e\n \u003cp\u003e109 (87.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e9 (22.5)\u003c/p\u003e\n \u003cp\u003e31 (77.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: ASCT : autologous stem cell transplantation; CAR-T, chimeric antigen receptor-T; CR, complete response; ECOG, Eastern Cooperative Oncology Group; FAS, full analysis set; IPI, international prognostic index; IPTW: Stabilized inverse probability of treatment weighting ; LDH : lactacte dehydrogenase; \u0026nbsp;PD, progressive disease; PR, partial response; PS, propensity score; SD, standard deviation; tisa-cel, tisagenlecleucel; ULN, upper limit of normal.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCovariate balance after weighting\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePS weighting aimed to balance covariates between the control arm and the glofitamab arm to account for measured confounding variables (Table S1) that have been shown to impact PFS and OS after CAR T-cell failure [2, 5, 19, 20].\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePrimary analysis (MI-sIPTW)\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eIn the primary MI-sIPTW analysis including all patients, except 11 patients with extreme propensity, adequate covariate balance was achieved after stringent adjustment on 9 parameters (Table S1). All absolute standardized mean differences (SMDs) were \u0026lt; 0.2 across the 15 imputed datasets (Figure S2).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSensitivity analyses\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eIn the MI-SMRW analysis, all SMDs were \u0026lt; 0.2, except for Ann Arbor stage where 1 out of 15 imputed datasets showed an SMD \u0026gt; 0.2. In the complete-case set (5 patients excluded for extreme PS, n=160), both sIPTW and SMRW reduced imbalances, with SMDs \u0026lt; 0.1 for all covariates except Ann Arbor stage, which could not be included due to very few stage I\u0026ndash;II cases, and number of previous treatment lines for SMRW (SMD 0.15). After adjustment, patients in the glofitamab arm had more advanced disease (95.7% vs 78.6% Ann Arbor stage III\u0026ndash;IV). For sIPTW, the effective sample size was 142. In MI-based analyses restricted to DESCAR-T patients, the number of previous treatment lines could not be included in the propensity score, but all SMDs were \u0026lt; 0.2. In MI-based analyses restricted to Ann Arbor stage III\u0026ndash;IV patients, all covariates could be included and all SMDs were \u0026lt; 0.2.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePrimary analysis\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePrimary weighted analysis (MI-sIPTW)\u003c/p\u003e\n\u003cp\u003eIn the primary MI-sIPTW analysis (all data sources), weighted median OS was 19.6 months (95% CI, 10.2\u0026ndash;not reached) in the glofitamab arm versus 7.6 months (95% CI, 5.5\u0026ndash;9.8) in the control arm (Figure 3). The pooled HR for death across imputed datasets was 0.49 (95% CI, 0.31\u0026ndash;0.79; \u003cem\u003eP\u003c/em\u003e=0.0072). The E-value was 2.65 (1.31 for the lower CI bound), indicating that one or several unmeasured confounders would need to be strongly associated with both treatment and survival to fully explain the observed effect.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSecondary and sensitivity analysis\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRestricted Mean Survival Time\u003c/p\u003e\n\u003cp\u003eThe mean survival time restricted at 24 months of follow-up was 15.6 months (95% CI, 12.3 - 18.9) in the glofitamab arm versus 10.6 months (95% CI, 9.0 - 12.2) in the control arm, corresponding to an average RMST difference of 5.0 months (95% CI, 1.4\u0026ndash;8.6; \u003cem\u003eP\u003c/em\u003e=0.007) favouring glofitamab.\u003c/p\u003e\n\u003cp\u003eSensitivity analyses\u003c/p\u003e\n\u003cp\u003eIn the unweighted cFAS, median OS from the start of post-CAR T therapy was 6.5 months (IQR, 3.2\u0026ndash;18.9; 95% CI, 4.8\u0026ndash;8.1) in the control arm versus 17.3 months (IQR, 5.7\u0026ndash;28.4; 95% CI, 8.8\u0026ndash;not estimable) in the glofitamab arm. Sensitivity analyses across various statistical models yielded consistent results (Table 3). Under the MI-SMRW model (all data), glofitamab was associated with a significant survival benefit (HR 0.46; 95% CI: 0.33\u0026ndash;0.66; \u003cem\u003eP\u003c/em\u003e=0.0087; E-value: 2.78). Similar findings were observed using complete-case sIPTW and SMRW (HR 0.51,95%CI: [0.31 \u0026ndash; 0.82], \u003cem\u003eP\u003c/em\u003e=0.0089 and HR 0.46, 95% CI: [0.33-0.65], p=0.0062 respectively). When restricting the control group to DESCAR-T registry patients only (n=162), the benefit remained robust (MI-sIPTW: HR 0.44, 95% CI: 0.26\u0026ndash;0.74, P=0.0057; MI-SMRW: HR 0.41, 95% CI: 0.29\u0026ndash;0.59, \u003cem\u003eP\u003c/em\u003e=0.0067). Finally, an analysis restricted to stage III\u0026ndash;IV disease (n=142) confirmed these results (MI-sIPTWHR 0.52; 95% CI: 0.33\u0026ndash;0.81; \u003cem\u003eP\u003c/em\u003e=0.0069). Across all analytic approaches, HR estimates consistently clustered between 0.40 and 0.55, uniformly favoring the glofitamab arm.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3.\u003c/strong\u003e Sensitivity analysis of overall survival evaluated in the indirect comparison study\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"869\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMultiple Imputations\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDESCAR-T population\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAnn-Arbor Stage III-IV\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 265px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eComplete cases\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRaw data\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eSMRW\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003esIPTW\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eSMRW\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003eSIPTW\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eSIPTW\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eSMRW\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eControl group (n=133)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eGlofitamab group (N=45)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eControl group (n=120)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eGlofitamab group (N=40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eControl group (n=120)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003eGlofitamab group (N=40)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eNumber of death, N (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e91 (75.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e22 (55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e91 (75.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e22 (55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e99 (74.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e25 (55.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003emOS, months\u0026nbsp;[IC\u003csub\u003e95%\u003c/sub\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e6.6\u003c/p\u003e\n \u003cp\u003e[5.2;9.7]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e17.3\u003c/p\u003e\n \u003cp\u003e[6.1;28.4]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e6.5\u003c/p\u003e\n \u003cp\u003e[4.8;8.1]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e17.3\u003c/p\u003e\n \u003cp\u003e[-;-]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e6.5\u003c/p\u003e\n \u003cp\u003e[4.8;8.1]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e17.3\u003c/p\u003e\n \u003cp\u003e[8.8;NA]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eHR\u0026nbsp;[IC\u003csub\u003e95%\u003c/sub\u003e]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.46\u0026nbsp;[0.326;0.659]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.44\u003c/p\u003e\n \u003cp\u003e[0.264;0.741]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.41\u003c/p\u003e\n \u003cp\u003e[0.286;0.591]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.52\u003c/p\u003e\n \u003cp\u003e[0.33;0.809]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.51\u003c/p\u003e\n \u003cp\u003e[0.331;0.819]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.46\u003c/p\u003e\n \u003cp\u003e[0.334;0.645]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e0.54\u003c/p\u003e\n \u003cp\u003e[0.348;0.840]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value (Log-Rank)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.0087\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.0057\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.0067\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.0069\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.0089\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e0.0062\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e0.0028\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eE-value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e2.784\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e2.903\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e3.087\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e2.529\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e2.576\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e2.779\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 170px;\"\u003e\n \u003cp\u003e2.517\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"11\" valign=\"top\" style=\"width: 869px;\"\u003e\n \u003cp\u003eOverall survival rates\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e9-months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e41.1\u003c/p\u003e\n \u003cp\u003e[33.8;50.2]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e65.0\u003c/p\u003e\n \u003cp\u003e[43.8;78.8]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e39.1\u003c/p\u003e\n \u003cp\u003e[30.2;47.9]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e66.0\u003c/p\u003e\n \u003cp\u003e[42.0;82.0]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e39.7\u003c/p\u003e\n \u003cp\u003e[31.3;48.0]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e63.7\u003c/p\u003e\n \u003cp\u003e[47.7;76.0]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e12-months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e33.8\u003c/p\u003e\n \u003cp\u003e[25.0;42.8]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e59.9\u003c/p\u003e\n \u003cp\u003e[38.8;75.7]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e31.0\u003c/p\u003e\n \u003cp\u003e[22.8;39.6]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e60.0\u003c/p\u003e\n \u003cp\u003e[36.2;77.4]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e31.5\u003c/p\u003e\n \u003cp\u003e[23.6;39.7]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e59.0\u003c/p\u003e\n \u003cp\u003e[43.0;71.9]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e18-months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e27.3\u003c/p\u003e\n \u003cp\u003e[19.0;36.3]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e48.7\u003c/p\u003e\n \u003cp\u003e[27.6;67.0]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e25.2\u003c/p\u003e\n \u003cp\u003e[17.6;33.6]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e49.3\u003c/p\u003e\n \u003cp\u003e[25.5;69.4]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e26.3\u003c/p\u003e\n \u003cp\u003e[18.9;34.3]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e47.9\u003c/p\u003e\n \u003cp\u003e[32.0;62.2]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e24-months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 151px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e19.7\u003c/p\u003e\n \u003cp\u003e[12.1;28.7]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e46.5\u003c/p\u003e\n \u003cp\u003e[25.3;65.2]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e18.6\u003c/p\u003e\n \u003cp\u003e[11.5;27.0]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e47.5\u003c/p\u003e\n \u003cp\u003e[23.7;68.1]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e20.2\u003c/p\u003e\n \u003cp\u003e[13.2;28.3]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e40.4\u003c/p\u003e\n \u003cp\u003e[24.5;55.9]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: OS: overall survival, SMRW: Standardized Mortality Ratio Weighting, sIPTW: Stabilized Inverse Probability of Treatment Weighting\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this comparative effectiveness study combining the BiCAR phase 2 trial with a pre-specified external control arm, short ramp-up glofitamab after anti-CD19 CAR T-cell failure was associated with a 51% reduction in the risk of death compared with contemporaneous non-bispecific salvage therapies. Weighted median OS increased from 7.6 months in the control arm to 19.6 months with glofitamab; a secondary RMST analysis confirmed a 5-month survival gain over 2 years. These findings were consistent across alternative weighting schemes, data-source restrictions, and stage-restricted analyses, with hazard ratio estimates ranging from 0.40 to 0.55.\u003c/p\u003e\n\u003cp\u003eThe primary BiCAR publication established the feasibility and activity of accelerated glofitamab dosing after CAR T-cell failure [11]. The present work extends these findings with longer follow-up (median 30.4 months), showing that OS benefit is maintained over time (median 17.3 months, 2-year OS 38.3%). Our control cohort, selected using strict eligibility criteria and contemporaneity constraints, had a median OS of 6.5–7.6 months, consistent with previous DESCAR-T analyses and other post-CAR T series [2–5], supporting the external validity of our findings.\u003c/p\u003e\n\u003cp\u003eThis study represents the first prospective phase II trial designed to evaluate a CD20×CD3 bispecific antibody exclusively in patients with DLBCL failing anti-CD19 CAR T-cell therapy. With a complete response rate of 45.7% and a median overall survival of 19.6 months in the weighted analysis, these results can be compared with outcomes reported for other bispecific platforms in this population. Four other CD20×CD3 bispecific antibodies have demonstrated activity in post-CAR T relapsed/refractory DLBCL. In the pivotal glofitamab study (NP30179) using standard ramp-up, 52 patients with prior CAR T-cell therapy achieved a 37% complete response rate with a median duration of complete response of 22.0 months at 32 months median follow-up [7]. For epcoritamab (EPCORE NHL-1), 61 post-CAR T patients (38.9% of the total cohort) achieved a 36% complete response rate at 25 months median follow-up [8]. Odronextamab demonstrated a 31.7% complete response rate in a dedicated post-CAR T expansion cohort of 60 patients, with a median OS of 10.2 months at 16.2 months follow-up [9]. Mosunetuzumab showed a 24% complete response rate in 30 post-CAR T patients [10]. Although response rates are lower than BiCAR trial (45.7%), they appear comparable across these bispecific platforms (24% to 37%). However, several methodological and design differences distinguish BiCAR from existing studies.\u003c/p\u003e\n\u003cp\u003eFirst, BiCAR is the only prospective phase II study enrolling exclusively patients in immediate relapse or progression after CAR T-cell therapy. In contrast, glofitamab, epcoritamab, and mosunetuzumab included post-CAR T patients as subgroups within larger heterogeneous cohorts of relapsed/refractory DLBCL, while odronextamab, though conducted in a dedicated post-CAR T cohort, was an expansion arm of a phase I dose-finding study. The design of our study ensures population homogeneity and reduces selection biases that can occur when post-CAR T patients represent a subset of a broader trial. Second, BiCAR employed standardized dosing, a unified treatment schedule, and prespecified endpoints, in contrast to the dose-escalation designs and heterogeneous dosing cohorts in phase I/II studies. This consistency improves the reliability and reproducibility of efficacy estimates. Third, OS was the primary endpoint of our comparative effectiveness analysis. While complete response rates are informative, they do not fully capture clinical benefit in heavily pretreated populations where durability of response and survival prolongation are relevant outcomes. The observed doubling of median overall survival (19.6 vs 7.6 months, HR 0.49) against contemporaneous external controls provides comparative evidence that is not available for other bispecific antibodies in the post-CAR T setting, as mosunetuzumab, epcoritamab, and odronextamab have not reported survival comparisons with contemporary controls in their post-CAR T cohorts.\u003c/p\u003e\n\u003cp\u003eThe external control arm was constructed from individual patient data in the French national DESCAR-T registry and the ALYCANTE trial, using propensity score weighting and sensitivity analyses. Given the difficulty of conducting randomized controlled trials comparing bispecific antibodies to salvage therapies in post-CAR T patients, this methodology provides an alternative approach to generate comparative evidence. The consistency of hazard ratio estimates across weighting schemes (sIPTW, SMRW), data source restrictions (DESCAR-T only analysis), stage-restricted analyses, and methods for handling missing data (complete-case and multiple imputation) supports the robustness of the findings. E-values exceeded 2.5, indicating that an unmeasured confounder would need to have an association of at least this magnitude with both treatment assignment and overall survival to fully explain the observed hazard ratio.\u003c/p\u003e\n\u003cp\u003eThis study has limitations. The non-randomized design and sample size in the glofitamab arm (n=45) preclude definitive causal inference, and residual confounding cannot be excluded despite propensity score adjustment. However, E-value (2.5) supports that it is unlikely that these potential confounders would substantially change the study conclusions. The heterogeneity of control treatments—spanning immunochemotherapy, lenalidomide-based regimens, targeted agents, and radiotherapy—reflects real-world practice but precludes conclusions regarding the comparative efficacy of glofitamab versus any single alternative strategy. Generalizability is limited to patients meeting BiCAR eligibility criteria, including ECOG performance status 0–1, adequate organ function, and CAR T-cell failure occurring at least one month after infusion.\u003c/p\u003e\n\u003cp\u003eThe fixed 11-cycle treatment protocol with short ramp-up schedule (8 days to full dose vs 15 days in standard glofitamab dosing), and in contrast to treatment until progression for epcoritamab [8] and odronextamab [9]) may offer practical advantages for patients requiring rapid disease control. The safety profile showed no grade ≥3 cytokine release syndrome or neurotoxicity.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eShort-ramp-up glofitamab after anti-CD19 CAR T-cell failure produces durable survival in a subset of patients with DLBCL and, in a pre-specified comparative effectiveness analysis using an academic external control arm, is associated with substantially longer OS than contemporaneous non-bispecific therapies. These findings support glofitamab as a preferred post-CAR T option for eligible patients and highlight the value of registry-based external controls to inform treatment decisions when randomised trials are not feasible.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cul\u003e\n \u003cli\u003eATE: average treatment effect\u003c/li\u003e\n \u003cli\u003eATC: average treatment effect in the control population\u003c/li\u003e\n \u003cli\u003eCAR: chimeric antigen receptor\u003c/li\u003e\n \u003cli\u003eCI: confidence interval\u003c/li\u003e\n \u003cli\u003eCR: complete response\u003c/li\u003e\n \u003cli\u003eCRS: cytokine release syndrome\u003c/li\u003e\n \u003cli\u003eDLBCL: diffuse large B-cell lymphoma\u003c/li\u003e\n \u003cli\u003eDoR: duration of response\u003c/li\u003e\n \u003cli\u003eECOG: Eastern Cooperative Oncology Group\u003c/li\u003e\n \u003cli\u003eFAS: full analysis set\u003c/li\u003e\n \u003cli\u003eHR: hazard ratio\u003c/li\u003e\n \u003cli\u003eLDH: lactate dehydrogenase\u003c/li\u003e\n \u003cli\u003eMI: multiple imputation\u003c/li\u003e\n \u003cli\u003eOS: overall survival\u003c/li\u003e\n \u003cli\u003ePD: progressive disease\u003c/li\u003e\n \u003cli\u003ePFS: progression-free survival\u003c/li\u003e\n \u003cli\u003ePR: partial response\u003c/li\u003e\n \u003cli\u003ePS: propensity score\u003c/li\u003e\n \u003cli\u003eRMST:\u0026nbsp;restricted mean survival time\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eSD: stable disease\u003c/li\u003e\n \u003cli\u003esIPTW: stabilized inverse probability of treatment weighting\u003c/li\u003e\n \u003cli\u003eSMRW: standardized mortality ratio weighting\u003c/li\u003e\n \u003cli\u003eULN: upper limit of normal\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cem\u003eEthics approval and consent to participate.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eBiCAR was approved by the Comité de Protection des Personnes Ile-de-France X and conducted in accordance with the Declaration of Helsinki and Good Clinical Practice; all participants provided written informed consent. DESCAR-T and ALYCANTE were approved by the appropriate institutional ethics committees. Use of de-identified registry and trial data for the external control analysis complied with applicable data-protection regulations.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConsent for publication\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable (no identifiable individual patient data are presented).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAvailability of data and materials\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analysed during the current study are not publicly available due to privacy and regulatory restrictions but are available from the corresponding author on reasonable request and with permission from LYSARC and the DESCAR-T/ALYCANTE data-holding institutions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCompeting interests\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eP.S. has received honoraria, and advisory/consultancy fees from Janssen, Roche,\u0026nbsp;Bristol-Myers Squibb, AbbVie, AstraZeneca, Chugai, Novartis, and Kite/Gilead. R.H. has received honoraria from Kite/Gilead, Novartis, Incyte, Janssen, MSD, Takeda, and Roche; and is a member on an entity’s Board of Directors or advisory committees of Kite/Gilead, Novartis, Bristol-Myers Squibb/Celgene, ADC Therapeutics, Incyte and Miltenyi. L.Y. has received honoraria, and advisory/consultancy fees from AbbVie, AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Gilead/Kite, Janssen, and Roche. S.C. has received honoraria, and advisory/consultancy fees from AbbVie, AstraZeneca, Atara, BeiGene, Gilead/Kite, Janssen, Novartis, Pierre Fabre, and Takeda. F.J. has received honoraria, and advisory/consultancy fees from Roche, Bristol-Myers Squibb, Novartis, Kite/Gilead, Takeda, AbbVie, and Janssen. F-X.G. has received honoraria, and advisory/consultancy fees from Bristol-Myers Squibb, Novartis, Kite/Gilead, AstraZeneca, Janssen, and Miltenyi. F.M. has received consultancy fees from AbbVie, Bristol-Myers Squibb, Gilead, Novartis, and Roche, serves as an advisor for AbbVie, Gilead and Roche and received honoraria from Chugai and Kaleda for scientific lectures. C.Ro. has received honoraria, and advisory/consultancy fees from Roche, Takeda, Gilead/Kite, Bristol-Myers Squib, MSD, AbbVie, BeiGene, Janssen, Lilly. T.G. has received travel and accommodation expenses from Roche.\u0026nbsp;C.T. has received honoraria, and advisory/consultancy fees from Roche, Bristol-Myers Squibb, Novartis, Kite/Gilead, Takeda, AbbVie, Janssen. L.D.L.R. has received honoraria, and advisory/consultancy fees from Gilead/Kite, Novartis, Bristol-Myers Squibb, Janssen, Takeda. P.F. has received honoraria, and advisory/consultancy fees from, BeiGene, Kite/Gilead, AstraZeneca, AbbVie, Janssen. S.G. is an employee of LYSARC. G.C. has received honoraria, and advisory/consultancy fees from Roche, Bristol-Myers Squibb, BeiGene, Novartis, Kite/Gilead, Takeda, AstraZeneca, AbbVie, Janssen, Onward Therapeutics, Incyte and Mabqi. Y.A.T., M.J., C.L., F.L.B., A.M., J-O.B., C.R., L.R., and K.T. declare that they have no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;BiCAR and ALYCANTE were sponsored by LYSARC and supported in part by an unrestricted grant from F. Hoffmann–La Roche (BiCAR) and Kite, a Gilead company (ALYCANTE) for drug supply and study conduct. The DESCAR-T registry received support from [GILEAD, Novartis, Bristol-Meyers Squibb]. The funders had no role in the design, analysis or interpretation of the external control comparison, or in the decision to submit this manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAuthors’ contributions\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eG.C., P.S., Y.A.L., K.T. and C.L. contributed to the conception, design, and planning of the study. G.C., R.H., Y.A.L., F.L.B., L.Y., S.C., F.J., J-O.B, F-X.G., F.M., C.Ro., T.G., C.T., M.J., L.R., C.R., L.D.L.R., P.F., A.M., S.G., K.T., C.L., and P.S. contributed to the acquisition and analysis of data. G.C., R.H., Y.A.L., F.L.B., L.Y., S.C., F.J., J-O.B, F-X.G., F.M., C.R., T.G., C.T., M.J., L.R., C.Ro., L.D.L.R., P.F., A.M., S.G., K.T., C.L., and P.S. contributed to the critical review and revision of the manuscript. All authors approved the final version of the manuscript and are accountable for all aspects of the work.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAcknowledgements\u003c/em\u003e\u003cbr\u003e\u0026nbsp;We thank the patients, their families and the study personnel involved in this trial. We also thank the BiCAR trial investigators, S. Doyen (Clinical Projects Manager, LYSARC, France) and the LYSARC study team, including Biostatistics teams, LYSA-IM and LYSA-P, for their precious contribution for providing medical writing support in accordance with the current Good Publication Practice guidelines.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGhobadi A, Munoz J, Westin JR, Locke FL, Miklos DB, Rapoport AP, et al. Outcomes of subsequent antilymphoma therapies after second-line axicabtagene ciloleucel or standard of care in ZUMA-7. Blood Adv. 2024;8(11):2982\u0026ndash;2990. https://doi.org/10.1182/bloodadvances.2024012345\u003c/li\u003e\n\u003cli\u003eSesques P, Manson G, Cartron G, Gros FX, Morschhauser F, Castilla-Llorente C, et al. Outcome of patients with large B-cell lymphoma relapsing after second-line CAR-T: insights from the DESCAR-T registry. Blood. 2025;146(Suppl 1):956. https://doi.org/10.1182/blood-2025.\u003c/li\u003e\n\u003cli\u003eDi Blasi R, Le Gouill S, Bachy E, Cartron G, Beauvais D, Le Bras F, et al. Outcomes of patients with aggressive B-cell lymphoma after failure of anti-CD19 CAR T-cell therapy: a DESCAR-T analysis. Blood. 2022;140(24):2584\u0026ndash;2593. https://doi.org/10.1182/blood.2022016418\u003c/li\u003e\n\u003cli\u003eSpiegel JY, Dahiya S, Jain MD, Tamaresis J, Nastoupil LJ, Jacobs MT, et al. Outcomes of patients with large B-cell lymphoma progressing after axicabtagene ciloleucel therapy. Blood. 2021;137(13):1832\u0026ndash;1835. https://doi.org/10.1182/blood.2020009849\u003c/li\u003e\n\u003cli\u003eIacoboni G, Iraola-Truchuelo J, O\u0026rsquo;Reilly M, Navarro V, Menne T, Kwon M, et al. Treatment outcomes in patients with large B-cell lymphoma after progression to chimeric antigen receptor T-cell therapy. HemaSphere. 2024;8(5):e62. https://doi.org/10.1097/HS9.0000000000000062\u003c/li\u003e\n\u003cli\u003eBourlon C, Roddie C, Menne T, Norman J, O\u0026rsquo;Reilly M, Gibb A, et al. Outcomes after chimeric antigen receptor T-cell therapy across large B-cell lymphoma subtypes. Haematologica. 2024;109(8):2716\u0026ndash;2720. https://doi.org/10.3324/haematol.2023.283456\u003c/li\u003e\n\u003cli\u003eHutchings M, Morschhauser F, Iacoboni G, Carlo-Stella C, Offner F, Sureda A, et al. Glofitamab monotherapy in relapsed or refractory large B-cell lymphoma: extended follow-up from a pivotal phase II study and subgroup analyses in patients with prior chimeric antigen receptor T-cell therapy and by baseline total metabolic tumor volume. Blood. 2023;142(Suppl 1):433. https://doi.org/10.1182/blood-2023.\u003c/li\u003e\n\u003cli\u003eThieblemont C, Karimi YH, Ghesquieres H, Cheah CY, Clausen MR, Cunningham D, et al. Epcoritamab in relapsed/refractory large B-cell lymphoma: 2-year follow-up from the pivotal EPCORE NHL-1 trial. Leukemia. 2024;38(12):2653\u0026ndash;2662. https://doi.org/10.1038/s41375-024-02345-7\u003c/li\u003e\n\u003cli\u003eTopp MS, Matasar M, Allan JN, Ansell SM, Barnes JA, Arnason JE, et al. Odronextamab monotherapy in relapsed/refractory DLBCL after progression with CAR T-cell therapy: primary analysis of the ELM-1 study. Blood. 2025;145(14):1498\u0026ndash;1509. https://doi.org/10.1182/blood.2024019876\u003c/li\u003e\n\u003cli\u003eChong EA, Penuel E, Napier EB, Lundberg RK, Budde LE, Shadman M, et al. Impact of prior CAR T-cell therapy on mosunetuzumab efficacy in patients with relapsed or refractory B-cell lymphomas. Blood Adv. 2025;9(4):696\u0026ndash;703. https://doi.org/10.1182/bloodadvances.2024017654\u003c/li\u003e\n\u003cli\u003eCartron G, Houot R, Al Tabaa Y, Le Bras F, Ysebaert L, Choquet S, et al. Glofitamab in refractory or relapsed diffuse large B-cell lymphoma after failing CAR T-cell therapy: a phase 2 LYSA study. Nat Cancer. 2025;6(7):1173\u0026ndash;1183. https://doi.org/10.1038/s43018-025-00876-2\u003c/li\u003e\n\u003cli\u003eDodero A, Ceparano G, Casadei B, Angelillo P, Bramanti S, Tisi MC, et al. Outcomes of CAR T-cell therapy in high-grade B-cell lymphomas compared to DLBCL: a weighted comparison analysis. Blood Adv. 2025;9(24):6491\u0026ndash;6501. https://doi.org/10.1182/bloodadvances.2024019234\u003c/li\u003e\n\u003cli\u003eThe Lymphoma Academic Research Organisation. French register of patients with hemopathy eligible for CAR-T cell treatment (DESCAR-T). ClinicalTrials.gov identifier: NCT04328298. https://clinicaltrials.gov/study/NCT04328298\u003c/li\u003e\n\u003cli\u003eHouot R, Bachy E, Cartron G, Gros FX, Morschhauser F, Oberic L, et al. Axicabtagene ciloleucel as second-line therapy in large B-cell lymphoma ineligible for autologous stem cell transplantation: a phase 2 trial. Nat Med. 2023;29(10):2593\u0026ndash;2601. https://doi.org/10.1038/s41591-023-02554-8\u003c/li\u003e\n\u003cli\u003eXu S, Ross C, Raebel MA, Shetterly S, Blanchette C, Smith D. Use of stabilized inverse propensity scores as weights to directly estimate relative risk and its confidence intervals. Value Health. 2010;13(2):273\u0026ndash;277. https://doi.org/10.1111/j.1524-4733.2009.00671.x\u003c/li\u003e\n\u003cli\u003eGreifer N, Stuart EA. Choosing the causal estimand for propensity score analysis of observational studies. arXiv. 2023;2106.10577. https://doi.org/10.48550/arXiv.2106.10577\u003c/li\u003e\n\u003cli\u003eVanderWeele TJ, Ding P. Sensitivity analysis in observational research: introducing the E-value. Ann Intern Med. 2017;167(4):268\u0026ndash;274. https://doi.org/10.7326/M16-2607\u003c/li\u003e\n\u003cli\u003eRoyston P, Parmar MK. Restricted mean survival time: an alternative to the hazard ratio for the design and analysis of randomized trials with a time-to-event outcome. BMC Med Res Methodol. 2013;13:152. https://doi.org/10.1186/1471-2288-13-152\u003c/li\u003e\n\u003cli\u003eBachy E, Le Gouill S, Di Blasi R, Sesques P, Manson G, Cartron G, et al. A real-world comparison of tisagenlecleucel and axicabtagene ciloleucel CAR T cells in relapsed or refractory diffuse large B-cell lymphoma. Nat Med. 2022;28(10):2145\u0026ndash;2154. https://doi.org/10.1038/s41591-022-01937-7\u003c/li\u003e\n\u003cli\u003eStephan P, Di Blasi R, Roulin L, Galtier J, Calvani J, Meignin V, et al. TRANSCAR: real-world outcomes of CD19 CAR T-cell therapy in relapsed/refractory transformed indolent lymphomas. Blood Adv. 2025;9(18):4693\u0026ndash;4704. https://doi.org/10.1182/bloodadvances.2024018123\u003c/li\u003e\n\u003cli\u003eErbella F, Bachy E, Cartron G, Gat E, Manson G, Morschhauser F, et al. Late failure of aggressive B-cell lymphoma following CAR T-cell therapy: a LYSA study from the DESCAR-T registry. Blood Adv. 2026;10(2):392\u0026ndash;401. https://doi.org/10.1182/bloodadvances.2025011123\u003c/li\u003e\n\u003cli\u003eShumilov E, Wurm-Kuczera R, Vucinic V, Seib M, Holtick U, Mazzeo P, et al. Time of CAR-T failure is a strong predictor of outcome for bispecific antibody therapy in relapsed/refractory large B-cell lymphoma. Blood. 2024;144(Suppl 1):114. https://doi.org/10.1182/blood-2024.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-hematology-and-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jhon","sideBox":"Learn more about [Journal of Hematology \u0026 Oncology](http://link.springer.com/journal/13042)","snPcode":"13045","submissionUrl":"https://submission.nature.com/new-submission/13045/3","title":"Journal of Hematology \u0026 Oncology","twitterHandle":"@SN_Oncology","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Diffuse large B-cell lymphoma, CAR T-cell therapy, glofitamab, bispecific antibodies, comparative effectiveness, external control, real-world data, LYSA.","lastPublishedDoi":"10.21203/rs.3.rs-9288467/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9288467/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003cbr\u003e\nFailure after anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in diffuse large B-cell lymphoma (DLBCL) is associated with poor survival and no established standard of care. We previously reported the phase 2 LYSA BiCAR trial of short-ramp-up glofitamab after CAR T-cell failure. Here, we present the final survival results and a pre-specified external comparative effectiveness analysis against a contemporary control arm constructed from academic data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003cbr\u003e\nBiCAR is a multicenter, single-arm trial in adults with CD20-positive DLBCL refractory to, or in first relapse/progression after anti-CD19 CAR T-cell therapy. Participants received obinutuzumab pretreatment followed by intravenous glofitamab with an accelerated step-up to 30 mg within 8 days, then 30 mg every 21 days for up to 11 cycles. For comparative analyses, we constructed an external control arm from patients included in the French DESCAR-T registry and the ALYCANTE phase 2 trial who experienced CAR T-cell failure, who subsequently started non-bispecific systemic therapy, met key BiCAR eligibility criteria, and initiated treatment within a ±1-month window around the BiCAR treatment period. To minimise datasource bias, both arms, glofitamab (BICAR) and control, were constructed from individual patient data from the DESCAR-T registry and the ALYCANTE trial. A propensity score including major prognostic variables was estimated and applied using stabilized inverse probability of treatment weighting with multiple imputation. Additional weighting schemes and restrictions were applied in sensitivity analyses, and restricted mean survival time (RMST) was evaluated by treatment arm.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003cbr\u003e\nAmong 47 enrolled BiCAR patients, 46 received glofitamab. At a median follow-up of 30.4 months, median overall survival (OS) was 17.3 months, and the 2-year OS rate was 38.3%. For comparative effectiveness, 45 glofitamab-treated patients and 133 controls formed the analysis cohort. In the primary weighted analysis, median OS was 19.6 months for glofitamab and 7.6 months for controls, with a hazard ratio for death of 0.49 (95% CI, 0.31–0.79; \u003cem\u003eP\u003c/em\u003e=0.007). Multiple sensitivity analyses yielded consistent estimates. Glofitamab significantly improved the RMST of 5 months (\u003cem\u003eP\u003c/em\u003e=0.007) over a 2-year follow-up.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003cbr\u003e\nIn this robust comparative effectiveness study, short-ramp-up glofitamab immediately after CAR T-cell failure significantly increases the chance of survival compared to contemporaneous non–bispecific salvage therapies, supporting its use as a preferred option for eligible patients with DLBCL who fail anti-CD19 CAR T-cell therapy.\u003c/p\u003e\n\u003cp\u003eTrial registration.ClinicalTrials.gov identifier NCT04703686.\u003c/p\u003e","manuscriptTitle":"Optimized Glofitamab Schedule Halves Mortality Risk After CAR T Failure in Diffuse Large B-Cell Lymphoma: A Phase 2 Trial with External Control Arm Conducted by The LYSA Group","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-10 06:56:55","doi":"10.21203/rs.3.rs-9288467/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-29T21:23:17+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-29T08:28:12+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-28T20:27:24+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-23T09:01:35+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-22T11:35:52+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-15T06:41:00+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"70298168113452844315549481803582222131","date":"2026-04-08T01:20:43+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"11847423140538131313443982056922250664","date":"2026-04-07T13:33:17+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"60911927034297235308662137493880116532","date":"2026-04-06T15:29:43+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"71135555529346982396153744142727769222","date":"2026-04-04T14:49:39+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"194774671648953737335347100064014936914","date":"2026-04-04T03:33:42+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"279749348876949960636745465954493079885","date":"2026-04-03T20:38:21+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-03T16:32:39+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-02T01:38:05+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-02T01:37:44+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Hematology \u0026 Oncology","date":"2026-04-01T07:49:10+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-hematology-and-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jhon","sideBox":"Learn more about [Journal of Hematology \u0026 Oncology](http://link.springer.com/journal/13042)","snPcode":"13045","submissionUrl":"https://submission.nature.com/new-submission/13045/3","title":"Journal of Hematology \u0026 Oncology","twitterHandle":"@SN_Oncology","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7cbc1802-d277-4c2d-b2c0-e10cd4dc6550","owner":[],"postedDate":"April 10th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Revision requested","date":"2026-04-29T21:23:17+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-04-29T21:38:25+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-10 06:56:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9288467","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9288467","identity":"rs-9288467","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}