Brooks, Taylor

Abstract The benefit of rituximab maintenance after first-line (1L) bendamustine-rituximab (BR) in patients with mantle cell lymphoma (MCL) remains uncertain, with inconsistent results from the phase 2 MAINTAIN trial and several retrospective studies. We conducted a large retrospective study at 27 US and Canadian academic centers to examine the benefit of rituximab maintenance after BR. A total of 911 patients received 1L BR between 2010 and 2020, and 703 had an objective response and no evidence of disease progression at the 3-month post-BR landmark. Among those, 394 (56%) received rituximab maintenance and 309 (44%) did not, with largely similar baseline patient and disease characteristics. In the landmark analysis, rituximab maintenance was associated with improved event-free survival (EFS; median, 49.9 vs 29.7 months; P< .001) as well as overall survival (OS; median, 109.5 vs 74.2 months; P< .001). The EFS and OS benefits were observed across most of the subgroups. EFS and OS differences were statistically significant in those who achieved a complete response to 1L BR (n = 590; median EFS, 62.7 vs 31.1 months [P< .001]; median OS, 136.1 vs 75.3 months [P< .001]), but the analysis among those who achieved a partial response to 1L BR was limited by the small sample size. These results provide additional evidence for the survival benefit of rituximab maintenance after BR in MCL and support its use in clinical trial design and routine practice.

Abstract Introduction: cBTKi have made a substantial impact in pts w/ MCL, but pts who develop PD while on treatment w/ cBTKi have historically had poor responses to subsequent lines of therapy (LOT). Brexucel, lisocel, and the non-covalent BTKi pirto have been approved in this population. While two RW studies have substantiated the benefit of brexucel, similar data for pirto are lacking. Accordingly, we aimed to evaluate the outcomes of pts treated w/ pirto in the RW setting. Methods: We performed a multi-center retrospective cohort study of adult pts w/ a diagnosis of MCL who experienced PD after any approved cBTKi and subsequently received pirto. Pts who received pirto w/ bridging intent and those who switched to pirto due to intolerance of cBTKi were excluded. The 95% exact binomial confidence intervals (CI) were calculated for overall response rate (ORR) and complete response rate (CRR). Progression-free survival (PFS) and overall survival (OS) were defined as the time from pirto start to PD or death, whichever occurred first, and the time from pirto start to death, respectively, and calculated w/ the Kaplan-Meier method. The log-rank test was used to compare survival curves. A multivariate (MV) Cox proportional hazard model was built to calculate adjusted hazard ratio (aHR). Analyses were performed w/ SAS, version 9.4. Results: Data on 111 pts w/ MCL treated across 21 institutions were collected. Median (mdn) age was 72 (range 33 – 93) years. Twenty-seven pts (24%) were female, 3 (3%) were Asian, 5 (5%) Black, 9 (8%) Hispanic, 86 (77%) White. Among the 53 (48%) pts w/ available MIPI-c at diagnosis, 28 (53%) pts were high-risk. Ki67 at diagnosis was available in 84 (76%) pts: of those, 58 (69%) had a Ki67 ≥30%, and 41 (49%) ≥50%. TP53 mutational status was available in 70 (63%) pts: 33 (47%) had documented TP53 mutation and 10/52 (19%) pts had a disease w/ complex karyotype. Pts had a mdn of 3 (range 1 – 9) prior LOT (n=106). Ninety-one pts (86%) received chemo-immunotherapy (CIT), 16 (15%) autologous stem cell transplant, 19 (18%) venetoclax (ven), 29 (27%) chimeric antigen receptor T-cell, 4 (4%) allogeneic stem cell transplant. For cBTKi, 39 (35%) pts received ibrutinib, 56 (50%) pts acalabrutinib, 33 (30%) pts zanubrutinib, and 17 (15%) pts received more than one cBTKi. The mdn time from the last dose of cBTKi to pirto start was 55 (range 0 – 2587) days, w/ 51 (46%) pts who switched from a cBTKi directly to pirto. Thirty (27%) pts had no response (stable disease or PD as best response) to cBTKi, and 40 (36%) pts had no response to the last LOT. Two (2%) pts received pirto in combination w/ CIT, 8 (7%) w/ an anti-CD20 monoclonal antibody (mAb), 11 (10%) w/ ven ± a mAb, while 86 (77%) pts as single agent. In 104 (94%) pts, pirto was given at full dose, 10 (9%) pts had a subsequent dose reduction. A total of 35 serious (grade ≥3) adverse events (AE) were documented in 27 (24%) pts: 4 (4%) pts had a serious bleeding AE, 5 (5%) pts a serious cardiac AE, 10 (9%) a serious GI AE, and 16 (14%) a serious infectious AE. Ninety-eight (88%) pts were evaluable for response. The ORR was 40% (95% CI 30% – 50%) w/ a CRR of 29% (95% CI 20%– 39%). At the last follow-up, 29 (26%) pts remained on pirto w/ a mdn treatment duration of 15.1 months (range 0.4 – 26). Fifty-eight (52%) pts died, 35 (78%) because of PD. At a mdn follow-up of 15.8 (range 0.4 – 26) months among survivors, the mdn PFS was 4.7 months (95% CI 3.3 – 8.2) and the mdn OS was 13 months (95% CI 9.2 – not available). Using the log-rank test, age (quartile groups), number of LOT (1-2 vs. 3-4 vs. 5+), time from cBTKi to pirto (quartile groups), Ki67≥30%, and high MIPI-C did not result in a statistically significant difference in PFS (p>0.05). Presence of TP53 mutation was associated w/ a non-statistically significant adverse trend in PFS (p=0.0585). No response to cBTKi and Ki67≥50% were associated w/ a statistically significant inferior PFS in log-rank test (p=<0.05), which persisted in a MV Cox regression model (aHR 2.4, 95% CI 1.4-4.2, and aHR 2.6, 95% CI 1.6-4.4, respectively). Conclusions: This is the first RW report on pirto in MCL pts. In this high-risk population, ORR to pirto was comparable to the BRUIN trial, while PFS was significantly worse, especially in pts w/ no response to cBTKi and w/ a high Ki67. However, prolonged remissions were seen in a subset of pts, suggesting that a better characterization of this population w/ durable benefit from pirto is needed.

Abstract Introduction: CD20xCD3 bispecific antibodies (BsAb) have been approved for use in relapsed/refractory (RR) large B-Cell lymphomas (LBCLs) with manageable toxicities. The main adverse events of clinical interest are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The risk factors for CRS and ICANS are not well understood. Knowledge of variables that contribute to increased risk may help clinicians identify and tailor management for high-risk patients (pts) and increase the comfort level for providers using these therapies in community practices. Methods: We performed a multicenter retrospective study at 21 US centers evaluating pts with RR LBCLs receiving commercially available epcoritamab (epco) or glofitamab (glofit) between 2023 and 2025. We obtained baseline characteristics, safety and efficacy outcomes. Univariate analysis was performed to identify associations between CRS, ICANS, and clinical variables of interest. Results: As of May 31, 2025, a total of 312 pts with RR LBCLs were treated with BsAb, Epco n=193 (62%), Glofit n= 119 (38%); median age 68; 63% male; 70% ECOG PS 0-1. Most common histologic type was diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS) (n=239, 84%) followed by high-grade B-cell lymphoma (HGBL) (n=46, 16%). 179 pts (57%) were previously treated with chimeric antigen receptor T-cell (CAR-T) therapy, with 47% receiving CAR-T <6 months (mo) prior to BsAb. Among pts with prior CAR-T, CRS with CAR-T therapy of any grade occurred in 63%, with 26% ≥ grade 2. ICANS of any grade (G) occurred in 25% of pts (9.4% ≥ G3). Overall and complete response (ORR and CR) rates to BsAb were 51% and 29%, respectively. With a median follow up of 5 mo, median progression-free and overall survival (PFS and OS) were 2.3 and 7.3 mo, respectively. With BsAb treatment, CRS of any grade occurred in 117 (39%) patients: 24% G1, 8.7% G2, 4% G3, 1% G4 and 1% G5. The max grade CRS occurred most frequently after the third dose of epco (35%) and the first dose of glofit (23%). CRS was managed with additional steroids in 24% of pts and tocilizumab in 22%. 13% of pts experienced ICANS: 5.8% G1, 3.4% G2, 2% G3, 1% G4 and 0.3% G5. Factors that increased the risk for any grade CRS included: bulky disease ≥ 7.5 cm at time of BsAb treatment (OR 2.04, 95% CI 1.17 – 3.55, p = 0.012), elevated LDH (OR 2.56, 95% CI 1.45– 4.76, p = 0.002) and treatment with epco compared to glofit (OR 1.69, 95% CI 1.04- 2.77, p = 0.036). As G ≥2 CRS generally requires inpatient monitoring and management, we next compared the risk factors between pts with no CRS or G1 CRS and G ≥2 CRS. Factors associated with increased risk for high grade CRS included: bone marrow involvement by lymphoma (OR 3.47, 95% CI 0.97 – 11.3, p = 0.043), platelet count ≤ 75 (OR 2.46, 95% CI 1.21 – 4.87, p = 0.011), ≥ 2 extra nodal sites (OR 2.04, 95% CI 1.07 – 3.97, p = 0.032) and ≥G2 CRS with prior CAR-T (OR 3.35, 95% CI 1.13 – 9.97, p = 0.027). Factors that increased the risk for ICANS included: bulky disease (OR 2.67, 95% CI 1.28 – 5.49, p = 0.008), elevated Cr ≥ 1.5x ULN (OR 3.79, 95% CI 1.25 – 10.4, p = 0.012), elevated AST/ALT ≥ 3x ULN (OR 4.65, 95% CI 0.92 – 19.9, p = 0.042), low albumin (OR 2.85, 95% CI 1.49 - 5.5, p = 0.002), and co-occurrence of CRS with BsAb (OR 9.1, 95% CI 3.85- 25, p < 0.001). No other clinical variables including older age, histologic subtype, ECOG PS, B symptoms, IPI score, cell of origin or histologic subtype, baseline labs such as ALC, CRP, fibrinogen or D-dimer were significantly associated with CRS or ICANS risk. There was no difference in ORR or CR rates in patients who experienced CRS or ICANS. Conclusions: Our analysis of pts treated with commercial BsAb for LBCL shows an increased risk for CRS and ICANs based on clinical variables that are routinely obtained at baseline including tumor bulk, sites of disease, laboratory parameters, and history of prior CRS with CAR-T therapy. Differences in baseline populations receiving epco and glofit treatments in this real-world analysis have been previously reported (Brooks et al, Blood 2025) and the comparative risk for CRS between these treatments remains unclear. Future plans including multivariable analysis may allow for development of a predictive model to identify pts at high risk of CRS and ICANS with BsAb treatment, potentially leading to prospective clinical trials evaluating prophylactic interventions for high-risk pts.

Abstract Introduction: Epcoritamab (epco) and glofitamab (glofit) are bispecific antibodies (BsAbs) approved for the treatment of patients (pts) with multiply relapsed or refractory (r/r) large B-cell lymphoma (LBCL). Though response rates are relatively high, most patients (pts) eventually experience progression of disease (POD). We sought to investigate the treatment patterns and clinical outcomes following POD post-BsAb for r/r LBCL Pts, as this has not previously been described. Methods: We performed a multicenter retrospective study including 21 US centers evaluating pts with r/r LBCL receiving commercially available epco or glofit between 2023 and 2025. Baseline characteristics and outcomes were extracted from medical records. Efficacy and survival outcomes were assessed by site investigators and included overall response rate (ORR), complete and partial response (CR, PR) rates, progression-free survival (PFS) and overall survival (OS), analyzed using the Kaplan Meier method. Results: As of May 15, 2025, a total of 312 pts with r/r LBCLs were treated with BsAb, of whom a total of 168 (53.8%) pts experienced POD [104 of 193 (53.8%) treated with prior epco and 64 of 119 (53.8%) treated with prior glofit]. Pts with POD had a median age at BsAb start of 67 years (interquartile range [IQR] 58-76), most were male (68.4%), and the most common histology was diffuse large B-cell lymphoma not otherwise specified (n=122 [71.8%]). Sixty-seven of 168 pts (39.9%) with POD after BsAb had experienced primary refractory disease defined as failure to achieve PR or CR to frontline therapy. A total of 102 (60.7%) pts with POD to BsAb had received chimeric antigen receptor (CAR) T-cell therapy prior to BsAbs, with 33.3% of these pts being refractory to CAR T and 30.4% progressing within 6 months of CAR T-cell infusion. The median time to progression following BsAb start was 48 days. Following POD, 70 pts received no further anti-lymphoma therapy. Among 98 pts receiving subsequent therapy, 85 initially received systemic therapy and 13 initially received local therapy with radiation (concurrently with systemic therapy in 8 pts). The most commonly-used next line of systemic therapies included: loncastuximab tesirine in 19 pts (ORR 16.7%, all PR); commercial CAR T in 11 pts (ORR 50% [CR 36.4%, PR 18.2%); tafasitamab with lenalidomide in 7 (no responses); and other chemotherapy in 46 pts (ORR 27.6% [CR 24.1%]). The median follow-up time from POD was 9.2 months among survivors (95% confidence interval [CI] 7.8-13.3). Among those who initiated subsequent-line therapy following BsAbs, the median progression-free survival (PFS2) was 1.9 months (95% CI 1.5-2.4) and median overall survival (OS) from initiation of subsequent-line therapy was 3.9 months (95% CI 2.4-5.5). The estimated 1-year OS following initiation of next therapy was 12%. Conclusions: We report the outcomes of largest cohort of pts with POD post-BsAbs in r/r LBCL. Progression events occurred early after initiation of single agent BsAbs, and almost half of pts who progressed did not receive subsequent therapy. For those who received standard subsequent-line therapy after POD, response rates and survival outcomes were poor. Pts with POD after BsAB should be strongly considered for clinical trials of novel therapeutics or combination therapies.

Abstract Background: Glofit, a CD20/CD3 bispecific antibody, has shown efficacy in prospective trials, including the Phase III STARGLO study evaluating glofit plus gemcitabine/oxaliplatin (GemOx) in transplant-ineligible patients (pts) with R/R large B-cell lymphoma (BCL). However, concerns raised by the FDA's Oncology Drug Advisory Committee regarding the generalizability of the STARGLO data to U.S. pts underscore the need for real-world evidence. We report real-world outcomes of Glofit-GemOx in U.S. pts with R/R aggressive BCL. Methods: We conducted a multicenter retrospective review across 8 U.S. academic centers, identifying 31 pts with R/R aggressive BCL treated with Glofit-GemOx outside clinical trials. Baseline characteristics, treatment history, and outcomes were abstracted from medical records. Results: At Glofit-GemOx initiation: median age was 72 years (range, 34–88); 90% had stage III/IV disease. Histologic subtypes included DLBCL in 58% (n=18), high-grade BCL in 29% (n=9), PTLD/DLBCL in 6.5% (n=2), follicular lymphoma (FL) grade 3B in 3.2% (n=1), and Burkitt lymphoma (BL) in 3.2% (n=1). Germinal center B-cell phenotype was seen in 80% of evaluable cases. Double- (n=8) or triple-hit (n=1) cytogenetics were observed in 31% (n=9). Elevated LDH was present in 74%, and 16% had B symptoms. Median ECOG performance status was 1 (range, 0–3), and 23% (n=7) had received prior CAR T-cell therapy. Pre-treatment biopsy was performed in 77% (n=24) with CD20 expression tested in 74% (n=23). CD20 expression was negative in 3 pts by flow cytometry and/or immunohistochemistry. Pts received a median 1 prior line of therapy (range, 0-6); Glofit-GemOx was administered as 1L in 7% (n=2), and 2L in 58% (n=18). Median 4 cycles (range, 1-11); both 1L pts had prior FL (1 and 3 prior lines for FL). Twelve pts remain on therapy, 2 on Glofit monotherapy. Four pts were unevaluable (2 death pre-assessment; 2 pending evaluation). Among 27 evaluable pts, ORR was 78% (21/27) and CR rate was 41% (11/27). Among CD20- negative cases on pre- Glofit-GemOx biopsy (n=3), ORR was 33% (1/3), with 1 CR lasting 3.5 months. Of 11 pts who progressed on Glofit-GemOx, 6 were rebiopsied; 1 showed CD20 loss, 1 was previously CD20-negative. Among the 24 pts who received Glofit-GemOx as destination therapy, ORR of 75% (15/20 evaluable). Among pts with prior CAR T (n=7), the ORR and CR rate were both 43% (3/7). None received Glofit-GemOx within 30 days of CAR T-cell infusion; 4 received within 6 mo; 2 of whom achieved CR. Seven pts (24%) received Glofit-GemOx as bridging to CAR T. ORR pre-CAR T was 86% (6/7); 4 pt successfully proceeded to CAR T, 2 are pending infusion, and 1 progressed after 2 cycles and transitioned to alternate therapy. Three pts were evaluable post-CAR T with an ORR of 100% (3/3) and CR rate of 67% (2/3). At data cutoff, 23/31 pts were alive. Full PFS and OS data will be presented at ASH. Notable individual responses included a patient with relapsed BL post–DA-EPOCH-R who received Glofit-GemOx as 2L therapy and achieved a 6 mo CR without consolidation before progression. Another patient treated with Glofit-GemOx in the 7L setting after prior allogeneic transplant achieved a 3 mo CR prior to progression. CRS occurred in 58% (18/31), with grade ≥3 in 13% (4/31), including 2 possible treatment-related deaths. One occurred in a frail patient after the 1st dose, though neutropenic fever was present prior to Glofit administration. The second followed influenza A infection, respiratory failure, and possible grade 4 ICANS after the 2nd dose; attribution to CRS vs. infection was unclear. ICANS occurred in 10% (3/31), with one possible grade ≥3 case. Conclusions: This is the first U.S.-based real-world analysis of Glofit-GemOx, including more U.S. pts than the STARGLO trial, appear to demonstrate comparable response rates, potentially supporting its use as both bridging and destination therapy. Notable toxicities, including CRS, were observed, with 2 possible treatment-related deaths, with plausible alternate non-treatment related causes. Favorable responses were seen in bridging therapy and high-risk subgroups (transformed, HGBCL) which were excluded in the STARGLO trial. These findings support the real-world utility of Glofit-GemOx in the management of R/R aggressive BCL but underscore the need for caution due to associated toxicities. Further real-world and prospective evaluation are warranted, particularly in rare subgroups and as bridging therapy.

Abstract Background Chimeric antigen receptor T-cell (CAR-T) and bispecific antibody (BsAb) therapies are both effective for patients with relapsed/refractory (R/R) follicular lymphoma (FL), but differ in treatment schedules and associated “time toxicity,” or contact days spent physically interacting with the healthcare system. While contact days can be estimated from clinical trials, real-world data provides a more nuanced depiction of treatment-related time burden, which may guide treatment decision-making. The comparative time toxicity of CAR-T vs BsAb in R/R FL is not defined. Methods We conducted a multicenter retrospective study of adults with R/R grade 1-3A FL who received standard-of-care CAR-T (axi-cel, tisa-cel, liso-cel) or BsAb (mosunetuzumab, epcoritamab) in the third-line or later setting before Jan 1, 2025. Time toxicity was defined as outpatient or inpatient days with physical health care system contact, counting multiple visits on the same day as only one day. All days after treatment initiation were counted, regardless of disease progression, therapy completion, or relation to FL therapy. Median contact days over 1-year time horizon were compared, stratified by CAR-T vs BsAb, prior lines of therapy (LOT, 2 vs 3+), and time intervals (0-1, 1-3, 3-6, 6-9, and 9-12 months). Progression-free survival (PFS) and overall survival (OS) were calculated from day of CAR-T infusion or day 1, cycle 1 for BsAb. Cox regression and propensity matching (by age, ECOG, refractory to prior LOT, POD24) were used to assess predictors and survival associations with contact days. Results Among 209 patients from 15 U.S. academic centers, median age was 64, 37% were female, 61% received CAR-T (80% axi-cel, 7% liso-cel, 13% tisa-cel) and 39% BsAb (93% mosun, 7% epcor). Most had Grade 1-2 FL (72%), advanced stage (84%), and extranodal disease (51%). Median prior LOT was 3 (range 2-15), 41% were refractory to prior LOT, and 52% had POD24. Median number of BsAb doses was 10 (range 1-36). Patients receiving BsAb were significantly older (p<.01) and had higher CIRS comorbidity scores (p<.02) in both 2 and 3+ prior LOT cohorts, and had higher ECOG scores (p=.01) and were less likely to be refractory to prior LOT (p=.029) in 3+ LOT cohort. There were no differences in POD24 rates between CAR-T and BsAb. Median PFS for the entire cohort was 3.6 yrs; median OS was not reached. In the 2 prior LOT cohort (N=75), 60% received CAR-T and 40% BsAb. With median follow-up of 1.5 years, median PFS was not reached for CAR-T and 1.6 yrs for BsAb (p<.0001). In the 3+ prior LOT cohort (N=134), 62% received CAR-T and 38% BsAb. With median follow-up of 2 yrs, median PFS was 3.6 yrs for CAR-T and 1.6 yrs for BsAb (p=.0044). In propensity matched analysis, PFS was shorter for BsAb in both 2 LOT (HR 9.0, 95% CI 1.14-71.04, p=.037) and 3+ LOT (HR 3.25, 95% CI 1.06-9.97, p=.039) cohorts as compared to CAR-T. There were no significant differences in OS between CAR-T and BsAb. Median contact days were significantly higher for CAR-T vs BsAb in the 0-1 month interval: 19 vs 8 days in 2 LOT (p<.0001) and 18 vs 7 days in 3+ LOT (p<.0001) cohorts. There were no differences in contact days between CAR-T vs BsAb in subsequent time intervals. Over 1 year, CAR-T had significantly more time toxicity than BsAb: median 51 vs 36 contact days in 2 LOT (p<.0001) and 64 vs 38 days in 3L+ LOT (p<.0001) cohorts; these remained significant in the matched analysis. B symptoms (p=.04) and Grade ≥3 cytopenias (p=.007) were associated with higher contact days in 3+ LOT cohort in univariable analysis. Higher contact days were associated with inferior PFS (HR 1.01, 95% CI 1.00-1.02, p=.032) and OS (HR 1.01, 95% CI 1.00-1.02, p=.038) in 3+ LOT cohort regardless of treatment type. Discussion In this large real-world cohort of patients with R/R FL, CAR-T therapy resulted in better PFS but more time toxicity over the first year as compared to BsAb therapy. Excess time toxicity from CAR-T was driven by more contact days in the first month of treatment. This study provides benchmark data for counseling patients about expected time burden of CAR-T (51-64 days) and BsAb (36-38 days) over the first year of these therapies. Further, with superior PFS of CAR-T in this study and minimal impact of time toxicity on survival outcomes, these data can be used to better support shared decision-making in R/R FL by addressing patient preferences regarding both contact days as well as duration of disease control.

Abstract The treatment patterns and clinical outcomes for patients experiencing progression of disease (POD) following CD19-directed chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory (R/R) mantle cell lymphoma (MCL) are undefined. We identified all patients who received CD19-directed CAR T-cell therapy for R/R MCL therapy across 15 international centers, and studied those experiencing POD post–CAR T-cell therapy in detail. We extracted clinical/treatment/pathologic variables, and associated these features with survival outcomes. In total, 384 patients received CAR T-cell therapy, and 135 (35%) experienced POD. POD occurred at a median of 6 months following CAR T-cell therapy infusion, and most (64%) patients with POD had complete response as best response to CAR T-cell therapy. Tumor features at POD included blastoid/pleomorphic morphology in 29 of 78 (37%) patients, and TP53 mutation in 21 of 41 (51%) patients. Following POD, 17 patients received no further therapy, 13 underwent local therapy, and 105 received systemic therapy. The most common first-line systemic therapies were chemo(immuno)therapy (22 patients; overall response rate [ORR], 40%), pirtobrutinib (17 patients; ORR, 36%), and bispecific antibodies (13 patients; ORR, 67%). Among patients experiencing POD, the median progression-free survival and overall survival (OS) were 2.5 months and 5.4 months, respectively, from POD. Lack of response to CAR T-cell therapy and short time from CAR T-cell therapy infusion to POD (<3 vs 3-6 vs >6 months), among other factors, were associated with inferior OS after POD. In conclusion, we confirm the challenging prognosis for patients experiencing POD following CD19 CAR T-cell therapy for R/R MCL, and establish a benchmark for future investigations in this patient population.

Abstract Epcoritamab and glofitamab are CD20-directed bispecific antibodies (BsAbs) approved in the United States for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Limited data exist for patients treated outside of trials. Patients with R/R DLBCL receiving commercial epcoritamab or glofitamab between 1 January 2023 and 15 October 2024 were collected from 21 United States institutions. Among 245 patients, 156 received epcoritamab and 89 received glofitamab, 113 were refractory to front-line therapy, 40 had MYC and BCL2 and/or BCL6 rearrangements, 147 received prior chimeric antigen receptor T-cell therapy, and 174 patients would have been ineligible for registrational trials. The overall response rate (ORR) for epcoritamab and glofitamab was 51% (23% complete response, [CR]) and 53% (30% CR), respectively. Median progression-free survival (PFS) was 2.6 months (95% confidence interval [CI], 2.0-3.8 months), and median overall survival (OS) was 7.8 months (95% CI, 6.2-11.0 months). The 6-month PFS was 36% (95% CI, 30-44) and the 6-month OS was 60% (95% CI, 54-67). Both trial ineligibility and undetectable CD20 pre-BsAbs portended shorter PFS and OS. Of 17 individuals with paired biopsies, 15 (88.2%) lost CD20 expression after BsAbs with a median time to progression of 3.7 months. This analysis including patients with R/R DLBCL shows the ORR to CD3/CD20 BsAbs was comparable to pivotal trials, although PFS and OS were lower. Baseline undetectable levels of CD20 were associated with poor outcomes. These results demonstrate the activity of BsAbs in R/R DLBCL, and underscore the importance of target antigen expression.

Background: CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy is an established treatment with high efficacy in treating relapsed or refractory (R/R) mantle cell lymphoma (MCL). However, with CAR-T therapy, refractory disease occurs and a continuous pattern of relapse over time has been observed. Limited data exist about post-CAR-T progression of disease (POD) management and outcomes in MCL. Such data would meaningfully inform practice and set a critical benchmark for future studies in the post-CAR-T setting. We characterized treatment patterns and outcomes for pts with POD after CD19 CAR-T therapy for R/R MCL. Methods: We queried institutional databases to identify pts with R/R MCL who received CD19-directed CAR-T therapy. Treatment may have occurred as standard-of-care or in a clinical trial. We performed chart review to extract variables and categorized therapies by mechanism(s) of action. We used descriptive statistics to characterize patient/disease characteristics and treatment patterns, the reverse Kaplan-Meier method to calculate follow-up, the Kaplan-Meier method to calculate survival, and Cox proportional hazards to associate clinical and disease features with survival outcomes. Results: Across 9 sites, we identified 306 pts who received CD19 CAR-T for R/R MCL, of which 104 (34%) experienced POD and were investigated in detail: pts with POD were mostly men (73%), had a median age of 67 yrs (range 36-86) at infusion, and had received a median of 3 lines of therapy pre-leukapheresis, including a BTK inhibitor (BTKi) in 97% of patients; 36% of BTKi-exposed patients had BTKi-unresponsive disease. High-risk tumor features were common pre-CAR-T: 47/68 (69%) with a TP53 mutation, 66/93 (71%) with Ki67 ≥50%, and 47/102 (46%) with blastoid/pleomorphic MCL. Most pts (75%) received bridging therapy. Pts received brexucabtagene autoleucel (88%) or lisocabtagene maraleucel (12%). Regarding best CAR-T response for pts with POD, 71% had a complete response (CR), 13% partial response (PR), and 15% had no response. The median time from CAR-T infusion to POD was 6 months (IQR 3-12). At time of POD, high-risk MCL features were again common: 55% blastoid/pleomorphic, 42/56 (75%) Ki67 ≥50%, 51/83 (61%) MIPIb high-risk, and 21/35 (60%) TP53-mutated MCL. Among 69 pts with CD19 assessed on a post-POD biopsy, 8 (12%) had CD19-negative disease. 30% of pts had an ECOG performance status of ≥2 at time of POD. After POD occurred, 15 pts received no anti-lymphoma therapy (Tx), 11 pts underwent excision or radiation, and 78 pts received systemic therapy. The most commonly used first-line systemic Tx post-CAR-T progression included: pirtobrutinib in 13 pts [overall response rate (ORR) 31%], chemoimmunotherapy in 12 pts (ORR 25%), venetoclax in 10 patients (ORR 20%), bispecific antibodies (BsAb) in 10 pts (ORR 60%), and small molecule combinations (at least 2 of BTK inhibitor, BCL2 inhibitor, and lenalidomide) in 8 patients with ORR 50%. The ORR to all first systemic Tx post-POD was 42%. The median follow-up from POD is 15.2 months among survivors. The median progression-free and overall survival (OS) from time of POD were 2.3 (95% CI 1.9-3.4) and 5.4 months (95% CI 4.5-9.4), respectively, and 1-year OS rate was 33%. TP53 mutations predicted inferior OS (HR 2.83, 95% CI 1.08-7.43, P = 0.026) as did age ≥65 years at time of POD (HR 1.83, 95% CI 1.07-3.15, P = 0.023), MIPIb high-risk (HR 3.56, 95% CI 1.08-11.7, P = 0.042), and non-response to CAR-T (HR 3.55, 95% CI 1.93-6.53, P < 0.001). Discussion: Our data, the largest reported cohort of pts with POD post-CAR-T with R/R MCL, confirm the poor prognosis in this patient population, with a median OS of 5.4 months. BsAbs showed promise with an overall response rate of 60%. The presence of a TP53 mutation significantly predicted inferior OS, corroborating the prognostic importance of this finding in the post-CAR-T context. Data from pts treated at additional sites and updated analyses will be presented at the meeting.