Hill, Brian T.

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 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.

Abstract ZUMA-8 evaluated the safety of brexucabtagene autoleucel (brexu-cel), a CD19-directed autologous chimeric antigen receptor (CAR) T-cell immunotherapy, for patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL). Patients with ≥2 prior lines of therapy (including a Bruton tyrosine kinase inhibitor) underwent leukapheresis, optional bridging therapy, and conditioning chemotherapy (fludarabine/cyclophosphamide) before infusion of 1 × 106 (cohort 1) or 2 × 106 (cohort 2) anti-CD19 CAR T cells per kg. Patients in cohort 3 (low tumor burden), and cohort 4A (postibrutinib) received 1 × 106 cells per kg. Fifteen patients, median age of 63 years (range, 52-79), were treated in cohorts 1 (n = 6), 2 (n = 3), 3 (n = 3), and 4A (n = 3). Median follow-up was 24.3 months. One dose-limiting toxicity was observed in cohort 3 (grade 4 cytokine release syndrome). Grade ≥3 neurologic events occurred in 3 patients (20%). Seven of 15 patients responded (overall response rate, 47%; complete response [CR], 7%), including all 3 patients in cohort 3 (1 with CR). CAR T-cell expansion occurred in 4 patients (27%), with an apparent weak inverse correlation with absolute lymphocyte count before apheresis. Brexu-cel had no new safety signals in R/R CLL. CAR T-cell expansion and responses occurred in patients with low tumor burden. This trial was registered at www.clinicaltrials.gov as #NCT03624036.

Abstract Chimeric antigen receptor (CAR) T-cell products axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), and lisocabtagene maraleucel (liso-cel) are approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Emerging evidence indicates that delayed CAR T-cell infusion, including prolonged time from leukapheresis to infusion, known as vein-to-vein time (V2Vt), may adversely impact clinical outcomes. We conducted a systematic literature review (SLR) and meta-analysis to identify differences in V2Vt in patients with R/R LBCL treated with axi-cel, tisa-cel, or liso-cel. The impact of V2Vt (<28 days vs ≥28 to <40 days vs ≥40 days) on effectiveness and safety outcomes was evaluated in patients treated with axi-cel enrolled in a post-authorization safety study using the Center for International Blood and Marrow Transplant Research data. SLR and meta-analysis showed that patients treated with axi-cel had the shortest median V2Vt (30.6 days) compared with tisa-cel (48.4 days) or liso-cel (35.9 days). Real-world analysis of patients treated with axi-cel demonstrated that V2Vt ≥40 days was associated with significantly lower complete response rate than V2Vt <28 days (odds ratio [OR], 0.61) or ≥28 to <40 days (OR, 0.66) and significantly worse overall survival than V2Vt <28 days (hazard ratio [HR], 1.33) or ≥28 to <40 days (HR, 1.36). Higher prolonged thrombocytopenia rates were observed in patients with axi-cel V2Vt ≥28 to <40 days or ≥40 days compared with <28 days (OR, 1.44 or 1.95, respectively). Together, these results show the impact of V2Vt on patient outcomes with axi-cel therapy and that earlier infusion with CD19-CAR therapies may be beneficial.

Introduction: Brexu-cel is an autologous anti-CD19 CAR T-cell therapy approved in the US and EU for treatment of adults with R/R MCL (after ≥2 prior therapies in EU) based on a high objective response rate (ORR; 93%; 67% complete response [CR] rate) in pts who received the pivotal dose (2×106 anti-CD19 CAR T cells/kg; Cohort 1; N=60) in ZUMA-2 (NCT02601313; Wang et al, N Engl J Med 2020). After ~4 years (y) of median follow-up, Brexu-cel demonstrated a median overall survival (OS) of 46.4 months (mo) in 68 pts with R/R MCL in Cohort 1 (Goy et al. ASH 2023). Cohort 2 was established to assess a lower dose (0.5 x 106 anti-CD19 CAR T cells/kg); however, the risk/benefit ratio of the Cohort 1 dose was deemed the optimal dose before Cohort 2 reached full enrollment. Here we report primary outcomes of Cohort 2 and 5-y outcomes of Cohorts 1 and 2. Methods: Pts with R/R MCL and ≤5 prior therapies including a BTKi received optional bridging therapy (protocol-defined), lymphodepleting chemotherapy, and 1 infusion of brexu-cel. The primary endpoint was ORR (CR + partial response [PR]) per Lugano classification (Cheson et al. J Clin Oncol. 2014) by independent radiology review committee (IRRC) assessment. Key secondary endpoints were duration of response (DOR), best objective response (BOR), progression-free survival (PFS), OS, and safety. After ≥24 mo of assessment, pts could transition to long-term follow-up (LTFU), NCT05041309, where they were monitored for late-onset targeted/serious adverse events (AEs) possibly related to brexu-cel, presence of replication-competent retrovirus (RCR), and/or insertional mutagenesis. Descriptive statistics are reported herein. Results: As of the primary analysis data cutoff date, July 24, 2019, 17 pts enrolled in Cohort 2, 14 (82%) of whom were treated with brexu-cel with median follow-up of 16.0 mo (range, 13.9-18.0). Pt characteristics for Cohort 2 (N=14) were similar to Cohort 1; median (range) age and number or prior therapies was 61.5 y (52-73) and 3 (2-5); 100% US-treated, 79% male, 71% extranodal disease, 50% intermediate or high s-MIPI scores, 50% refractory to last therapy, and 43% had prior autologous stem cell transplantation. ORR was 93% (95% CI, 66.1-99.8) per IRRC; 64% had a CR (95% CI, 35.1-87.2), 29% had a PR (95% CI, 8.4-58.1) and 1 pt was not assessed. All 14 pts had ≥1 AE of any grade (Gr), with Gr ≥3 AEs occurring in 93% of pts; the most common being hypotension (50%), white blood cell count decrease (50%), anemia (43%), and neutrophil count decrease (43%). Rates of Gr ≥3 cytokine release syndrome (CRS) and neurological events were 7% and 43%, respectively. As of April 1, 2024, median follow-up (range) for Cohort 1 and 2 was 67.8 mo (58.2-88.6; N=68) and 72.3 mo (70.1-74.3; N=14), respectively. In Cohort 1, 24 pts were still alive (35%; 2 withdrew consent and 1 lost to follow up) and 44 pts died (65%). In Cohort 2, 8 pts were still alive (57%; 2 withdrew consent and 1 lost to follow up) and 6 pts died (43%). A total of 27 pts (Cohort 1, n=23; Cohort 2, n=4) enrolled in the LTFU study by data cutoff with a median follow-up time of 70.2 mo (range, 58.2-88.6). Median (95% CI) investigator-assessed DOR and PFS were 36.5 mo (17.7-48.9; n=60; 17 patients in ongoing response, all CR) and 25.3 mo (12.7-46.6; N=68) in Cohort 1; and 57.5 mo (4.7-not estimable [NE]; n=12; 3 pts in ongoing response, all CR) and 29.5 mo (3.3-NE; N=14) in Cohort 2. Median OS (95% CI) and 60-mo OS rates (95% CI) were 46.5 mo (24.9- 60.2) and 38.5% (26.7-50.1) in Cohort 1; and not reached (9.4-NE) and 53.6% (23.8-76.2) in Cohort 2. One pt had 3 ongoing AEs on LTFU, hypogammaglobulinemia and 2 viral infections that arose prior to LTFU. Two pts died on LTFU, both due to progressive disease; no new secondary malignancies or RCR cases were reported. Conclusions: Consistent with Cohort 1, brexu-cel demonstrated a high ORR, durable responses, and an expected safety profile in pts with R/R MCL in Cohort 2 despite the lower dose. However, small sample size limits interpretation of these results. With >5 y of median follow-up, pts in Cohort 1 and 2 continued to experience durable responses with high 60-mo OS rates. No new safety signals were detected and no secondary malignancies or RCR cases were reported in LTFU. Additionally, ZUMA-2 results are consistent with real-world outcomes of brexu-cel in the post BTKi R/R MCL setting (89% ORR and 81% CR rate; Wang Y, et al. J Clin Oncol. 2023). These results support the continued use of brexu-cel in R/R MCL.

Introduction: Bispecific antibodies (BsAbs) epcoritamab (Epco) and glofitamab (Glofit) are approved in the US for the treatment of patients (pts) with relapsed or refractory (r/r) large B-cell lymphomas (LBCLs) based upon high response rates and manageable toxicity profiles reported in pivotal trials. However, data on outcomes for pts treated with BsAbs outside of clinical trials are limited. As such, we sought to investigate the safety and efficacy of Epco and Glofit for the treatment of pts with r/r LBCLs in real-world settings. Methods: We performed a retrospective study including 19 US centers evaluating pts with r/r LBCLs receiving commercially available Epco or Glofit between 2023 and 2024. Baseline characteristics and outcomes were extracted from medical records. Efficacy outcomes 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. Key safety outcomes included cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Results: As of May 31, 2024, a total of 209 pts with r/r LBCLs were treated with Epco (n=139) or Glofit (n=70). Median age at BsAb start was 67 years (interquartile range [IQR] 58-76). Most were male (62.2%), and the most common histology was diffuse large B-cell lymphoma (n=155 [74.2%]). Of pts with molecular testing (n=168), 34 (20.2%) had double/triple hit lymphoma. Most (78.9%) had Ann Arbor stage III-IV disease and 91% had an ECOG performance status of ≤1. Median number of lines of treatment before BsAb was 3 (range 1-12). Of pts with known response assessment following front-line therapy, 54 (32.1%) had primary refractory disease, defined as failure to achieve PR or CR to front-line therapy. Most pts (n=126 [60.3%]) received prior chimeric antigen receptor (CAR) T-cell therapy and 21 (10.0%) received prior autologous hematopoietic progenitor cell transplant. CD20 expression was assessed in 106 biopsies (50.7%) prior to BsAb and was positive in 90 (84.9%). A total of 172 pts were response-evaluable. The best ORR was 50.6%, with CR in 41 (23.8%), PR in 46 (26.7%), stable disease in 10 (5.8%), and progressive disease in 75 (43.6%). The ORR and CR rates were 49% and 23% for Epco, and 53% and 25% for Glofit, respectively. With a median follow-up of 5 months, the median PFS was 2.7 months (95% CI 2.0, 3.9) and median OS was 7.2 months (95% CI 6.1, not reached [NR]). The estimated PFS and OS at six months were 35% (95% CI 29%-43%) and 59% (95% CI 52%-67%), respectively. For pts who relapsed after CAR T-cell therapy, the median PFS and OS were 2.5 (95% CI 1.8, 4.7) and 7.8 (95% CI 6.2, NR) months, respectively. Pts without detectable CD20 expression via immunohistochemistry or flow cytometry prior to BsAb therapy had significantly inferior outcomes (PFS 1.1 vs 3.4 months, P < 0.001 and OS 1.3 vs 13 months, P < 0.001) compared to pts with detectable CD20. CRS of any grade occurred in 82 pts (39.2%), corresponding to 51.1% and 28.6% of pts treated with Epco and Glofit, respectively. Grade ≥3 CRS occurred in 9 (4.3%), all of whom received Epco. CRS was treated with tocilizumab in 43 pts (53.1%). ICANS occurred in 24 (11.5%) pts; any grade ICANS occurred in 13.7% and 7.1% of pts treated with Epco and Glofit, respectively. Grade ≥3 ICANS occurred in 6 pts (2.9%), 5 of which received Epco (3.6%). Of those experiencing ICANS, 66.0% were treated with corticosteroids. Two pts had deaths attributed to ICANS and one to CRS. A total of 122 (58.4%) pts discontinued therapy after a median of 3 cycles (range 0-48), 91 (74.6%) due to disease progression and 31 (25.4%) due to adverse events (15 due to infection, 3 due to ICANS, 2 due to CRS, and 11 for other reasons). Conclusions: In this heavily pretreated group with adverse disease features and high rate of CAR T exposure, the response rates, PFS, and OS following BsAb therapy were lower compared to pivotal trials. Poor outcomes were observed for those without detectable CD20. Rates of ICANS and grade ≥3 CRS were higher than reported in pivotal trials, as was the rate of discontinuation of therapy due to adverse events. Future efforts to improve outcomes may include intensified dose escalation protocols to more rapidly achieve disease control, combination therapies, and characterization of clinicopathologic factors that predict response to BsAb to identify subgroups of pts who can derive maximal benefit from these agents.

PURPOSE Axicabtagene ciloleucel (axi-cel) is an autologous CD19 chimeric antigen receptor (CAR) T-cell therapy that is approved for the treatment of relapsed or refractory large B-cell lymphoma. Little is known about the long-term survivorship after CAR T-cell therapy. METHODS We previously reported the results of 298 patients who were leukapheresed with the intent to receive standard-of-care axi-cel (n = 275 infused) after two or more previous lines of therapy at a median follow-up of 12.9 months. Here, we report extended follow-up of this cohort to a median of 58 months, with a focus on late survivorship events. RESULTS Among axi-cel–infused patients, progression-free survival at 5 years was 29% and overall survival (OS) at 5 years was 40%. The 5-year lymphoma-specific survival was 53% with infrequent late relapses. However, the 5-year nonrelapse mortality (NRM) was 16.2%, with over half of NRM events occurring beyond 2 years. Patients who were 60 years and older had a lower risk of relapse ( P = .02), but a higher risk of NRM compared with patients younger than 60 years (NRM odds ratio, 4.5 [95% CI, 2.1 to 10.8]; P < .001). Late NRM was mainly due to infections and subsequent malignant neoplasms (SMNs). In total, SMNs occurred in 24 patients (9%), including therapy-related myeloid neoplasms (n = 15), solid tumors (n = 7), and unrelated lymphoid malignancies (n = 2). CONCLUSION In the standard-of-care setting, axi-cel exhibits outcomes consistent with those reported in clinical trials, with sustained, durable responses observed at the 5-year time point. However, late infections and the development of SMN are key survivorship issues that reduce long-term survival after CAR T-cell therapy, particularly in the elderly.

7006 Background: Rituximab maintenance (RM) after first-line (1L) bendamustine and rituximab (BR) in MCL did not improve progression-free survival in the MAINTAIN trial (Rummel et al, ASCO 2016) but was associated with improved survival outcomes in a North American observational study (Martin et al, JCO 2023). We sought to examine the potential benefit of RM after BR using a large observational cohort from 26 US academic centers. Methods: Patients with MCL who received 1L BR (without stem cell transplant) outside of clinical trials were included. At the landmark of 3 months after the end of BR, patients who achieved a complete response (CR) or partial response (PR) to BR and had no evidence of progressive disease (PD) or second-line (2L) therapy were deemed eligible for RM. Event-free survival (EFS) was defined as time from landmark to progression, relapse, retreatment, or death. EFS2 was defined as time from landmark to progression, relapse, or retreatment following 2L therapy or death. RM was not considered a line of therapy for either endpoint. OS was defined as time from landmark to death. Survival analysis was done with Kaplan-Meier methods and Cox regression models adjusting for sex and simplified MIPI. Results: Among 796 patients who received 1L BR in 2007-2020, 693 achieved a CR or PR. At the 3-month post-BR landmark, 613 had no evidence of PD, among whom 318 (52%) received RM and 295 did not. The RM group was younger (median age 70 vs 72, p = 0.010) and more predominantly male (78% vs 69%, p = 0.047). There was no statistical difference in stage, simplified MIPI, histology (blastoid or pleomorphic vs classic), Ki-67, TP53 alteration, complex karyotype, year of BR start, or best response to BR between the two groups. The median follow-up after the 3-month post-BR landmark was 61.3 months (95% CI 62.6-70.4). The median number of doses of RM was 10 (IQR 5-12). RM was associated with improved EFS (median 47.1 vs 29.7 months, adjusted HR 0.59, 95% CI 0.48-0.73), EFS2 (median 89.1 vs 48.3 months, adjusted HR 0.63, 95% CI 0.50-0.81), and OS (median 136.1 vs 74.3 months, adjusted HR 0.57, 95% CI 0.44-0.75) (all p values < 0.001). In patients with CR to 1L BR (n=527), 271 (51%) received RM, for a median of 11 (IQR 6-12) doses. In this subgroup, RM was associated with improved EFS (median 60.6 vs 31.5 months, adjusted HR 0.56, 95% CI 0.44-0.71), EFS2 (median 89.1 vs 48.3 months, adjusted HR 0.62, 95% CI 0.48-0.81), and OS (median 136.1 vs 75.6 months, adjusted HR 0.59, 95% CI 0.44-0.79) (all p values < 0.001). Analysis in patients with PR to 1L BR was limited by the sample size (n=86, 47 received RM). The numeric differences in median EFS (20.8 vs 11.5, log-rank p = 0.370), EFS2 (48.9 vs 30.3, log-rank p = 0.210) and OS (87.3 vs 46.9, log-rank p = 0.067) were not statistically significant. Conclusions: In this large multicenter study, RM after 1L BR was associated with improved EFS and OS, supporting its use in routine practice for patients with newly diagnosed MCL.