Prior Autologous Stem Cell Transplant Research Articles

Abstract 6327: Impact of G-CSF on safety and efficacy of CAR T-cell therapy in non-Hodgkin lymphoma

Abstract Introduction: Chimeric antigen receptor T-cell (CAR-T) therapy is an established treatment modality for the management of refractory and/or relapsed non-Hodgkin lymphoma (NHL). Despite restrictions on granulocyte colony-stimulating factor (G-CSF) use in registration clinical trials due to potential worsening of cytokine release syndrome (CRS), G-CSF is often prescribed for neutrophil recovery post-CAR-T in clinical practice. We conducted a retrospective study to assess the association between G-CSF use and the safety and efficacy of CAR-T. Methods: Following Institutional Review Board approval, we retrospectively analyzed NHL patients receiving commercial CD19-targeted CAR-T across Mayo Clinic sites (Arizona, Florida, and Minnesota) between October 2017 and May 2023. Demographics, labs, and post CAR-T events were collected. Electronic medical records were reviewed for G-CSF exposure within Day 1 - 100 post-CAR T. Differences by G-CSF status were examined using a Chi-square test and Kruskal Wallis tests. Hazard ratios (HR) and 95% confidence intervals (CI) for overall survival (OS) were calculated using Cox model. Results: Among 270 CAR-T patients; 106 received G-CSF within 30 days and 164 did not. Median age was 56.9 with G-CSF and 58.3 without G-CSF. Most were male (75.2% G-CSF, 62.6% no G-CSF). Diffuse large B cell lymphoma was the predominant NHL subtype (67.0% G-CSF, 65.2% no G-CSF). G-CSF within 30 days was not associated with reduced incidence of neutropenic fever (11.7% G-CSF vs 9.9% no G-CSF, p = 0.6593) or documented infection (22.1% vs 18.3%, p = 0.4439). G-CSF correlated with decreased profound neutropenia duration (ANC < 100 μL, 0 vs 2 days, p < 0.0001) and incidence within 30 days ( 31.7% vs 60.4%, p < 0.0001) as well as incidence of protracted profound neutropenia (> 7 days, 3.8% vs 22.8%, p < 0.0001). G-CSF was associated with a higher incidence of cytopenias between days 30 -100: severe neutropenia (ANC < 500/uL, 28.8% vs 15.2%, p = 0.0075), severe anemia (Hb < 8 g/dL, 21% vs 9.7%, p = 0.0114), and severe thrombocytopenia (Plt < 50 g/L, 35.2% vs 20.9%, p = 0.0099). Logistic regression analysis showed that none of the examined covariates, including prior autologous stem cell transplant, ECOG PS score, and receipt of bridging therapy, were associated with severe neutropenia likelihood. G-CSF was associated with a higher CRS incidence (89.6% vs 79.9%, p = 0.0343), but grade 3 CRS or higher (4.7% vs 3.7%, p = 0.6675) was no different. No difference in complete response rates (66% vs 61.1%, p = 0.4707) or 2-year OS (p = 0.523) was observed between the 2 groups. Conclusion: G-CSF within 30 days was associated with reduced duration and incidence of profound neutropenia without a significant impact on incidence of neutropenic fever or documented infections. There was a signal of association between G-CSF and increased incidence of low-grade CRS and delayed cytopenias (day 30-100) that warrants confirmation in larger studies. Citation Format: Lay She Ng, Claire I. Yee, Radhika Bansal, Mohamed A. Kharfan-Dabaja, Grzegorz S. Nowakowski, Allison C. Rosenthal, Javier Munoz, Januario Castro, Wern Lynn Ng, Hemant S. Murthy, Yi Lin, Matthew R. Buras, Madiha Iqbal, Yucai Wang, Talal Hilal. Impact of G-CSF on safety and efficacy of CAR T-cell therapy in non-Hodgkin lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6327.

Matching-Adjusted Indirect Comparison of Brexucabtagene Autoleucel (ZUMA-2) and Pirtobrutinib (BRUIN) in Patients with Relapsed/Refractory Mantle Cell Lymphoma Previously Treated with a Covalent Bruton Tyrosine KinaseInhibitor.

Patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) often require multiple lines of treatment and have a poor prognosis, particularly after failing covalent Bruton tyrosine kinase inhibitor (cBTKi) therapy. Newer treatments such as brexucabtagene autoleucel (brexu-cel, chimeric antigen receptor Tcell therapy) and pirtobrutinib (non-covalent BTKi) show promise in improving outcomes. Without direct comparative evidence, an unanchored matching-adjusted indirect comparison was conducted to estimate the relative treatment effects of brexu-cel and pirtobrutinib for post-cBTKi R/R MCL. Using logistic propensity score models, individual patient-level data from ZUMA-2 brexu-cel-infused population (N = 68) were weighted to match pre-specified clinically relevant prognostic factors based on study-level data from the BRUIN cBTKi pre-treated cohort (N = 90). The base-case model incorporated the five most pertinent factors reported in ≥ 50% of both trial populations: morphology, MCL International Prognostic Index, number of prior lines of therapy, disease stage, and prior autologous stem cell transplant. A sensitivity analysis additionally incorporated TP53 mutation and Ki-67 proliferation. Relative treatment effects were expressed as odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals (CIs). In the base-case model, brexu-cel was associated with higher rates of objective response (OR 10.39 [95%CI 2.81-38.46]) and complete response (OR 10.11 [95%CI 4.26-24.00]), and improved progression-free survival (HR0.44 [95%CI 0.25-0.75]), compared to pirtobrutinib. Overall survival and duration of response favored brexu-cel over pirtobrutinib but the differences crossed the bounds for statistical significance. Findings were consistent across the adjusted and unadjusted analyses. Findings suggest that brexu-cel may offer clinically and statistically significant benefits regarding objective response, complete response, and progression-free survival compared to pirtobrutinib among patients with R/R MCL after prior cBTKi therapy. Given the short follow-up and high degree of censoring in BRUIN, an analysis incorporating updated BRUIN data may provide more definitive overall survival results.

Efficacy of Selinexor in Relapsed/Refractory Multiple Myeloma (RRMM) Patients with del17p and Other High-Risk Abnormalities (A Retrospective Single-Center Study).

Selinexor (Seli) is a first-in-class, oral selective inhibitor of the nuclear export protein, exportin-1 (XPO1). Seli exhibits its antitumor effect through the blockage of XPO1, which increases nuclear retention of tumor suppressor proteins (TSPs), including p53, thereby limiting the translation of oncogenes, triggering cell cycle arrest and the death of malignant cells. Multiple Myeloma (MM) patients with del17p are deficient in TP53 and have a particularly poor prognosis. Given its unique mechanism of action, we investigated whether Seli has increased efficacy in RRMM patients with del17p compared to other high-risk cytogenetics (OHRC). This is an IRB-approved observational study of RRMM patients with high-risk cytogenetics (del17p, t (4;14), t (14;16) or gain 1q) or standard-risk cytogenetics treated at the Levine Cancer Institute (LCI) with a Seli-based regimen between January 2019 and December 2022. Time-to-event endpoints (PFS, OS) were evaluated using Kaplan-Meier (KM) methods. Log-rank tests compared time-to-event endpoints between cohorts [del17p vs. OHRC vs. standard risk]. We identified 40 RRMM patients with high-risk cytogenetics, including 16 patients with del17p and 24 patients with OHRC, as well as 20 with standard-risk cytogenetics. The median age was 62.5 vs. 69 vs. 65.5 years (del17p group vs. OHRC vs. standard risk). The median prior line of therapies was five (range: 3-16) with similar rates of prior autologous stem cell transplant in all arms (68.8% vs. 62.5% vs. 70.0%). The most frequently used regimens were Seli-Pomalidomide-dexamethasone(dex) or Seli-Carfilzomib-dex (Seli-Kd) in the del17p group and Seli-Kd in the OHRC and standard-risk groups. The median time to start the Seli-based regimen after initial MM diagnosis was 5.6 years for the del17p group, 4.1 years in OHRC, and 4.8 years in the standard-risk group. The median follow-up time after the start of the Seli-based regimen was 10.5 months (mos) in the del17p group, 8.4 mos in OHRC, and 10.3 mos in the standard-risk group. In the del17p group, 50% had an objective response, 41.7% in the OHRC, and 35% in the standard-risk group (p = 0.71). Depth of response was also similar across the arms (12.5% vs. 12.5% vs. 10.0% VGPR p = 0.99). The median OS was 10.9 mos in the del17p group, 10.3 mos in the OHRC, and 10.3 mos in the standard-risk group (p = 0.92). The median OS was 15.5 mos for patients who received Seli as a bridging therapy versus 9 mos for Seli use for other reasons rather than as a bridge. Overall, Seli-based regimens showed promising responses even in this heavily pretreated population. Our analysis suggests that Seli-based regimens lead to similar outcomes among RRMM patients with del17p, OHRC, and standard-risk cytogenetics. This contrasts with previously reported outcomes using combinations of novel therapies in this population, where the del17p patients often have a poorer prognosis. Interestingly, our data suggest that Seli is a particularly effective bridging modality for patients preparing for CAR-T cell therapies in our population. Further investigation into this population is warranted, including in earlier lines of therapy, in hopes of seeing a more durable response.

Treatment-Related Risk Factors for Adverse Outcomes of COVID-19 in Patients Treated for Lymphoid Malignancies in the Pre-Omicron Era-A Study of KroHem, the Croatian Group for Hematologic Diseases.

Patients with lymphoid malignancies are at increased risk of death or prolonged infection due to COVID-19. Data on the influence of different antineoplastic treatment modalities on outcomes are conflicting. Anti-CD20 monoclonal antibodies increase the risk of prolonged infection. It is unclear whether this risk is affected by the choice of the antibody (rituximab vs. obinutuzumab). To elucidate the role of antineoplastic therapy on COVID-19 outcomes, KroHem collected data on patients with lymphoid malignancies diagnosed with COVID-19 between October 2020 and April 2021. A total of 314 patients were identified, 75 untreated, 61 off treatment and 178 on treatment. The mortality rate in untreated and off-treatment patients was 15% and 16%; 9% and 10% had prolonged infection. In the on-treatment group, 3% were still prolonged positive at time of data collection, 62% recovered and 35% died; 42% had prolonged infection. Disease type, use of anti-CD20 monoclonal antibodies, prior autologous stem-cell transplantation (ASCT) and line of treatment did not significantly affect mortality. Mortality was higher in older patients (p = 0.0078) and those treated with purine analogues (p = 0.012). Prolonged COVID-19 was significantly more frequent in patients treated with anti-CD20 monoclonal antibodies (p = 0.012), especially obinutuzumab, and purine analogues (p = 0.012). Age, prior ASCT and treatment line did not significantly affect risk of prolonged infection. These data suggest that increased age and use of purine analogues are main risk factors for increased mortality of COVID-19 in patients with lymphoid malignancies. Obinutuzumab further increases the risk of prolonged disease, but not of death, in comparison to rituximab. Epidemiological considerations should be taken into account when choosing the appropriate antineoplastic therapy for patients with lymphoid malignancies.

Long-Term Outcomes from the Phase 3 OCEAN (OP-103) Study: Melflufen and Dexamethasone (Dex) Versus Pomalidomide (Pom) and Dex in Relapsed Refractory Multiple Myeloma (RRMM)

Background/Introduction: Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases resulting in rapid release of alkylating agents inside tumor cells. Based on the phase 2 HORIZON study and supported by the phase 3, randomized, controlled OCEAN study, melflufen was approved in Europe for use in patients (pts) with triple-class refractory RRMM with ≥3 prior lines of therapy (LoTs) and without prior autologous stem cell transplantation (ASCT) or with a time to progression (TTP) >36 mo after prior ASCT. In the OCEAN study (NCT03151811), melflufen + dex showed superior progression-free survival (PFS) compared with pom + dex (6.8 vs 4.9 mo; hazard ratio [HR]: 0.79; P=0.032); PFS benefit in the melflufen + dex group was mainly driven by pts who had not received prior ASCT. Overall survival (OS) trended in favor of melflufen + dex in pts without prior ASCT and favored pom + dex in pts with prior ASCT (Schjesvold et al. Lancet Haematol. 2022;9:e98). Post-hoc analyses of OCEAN and HORIZON demonstrated that a TTP <36 mo after prior ASCT was a negative prognostic factor for OS with melflufen + dex (Sonneveld et al. Clin Lymphoma Myeloma Leuk. 2023;S2152). Here, we present long-term OS and safety data from the final analysis of the OCEAN study. Methods: Pts with RRMM (2-4 prior LoTs including lenalidomide [len] and a proteasome inhibitor) refractory to len and last LoT were randomized 1:1 (stratified by age, no. of prior LoTs, and International Staging System score) to receive 28-day (d) cycles of melflufen 40 mg intravenously on d1 or pom 4 mg orally (PO) daily on d1 to 21. All pts received dex 40 mg (20 mg for pts ≥75 y) PO on d1, 8, 15, and 22. Pts received therapy until disease progression or unacceptable toxicity. The primary endpoint was PFS, as assessed by independent review committee per IMWG Uniform Response Criteria, and key secondary endpoints were overall response rate, OS, and safety. Results: As of 3 Feb 2023, 495 pts were randomized (246 to melflufen; 249 to pom); median age was 68 y (range, 39-91) and median prior LoTs was 3. In the intent-to-treat (ITT) melflufen and pom populations, median OS was 20.2 mo vs 24.0 mo (HR, 1.09 [95% CI, 0.88-1.35]), at a median follow-up of 40.3 mo and 38.1 mo, respectively. In the target subgroup of the melflufen and pom groups (pts without a prior ASCT or TTP >36 mo after an ASCT), median OS was 23.6 mo vs 19.1 mo (HR, 0.88 [95% CI, 0.67-1.16]); in the non-target population (pts with TTP <36 mo after ASCT), median OS was 15.7 mo vs 27.5 mo (HR, 1.60 [95% CI, 1.15-2.21]), respectively. While any grade hematologic toxicities were more common with melflufen, the occurrence of non-hematologic toxicities was similar in the 2 groups. Grade 3/4 (G3/4) treatment-emergent adverse events (TEAEs) in the safety population (melflufen [n=228] and pom [n=246]) occurred in 90% vs 76% of pts, respectively; most commonly thrombocytopenia (78% vs 13%; occurring with G3/4 hemorrhage in 1% vs 0%), neutropenia (64% vs 50%; occurring with G3/4 infections in 4% vs 7%), anemia (43% vs 19%), and infection and infestations (14% vs 24%). Serious AEs occurred in 43% vs 50% of pts (including pneumonia [6% vs 9%], COVID-19 pneumonia [5% vs 6%], and anemia [4% vs 2%]), and fatal AEs in 14% vs 15% (including COVID-19 pneumonia [4% vs 2%] and pneumonia [2% vs 2%]) in the melflufen and pom groups, respectively. With melflufen and pom, TEAEs led to dose reductions in 52% vs 28% of pts (most frequently thrombocytopenia [32% vs 2%] and neutropenia [12% vs 8%]), and discontinuations in 30% vs 24% of pts, respectively. Deaths occurred in 74% vs 68% of pts in the melflufen and pom groups, with AEs being the primary cause of death ≤30 d after last dose in 8% and 11%, respectively. Conclusion: Long-term results were consistent with those of previous analyses (Schjesvold, et al. Lancet Haematol. 2022;9:e98-e110). While OS trended in favor of pom in the ITT population, OS outcomes continued to be more favorable with melflufen in pts with no prior ASCT or with TTP >36 mo after ASCT. No new safety signals were reported, and AEs were manageable with dose modifications, consistent with previous reports. This long-term follow-up of OCEAN confirms the favorable safety and OS outcomes of melflufen + dex in the target population and supports its continued use as an alternative treatment choice for pts with RRMM who have received ≥2 prior LoT and who have not received ASCT.

Outcomes in Patients with Classical Hodgkin Lymphoma Refractory or Intolerant to Brentuximab Vedotin and Anti-PD-1 Therapy: Real World Analysis from 14 U.S. Academic Centers

Background: Brentuximab vedotin (BV) and anti-PD-1 therapies (nivolumab and pembrolizumab) have changed the therapeutic landscape for patients (pts) with classical Hodgkin lymphoma (cHL) over the past decade. Although first proven to be beneficial in relapsed and refractory cHL, these therapies have moved earlier in the treatment algorithm given superior response rates and survival compared to cytotoxic chemotherapy alone. However, there is limited data regarding outcomes in pts who progress after both BV and anti-PD-1 therapies (double refractory, DR) or become intolerant (INT) of these therapies. Knowledge of outcomes in this subset of pts is important as BV and anti-PD-1 therapies are increasingly used in front-line treatment and early relapsed cHL. Methods: We conducted a retrospective study of adult pts from 14 U.S. academic medical centers who developed DR cHL or became INT of BV and/or anti-PD-1 therapy between January 2011 and December 2021. DR was defined as treatment failure (evidence of progression by imaging or biopsy) during therapy or within 3 months of the last dose of both BV and anti-PD-1 therapy. INT was defined as any toxicity limiting further cycles of BV or anti-PD-1 therapy. Pts with INT were either intolerant to both BV and anti-PD-1 or intolerant and refractory to BV or anti-PD-1. The primary endpoint was assessment of overall survival from time of cHL diagnosis (OS-1) and from DR or INT (OS-2). Secondary endpoints included description of pt characteristics developing DR or INT cHL, estimate of OS comparing DR versus INT, and estimate of OS stratified by prior autologous stem cell transplant (ASCT) at the time of DR/INT. Time-to-event analyses were evaluated by Kaplan-Meier methodology. INT pts were not included in time to progression (TTP) analysis for initial BV or anti-PD-1 therapy. Results: 158 pts were eligible. Clinical characteristics at diagnosis included median age 33 years (range 16-89), 61% male, 77% white race, 66% nodular sclerosing subtype, 47% stage IV, and 56% with B symptoms. Front-line treatment was ABVD/AVD in 122 pts (77%) and BV or anti-PD-1 therapy in 28 pts (18%). 60% had primary refractory cHL (n=94). Table 1 describes pt characteristics in detail. Initial BV treatment was after a median of 2 lines of therapy (LOT) (range 0-7). The majority (60%, n=94) were treated with BV monotherapy and 15% (n=24) were treated with BV combined with anti-PD-1 therapy. Median TTP of BV refractory pts was 168 days (95%CI 138-190). Initial anti-PD-1 therapy was after a median of 3 LOT (range 0-12). Nivolumab was the most commonly used (72%) anti-PD-1 therapy. Median TTP of anti-PD-1 refractory pts was 223 days (95%CI 166-271). DR cHL was observed in 119 pts (75%), while 39 pts (25%) were INT. The median time from cHL diagnosis to DR/INT was 3.3 years (95%CI 0.5-23.1). At the time of DR/INT, 47% (n=75) had prior ASCT. The majority (87%, n=137) received subsequent LOTs after DR/INT (median 2, range 0-14). Table 1 describes DR/INT in detail. The median OS from the time of cHL diagnosis (OS-1) in all pts was 15.0 years (95%CI 9.4-20.9). There was no difference in OS-1 between DR and INT pts (log-rank p=0.83) or primary refractory and front-line relapsed pts (log-rank p=0.94). Pts who developed DR/INT at any time after ASCT had a significantly longer OS-1 compared to DR/INT without prior ASCT with a median OS of 19.1 years (95%CI 19.1-NR) versus 8.6 years (95%CI 5.3-15.0), respectively (log-rank p<0.001, Figure 1). Comparing pts with prior ASCT and no prior ASCT, the median age at DR/INT was 35 (range 20-75) versus 49 (range 18-90) years, Fisher's exact p=0.01. Adjusting for age at DR/INT did not impact the association between prior ASCT and improved OS, Cox proportional hazard ratio 0.48 (95%CI 0.25-0.90, p=0.02). Median OS from time of DR/INT (OS-2) was 7.4 years (95%CI 4.1-NR). OS-2 was not different between DR and INT pts (log-rank p=0.33). Conclusion: To our knowledge, this is the largest cohort of pts refractory to, or intolerant of BV and anti-PD-1 therapy. OS was longer than anticipated both from diagnosis and from time of DR/INT. Pts who were DR/INT after ASCT had a significantly longer OS. Further investigation is needed to determine if OS differences by ASCT may be due to disease biology or sequencing of therapies. Importantly, OS-2 serves as a benchmark for future clinical trials evaluating DR/INT cHL pts.

Real-World Multicenter Study of PD-1 Blockade in HIV-Associated Hodgkin Lymphoma across the United States

Background: Despite a 5 to 20-fold higher risk of Hodgkin lymphoma (HL) in people with HIV (PWH) than the general population, PWH were excluded from clinical trials that led to the approval of anti-PD-1 agents (PD-1) in HL. PD-1 have overall response rates (ORR) of 65-70% in the general population and are used in all lines of HL therapy. Several prospective and retrospective studies have shown PD-1 are safe in PWH, but they remain underutilized in HIV-associated HL (HIV-HL) where data are limited. Methods: Patients (pts) with HIV-HL were identified from the retrospective, international database, “Cancer Therapy using Checkpoint inhibitors in PWH-International (CATCH-IT)” consortium, that is maintained at the Dana-Farber Cancer Institute (DFCI) and approved by DFCI and local institutional review boards. Pts who received either nivolumab or pembrolizumab, alone or in combination with other agents were included. Records were reviewed for demographics, HL and HIV characteristics, and treatment data. Safety was evaluated by the occurrence of immune-related adverse events (irAEs) per Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Response to treatment was evaluated using descriptive statistics, and immune reconstitution was measured by changes in CD4 + T cell counts (CD4) from prior to end of PD-1 therapy via paired t-tests. ORR was defined as the proportion of pts with partial or complete response (PR/CR) per the 2014 Lugano classification for HL. Duration of response (DOR) was defined as the time from the date of the first CR or PR to the date of progressive disease (PD) or death. Progression-free survival (PFS) was defined as the time from PD-1 initiation to disease progression, death, or censored on the date of the last follow-up. Overall survival (OS) was defined as the time from PD-1 initiation to death or censored at the last follow-up. DOR, PFS, and OS were evaluated by Kaplan-Meier methodology. Results: We identified 23 pts with HIV-HL from 12 institutions in the United States: 20 cisgender men, 3 cisgender women; 10 Black,10 White, and 10 Hispanic; median age 48 years [interquartile range (IQR): 36-58]. At HL diagnosis, 19 (83%) pts had advanced stage disease, and in 20 pts where EBV status of the tumor was known, all were positive. Nine (39%) pts had primary refractory disease. The median number of prior systemic therapies was 2 (IQR: 1-3). One pt had PD-1 as 1 st-line therapy, 6 had PD-1 as 2 nd-line therapy, and 16 had PD-1 as ≥3 rd-line therapy. Fourteen (61%) pts received doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as 1 st-line therapy. Two pts had prior autologous stem cell transplant (ASCT). At the time of PD-1 initiation, 22 pts (96%) had advanced stage disease, 17 (46%) had extranodal disease, and the median ECOG performance status was 1 (IQR: 0-2). Seventeen (74%) pts received PD-1 monotherapy, 5 (22%) received nivolumab + brentuximab vedotin, and 1 received nivolumab + ifosfamide, carboplatin, and etoposide. Four pts had uncontrolled HIV at the time of PD-1 initiation (HIV viral load range=10,000-2,000,000 copies/mL). All pts received antiretroviral therapy during treatment. Median baseline CD4 was 155 cells/µL (IQR: 66-297) and CD8 was 429 cells/µL (IQR: 158-716). Median CD4 and CD8 increased to 310 and 653 cells/µL at the end of PD-1 treatment (P=0.0084, P=0.32). The median number of PD-1 cycles was 6 (IQR: 4-21). Three (13%) pts had irAEs (all grade 3): hypothyroidism, autoimmune pancreatitis, and pneumonitis. None required PD-1 discontinuation. The ORR was 83% in the overall cohort. Sixteen pts (70%) had CR, 3 (13%) PR, and 4 (17%) PD as best response. Among the 19 pts with CR or PR, the median DOR was 19.7 months; 8 had PD after initial response and 11 had ongoing CR at data cut-off. Ten pts received consolidation with ASCT after PD-1, 6 of whom had received PD-1 at ≥3 rd line treatment. All pts who received ASCT had ongoing CR at data cut-off. Median PFS was 21.2 months in the overall cohort. Among pts with CD4 <200 and >200 cells/µL, PFS was not statistically different (17.3 vs 29 months; P=0.95). At data cut-off, 17 pts (74%) were alive and 6 (26%) had died due to HIV-HL. Median OS was 23.6 months in the overall cohort. Conclusion: In HIV-HL, PD-1 blockade was safe, had a high ORR and CR rate, and allowed for immune reconstitution in pts across a wide range of CD4 counts and HIV viral loads. These data add to the evidence that anti-PD-1 agents are effective in PWH and should be used in HIV-HL.

A Real-World Comparison of Idecabtagene Vicleucel and Ciltacabtagene Autoleucel CAR-T Therapy: A Single Center Experience for Relapsed/ Refractory Multiple Myeloma

Background Chimeric antigen receptor modified T-cell therapy is a promising new treatment for patients with heavily pre-treated multiple myeloma (MM). BCMA (B-cell maturation antigen) directed therapies including idecabtagene vicleucel (Ide-Cel) and ciltacabtagene autoleucel (Cilta-Cel) are currently approved for use in patients with four prior lines of therapy. Both therapies have shown efficacy producing a high overall response rates and durable responses. Both are second-generation designs with identical endodomain (CD3ζ - 4-1BB) to target BCMA on the target cells for patients with relapsed and refractory MM who have been triple-class exposed. The two distinct differences are ectodomain structure and recommended dose. In this single center retrospective study, we report our experience with the use of both CAR-T therapies in patients with heavily pre-treated MM. Methods Following institutional review board approval, we included all patients with MM who were treated with commercially approved BCMA directed CAR-T therapy. Demographic characteristics, molecular studies, treatment and response information were recorded and included in the study. Safety outcomes included the incidence and severity of adverse events (AEs). AEs were graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE 5.0). Cytokine release syndrome (CRS) and immune effector associated neurotoxicity syndrome (ICANS) were graded as per the American Society for Transplantation and Cellular Therapy criteria. Efficacy outcomes included overall response rates (ORR), progression free survival (PFS), overall survival (OS), duration of response (DOR). Survival analysis was performed using the Kaplan-Meier method including PFS and Overall survival (OS). PFS was defined as time from initiation of treatment to progression of disease or death whichever occurred first. OS was defined as time from initiation of treatment to death. The IMW response criteria was utilized for response assessment. Results We identified 56 patients who were treated consecutively at Hackensack University Medical Center between 6/28/2021 and 7/3/2023. 53 patients had data available for evaluable responses and were included in our analysis. 35(66%) patients received Ide-cel, whereas 18(34%) patients received Cilta-Cel. For the entire cohort, 30(56.6%) were male, median age was 69.6 years median time from diagnosis to treatment was 8.1 years. Patients had received a median of 5 prior lines of therapy. 50(94.3%) patients were triple class refractory, all except one patient (98.1%) had a prior autologous stem cell transplant (ASCT). 27(60%) patients had high risk FISH defined as those with t(4;14), t(14;16), 17p(-) or 1q(+), 24(60%) patients were ISS-2 or 3 at diagnosis. Treatment was overall well tolerated, with only one therapy related mortality, 42(79.3%) patients experienced CRS, with only 1(1.9%) having grade 3 or higher CRS. 6(11.3%) patients experienced ICANS, with 2(3.8%) having grade 3 or higher ICANS. Baseline characteristics are summarized in table 1. Overall response rate for the entire cohort was 75.4%, with a median PFS of 11.9 months, median DOR of 13.2 months and mOS was not reached (NR). The median ORR for cilta-cel vs ide-cel was 94.4 % and 65.7% (p=0.01) respectively. The median PFS for cilta- cel vs ide-cel was NR vs 10.9 months (p=0.09) respectively (Figure 1), follow-up being very short for cilta- cel. Baseline characteristics, safety and efficacy data for the cohort and comparison between the two therapies are summarized in table 1. Conclusions In our single center experience, cilta-cel has shown superiority in terms of efficacy compared to ide-cel. Having said that, the authors do strongly recognize that longer manufacturing time for cilta-cel introduces a bias in favor of using ide-cel for patients with more aggressive/rapidly progressing disease, which may therefore result in inferior outcomes. The safety profile for both therapies is very similar and both offer promising results to patients with MM.

French Early Nationwide Idecabtagene Vicleucel (Ide-Cel) Chimeric Antigen Receptor (CAR) T-Cell Therapy Experience in Patients with Relapsed/Refractory Multiple Myeloma (FENIX): Update of the IFM Study from the Descar-T Registry

Introduction Prognosis of patients with relapsed/refractory multiple myeloma (RRMM) is poor, particularly in triple-class refractory patients (refractory to a proteasome inhibitor, an immunomodulatory drug and an anti-CD38 monoclonal antibody). Idecabtagene vicleucel (Ide-Cel) is the first chimeric antigen receptor (CAR) T-cell therapy targeting the B-cell maturation antigen (BCMA) approved by both the European Medicines Agency and the US FDA and the only one available in France through the Early Access Program for treatment (≥ 3 lines) of RRMM. Here we present an update of characteristics and outcome of patients enrolled in this program. Methods We conducted a multicenter, retrospective, observational study that included all consecutive patients with RRMM registered in the DESCAR-T database of patients treated with CAR T therapy, who underwent apheresis up to November 2022 to be treated by commercial Ide-Cel in France. The main objective was to analyze efficacy in terms of response rates, progression free survival (PFS) and overall survival (OS). Secondary objectives included evaluation of safety in terms of cytokine release syndrome (CRS), neurotoxicity, cytopenia, infections and management of relapse including subsequent anti myeloma therapies (sAMT). Results From June 2021 to November 2022, 207 patients were registered in DESCAR-T and underwent leukapheresis to be treated with Ide-cel, 164 (79%) were infused; 43 were not infused: 13 due to rapidly progressive disease or death and 5 due to manufacturing failure. Fifty seven (28%) patients did not meet KarMMa inclusion criteria: cytopenia (n=23), kidney failure (n=13), performance score (PS) >1 (n=15), prior anti BCMA drug conjugate antibody (n=8), prior allograft (n=5). Median age of the 164 patients was 60.5 years (range 34-82), 59% were male, median number of prior treatment lines was 4 (range 2-12) including prior autologous stem cell transplantation in 147 (90%); 130 (80%) were triple-refractory, 47 (29%) were penta-refractory. At diagnosis, 12 (16%) patients had R-ISS stage III disease (89 missing). High tumor burden (> 30% BMPCs) was present in 71 patients (54%) (33 missing). High risk cytogenetic abnormalities defined by del(17p) or t(4;14) were present in 63 patients (58%) (56 missing) and 15 (23%) had extramedullary disease (EMD) (98 missing). One hundred and forty-two (87%) received bridging therapy of which 39 (27%) responded: 25 had partial response (PR); 8 very good partial response (VGPR); 6 complete response (CR). Median time from apheresis to infusion was 62 days. Median follow-up after infusion was 6.2 months. In the first 3 months, overall response rate was 82% (n=134), best achieved response was CR, VGPR and PR in 60 (38%), 36 (23%) and 38 (24%) respectively. Median PFS was 11.6 months (95% CI (7.1; NA)). The 12-month OS was 73% (95% CI (64; 84)). In the first 6 months post-infusion, MRD was analyzed for 45 patients and reached negativity rate in 77%. In univariate analysis, only EMD had a significant impact on PFS: median PFS was 6.3 months (95% CI (3; NA)) for patients with EMD (p = 0.003; HR 3.5, 95% CI (1.55; 7.9)). CRS occurred in 146 (89%) patients, with only 3 cases (2%) of grade ≥ 3. Neurotoxicity occurred in 19 (12%) patients (5 with grade ≥ 3). Ninety-eight (60%) patients received tocilizumab, and 37 (23%) received steroids. Persistent grade ≥ 3 thrombocytopenia, anemia and neutropenia at M1 were observed in 55 (34%), 20 (12%) and 90 (55%) patients, respectively. Forty (24%) patients presented infections grade ≥ 3 in the first six months after infusion. Fifty-two patients progressed during follow-up. 34/52 patients (65%) received a sAMT. Median time from relapse to first administration of sAMT was 0.6 months. Eighteen received bispecific antibodies including 12 anti-BCMA and 6 anti-GPRC5D. Among these 34 patients, a total of 13 (38%) died. Overall, at data cut-off, 26 patients had died, including 9 after disease progression, 4 of acute toxicity and 2 of sepsis. Conclusion This updated study confirms safety and efficacy of Ide-cel in patients with RRMM in real world settings. Response rates and safety were comparable to those reported in the registration trial (Munshi et al., 2021) and American real world study (Hansen et al., 2023). Importantly, patients with EMD had a significant lower PFS. Prognosis data at relapse following ide-cel require a longer follow up and will be presented at ASH.

Copanlisib in Combination with Nivolumab in Subjects with Relapsed/Refractory Diffuse Large B-Cell Lymphoma and Primary Mediastinal Large B-Cell Lymphoma: A Phase II Study

Introduction: Diffuse Large B-cell Lymphoma (DLBCL) are aggressive B-cell non-Hodgkin lymphomas (NHL). One particular subtype, Primary Mediastinal B-cell Lymphoma (PMBCL), is often grouped with DLBCL, but it possesses distinct biological and clinical characteristics. While initial therapy successfully cures approximately two-thirds of patients (pts), those who do not respond or experience progression within the first two years have a poor prognosis despite novel cellular therapies and bispecifics and ultimately succumb to their disease. There is a pressing need for more effective therapeutic approaches in this patient population. Recent advances in the understanding of DLBCL pathogenesis have led to the targeting of various signaling pathways, including the PI3K-AKT-mTOR pathway. One such drug, copanlisib (C), a pan-PI3K inhibitor with potent PI3K-α/PI3K-δ inhibition, exhibited activity in both indolent and aggressive NHL. In preclinical studies using a DLBCL mouse model, treatment with C effectively reduced the immunosuppressive tumor-infiltrating T-regulatory cells (Tregs). Moreover, when combined with a surrogate anti-mouse programmed death -1 (PD-1) blocker, C demonstrated significant in vivo responses (75%) compared to the monotherapy groups (0%). These findings support the rationale for exploring the combination of nivolumab, a PD-1 blocker, and copanlisib (C-N) in DLBCL. Thus, a phase 2 prospective study has been developed, focusing on two relapsed/refractory (RR) cohorts (DLBCL and PMBCL), treated with the combination of C-N. A prespecified interim analysis was planned upon enrollment of 14 pts. Herein, we report outcomes of the 12 enrolled pts, as the study was halted prematurely due to a safety signal deemed possibly related to the combination. Study design: C 60 mg was given intravenously on days 1, 8, and 15 during cycles 1-8, and on days 1 and 15 in subsequent cycles. N 240 mg IV was given on days 1 and 15 during cycles 1-8, and 480 mg on day 1 on subsequent cycles. Each treatment cycle is 28 days. Therapy was given for up to 2 years, as long as there is no disease progression or unacceptable side effects. The primary objective of the study is to determine the ORR, which includes complete and partial responses (CR+PR). Secondary objectives include evaluating the safety of the combination, as well as assessing progression-free survival (PFS), duration of response (DOR), CR, and overall survival (OS). The study plan was to enroll a maximum of 106 pts, including a safety cohort of 6 pts. The study received funding from Bayer and conducted through NCI-CTEP (NCI Protocol #10193; NCT03484819). Results: Twelve pts who received at least one cycle of C-N were included in this analysis. Pt characteristics are illustrated in table 1. All enrolled pts had DLBCL histology. Only one patient received a prior autologous stem cell transplant. Interestingly 4/12 received prior chimeric antigen receptor T-cell therapy (CART). Of the 12 enrolled pts, seven were evaluated for response. The ORR was 25% (3/12) (95% CI: 5 - 57%), all CR. The median number of cycles received was 2.5 (range 1-24) with two pts receiving 23 and 24 cycles. Observed grade 3 and higher adverse events (AEs) were as follows: non-hematologic AEs in 10/12 (83.3%), while hematologic AEs were seen in 5/12 (41.7%) pts. A relatively higher incidence of cardiac events (4/12) were noted including one cardiac arrest after one cycle of therapy, and four atrial fibrillation events, all grade 3, but only two were deemed possibly attributed to therapy. The cardiac arrest was deemed unrelated to therapy. Conclusions: C-N combination had modest clinical activity in pts with R/R DLBCL with some prolonged responses. However, due to the relatively high number of cardiac events and the changing therapeutic landscape with recent approvals, a decision was made to halt the study. These findings likely reflect possibly older and sicker patient population. Biomarker studies for predictors of response are under consideration.

Bendamustine Lymphodepletion (LD) Prior to Idecabtagene Vicleucel (Ide-cel) Is Associated with Inferior Outcomes in Relapsed Refractory Multiple Myeloma (RRMM)

Background Chimeric antigen receptor therapy (CART) has revolutionized the management of RRMM. LD prior to CART cells modulates the immune environment creating optimal conditions for T cell expansion and subsequent efficacy. Fludarabine/cyclophosphamide (FLU/CY) is an effective LD regimen, and its use has been adopted widely prior to CART cells for all indications. Since the safety of FLU/CY is not established in patients with substantial renal impairment and given recent nationwide fludarabine shortage, alternative lymphodepletion strategies have been explored. Bendamustine (BENDA) has been shown to be a safe alternative with equivalent efficacy and reduced toxicity in non-Hodgkin's lymphoma (NHL). While its use has been extrapolated to RRMM, efficacy and long-term outcomes have not been examined. Methods We retrieved and analyzed data on sequential patients (pts) with RRMM treated with commercial Ide-cel at a single institution from its approval in 3/2021 until 5/2023. We captured baseline patient, disease and treatment characteristics. We used IgG (with monoclonal component deducted) and uninvolved FLC as indirect surrogate of CAR-T expansion and on target, off tumor killing of non-malignant plasma cells. We assessed cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity (ICANS) based on the American Society for Transplantation and Cellular Therapy criteria and disease responses using the International Myeloma Working Group response criteria. We graded hematologic toxicity using the Common Terminology Criteria for Adverse Events version 5.0. We compared efficacy between the cohorts using overall response rate (ORR) and progression-free survival (PFS), since overall survival is expected to be affected by choice of subsequent, often experimental therapies. Results We identified 28 pts with RRMM who met the inclusion criteria. Nine pts received alternative LD with BENDA (2 pts - renal dysfunction with creatinine clearance <30ml/min; 7 - fludarabine shortage) and 19 received FLU/CY as LD. Baseline characteristics are summarized in Table. Prior autologous stem cell transplant (ASCT) and prior B cell maturation antigen (BCMA) targeting therapy were more frequent in the FLU/CY cohort. Median absolute lymphocyte count (measured in 10^3/ cmm) prior to LD chemotherapy was similar in both cohorts (0.85 in BENDA vs 0.80 in FLU/CY). Median duration of absolute neutrophil count <1,000/μL was shorter in the BENDA cohort. The incidence of any grade CRS (56% vs. 90%, p=0.06) and tocilizumab use (56% vs. 84%, p=0.16) was lower with BENDA compared to FLU/CY. In the absence of ide-cel expansion data, we used nadir polyclonal IgG and uninvolved free light chain (uFLC) in the initial 90 days post CART cell infusion as surrogate of non-malignant plasma burden and therefore ide-cel expansion. We noted lower median uFLC and median IgG with FLU/CY vs. BENDA. The overall response rate was lower with BENDA (22%) vs. FLU/CY (79%, p=0.01). With median follow up of 4.8 mo., all pts in the BENDA cohort progressed with median PFS of 1.6 months vs 7.8 months for FLU/CY (p<0.001, Figure). The median OS for both cohorts is not yet reached. Conclusion: BENDA LD prior to ide-cel infusion results in suboptimal lymphodepletion and subsequent inferior outcomes including low rate of objective responses and decreased progression free survival. The inferior efficacy of BENDA as LD likely results from inferior ide-cel expansion and persistence resulting in less frequent and severe CRS and cytopenias and less suppression of unaffected immunoglobulins. Future efforts to study alternative lymphodepletion approaches is essential given inability to use fludarabine in patients with severe renal dysfunction and periods of critical drug shortages. While there is a need to develop alternatives for LD prior to ide-cel, BENDA is an inadequate substitute of FLU/CY.

A Propensity Score-Matched Analysis on the Outcomes of Brexucabtagene Autoleucel from Zuma-2 Study and Allogeneic Stem Cell Transplantation from the EBMT Database in Relapsed and Refractory Post-Btki Mantle Cell Lymphoma

Introduction Brexucabtagene autoleucel (brexu-cel), an autologous anti-CD19 CAR T-cell therapy, is approved in the US for the treatment of relapsed/refractory (r/r) mantle cell lymphoma (MCL) and in Europe for r/r MCL after ≥2 prior lines of therapies, including Bruton's tyrosine kinase inhibitor (BTKi). The pivotal ZUMA-2 trial demonstrated very good efficacy of brexu-cel in r/r MCL and tolerable safety including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (Wang et al. J Clin Oncol. 2022). Allogeneic stem cell transplantation (alloSCT) is potentially curative but is associated with high treatment related mortality (TRM) and clinically significant graft-versus-host disease (GvHD). The optimal choice of treatment between brexu-cel and alloHCTs is unclear. We conducted a propensity score matched (PSM) analysis of brexu-cel and alloSCT in patients (pts) with r/r MCL. Methods Pts from ZUMA-2 were matched with alloSCT pts from the EBMT database. Selection criteria to identify pts in the EBMT registry were: r/r MCL diagnosis and receipt of alloSCT from 2010 to 2020, age ≥18 years, prior treatment with anti-CD20, prior anthracycline- or bendamustine containing regimens, and prior BTKi. We performed a 1:1 nearest neighbor matching without replacement, balanced for 5 baseline parameters: age, sex, number of prior treatment lines, time from diagnosis to cellular immunotherapy, and prior autologous stem cell transplantation (autoSCT). The primary endpoint was overall survival (OS) from cellular immunotherapy. The following secondary endpoints were analyzed: progression-free survival (PFS), TRM, defined as incidence of deaths which are related to the treatment and occurred in absence of disease progression, and rate of GvHD. Competing risks were defined as relapse, progression or treatment-unrelated death for TRM, and death for GvHD. The EBMT registry includes pts who actually underwent alloSCT. To characterize the dropout rate prior to cellular therapy, we conducted a multicenter intent-to-treat (ITT) analysis and identified 77 pts with r/r MCL for whom an unrelated donor search was initiated and an alloSCT was intended. Results Sixty-four of 68 pts from the ZUMA-2 cohort were included in the study; 4 pts were excluded because of inability to anonymize. A total of 270 pts who had undergone alloSCT and met eligibility criteria were identified in the EBMT registry. Patient characteristics between the brexu-cel and the alloSCT cohorts were imbalanced. Brexu-cel pts were older (p<0.001), had more prior lines of treatment (median 3 vs 2, p<0.001), had less prior autoSCT (41% vs 71%, p<0.001), and had longer time between diagnosis and treatment (53 vs 40 months, p=0.01). After 1:1 PSM matching, criteria were well balanced between cohorts. Median follow-up time was 36.5 and 46.4 months for the brexu-cel and the matched alloSCT cohort, respectively. PFS and long-term OS were similar between both cohorts (Fig. 1A). However, the risk of death within the first 12 months was significantly lower in the brexu-cel cohort vs the alloSCT cohort (logistic regression with inverse probability of censoring weighting, risk ratio=0.5, 95% confidence interval [CI] 0.3-0.9, p=0.02). This was mainly attributable to the significantly higher TRM rate in the alloSCT cohort (alloSCT vs brexu-cel: cause specific hazard ratio=7.7, 95% CI 1.9-31.6, p=0.005, Fig. 1B). The cumulative incidence of acute GvHD grade ≥3 at 3 months and chronic GvHD at 24 months was 17.9% (95% CI 9.1-29.0%) and 44.3% (95% CI 30.6-57.2%), respectively. In our ITT analysis, the dropout rate was significantly higher in the cohort intended to receive alloHCT (23%, [18/77]) vs the cohort intended to receive brexu-cel (8% [6/74]; Fisher test, p=0.01). For alloSCT, failure to proceed to cellular therapy was related to progression in 13%, change of patient's preference in 5% and ineligibility in 4%; in the brexu-cel cohort this was due to manufacturing failures in 4% and progression in 3%. Conclusion Brexu-cel is an effective treatment in pts with r/r MCL post-BTKi with a superior safety profile compared with alloSCT, as indicated by lower 12-month mortality, lower TRM, and absence of chronic GVHD-related morbidity. Despite efforts to match pts between the cohorts, the inherent limitations of this study, such as incongruent data sources and case selection bias, have to be considered. Additional analyses will be presented.

Lisocabtagene Maraleucel in Relapsed/Refractory Large B-Cell Lymphoma: Real World Analysis from the Cell Therapy Consortium

Introduction Lisocabtagene maraleucel (liso-cel) is an autologous CD19-directed CAR T cell therapy approved for the treatment of relapsed/refractory (R/R) large B-cell lymphoma (LBCL) based on the TRANSCEND (Abramson et al, Lancet 2020), TRANSFORM (Kamdar et al, Lancet 2022), and PILOT studies (Sehgal et al, Lancet Oncol 2022). Extending clinical trial results for liso-cel to the real-world setting, we performed a multicenter retrospective study to evaluate the safety and efficacy of liso-cel in standard of care practice. Methods Patients (pts) aged ≥18 years with LBCL who received commercial liso-cel infusion between February 2021 (time of FDA approval) and June 2023 at 7 academic US medical centers were identified from the Cell Therapy Consortium registry. Pt and treatment characteristics were summarized descriptively, and the Kaplan Meier method was used for survival outcomes. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded per ASTCT consensus criteria. Tumor response was assessed per Lugano criteria locally by the treating clinician. Results As of 6/10/2023, 101 pts underwent liso-cel infusion. Detailed baseline pt characteristics are shown in Table 1. Median age at apheresis was 71 years (range: 30-85) with 35% of pts ≥75 years, 60% were male, 16% had an ECOG PS of ≥2 at apheresis, and 11% had active secondary CNS involvement. By histology, 86% of pts had DLBCL, 7% HGBL, 5% TFL, and 2% PMBCL. Baseline comorbidities included diabetes (18%), stage IV chronic kidney disease (5%), cerebrovascular disease (5%), impaired cardiac ejection fraction (2%), pulmonary dysfunction (2%), impaired hepatic function (2%), and active infection (3%), with 68% having a Charlson Comorbidity Index score of ≥3. Due to comorbidities, 30% of pts would have been ineligible for the TRANSCEND clinical trial. The median number of prior therapies was 3 (range: 1-8) and 16% of pts underwent prior autologous stem cell transplant. Bridging therapy was used in 62% of pts including 41% receiving polatuzumab-based treatment, 24% chemoimmunotherapy, and 21% radiation therapy. Seven (7%) pts received liso-cel on an expanded access trial (NCT04400591) due to a non-conforming product. Median time from apheresis to CAR T-cell infusion was 39 days (IQR: 34-43) and 85% of CAR T-cell infusions occurred inpatient. Any Grade CRS occurred in 49% (3% were Grade ≥3) and any Grade ICANS occurred in 26% (10% were Grade ≥3). Median onset of CRS and ICANS was 4 and 6 days following liso-cel infusion, respectively. Tocilizumab was administered in 31% and 31% of pts received steroids for toxicity management. Nine deaths (9%) unrelated to lymphoma progression occurred at a median of 1.2 months (range: 0.3-4.3) with 2 due to infectious complications, 2 due to other malignancy, 1 due to grade 5 neurologic toxicity, 1 due to concurrent grade 5 neurologic toxicity and grade 5 CRS, 1 due to accidental death, and 2 due to unknown causes. The 6-month incidence of non-relapse mortality was 8% (95% CI, 3.4% - 15%). The overall response rate (ORR) to bridging therapy, as assessed prior to lymphodepletion, was 45% with 17% achieving a complete response (CR). Following liso-cel infusion, response assessment was performed at day 30 and/or day 90 according to treating center practice, or in those determined to have clinical progression. Of the 89 pts evaluable at day 30, the ORR was 81% with 63% achieving a CR. Among 76 pts evaluable at day 90, the ORR was 63% with 58% achieving a CR. With a median follow-up of 10.3 months (range 0.3-22.8), month 6 outcomes were 62.7% (95% CI, 52.8% - 74.3%) for progression-free survival, 71.6% (95% CI, 60.9% - 84.1%) for duration of response, and 77.1% (95% CI, 68.4% - 86.9%) for overall survival ( Figure 1). Conclusions These analyses confirm that efficacy and safety are similar or superior to those of patients enrolled in liso-cel prospective clinical trials for R/R LBCL. Notably, these outcomes were achieved in pts predominately of advanced age and with a significant comorbid burden, recognizing that one-third would have been ineligible for TRANSCEND. These results also likely reflect advancements in patient selection and toxicity management including the real world utilization of novel bridging therapy to temporize and debulk disease. Follow-up is ongoing and updated data will be presented at the meeting.

Indirect Comparison of Efficacy of Zanubrutinib Versus Orelabrutinib in Patients with Relapsed or Refractory Mantle Cell Lymphoma (R/R MCL): An Updated Analysis with Long-Term Follow up

Introduction Zanubrutinib and orelabrutinib, both the next generation Bruton's tyrosine kinase inhibitors (BTKis), are used in China as treatment options for R/R MCL. A further evaluation to understand the differences between these two novel BTKis is helpful for future study. Our previously indirect comparison has suggested a favorable PFS trend in zanubrutinib over orelabrutinib in R/R MCL patients (Song Y, et al. Invest New Drugs 2023). Here, we conducted an updated analysis to indirectly compare the long-term efficacy between zanubrutinib (median follow up: 35.3 months) and orelabrutinib (median follow up: 23.8 months) in patients with R/R MCL. Methods Individual patient data from zanubrutinib study (BGB-3111-206, n=86; NCT03206970) were adjusted to match the patients population profile of the orelabrutinib study (ICP-CL-00102, n=106; NCT03494179). As both trials were single-arm and were not linked through a common control arm, an unanchored matching-adjusted indirect comparison (MAIC) was performed to adjust for effect modifiers and prognostic variables. The baseline characteristics included in population adjustment were identified from literature review and clinical experts' assessment, which were sex, bulky disease, bone marrow involvement, disease stage, simplified Mantle Cell Lymphoma International Prognostic Index, prior autologous stem cell transplantation, and the number of prior lines of treatment. The efficacy outcomes included investigator-assessed progression free survival (PFS), overall survival (OS), and overall response rate (ORR). After matching, a weighted Cox model or a weighted logistic model will be employed to analyze the PFS and OS through hazard ratio (HR) or to analyze the ORR through odds ratio (OR). Response evaluations were only CT-based assessment in orelabrutinib study, while PET- and CT-based assessment were both performed in zanubrutinib study. Thus, the PFS assessed by PET and CT of zanubrutinib study were used to compare with the PFS assessed by CT of orelabrutinib study, respectively. Results After matching, the baseline characteristics were balanced between zanubrutinib and orelabrutinib, with the (effective) sample size of 70 and 106 in zanubrutinib and orelabrutinib, respectively (Table). PFS assessed by CT was significantly longer in the zanubrutinib versus the orelabrutinib (median PFS: not estimable [NE] vs. 22.0 months; HR, 0.54 [95% CI: 0.34-0.86]; P = 0.009) (Figure). Additionally, PFS assessed by PET of zanubrutinib was also significantly longer than the PFS assessed by CT of orelabrutinib (median PFS: NE vs. 22.0 months; HR, 0.63 [95% CI: 0.40-0.99]; P = 0.044). There are clinically meaningful differences observed for both the PFS (assessed by CT or PET) of zanubrutinib versus the PFS assessed by CT of orelabrutinib and the 24-month PFS rate (assessed by CT or PET) in the zanubrutinib versus that assessed by CT in the orelabrutinib (67.3% vs. 46.5% and 62.2% vs. 46.5%, respectively). Due to very limited number of OS events, the analysis of OS was not powered enough to detect a statistical meaningful difference between two groups (median OS: NE vs. NE; HR, 0.68 [95% CI: 0.36-1.27]; P = 0.223). However, the 24-month OS rate was numerically higher in the zanubrutinib than the orelabrutinib (83.7% vs. 74.3%). ORR was comparable between zanubrutinib and orelabrutinib (85.5% vs. 82.1%; OR, 1.28 [95% CI: 0.56-2.94]; P = 0.556). Conclusions MAIC results demonstrated that zanubrutinib had significantly longer PFS compared with orelabrutinib in the treatment of R/R MCL patients.

Results of an Open-Label Phase 1 Study Repurposing Oral Metformin and Nelfinavir in Combination with Subcutaneous Bortezomib in Patients with Relapsed and/or Refractory Multiple Myeloma

Background: GLUT4 inhibition via the use of a protease inhibitor, such as nelfinavir (NEL), is an attractive therapeutic option in multiple myeloma (MM), given the dependence of MM cells on glucose. Furthermore, combining a GLUT4 inhibitor with an oxidative phosphorylation inhibitor, such as metformin (MET), may counter the possibility of therapeutic resistance to GLUT4 inhibition in MM cells, showing synergistic promise (Dalva-Aydemir et al., Clin Can Res 2015). In addition to GLUT4 inhibition, NEL also lowers the cytotoxicity resistance of MM cells against proteasome inhibitors such as bortezomib (BOR) (Driessen et al., Blood 2018). Thus, this study evaluated the safety and tolerability of repurposing MET and NEL, in combination with BOR for the treatment of relapsed/refractory MM (RRMM) that had progressed on all standard of care (SOC) therapies. Methods: This trial utilized a 3+3 dose escalation design with 3 dose levels planned for up to a maximum of six (21-day) cycles. MET was administered for 14/21 days and started at a dose of 500 mg BID with plans to be investigated at a maximum dose of 1000 mg BID. NEL was administered for 14/21 days and started at a dose of 1250 mg BID with plans to be investigated to a maximum dose of 2500 mg BID. SubQ BOR was administered on days 1, 8, and 15 of a 21-day cycle at a dose of 1.3 mg/m 2 to a portion of patients. Patients with RRMM were required to have had 2 prior lines of therapy and prior exposure to proteasome inhibitors (PIs), immunomodulators (IMiDs), and Anti-CD38 monoclonal antibodies. The primary objective was to determine the maximal tolerated dose (MTD) of this combination. The secondary objective was to evaluate the safety as well as the overall response rate (ORR) of this combination. This trial was funded by the Helen Diller Family Foundation. Results: From 4/2019 until 9/2022, nine patients were accrued with a median age of 65 (range: 42-81) that received a median of 7 prior lines of therapy (Range: 6-13). All but one patient had a prior autologous stem cell transplant. Only one patient was not triple-class refractory, and 2/3 rd (n = 6) also had prior anti-BCMA therapy. The first three patients received only MET (500 mg BID) and NEL (1250 mg BID) at the first dose level for up to one cycle before experiencing progressive disease and coming off the study. Given the limited activity of MET and NEL in the initial treatment of these three patients, two subsequent amendments to the protocol allowed for the upfront addition of BOR 1.3 mg/m2 to the original combination, as well as shortened the DLT evaluation period from two cycles to just one. Thus, the following six patients received MET (500 mg BID) and NEL (1250 mg BID) at the first dose level in addition to weekly BOR at 1.3 mg/m2. Four (44%) patients experienced grade 3+ hematological AEs and six (67%) experienced grade 3+ non-hematological AEs. The most common hematologic grade 3+ AE observed was anemia (44%). The nonhematologic grade 3+ AEs observed were dyspnea, fatigue, nausea, and vomiting (11% each). None of the AEs were possibly related to treatment, suggesting good overall safety of the combination. While eight of nine patients have since died of progressive disease, no deaths were attributable to the treatment. All six patients who received BOR upfront with MET and NEL were previously refractory to BOR in prior lines of therapy; however, none had received BOR as their last line of therapy prior to accrual to this study. Four of these six patients had progressive disease after one cycle of therapy and went off study. However, the remaining two were able to receive 2 or more cycles of therapy, with one experiencing an unconfirmed minor response (MR) in the first cycle and the other experiencing stable disease (SD) for all six cycles. The patient who experienced SD was safely able to transition to a subsequent clinical trial utilizing an anti-BCMA bispecific antibody therapy and remains alive at the time of this analysis. The study was closed before accrual to the next dose level was started. Conclusions: This is the first study to evaluate the safety and efficacy of this repurposed drug combination in this very difficult-to-treat population of RRMM. While no ORR was observed, identification of biomarkers used for selection of patients with no other SOC options who could experience at least SD responses may be beneficial in allowing this combination to slow or stabilize the disease progression until other novel therapies or clinical trials are available.

Carfilzomib in Combination with Dexamethasone, Cyclophosphamide, Etoposide, and Cisplatin (KDCEP) for the Treatment of Relapsed/Refractory Aggressive Plasma Cell Dyscrasias

Background: Dexamethasone with Cyclophosphamide, Etoposide and Cisplatin (DCEP) is an effective regimen in aggressive relapsed/refractory MM (RRMM) with overall response rates (ORR) as high as 58% [Dadacaridou, M. et al JBUON 2007]. ORR is lower (35 - 45%) in patients (pts) exposed to novel therapeutics such as immunomodulatory agents (IMiD), proteasome inhibitors (PI), and anti-CD38 antibodies (mAb) [Park, Silvia et al Ann. Hematol 2014; Goldsmith, Scott et al. Blood2021]. The addition of bortezomib (V) to DCEP demonstrated ORR of 47% [Valla, Kelly et al. Blood 2014]. Due to common use of V front-line, most pts are V exposed by the time treatment for relapse is indicated; therefore, we began using carfilzomib (K) with DCEP. K has been utilized with DPACE with ORR of 77% [Alsouqi, A. et al. Clin Lymphoma Myeloma Leuk 2021], however an anthracycline may not be feasible in heavily pretreated pts. We present the first reported outcomes of RRMM pts treated with KDCEP. Methods:This is a case series from the University of Utah Huntsman Cancer Institute of all consecutive pts treated with KDCEP from 2017-2022, conducted under IRB approval. Demographic, disease, treatment, and response data were retrospectively collected. Responses were assessed by IMWG criteria, and adverse events were graded by CTCAE v.5. Descriptive statistics were utilized; a Kaplan-Meier estimate was used for the time to event analysis. Results:Six pts received KDCEP (Table 1). The median age was 63.5 years (range 47 - 73). All pts had ECOG performance status of 1-2, and 67% were male. Median prior treatment lines were 2.5 (range 2 - 7) with 33% undergoing prior autologous stem cell transplant (autoHCT). All pts were exposed to V with 67% refractory. Thirty-three percent had prior K exposure, however none were considered refractory to K, and 67% were refractory to a PI, IMiD and mAb. Two pts received KDCEP as chemo-mobilization prior to autoHCT. All pts had IgG or IgA disease with 67% having high risk cytogenetics (33% 17p del, 50% gain 1q21) and 1 pt had primary plasma cell leukemia. R-ISS stage at diagnosis was: stage 3 (n=2), stage 2 (n=1) unknown (n=3). All pts had baseline echocardiograms with ejection fractions prior to treatment ranging from 57 - 78%. Pts received K on Days 1 and 8 of each 28-day cycle, prophylactic growth factor, and standard antimicrobial prophylaxis. Two pts received 2 cycles, all others received 1. The overall response rate was 100% and included the following best responses: PR (n = 4), VGPR (n = 1), CR (n = 1). One patient that initially achieved a PR relapsed within 60 days and died awaiting enrollment on a clinical trial, however all other pts were successfully bridged to their next line of therapy. Five pts had MRD data available after treatment, each demonstrating detectable MRD. Median progression free survival was 6.7 months. Median time to ANC nadir was 11 days (range 9-14) and to ANC recovery, defined as ANC > 1000/uL, was 18 days (range 14 - 23). Median time to platelet nadir was 12.5 days (range 9-23) and to platelet recovery, defined as platelets > 100 k/uL, was 25 days (range 20 - NR). Median time to next cycle or treatment was 43 days (range 31-54). Sixty-seven percent of pts had a grade ≥ 3 toxicity including neutropenic fever (n=2), sepsis due to pseudomonas bacteremia (n=1), and septic thrombophlebitis (n=1). No cardiac toxicities or treatment related deaths were observed. Discussion:In this cohort of heavily pre-treated pts who received KDCEP, ORR was high indicating the regimen is active in this population. KDCEP may be a viable option for RRMM pts, particularly in those who are triple class refractory or with high risk cytogenetic abnormalities. Our data suggests that KDCEP may be an effective regimen to bridge patients to the next line of therapy; however all patients should be monitored closely for infection.

Brentuximab Vedotin in Combination with Nivolumab in CD30+ Malignancies Refractory to Brentuximab Vedotin

Introduction Brentuximab vedotin (BV), in combination with multi-agent chemotherapy, is considered a standard of care for newly diagnosed CD30+ lymphomas. Despite high reported efficacy, some patients fail to respond to initial BV exposure and many more eventually progress despite ongoing BV therapy. In addition to direct cytotoxicity, BV may also induce immunogenic cell death (Gardai, et al. Cancer Res 2015) and foster a reduction of regulatory T-cells (Herrera, et al. Blood 2018) that may synergize with immune checkpoint inhibitors. To date, the high response rates reported with BV and anti-PD-1 combinations have been limited to patients naïve to both of these agents (Advani, et al. Blood 2021). To address the more clinically relevant scenario of prior BV +/- anti-PD-1 exposure, we designed a study to evaluate the combination of BV and nivolumab in patients with CD30+ lymphoma refractory to prior BV, including those with prior anti-PD-1 therapy. We report the final safety, efficacy and correlative analysis of BV in combination with nivolumab in R/R CD30+ lymphomas refractory to BV. Methods We conducted an open-label trial (NCT01703949) involving patients 18 years and older with CD30+ lymphomas refractory to BV therapy. Refractoriness was defined as lack of disease response or progression within 6 months following a minimum of 2 cycles of BV. BV was given at 1.8 mg/kg in combination with nivolumab at 3 mg/kg every 3 weeks for 4 cycles. The primary endpoint was overall response rate (ORR). Secondary endpoints included complete response (CR) rate, progression-free survival, overall survival, time to next treatment, safety and tolerability and immune response biomarkers. Results As of July 27, 2023, 19 patients have enrolled and 17 have initiated therapy (Table 1). Fourteen patients had classical Hodgkin lymphoma (cHL), 2 had ALK-negative anaplastic large cell lymphoma (ALK- ALCL) and 3 had CD30+ mycosis fungoides (MF). Median age was 35 (range 27-71) years and the median number of prior regimens was 5 (range 1-9), including a median of 6 prior cycles of BV (range 2-19). All patients had BV-refractory disease including 16 (84%) who were non-responsive to and 3 (16%) who relapsed within 6 months of BV. Five (26%) patients with cHL received prior anti-PD-1 therapy and 4 (21%) had anti-PD-1 refractory disease. Median time from last BV and anti-PD-1 therapy to study treatment was 5.2 and 1.1 months, respectively. Eight (42%) patients had prior autologous stem cell transplant. Of response evaluable patients, the ORR and CR rate was 44% and 6% after 2 cycles and 44% and 19% after 4 cycles of therapy. Of patients who were refractory to prior BV and anti-PD-1 therapy, 1 (25%) and 1 (25%) achieved a PR and CR, respectively. ORR and CR rate was 43% and 14% for patients with cHL, 100% and 50% for patients with ALK- ALCL, and 100% and 100% for patients with MF, respectively. At completion of study, 1 patient with cHL, 1 with MF and 2 with cHL continued BV with nivolumab, BV monotherapy and nivolumab monotherapy, respectively. Median time to progression and next therapy was 4.5 (range 1.8-45.6) and 5.0 (range 1.8-45.6) months, respectively. Of the 3 patients who achieved a CR after 4 cycles of therapy, 2 (67%) continued treatment (1 with BV and nivolumab and 1 with BV monotherapy), and 1 (33%) has been on surveillance for 45.6 months with no evidence of relapse. At a median follow-up of 21.7 (range 0.5-60.4) months, 15 (79%) patients are alive with 3 in CR. Eleven (58%) and 8 (42%) patients reported no and grade 1 peripheral neuropathy (PN) at baseline, respectively. At end of treatment, 12 (63%) and 1 (5%) patients reported grade 1 and 2 PN, respectively. No patients experienced grade ≥3 PN, transaminitis, infections or infusion reactions. One (5%) patient had a 1-week dose delay due to grade 1 ALT/AST elevation. Two (11%) deaths were noted on study; one patient developed respiratory failure secondary to pneumonitis and influenza and another patient experienced cardiac arrest due to benzodiazepine withdrawal. Correlative PD-1 levels drawn at baseline and at the end of treatment did not correlate with response. Conclusions Despite the presence of BV-refractory disease, 4 cycles of BV and nivolumab is tolerable and associated with encouraging efficacy in patients with heavily treated CD30+ lymphoma. This treatment option may have increasing relevance as more patients receive BV or anti-PD-1 therapy as part of initial treatment.

Interim Results of the Launch Study-a Multicenter, Open-Label Study of Selinexor, Dexamethasone and Chemotherapy Drugs in Relapsed/ Refractory Multiple Myeloma

Background: Exportin 1 (XPO1) is involved in the nuclear export of tumor suppressor proteins (TSPs) and associated with poor prognosis and drug resistance in multiple myeloma. Selinexor is a novel, oral, first-in-class selective inhibitor of XPO1 that was approved by the US FDA for the treatment of patients with relapsed/ refractory multiple myeloma (RRMM) based on the STORM study of selinexor (80mg biweekly) in combination with dexamethasone (20mg biweekly) (Xd). Furthermore, in pre-clinical studies, selinexor played a synergistic anti-tumor role with chemotherapy drugs, however clinical data is lacking on such combination treatment. Methods: The LAUNCH study is a multicenter, open-label study (NCT04877275) which enrolled RRMM patients at least one prior treatment. There are two arms in this study, with 25 patients in each arm. XDd Arm: Selinexor 80mg d1,8,15,22, Dexamethasone 40mg d1,8,15,22, and Liposomal Doxorubicin 25-35 mg/m 2 d1; XCd Arm: Selinexor 100mg d1,8,15,22, Dexamethasone 40mg d1,8,15,22, and Cyclophosphamide 300mg/m2 d1,8,15,22. 28d per cycle in both arms. The primary endpoint is objective response rate (ORR), secondary endpoints including clinical benefit rate (CBR), duration of response (DOR) and 1-year progression free survival (PFS) Results: As of July 26, 2023, 44 patients were enrolled (25 in XDd and 19 in XCd), XDd arm has completed recruitment. Of these, 23 patients were male and 21 were female. The median age was 60 years (range: 29-74years). The median time since initial diagnosis was 4.0 years (range: 0.5-15.5years). The median number of prior treatments was 3 (range: 1- 10). There were 13 patients (29.5%) with high-risk cytogenetic abnormalities, 8 patients (18.2%) with extramedullary disease (EMD). Eight patients (18.2%) received prior autologous stem cell transplantation and 7 patients (15.9%) received CAR-T therapy. Forty-two patients (95.5%) were exposed to bortezomib, 35 patients (79.5%) were exposed to lenalidomide, 18 patients (40.9%) exposed to pomalidomide, and 10 patients (22.7%) exposed to daratumumab. The median treatment duration of all patients was 13 weeks (range: 1- 48). Thirteen patients remained on treatment. Based on the 35 patients evaluated for efficacy, the ORR was 48.6% (52.4% in XDd arm, n=21; and 42.9% in XCd arm, n=14) including 1 CR, 1 VGPR and 15 PRs. Three patients achieved MR and 12 patients had stable disease. The most common hematological adverse events (AEs) (All Grades, Grade ≥3) were thrombocytopenia (61.4%, 27.3%), leukopenia (54.5%, 34.1%), and anemia (45.5%, 29.5%). The most common non-hematological AEs (All Grades, Grade ≥3) were fatigue (47.7%, 2.3%) nausea (45.5%, 2.3%) and vomiting (31.8%, 4.5%). Most treatment related adverse events occurred in the first 8 weeks and were alleviated over time. Conclusion: Once weekly selinexor and dexamethasone (Xd) combined with cyclophosphamide or liposome doxorubicin showed encouraging efficacy and manageable safety in treatment for RRMM. This enrollment is still ongoing and data on all participants will be reported in due course.

Matching-Adjusted Indirect Comparison (MAIC) of Brexucabtagene Autoleucel (Brexu-cel) and Pirtobrutinib in Patients with Relapsed/Refractory (R/R) Mantle Cell Lymphoma (MCL) Previously Treated with a Covalent Bruton Tyrosine Kinase Inhibitor (cBTKi)

Introduction: Patients with MCL often require multiple lines of therapy and exhibit a generally unfavorable prognosis, particularly following failure of cBTKi therapy. Therapies such as chimeric antigen receptor (CAR) T-cell therapies and non-covalent BTKi therapies have shown promise in improving outcomes. Brexu-cel (formerly known as KTE-X19) is the only CAR T-cell therapy approved in the US for R/R MCL based on results from a phase 2 multicenter, single-arm trial (ZUMA-2; NCT02601313) in patients with R/R MCL who had 1-5 prior therapies, including a BTKi. Pirtobrutinib, a highly selective, non-covalent BTKi, was recently approved in the US for treatment of R/R MCL after at least two lines of systemic therapy including a BTKi, based on ongoing results from a multicenter phase 1/2 study (BRUIN; NCT03740529). In the absence of a direct head-to-head trial comparing brexu-cel and pirtobrutinib, we performed an unanchored MAIC to estimate the relative treatment effects of these therapies in the post-BTKi setting for R/R MCL. Methods: Individual patient-level data were available for ZUMA-2 (N=68; 35.8 months median follow-up as of July 24, 2021 data cut-off) whereas study-level data were available for BRUIN (N=90 in the BTKi pre-treated cohort; 23.5 months median follow-up as of July 29, 2022 data cut-off). Longer-term overall survival (OS) data for ZUMA-2 from the July 23, 2022 data cut-off (46.1 months median follow-up) were available and used. Logistic propensity score models were used to weight the brexu-cel infused population from ZUMA-2 to match the aggregate baseline characteristics of the BTKi pre-treated cohort in BRUIN. These baseline characteristics represented clinically relevant prognostic factors which were pre-specified based on input from clinical experts and data availability. The base-case model incorporated the top five most pertinent factors, which were reported in at least 50% of patients in both trials: blastoid morphology, MCL International Prognostic Index, number of prior lines of therapy, disease stage, and prior autologous stem cell transplantation. A sensitivity analysis additionally incorporated TP53 mutation (missing in >50% of patients in ZUMA-2 and BRUIN) and Ki-67 proliferation index (missing in >50% of patients in BRUIN). Several prognostic factors (response to prior BTKi therapy, response to last therapy, and duration on prior BTKi therapy) could not be considered due to not being reported for BRUIN. The effective sample size was calculated as a measure of the degree of precision after weighting, reflecting the extent of overlap in the distribution of covariates between the trial populations. Relative treatment effects were expressed as odds ratios or hazard ratios with 95% confidence intervals. Outcomes included objective response (ORR), complete response (CR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results: In the base-case MAIC, a significant difference in the odds of ORR and CR in favor of brexu-cel versus pirtobrutinib was observed (Table 1). Similarly, brexu-cel demonstrated a significant improvement in PFS (Table 2). OS and DOR point estimates were in favor of brexu-cel when compared to pirtobrutinib, although not statistically significant. These findings were consistent with unadjusted naïve analyses as well as the sensitivity analyses including adjustment for TP53 mutation and Ki-67 proliferation index. Conclusions: While acknowledging the inherent limitations of an unanchored indirect comparison, our findings suggest that brexu-cel offers clinically and statistically significant efficacy benefits in terms of ORR, CR, and PFS compared to pirtobrutinib in patients with R/R MCL after prior cBTKi therapy. Both treatments were not statistically different in terms of OS and DOR although the estimated hazard ratios indicated a favorable trend for brexu-cel; however, given the relatively shorter follow-up and the high degree of censoring in BRUIN, an updated analysis incorporating longer follow-up data with more events from BRUIN could provide more reliable results. Although efforts were made to ensure a robust approach to the selection of prognostic factors for inclusion in the model, the possibility of some residual confounding variables cannot be completely ruled out. Nevertheless, these results provide valuable insights that may help inform treatment decisions for this population.

Efficacy of Subcutaneous Epcoritamab Vs Tisa-Cel in R/R LBCL CAR T-Naive and CAR T-Eligible Patients: An Indirect Comparison

Background: Epcoritamab is a subcutaneous, off-the-shelf, T-cell-engaging CD3xCD20 bispecific antibody (bsAb) with powerful single-agent activity and a manageable safety profile in relapsed/refractory (R/R) large B-cell lymphoma (LBCL), recently approved in the US for the treatment of adults with R/R diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma after ≥2 lines of systemic therapy. While chimeric antigen receptor T-cell therapy (CAR T) has demonstrated remarkable efficacy in R/R LBCL, there are still barriers to wide adoption, including logistical restrictions and manufacturing limitations. In the absence of head-to-head clinical trial data comparing CAR T with T-cell-engaging bsAbs, we conducted an indirect treatment comparison between CAR T-naive patients treated with epcoritamab in EPCORE NHL-1 (NCT03625037), including a subgroup of CAR T-eligible patients, identified according to ZUMA-1 (NCT02348216) eligibility criteria and utilized in a prior unanchored, matching-adjusted indirect comparison (MAIC) of epcoritamab and axicabtagene ciloleucel (axi-cel) in patients with R/R DLBCL (Thieblemont et al EHA 2023 #P1154), and patients treated with tisagenlecleucel (tisa-cel) in the JULIET trial (NCT02445248). The CAR T-eligible population was of interest for the comparison of epcoritamab vs tisa-cel as it was most similar in baseline clinical characteristics and comparable to patients examined in CAR T trials. Methods: Published data on the overall response rate (ORR), complete response (CR) rate, digitized progression-free survival (PFS), and overall survival (OS) for tisa-cel from JULIET publications were used in MAIC vs individual patient-level data (IPD) of CAR T-naive and CAR T-eligible patients from EPCORE NHL-1 (Nov 2022 data cut). Analyses were adjusted for imbalances in the following baseline characteristics between IPD from EPCORE NHL-1 and aggregate data from JULIET: age 65 years or older, gender, Eastern Cooperative Oncology Group performance status, disease stage, DLBCL, refractory to last therapy, and prior autologous stem cell transplant. Kaplan-Meier methodology was used to estimate survival. Results: A total of 96 CAR T-naive patients from EPCORE NHL-1 were included in the analysis, with an effective sample size of 33 CAR T-naive patients after adjustment. The CAR T-eligible subgroup from EPCORE NHL-1 included 57 patients with an effective sample size of 21 patients after adjustment. After adjustment there was a significant difference in ORR for epcoritamab vs tisa-cel (77.9% vs 53.0%, respectively; difference [95% confidence interval (CI)]: 24.8% [9.5, 40.2]; P=0.002) in the CAR T-naive cohort, and in CR rate (52.3% vs 39.1%, respectively; difference [95% CI]: 13.2% [ 5.9, 32.3]; P=0.174). Also, in the CAR T-naive cohort there was a trend toward PFS benefit for epcoritamab vs tisa-cel after adjustment (hazard ratio [HR]: 0.725; 95% CI: 0.447, 1.177; P=0.194) and OS (HR: 0.611; 95% CI: 0.356, 1.049; P=0.074). In the CAR T-eligible subgroup there was a significant difference in ORR (80.8% vs 53.0%, respectively; difference [95% CI] 27.7% [11.0, 44.4]; P=0.001) and CR rate (61.9% vs 39.1%, respectively; difference [95% CI]: 22.8% [1.5, 44.1]; P=0.036) for epcoritamab vs tisa-cel after adjustment. Also, there was a statistically significant survival benefit for OS (HR: 0.450; 95% CI: 0.227, 0.891; P=0.022) and a numerical trend toward benefit for PFS (HR: 0.548; 95% CI: 0.300, 1.003; P=0.051) when comparing epcoritamab vs tisa-cel after adjustment. Conclusion: In the absence of head-to-head data, this MAIC of the R/R LBCL CAR T-naive cohort and the eligible subgroup treated with epcoritamab vs tisa-cel demonstrated improved response rates and survival outcomes. This study underscores the therapeutic potential of epcoritamab as a novel, subcutaneous, off-the-shelf, core therapy for the treatments of patients with R/R LBCL. Indirect comparisons can be biased by cross-trial differences and further comparisons with longer follow-up are warranted.