Abstract: Introduction Although the labeled CD19 targeting CAR-T cell constructs axi-cel and tisa-cel are generally associated with an acceptable safety profile, non-relapse deaths can occur. Little is known about timing, causes and predictors of NRM following SOC CAR-T cell therapy for LBCL. Here, we analyzed frequency, causes, and risk factors of non-relapse deaths with focus on late NRM (beyond 4 weeks after dosing) using registry data provided by the DRST, the national partner of the EBMT. Methods Patients were selected from 356 consecutive patients who received SOC CAR-T treatment of LBCL between November 2018 and April 2021 at 21 German centers and were registered with the DRST/EBMT. Baseline patient, disease, and transplant data were collected from MED-A cellular therapy forms. Centers were contacted to provide additional treatment and follow-up information. Patients with late NRM (defined as NRM occurring beyond 4 weeks after dosing without prior LBCL relapse or progression) were compared with all patients surviving progression-free the 4-week landmark after dosing without subsequent NRM. Cumulative incidences of NRM were calculated considering relapse/progression as competing event. Results The analysis set consisted of 312 patients surviving progression-free at least 28 days after CAR-T treatment and remained alive until the end of follow-up or had a documented cause of death. Median age was 61 years (19-83), 66% were male, 52% had an IPI ≥3, 13 had an ECOG score & gt;1, 70% had received ≥3 treatment lines, 33% had failed a prior HCT, and 78% were refractory at lymphodepletion. 50% had been treated at a center contributing ≥20 cases with axi-cel (52%) or tisa-cel (48%). Grade ≥3 CRS and grade ≥3 neurotoxicity (NT) had occurred in 11% each, and 7% had no neutrophil recovery at day 100 post dosing or at last follow-up, whatever was earlier. With a median follow-up of 11.2 months, 124 patients (40%) had died, 109 (35%) LBCL-related, and 15 (5%) because of NRM. The cumulative incidence of late NRM at 12 months post dosing was 4.3% (95%CI 2.0-6.6). Causes of NRM were infections in 10 patients (bacterial or fungal sepsis/pneumonia 6; viral/atypical pneumonia/encephalitis 4); late NT 2; hyperinflammatory syndrome 1; 2 nd malignancy 1; unknown 1). Of note, 5 of the 6 lethal fungal/bacterial infections occurred subsequent to high grade NT. There was no significant difference between patients experiencing and not experiencing NRM in terms of age, gender, IPI, ECOG, pretreatment lines, prior HCT, disease status at lymphodepletion, and grade ≥3 CRS frequency. However, a significantly larger proportion of patients with late NRM had failed neutrophil recovery (27% vs 5%, p 0.011), had experienced grade ≥3 NT (40% vs 10%, p 0.0031), and/or had received axi-cel (93% vs 51%, p 0.001). Patients having neutrophil non-recovery and/or grade ≥3 NT had a 12-month NRM incidence of 16% (95%CI 5.1-26.9) vs 2.5% (95%CI 0.3-4.7) in patients with none of these 2 factors. Conclusions Late NRM in patients receiving SOC CAR-T treatment for LBCL is largely driven by infections. Risk factors for late NRM appear to be protracted neutropenia and higher grade NT, suggesting that intensified anti-bacterial/anti-fungal prophylaxis may be considered in patients with persisting critical neutropenia or exposed to high-dose steroids for NT treatment. Figure 1 Figure 1. Disclosures Dreger: BMS: Consultancy; AstraZeneca: Consultancy, Speakers Bureau; Bluebird Bio: Consultancy; AbbVie: Consultancy, Speakers Bureau; Gilead Sciences: Consultancy, Speakers Bureau; Janssen: Consultancy; Novartis: Consultancy, Speakers Bureau; Riemser: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Speakers Bureau. Schubert: Gilead: Consultancy. Holtick: Sanofi: Honoraria; Celgene: Honoraria. Subklewe: Miltenyi: Research Funding; Takeda: Speakers Bureau; Gilead: Consultancy, Research Funding, Speakers Bureau; Klinikum der Universität München: Current Employment; MorphoSys: Research Funding; Novartis: Consultancy, Research Funding, Speakers Bureau; Roche: Research Funding; Seattle Genetics: Consultancy, Research Funding; Pfizer: Consultancy, Speakers Bureau; Janssen: Consultancy; BMS/Celgene: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau. Bastian: Abbvie: Other; Amgen: Consultancy, Honoraria; Astra Zeneca: Honoraria, Other; BMS and Celgene: Consultancy, Honoraria, Other; Kite-Gilead: Consultancy, Honoraria; MSD: Consultancy, Honoraria, Other, Research Funding; Novartis: Consultancy, Honoraria, Other, Research Funding; Pentixafarm: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other, Research Funding. Ayuk: Gilead: Honoraria; Celgene/BMS: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Miltenyi Biomedicine: Honoraria; Mallinckrodt/Therakos: Honoraria, Research Funding; Novartis: Honoraria. Marks: Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Honoraria; Merck: Consultancy; AbbVie: Other: Meeting attendance. Penack: Priothera: Consultancy; Takeda: Research Funding; Incyte: Research Funding; Neovii: Honoraria; Pfizer: Honoraria; Therakos: Honoraria; Novartis: Honoraria; MSD: Honoraria; Jazz: Honoraria; Gilead: Honoraria; Astellas: Honoraria; Shionogi: Consultancy; Omeros: Consultancy. Koenecke: EUSA Pharm: Consultancy; Kite/Gilead: Consultancy; BMS/Celgene: Consultancy; Janssen: Consultancy; Novartis: Consultancy. Von Bonin: Daiichi Sankyo: Other: traveling support and advisory fees; Novartis: Other: traveling support and advisory fees; Kite/Gilead: Other: traveling support and advisory fees. Stelljes: Novartis: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Medac: Speakers Bureau; Celgene/BMS: Consultancy, Speakers Bureau; Kite/Gilead: Consultancy, Speakers Bureau. Glass: BMS: Consultancy; Helios Klinik Berlin-Buch: Current Employment; Kite: Consultancy; Novartis: Consultancy; Riemser: Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau. Baldus: Novartis: Honoraria; Amgen: Honoraria; Celgene/BMS: Honoraria; Jazz: Honoraria. Vucinic: MSD: Honoraria; Novartis: Honoraria; Gilead: Honoraria, Other: Travel Sponsoring; Janssen: Honoraria, Other: Travel Sponsoring; Abbvie: Honoraria, Other: Travel Sponsoring. Topp: Universitatklinikum Wurzburg: Current Employment; Celgene: Consultancy, Research Funding; Janssen: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy; Roche: Consultancy, Research Funding; Gilead: Research Funding; Regeneron: Consultancy, Research Funding; Macrogeniecs: Research Funding; Amgen: Consultancy, Research Funding. Schroers: BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Takeda: Honoraria. Hanoun: AstraZeneca: Honoraria; Abbvie: Other: travel expenses; Novartis: Research Funding. Thomas: AbbVie: Honoraria, Speakers Bureau; Art tempi: Honoraria, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other; Kite/Gilead: Honoraria, Other, Research Funding, Speakers Bureau; Medigene: Consultancy, Honoraria, Other; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other; Pfizer: Consultancy, Honoraria, Other, Speakers Bureau. Kröger: Novartis: Research Funding; Riemser: Honoraria, Research Funding; Sanofi: Honoraria; Neovii: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Gilead/Kite: Honoraria; Celgene: Honoraria, Research Funding; AOP Pharma: Honoraria. Bethge: Novartis: Consultancy, Honoraria, Speakers Bureau; Miltenyi Biotec: Consultancy, Honoraria, Research Funding, Speakers Bureau; Kite-Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau.

Abstract: CD19-directed chimeric antigen receptor (CAR) T cells have evolved as new standard-of-care (SOC) treatment in patients with relapsed/refractory large B-cell lymphoma (LBCL). Here, we report the first German real-world data on SOC CAR-T cell therapies with the aim to explore risk factors associated with outcome. Patients who received SOC axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) for LBCL and were registered with the German Registry for Stem Cell Transplantation (DRST) were eligible. Main outcomes analyzed were toxicities, response, overall survival (OS), and progression-free survival (PFS). We report 356 patients who received axi-cel (n=173) or tisa-cel (n=183) between November 2018 and April 2021 at 21 German centers. Whereas the axi-cel and tisa-cel cohorts were comparable for age, sex, LDH, IPI, and pretreatment, the tisa-cel group comprised significantly more patients with poor performance status, ineligibility for ZUMA-1, and need for bridging, respectively. With a median follow-up alive of 11 months, Kaplan-Meier estimates of OS, PFS, and non-relapse mortality (NRM) 12 months after dosing were 52%, 30%, and 6%, respectively. While NRM was largely driven by infections subsequent to prolonged neutropenia and/or severe neurotoxicity and significantly higher with axi-cel, significant risk factors for PFS on multivariate analysis included bridging failure, elevated LDH, age, and tisa-cel use. In conclusion, this study suggests that important outcome determinants of CD19-directed CAR-T cell treatment of LBCL in the real-world setting are bridging success, CAR-T product selection, LDH, and the absence of prolonged neutropenia and/or severe neurotoxicity. These findings may have implications for designing risk-adapted CAR-T cell therapy strategies.

Abstract: Introduction The CD19 targeting CAR-T cell constructs axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) have become an accepted standard salvage treatment of LBCL beyond the second line. Patients scheduled for approved CAR-T cell therapies usually have 4-8 weeks wait time for CAR-T cell infusion, thus often requiring bridging strategies in rapidly progressing patients to achieve disease control until start of lymphodepletion. It is still unclear, however, if the adverse impact of active progressive lymphoma can be overcome by successful bridging. We have addressed this question using registry data provided by the German Registry for Stem Cell Transplantation (DRST), the national partner of the EBMT. Methods We analyzed 356 consecutive patients who received standard of care axi-cel (n=173) or tisa-cel (n=183) treatment of LBCL between November 2018 and April 2021 at 21 German centers and were registered with the DRST/EBMT. Baseline patient, disease, and transplant data were collected from MED-A cellular therapy forms. Centers were contacted to provide additional treatment and follow-up information. Predictors of progression-free survival (PFS) were analyzed by uni- and multivariate comparisons. Results Compared to the approval trials, patients were of poor risk with 58% presenting with elevated LDH at lymphodepletion and 71% having received ≥3 pretreatment lines, resulting in ineligibility for the ZUMA-1 study in 87% of cases. Kaplan-Maier estimates of overall survival, PFS and non-relapse mortality (NRM) 12 months after dosing were 52%, 30% and 7%, respectively. Information on bridging was available for 355 patients (99%). Of these, 279 patients (78%) underwent at least one line of bridging attempt, whereas bridging was deemed unnecessary in 76 patients (22%). A wide variety of modalities were employed for bridging, with the most frequent being chemoimmunotherapy (n=188), chemotherapy (n=41), radiation (n=30), immunotherapy (n=12) and steroids (n=6). Bridging resulted in disease control (CR/PR) in 58 of 270 patients evaluable for response (21%). With a median follow-up of 11 months, 12-month PFS rates for patients without bridging, successful bridging, and bridging failure were 41%, 52%, and 20%, respectively, p= & lt;0.001 (Figure). Of note, an increased LDH at lymphodepletion did not impair PFS within the bridging responders, but affected the outcome of those patients who did not respond or not undergo bridging (p & lt;0.0001). The adverse impact of bridging failure on PFS was confirmed after multivariable adjustment for confounders (p=0.001, HR 2.083; 95% CI 1.358-3.195). Other significant risk factors for PFS on multivariate analysis were elevated LDH (p=0.012, HR 1.46; 95% CI 1.08-1.96), tisa-cel (p=0.0109, HR 1.41; 95% CI 1.06-1.88) and ECOG (p=0.021, HR 1.22; 95% CI 1.03-1.45). Conclusion The results of this large German GLA/DRST analysis suggest that effective bridging can overcome the adverse impact of active disease on the outcome of standard-of-case CD19 CAR-T therapy. With current treatment strategies, however, bridging is often unsuccessful, highlighting the need for exploring innovative tools for inducing temporary LBCL control for CAR-T therapy preparation. Figure 1 Figure 1. Disclosures Bethge: Novartis: Consultancy, Honoraria, Speakers Bureau; Kite-Gilead: Consultancy, Honoraria, Speakers Bureau; Miltenyi Biotec: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Schmitt: TolerogenixX: Current holder of individual stocks in a privately-held company; Novartis: Other: Travel grants, Research Funding; Kite Gilead: Other: Travel grants; Apogenix: Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Other: Travel grants; Hexal: Other: Travel grants, Research Funding. Holtick: Celgene: Honoraria; Sanofi: Honoraria. Borchmann: Gilead Sciences: Honoraria; BMS/Celgene: Honoraria; Janssen: Honoraria; Miltenyi Biotech: Honoraria; Novartis: Honoraria. Subklewe: Klinikum der Universität München: Current Employment; Pfizer: Consultancy, Speakers Bureau; Roche: Research Funding; Novartis: Consultancy, Research Funding, Speakers Bureau; MorphoSys: Research Funding; Janssen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Takeda: Speakers Bureau; Miltenyi: Research Funding; Gilead: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; BMS/Celgene: Consultancy, Research Funding, Speakers Bureau. von Tresckow: Roche: Consultancy, Honoraria; Kite-Gilead: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Pentixafarm: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: congress and travel support, Research Funding; MSD: Consultancy, Honoraria, Other: congress and travel support, Research Funding; BMS-Celgene: Consultancy, Honoraria, Other: congress and travel support; AstraZeneca: Honoraria, Other: congress and travel support; Amgen: Consultancy, Honoraria; AbbVie: Other: congress and travel support; Takeda: Consultancy, Honoraria, Other, Research Funding. Ayuk: Gilead: Honoraria; Mallinckrodt/Therakos: Honoraria, Research Funding; Janssen: Honoraria; Takeda: Honoraria; Miltenyi Biomedicine: Honoraria; Celgene/BMS: Honoraria; Novartis: Honoraria. Kroeger: Novartis: Honoraria; AOP Pharma: Honoraria; Gilead/Kite: Honoraria; Riemser: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Sanofi: Honoraria; Neovii: Honoraria, Research Funding. Wulf: Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Clinigen: Consultancy, Honoraria. Marks: Merck: Consultancy; Kite/Gilead: Honoraria; AbbVie: Other: Meeting attendance; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees. Penack: Astellas: Honoraria; Gilead: Honoraria; Jazz: Honoraria; Omeros: Consultancy; Shionogi: Consultancy; Priothera: Consultancy; Incyte: Research Funding; Takeda: Research Funding; Therakos: Honoraria; Pfizer: Honoraria; Neovii: Honoraria; Novartis: Honoraria; MSD: Honoraria. Koenecke: Kite/Gilead: Consultancy; BMS/Celgene: Consultancy; Janssen: Consultancy; Novartis: Consultancy; EUSA Pharm: Consultancy. Von Bonin: Kite/Gilead: Other: traveling support and advisory fees; Novartis: Other: traveling support and advisory fees; Daiichi Sankyo: Other: traveling support and advisory fees. Stelljes: Amgen: Consultancy, Speakers Bureau; Celgene/BMS: Consultancy, Speakers Bureau; Medac: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Kite/Gilead: Consultancy, Speakers Bureau. Glass: BMS: Consultancy; Helios Klinik Berlin-Buch: Current Employment; Kite: Consultancy; Novartis: Consultancy; Riemser: Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau. Baldus: Novartis: Honoraria; Amgen: Honoraria; Celgene/BMS: Honoraria; Jazz: Honoraria. Vucinic: Janssen: Honoraria, Other: Travel Sponsoring; Novartis: Honoraria; Abbvie: Honoraria, Other: Travel Sponsoring; Gilead: Honoraria, Other: Travel Sponsoring; MSD: Honoraria. Topp: Celgene: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy; Amgen: Consultancy, Research Funding; Gilead: Research Funding; Regeneron: Consultancy, Research Funding; Macrogeniecs: Research Funding; Universitatklinikum Wurzburg: Current Employment. Schroers: BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Takeda: Honoraria. Thomas: Abbvie: Honoraria, Speakers Bureau; Art tempi: Honoraria, Speakers Bureau; BMS-Celgene: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: travel support; Kite-Gilead: Honoraria, Other: travel support, Research Funding, Speakers Bureau; Medigene: Consultancy, Honoraria, Other: Travel support; Novartis: Consultancy, Honoraria, Other: travel support, Speakers Bureau; Pfizer: Consultancy, Honoraria, Other: Travel support, Speakers Bureau. Dreger: Bluebird Bio: Consultancy; BMS: Consultancy; AbbVie: Consultancy, Speakers Bureau; Riemser: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Gilead Sciences: Consultancy, Speakers Bureau; Janssen: Consultancy; AstraZeneca: Consultancy, Speakers Bureau.