Abstract: Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are CD19-targeted chimeric antigen receptor (CAR) T cells approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). We performed a retrospective study to evaluate safety and efficacy of axi-cel and tisa-cel outside the setting of a clinical trial. Data from consecutive patients with R/R LBCL who underwent apheresis for axi-cel or tisa-cel were retrospectively collected from 12 Spanish centers. A total of 307 patients underwent apheresis for axi-cel (n=152) and tisa-cel (n=155) from November 2018 to August 2021, of which 261 (85%) received a CAR T infusion (88% and 82%, respectively). Median time from apheresis to infusion was 41 days for axi-cel and 52 days for tisa-cel (P=0.006). None of the baseline characteristics were significantly different between both cohorts. Both cytokine release syndrome and neurologic events (NE) were more frequent in the axi-cel group (88% vs. 73%, P=0.003, and 42% vs. 16%, P 〈 0.001, respectively). Infections in the first 6 months post-infusion were also more common in patients treated with axi-cel (38% vs. 25%, P=0.033). Non-relapse mortality was not significantly different between the axi-cel and tisa-cel groups (7% and 4%, respectively, P=0.298). With a median follow-up of 9.2 months, median PFS and OS were 5.9 and 3 months, and 13.9 and 11.2 months for axi-cel and tisa-cel, respectively. The 12-month PFS and OS for axi-cel and tisa-cel were 41% and 33% (P=0.195), 51% and 47% (P=0.191), respectively. Factors associated with lower OS in the multivariate analysis were increased lactate dehydrogenase, ECOG ≥2 and progressive disease before lymphodepletion. Safety and efficacy results in our real-world experience were comparable with those reported in the pivotal trials. Patients treated with axi-cel experienced more toxicity but similar non-relapse mortality compared with those receiving tisa-cel. Efficacy was not significantly different between both products.

Abstract: Introduction Tisagenlecleucel (tisa-cel) is a second generation, CD19-targeted Chimeric Antigen Receptor (CAR) T-cell therapy for relapsed or refractory (R/R) large B-cell lymphoma (LBCL). The pivotal phase 2 trial JULIET included 93 patients and reported an overall response rate (ORR) of 52% and a complete response rate of 40% among treated patients. However, very little is known regarding its safety and efficacy in the commercial or real-world setting as well as from an intention-to-treat perspective. In our study, we report clinical outcomes of patients with R/R LBCL treated with commercial tisa-cel in 10 Spanish institutions. Methods Data were collected retrospectively from all consecutive patients with R/R LBCL who underwent apheresis for tisa-cel at a Spanish site from December 2018 until June 2020. Evaluable patients included those who received a CAR-T infusion and had at least 1 month of follow-up. Adverse events after infusion were graded according to the ASTCT consensus and efficacy outcomes were assessed according to the Lugano criteria. Efficacy outcomes were calculated in the patients who received a CAR T-cell infusion and in all patients who underwent apheresis for tisa-cel (intention-to-treat). Results During the study period 91 patients with R/R LBCL underwent apheresis for tisa-cel. At the study cutoff, 69 (76%) patients had received a CAR T-cell infusion whereas 22 (24%) had not due to progressive disease (n=10, 45%), pending manufacturing process (n=7, 32%), out of specification (OOS) or manufacturing failure (n=4, 18%), or others (n=1, 5%). Sixty-one patients had at least the first disease response evaluation at 1-month post-infusion. Baseline characteristics of the whole cohort and the infused patients are summarized in Table 1. Among infused patients, median age was 57 years (range 24-77) and 65% were male. Most of the patients had a high-risk International Prognostic Index score (62%), an advanced stage at diagnosis (91%) and were refractory to the previous therapy (80%). Median follow-up after CAR T-cell infusion was 4 months (1-16). Fifty-six patients (81%) received bridging therapy before infusion, including chemotherapy in most cases (n=51, 91%). All patients received fludarabine and cyclophosphamide as lymphodepleting chemotherapy. Median time from apheresis to infusion was 53 days (range 29-225). Median infused cell dose was 2.2 x 108 CAR positive viable T-cells (range 0.4-4.2 x 108). Eleven (16%) products were considered OOS although 45% of them were infused. Among the infused patients, 47 (68%) and 9 (13%) developed any grade of cytokine release syndrome (CRS) and neurotoxicity, respectively. Grade & gt;2 CRS and neurotoxicity events occurred in 3 (4%) and 0 patients, respectively. Tocilizumab was administered to 21 (30%) patients and steroids to 13 (19%) patients. Nine (13%) patients required admission to the Intensive Care Unit. By day 100, 2 (3%) patients experienced non-relapse mortality. Other adverse events including infections and tumor lysis syndrome are summarized in table 2. Best response achieved among the infused patients included complete remission in 17 (28%) patients and partial remission in 22 (36%) patients, with an ORR of 64%. Stable disease and progressive disease were the best response in 4 (7%) and 18 (29%) patients, respectively. Considering all patients who underwent apheresis, CR and PR were obtained in 19% and 24% (ORR 43%), respectively. Median progression-free survival (PFS) and overall survival (OS) for infused patients were 3 months (95%CI 2.1-3.4) and 8 months (95%CI 5.7-10.8), respectively. In the univariate analysis, patients with ECOG score & gt;1 (HR 4.3 95%CI 1.5 - 40.9) (p & lt; 0.001) and IPI score & gt;2 (HR 4.8 95%CI 1.6 - 14.4) (p = 0.002) were associated with lower PFS while an ECOG score & gt;1 was also associated with lower OS (HR 3.4 95%CI 1.15 - 34.4) (p = 0.04). In the intention-to-treat analysis for all patients who underwent apheresis, median PFS and OS from apheresis were 4 months (95%CI 2.8-5.8) and 9 months (95%CI 5.8-11.8), respectively. Conclusions Treatment with tisa-cel was able to induce disease response with a good toxicity profile in a population of patients with LBCL treated in a European country. Poor performance status at the time of CAR T-cell infusion was associated with lower PFS and OS. Disclosures Iacoboni: Novartis, Gilead, Celgene, Roche: Honoraria. Guerreiro:Novartis: Honoraria. Mussetti:Novartis, Gilead: Honoraria, Research Funding. Sancho:Roche, Janssen, Celgene, Novartis, Gilead, Sandoz, Mundipharma y Takeda; Advisory y/o consultor para Roche, Janssen, Celgene, Novartis, Gilead, Sandoz, Celltrion y Kern-Pharma.: Honoraria. Hernani:Gilead: Honoraria. Sureda Balari:Takeda: Consultancy, Honoraria, Speakers Bureau; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Merck Sharpe and Dohme: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Gilead/Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Incyte: Consultancy; Celgene: Consultancy, Honoraria; BMS: Speakers Bureau; Roche: Honoraria. Martin Garcia-Sancho:Celgene, Eusa Pharma, Gilead, iQuone, Kyowa Kirin, Roche, Morphosys: Consultancy; Roche, Celgene, Janssen, Servier, Gilead: Honoraria. Kwon:Jazz: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Reguera:Celgene, Novartis: Consultancy; Novartis, Gilead: Honoraria. Barba:Novartis, Celgene, Gilead, Pfizer, Amgen, Roche: Honoraria.

Abstract: Tisagenlecleucel (tisa‐cel) is a second‐generation autologous CD19‐targeted chimeric antigen receptor (CAR) T‐cell therapy approved for relapsed/refractory (R/R) large B‐cell lymphoma (LBCL). The approval was based on the results of phase II JULIET trial, with a best overall response rate (ORR) and complete response (CR) rate in infused patients of 52% and 40%, respectively. We report outcomes with tisa‐cel in the standard‐of‐care (SOC) setting for R/R LBCL. Data from all patients with R/R LBCL who underwent leukapheresis from December 2018 until June 2020 with the intent to receive SOC tisa‐cel were retrospectively collected at 10 Spanish institutions. Toxicities were graded according to ASTCT criteria and responses were assessed as per Lugano 2014 classification. Of 91 patients who underwent leukapheresis, 75 (82%) received tisa‐cel therapy. Grade 3 or higher cytokine release syndrome and neurotoxicity occurred in 5% and 1%, respectively; non‐relapse mortality was 4%. Among the infused patients, best ORR and CR were 60% and 32%, respectively, with a median duration of response of 8.9 months. With a median follow‐up of 14.1 months from CAR T‐cell infusion, median progression‐free survival and overall survival were 3 months and 10.7 months, respectively. At 12 months, patients in CR at first disease evaluation had a PFS of 87% and OS of 93%. Patients with an elevated lactate dehydrogenase showed a shorter PFS and OS on multivariate analysis. Treatment with tisa‐cel for patients with relapsed/refractory LBCL in a European SOC setting showed a manageable safety profile and durable complete responses.

Abstract: Introduction: Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are the two autologous anti-CD19 chimeric antigen receptors T cells commercially approved in Europe for relapsed/refractory (R/R) DLBCL. We performed a retrospective study to evaluate patients characteristics, efficacy and safety for axi-cel and tisa-cel in a large cohort of patients within the GETH-TC (Spanish Group of Stem Transplantation and Cell Therapy)-GELTAMO (Spanish Group of Lymphoma and Autologous Stem Cell Transplantation). Methods: Ten Spanish centers contributed data. Data were collected retrospectively from consecutive patients with DLBCL in whom apheresis was performed for axi-cel or tisa-cel treatment. CRS and ICANS were graded with the ASTCT consensus criteria. Response was assessed according to the Lugano criteria. Patients included had at least 30 days of follow-up. Results: A total of 268 patients with R/R DLBCL underwent apheresis for axi-cel (n=123) and tisacel (n=145) from Nov-2018 to May-2021, of which 232 (86%) received CART-cell infusion (n=110, 89% and n=122, 84%, respectively). Reasons for not undergoing infusion were progression in 10 cases, tumor lysis syndrome in 1, infection in 1, and CR after bridging therapy in 1 for the axi-cel cohort, and progression in 21 (4 after manufacture failure), psychiatric disorder in 1, and post-apheresis cerebral hemorrhage in 1 case for the tisa-cel cohort. Time between apheresis and infusion was 41 days (IQR 40-56) and 49 days (IQR 46-62) (p=0.006), respectively. Characteristics at baseline, apheresis and at lymphodepletion are summarized in Tables 1 and 2. Median age was 60 (range 19-79), 61% of patients were male, most of them treated for DLBCL NOS (66%). There were no significant differences between patients intended to be treated with axi-cel and tisa-cel. 82% of the infused patients received bridging therapy. At apheresis and at lymphodepletion ECOG performance status score was 0-1 in 93% and 91%, and 7 and 32 patients were in response, respectively. The overall response rates (ORRs) at 1 month and 3 months were 65% and 56%, respectively, with 34% and 45% achieving a complete response (CR), respectively. In the intention-to-treat analysis, with a median follow-up of 9 months (IQR 5-15), EFS and OS at 9 months was 44% (95%CI 38-51)(Figure 1) and 59% (95%CI 53-66) with a median EFS and OS of 6 months and 11 months, respectively. At lymphodepletion, characteristics of infused patients and disease were not significantly different between axi-cel and tisa-cel cohorts. Rates of CRS, CRS grade 3-4, ICANS, ICANS grade 3-4 were 89% and 71% (p=0.001), 10% and 7% (p=0.34), 42% and 16% (p=0.001), 20% and 4% (p=0.001) for the axi-cel and tisa-cel cohorts, respectively. ICU admission was needed in 25% and 15% of patients (p=0.06), respectively. Non-relapse mortality at days 100 were 2.5% and 1.4%, and at day 180, 5.4% and 2.2% (p=0.08) for the axi-cel and tisa-cel groups, respectively. With a median follow-up of 8 months for patients who received infusion with axi-cel and 12 months for patients infused with tisa-cel, EFS and OS at 12 months were 48% and 33% (p=0.33), and 53% and 50% (p=0.27), respectively, with a median EFS of 11 and 6 months and a median OS of 13 and 12 months, respectively. In the multivariate analysis, the only factor associated with poor PFS was having ECOG-PS ≥2 at lymphodepletion (HR13, p=0.03). No factors were identified as associated independently to OS. Factors associated to CRS grade 3-4 were IPI score 4-5 at lymphodepletion (OR 1.4, p=0.03) and ECOG-PS ≥2 at apheresis (OR 1.5, p=0.03). For ICANS grade 3-4, factors associated were the use of axi-cel (OR 8, p=0.04) and diagnosis of HG double/triple hit lymphoma (OR 9, p=0.022). Conclusions:This multicentric analysis describes one of the largest real-life cohorts of patients treated with axi-cel and tisa-cel for R/R aggressive B cell lymphoma in Europe. Results are comparable to those from the pivotal studies and other large real-life experiences. Up to now, patients included for one or other product in Spain do not differ significantly in terms of baseline characteristics, and within this setting, results are comparable between both products in terms of efficacy. The use of axi-cel was associated to higher rates of CRS and especially, severe forms of ICANS. However, mortality associated to toxicity were low and not significantly different between both cohorts. Figure 1 Figure 1. Disclosures Kwon: Novartis, Celgene, Gilead, Pfizer: Consultancy, Honoraria. Iacoboni: BMS/Celgene, Gilead, Novartis, Janssen, Roche: Honoraria. Reguera: Janssen, Kite/Gilead, Novartis: Speakers Bureau; BMS-Celgene, Novartis: Membership on an entity's Board of Directors or advisory committees. Lopez Corral: Gilead, Novartis: Consultancy, Honoraria. Guerreiro: Novartis, Gilead: Consultancy, Honoraria. Caballero: Novartis, Gilead: Honoraria. Ortiz-Maldonado: Kite, Novartis, BMS, Janssen: Honoraria. Sanchez: Janssen, Jazz Pharmaceuticals, Gilead, Novartis, Amgen: Consultancy. Sancho: Roche, Janssen, Celgene-BMS, Gilead, Novartis, Takeda: Honoraria, Speakers Bureau; Roche, Janssen, Celgene-BMS, Gilead, Novartis, Incyte, Beigene: Speakers Bureau. Bastos-Oreiro: Janssen: Honoraria, Speakers Bureau; F. Hoffmann-La Roche: Honoraria, Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Novartis: Honoraria, Speakers Bureau; BMS-Celgene: Honoraria, Speakers Bureau; Gilead: Honoraria; Kite: Speakers Bureau. Oarbeascoa: Gilead: Honoraria, Speakers Bureau. Mussetti: Gilead: Other: Unspecified, Research Funding; Novartis: Honoraria, Other: Unspecified; Takeda: Honoraria. Bailen: Gilead, Pfizer: Speakers Bureau. Martin Garcia-Sancho: Takeda: Honoraria; Novartis: Consultancy; Incyte: Consultancy; Celgene/BMS: Consultancy; Celgene: Honoraria, Other: travel; Roche: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses; Janssen: Honoraria, Research Funding; Servier: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses; Gilead: Consultancy, Honoraria; Morphosys: Consultancy; Kyowa Kirin: Consultancy; Clinigen: Consultancy; Eusa Pharma: Consultancy; Kern Pharma: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Barba: Amgen, Celgene, Gilead, Incyte, Jazz Pharmaceuticals, MSD, Novartis, Pfizer and Roche, Jazz Phar,aceuticals: Honoraria; Cqrlos III heqlth Institute, aSOCIACION espanola contra el cancer, PERIS: Research Funding.