Inferior Outcomes of EU Vs. US Patients with Relapsed/Refractory Large B-Cell Lymphoma after CD19 CAR T-Cell Therapy Are Associated with Differences in Tumor Burden, Systemic Inflammation, Bridging Therapy Utilization and CAR-T Product Selection

CD19 CAR T-cell therapy (CAR-T) has significantly improved the prognosis of patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Real-world evidence has largely mirrored the clinical outcomes observed in registrational trials for these patients. However, a trend towards inferior survival in European (EU) patients and with tisagenlecleucel has been noted (Bethge WA et al., Blood 2022; Bachy E et al, EHA Annual Meeting 2022). The underlying logistic, patient- and disease-related reasons for these discrepancies remain poorly understood.

Here, we sought to characterize potential differences between EU and US R/R LBCL patients treated with standard-of-care tisagenlecleucel (Tisa-cel) or axicabtagene ciloleucel (Axi-cel) and their influence on survival outcomes. To this end, we retrospectively evaluated CAR-T time intervals from indication (usually time of tumor board decision) to infusion, baseline demographic, disease and laboratory features together with survival in 374 patients treated at five EU and one US CAR-T centers.

A significant proportion of patients received intermediary anti-lymphoma therapy not only between apheresis and CAR-T infusion ("bridging"), but also between indication to CAR-T therapy and apheresis (coined "holding therapy"). While 22% of EU patients and 27% of US patients received holding therapy (p=0.33), a significantly higher proportion of EU patients were treated with bridging therapy (90% vs. 70% in US, p<0.0001). EU patients displayed prolonged apheresis-to-infusion intervals (49 vs. 30 days, p<0.0001). Tisa-cel was significantly more frequently applied in Europe (74% of EU patients) than in the US (15%, p<0.0001).

Baseline characteristics are summarized in table 1. Interestingly, LDH levels (321 vs. 271 U/l in US, p=0.02) and the inflammatory marker ferritin (675 vs. 425 ng/ml in US, p=0.004) were significantly elevated in the EU vs. the US cohort.

Overall, we observed inferior survival outcomes in the patients treated in the EU cohort (median progression-free survival [PFS] 3.1 vs. 9.2 months in the US, p<0.0001; 1-year PFS estimate 26% in EU vs. 48% in US) and with Tisa-cel (median PFS 3.2 vs. 9.2 months with Axi-cel, p<0.0001, 1-year PFS estimate 23% with Tisa-cel vs. 49% with Axi-cel). In univariate Cox regression analysis, more prior therapy lines, refractoriness to the latest therapy prior to CAR-T indication, ECOG ≥ 2, Ann-Arbor stage ≥ III, presence of extranodal disease (END), longer apheresis-to-infusion intervals, higher ferritin, CRP and LDH levels, non-response to bridging, and Tisa-cel use were significantly associated (p<0.05) with impaired progression-free survival (PFS).

On multivariate Lasso modelling of these variables (from n=277 patients, excluding CAR-T product to delineate product-independent risk factors), non-response to bridging, elevated ferritin, and increased CRP remained independent risk factors for inferior PFS. These factors were weighted into a patient-individual "HRscore" using factor-specific Lasso coefficients (non-response to bridging: 0.35, ferritin: 0.10, CRP: 0.01). The HRscore was significantly elevated in EU patients (p=0.03 for EU vs. US), and notably also in the Tisa-cel cohort (p=0.0009 for Tisa-cel vs. Axi-cel). Risk stratification by the HRscore was confirmed by a second Lasso model only incorporating variables that were available at CAR-T indication (ferritin: 0.13, LDH: 0.09, END: 0.04, CRP: 0.03). Notably, PFS of Axi-cel was superior to Tisa-cel in patients with lower HRscores (median PFS not reached for Axi-cel vs. 7.4 months for Tisa-cel, p=0.002). In patients with high HRscores, PFS was similar for Axi-cel and Tisa-cel (2.9 months for both products, p=0.49).

Taken together, these data provide insight on potential explanations for the inferior survival outcomes in EU patients receiving CD19 CAR-T cells for r/r LBCL. Differences in tumor burden and chemo-sensitivity (evidenced by LDH, END and non-response to bridging), systemic inflammation (ferritin, CRP), and CAR-T product were associated with observed PFS disparities between EU and US. Of note, superior outcomes with Axi-cel were mainly observed in patients with lower-risk disease. Our results highlight the importance of careful patient selection and, importantly, identify a high-risk patient cohort with significant medical need for further CAR-T treatment optimization.

Buecklein:Gilead: Honoraria; Pfizer: Research Funding, Speakers Bureau; Miltenyi Biotech: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria. Rejeski:Novartis: Honoraria; Kite/Gilead: Other: Travel Support, Research Funding. Iacoboni:NOVARTIS, KITE/GILEAD, BMS/CELGENE, ASTRAZENECA, ROCHE, ABBVIE, JANSSEN, MILTENYI: Honoraria; NOVARTIS, KITE/GILEAD, BMS/CELGENE: Consultancy. Holtick:BMS/Celgene: Honoraria; Miltenyi Biotech: Honoraria; Novartis: Honoraria, Research Funding; Amgen: Consultancy, Honoraria; CLS Behring: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Kite/Gilead: Honoraria. Penack:SOBI: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees; Priothera: Membership on an entity's Board of Directors or advisory committees, Research Funding; Omeros: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Equillium Bio: Membership on an entity's Board of Directors or advisory committees; Therakos: Honoraria; Pfizer: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Blumenberg:Novartis: Honoraria, Research Funding; Celgene: Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Research Funding. Schmidt:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Janssen: Other: Travel Support; Bayer Healthcare: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Kite Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support. Gödel:Kite/Gilead: Other: Travel Grant. Bullinger:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Oncology: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mackensen:Novartis: Honoraria; Miltenyi Biomedicine: Honoraria; BMS/Celgene: Honoraria; Kite/Gilead: Honoraria. Locke:Leukemia and Lymphoma Society: Research Funding; Aptitude Health: Other: Education or editorial activity; ASH: Other: Education or editorial activity; BioPharm Communications: Other: Education or editorial activity; CAREducation: Other: Education or editorial activity; Clinical Care Options Oncology: Other: Education or editorial activity; Imedex: Other: Education or editorial activity; Society for Immunotherapy of Cancer: Other: Education or editorial activity; Takeda: Consultancy; Sana: Consultancy; CERo Therapeutics: Research Funding; ), National Cancer Institute: Research Funding; Daiichi Sankyo: Consultancy; BMS: Research Funding; A2: Consultancy; Celgene: Consultancy; Other: Patents & Royalties: patents, royalties, other intellectual property from several patents held by the institution in my name (unlicensed) in the field of cellular immunotherapy.; Wugen: Consultancy; Umoja: Consultancy; Novartis: Consultancy, Research Funding; Legend Biotech: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Janssen: Consultancy; Iovance: Consultancy; GammaDelta Therapeutics: Consultancy; Emerging Therapy Solutions Gerson Lehrman Group: Consultancy; EcoR1: Consultancy; Cowen: Consultancy; Calibr: Consultancy; Cellular Biomedicine Group: Consultancy; Bristol Myers Squibb/Celgene: Consultancy; Bluebird Bio: Consultancy, Research Funding; Allogene: Consultancy, Research Funding; Amgen: Consultancy. Barba:BMS: Honoraria; Amgen: Honoraria; Gilead: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Jain:BMS: Consultancy; MyeloidTx: Consultancy; Incyte: Research Funding; Novartis: Consultancy; Kite Pharma: Consultancy, Research Funding. Subklewe:Miltenyi Biotech: Research Funding; Pfizer: Consultancy; Roche: Consultancy, Research Funding; Seagen: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Gilead: Consultancy, Research Funding, Speakers Bureau; Takeda: Other: Travel support; Morphosys: Research Funding; Seattle Genetics: Research Funding; Celgene/BMS: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Research Funding; Novartis: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau.