Evaluation of Outcomes and Toxicities of Commercial Axicabtagene Ciloleucel (axi-cel) and Tisagenlecleucel (tisa-cel) for Relapsed or Refractory (R/R) Follicular Lymphoma (FL): Real-World Evidence (RWE) from 10 US Academic Centers

Background: The advent of chimeric antigen receptor T-cell (CAR-T) therapy revolutionized the treatment landscape in R/R FL, including those with progression of disease within 24 months (POD24). However, RWE describing outcomes for patients with R/R FL treated with CAR-T is lacking. Hence, we sought to evaluate outcomes and toxicities of axi-cel vs tisa-cel in R/R FL from 10 US academic centers. Methods: This is a multi-center retrospective cohort study of patients (pts) with R/R FL who received commercial CAR-T with axi-cel or tisa-cel between 2021 and 2024. Pts with biopsy-proven transformed lymphoma were excluded. Endpoints included day +90 overall response rate (ORR) and complete response rate (CRR), progression-free survival (PFS), overall survival (OS) and rates of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). ORR was defined as partial response (PR) rate + CRR according to Lugano criteria. PFS was calculated from CAR-T infusion to progression or death, censoring those alive without progression at last contact, and OS was calculated from CAR-T infusion to death, censoring those alive at last contact. CRS and ICANS were graded according to American Society for Transplantation and Cellular Therapy criteria. Kaplan-Meier method was used to estimate survival functions with log-rank test to compare groups. Cox regression was done to identify prognostic factors for PFS and OS. Results: A total of 111 pts were included. Among these, 91 (82%) received axi-cel and 20 (18%) received tisa-cel. Pts receiving tisa-cel were older (median age, 74 yrs [range: 29-82] vs 60 yrs [range: 38-82], p<0.001) with female predominance (60% vs 23%, p=0.003), and were more likely to receive bendamustine lymphodepletion (35% vs 3%, p<0.001) compared to those receiving axi-cel. Otherwise, groups were similar between axi-cel and tisa-cel with regards to race (white 86% vs 85%, black 6% vs 5%, p=1.0), Eastern Cooperative Oncology Group performance status (0-1 96% vs 100%, ≥2 4% vs 0%, p=1.0), stage at diagnosis (I-II 20% vs 13%, III 29% vs 25%, IV 52% vs 63%, p=0.82), bulky disease at diagnosis (44% vs 53%, p=0.71), primary refractory disease (24% vs 16%, p=0.56), POD24 (62% vs 56%, p=0.83), median prior lines of therapies (3 [range: 3-12] vs 3 [range: 2-5], p=0.57), receipt of bridging therapy (43% vs 65%, p=0.12), disease status immediately prior to CAR-T (CR/PR 21% vs 16%, stable disease 18% vs 16%, progressive disease (61% vs 68%, p=1.0), and pre-lymphodepletion lab values. The median follow up was 1.3 yrs (range: 0.9 - 3). Day +90 ORR and CRR were comparable between axi-cel and tisa-cel (ORR 89% [95% CI: 80, 95] vs 83% [95% CI: 57, 96], p=0.43, CRR 85% [95% CI: 76, 92] vs 71% [95% CI: 44, 90], p=0.16). Median PFS was significantly longer with axi-cel vs tisa-cel (not reached (NR) [95% CI: 24.6 months, NR] vs 9.1 months [95% CI: 7.4 months, NR], p=0.003) with 1 yr PFS estimates of 71% (95% CI: 61, 82) vs 31% (95% CI: 14, 68), respectively. Median OS was NR in both groups (95% CI: NR, NR for both) with 1 yr OS estimates of 90% (95% CI: 83, 97) in axi-cel vs 87% (95% CI: 72, 100, p=0.32) in tisa-cel. There was no difference in frequency of any grade CRS (78% vs 70%, p=0.56) or grade ≥3 CRS (6% vs 5%, p=1.0) between axi-cel vs tisa-cel. Rates of any grade (43% vs 20%, p=0.10) and grade ≥3 ICANS (20% vs 5%, p=0.19) were numerically higher with axi-cel vs tisa-cel. Notably, more patients received tisa-cel in the outpatient setting (40% vs 9%, p=0.002). Among patients receiving outpatient CAR-T, frequencies of unexpected hospitalizations within 30 days between axi-cel (6 of 8 pts) and tisa-cel (5 of 8 pts) were comparable (p=1.0). Among patients receiving inpatient CAR-T, frequency of re-admissions within 30 days between axi-cel (20 of 83 pts) and tisa-cel (1 of 12 pts) were comparable (p=0.29). In Cox model, receipt of tisa-cel (vs axi-cel) and POD24 were associated with inferior PFS (HR 4.6, 95% CI: 1.5, 13.7, p=0.007, HR 5.03, 95% CI: 2.0,12.9, p<0.001, respectively). No variables were prognostic for OS. Discussion: This is the first RWE analyzing outcomes and toxicities of axi-cel and tisa-cel in R/R FL. ORR and CRR were comparable between the two CAR-T products. Rates of any and grade ≥3 ICANS were numerically higher with axi-cel, though this did not reach statistical significance. PFS was significantly inferior for recipients of tisa-cel compared to axi-cel with the caveat that the tisa-cel group was relatively small.