Double-dose axicabtagene ciloleucel (Axi-Cel-2) as second-line therapy for high-risk relapsed or refractory large B-cell lymphoma (r/rLBCL): Interim results from a Phase 1b study

Abstract

Abstract Background Axicabtagene ciloleucel(axi-cel) has improved outcomes in relapsed or refractory large B-cell lymphoma(r/rLBCL); however, more than half of patients(pts) experience disease progression or death especially among pts with elevated lactate dehydrogenase(LDH). Axi-Cel-2, a second axi-cel infusion administered shortly after standard-of-care(SOC) axi-cel, aims to improve target to effector ratio and increase exposure to less-exhausted CAR T-cells(CAR-T). We report interim Phase 1b results examining the safety and efficacy of Axi-Cel-2(NCT05794958). Method Adults with r/rLBCL, elevated LDH, and second-line(2L) axi-cel eligibility are included. Bridging therapy(BT) with steroids and/or radiation is permitted. After lymphodepleting chemotherapy(LDC), all pts receive SOC axi-cel. Pts without grade(gr) ≥3 cytokine release syndrome(CRS) or immune effector cell–associated neurotoxicity(ICANS) are eligible for Axi-Cel-2, administered 7–14 days after the SOC infusion, at 0.5×10⁶ CAR+ cells/kg(safety run-in) or 2×10⁶ CAR+ cells/kg(phase 1b). Single LDC is used for both infusions. Target enrollment is 20 pts receiving Axi-Cel-2. The primary endpoint is incidence of dose-limiting toxicity(DLT) with key secondary endpoint being 12-month(mo) progression-free survival(PFS). Results are referenced to SOC axi-cel infusion(day 0). Blood samples are collected over 28 days post SOC axi-cel to assess CAR-T kinetics and phenotype(Hamilton, Blood Adv 2024), as well as gene expression and clonal dynamics on days 7 and 17 in fold change(FC) using single-cell multi-omics(Good, Nat Med 2022). Molecular responses are assessed using PhasED-Seq(Kurtz, Nat Biotechnol 2021) to quantify pretreatment circulating tumor DNA(ctDNA) and minimal residual disease(MRD) while EPIC-Seq(Esfahani, Nat Biotechnol 2022) is used to evaluate CD19 antigen loss. Results As of July 15, 2025, 16 pts have been enrolled(15 evaluable). The median age was 61.5 years(range/r, 19–83), with 38% aged ≥65 years. Sixty-nine % of pts had refractory disease, and 56% had an IPI score ≥3. BT was administered in 81% of pts, and all received prophylactic steroids. Four pts were ineligible for Axi-Cel-2 due to gr ≥3 ICANS or active infection. Eleven pts received Axi-Cel-2(3 in the safety lead-in and 8 in the Phase 1b), and the analysis focuses on these pts. The median day of Axi-Cel-2 infusion was 10(r, 7-12). No DLT or serious adverse event were observed within 28 days of Axi-Cel-2. Following Axi-Cel-2 infusion, 3 patients experienced gr 1 CRS or ICANS, all with onset within 1 day and resolution within 1 day. All 11 pts were discharged within a median of 2 days(r, 2–4) after Axi-Cel-2, with 55% discharged at the minimum 2-day stay. One pt died due to progressive disease. At a median follow-up of 5.8 mos(IQR: 3.1–14.9), the overall response rate(95% CI) was 90.9%(58.7–99.8), including complete response rate of 72.7%(39.0–94.0). The 6-mo rates(95% CI) were 79.5%(39.3–94.5) for duration of response, 78.7%(38.1–94.3) for PFS, and 100% for overall survival. A second CAR-T expansion was observed in 88% of pts receiving the phase 1b dose. Median area-under-the-curve over 28 days was 259 cells/µL×day(n=11; IQR: 63–1094) in pts receiving Axi-cel-2 and 134 cells/µL×day(n=30; IQR: 26–557) in the 2L SOC historical cohort. Spectral flow cytometry showed higher GZMB+ CD8+ and lower PD-1+ proportions in CAR+ cells after Axi-Cel-2 vs SOC axi-cel(n=4; p<0.02). Single-cell RNA-seq revealed increased CX3CR1(2.7 log2FC) and TBX21(T-bet; 1.5 log2FC) and decreased NFKBIA(−1.7 log2FC) (all adj. p<0.001) in circulating CAR-T cells. These findings indicate reduced CAR-T exhaustion with enhanced cytotoxicity, activation, and migration after Axi-Cel-2. Using PhasED-Seq, ctDNA was measured in 7 pts receiving Axi-Cel-2(5 responders and 2 progressors), and median pretreatment ctDNA was 227 hGE/mL(r, 36–891). Among the responders, MRD negativity was 60% at 1 mo and 80% at 3 mos; the remaining pt had decline in ctDNA level to <1 hGE/mL by 3 mos. Both progressors had early ctDNA rise with CD19 antigen escape, confirmed by expression profiling and EPIC-Seq. Conclusion Interim Phase 1b results(n=11) show Axi-Cel-2 was well-tolerated without DLTs and induced a second CAR-T expansion with more cytotoxic, less-exhausted phenotypes and deep molecular responses. These findings support the potential of Axi-Cel-2 to improve outcomes in this high-risk population. Updated results will be presented at the meeting.