Treatment of pediatric patients (pts) with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) with obecabtagene autoleucel (obe-cel), a CD19-directed chimeric antigen receptor (CAR) T-cell therapy: Preliminary findings from the Phase

Abstract Background: Obe-cel is an autologous, fast off-rate 4-1BB-ζ CD19-directed CAR T-cell therapy that demonstrated long-term efficacy and low severe immunotoxicity in adult R/R B-ALL (Roddie et al. NEJM 2024). In the Phase I CARPALL study (NCT02443831), obe-cel (AUTO1 in CARPALL) showed promising efficacy and a favorable safety profile in pediatric R/R B-ALL (Ghorashian et al. Nat Med 2019). The ongoing Phase Ib/II CATULUS study (NCT06173518) will evaluate the safety and efficacy of obe-cel in pts aged <18 years (y) with CD19-positive R/R B-ALL or B-cell Non-Hodgkin Lymphoma. Here, we present preliminary results from the Phase Ib B-ALL cohort. Methods: CATULUS is a single-arm, open-label, international multi-center study. Eligible pts (<18 y; with R/R B-ALL that is primary refractory, in high-risk first relapse, or in second or later relapse) received bridging therapy at the investigator's discretion before lymphodepletion (fludarabine 4×30 mg/m2; cyclophosphamide 2×500 mg/m2), followed by a single obe-cel infusion (target dose: 1.0×106/kg CAR T-cells). The Phase Ib primary endpoints include frequency and severity of treatment-emergent adverse events (TEAEs). Secondary endpoints include overall remission rate (ORR; complete remission [CR]/CR with incomplete hematologic recovery [CRi]), CAR T-cell expansion (measured by droplet digital polymerase chain reaction in peripheral blood; maximal expansion of CAR-positive T-cells post infusion [Cmax], time to maximal expansion [Tmax], and area under the curve [AUC0–28d]), CAR T-cell persistence, and B-cell aplasia. Results As of 30 April 2025, 20/21 (95.2%) enrolled pts with R/R B-ALL were infused with obe-cel; all pts received the target dose. Median time from leukapheresis to product certification was 19 days (range: 15–31 days); all products were in specification. The median age was 9.5 y (range: 9 months [mos]–17.8 y). Twelve (60.0%) pts were female; five (25.0%) pts were Hispanic/Latino, and 17 (85.0%) were White. Five (25.0%) and two (10.0%) pts received prior blinatumomab or prior allogeneic stem cell transplant (SCT), respectively. At screening, the median bone marrow blast percentage was 5.5% (range: 0–95.1%); extramedullary disease was present in four (20.0%) pts, three of whom had central nervous system involvement. Following infusion, Grade ≥3 cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) each occurred in two pts (10.0%); one pt experienced both Grade 3 CRS and Grade 3 ICANS. Five (25.0%) pts had Grade ≥3 infections post obe-cel (all were assessed to be unrelated to obe-cel). One pt died due to progressive disease. At data cut-off (median follow up: 6.7 mos [range: 0.9–15.2 mos]), the ORR (CR/CRi) was 95.0% (n=19; 95% confidence interval: 75.1–99.9). Following obe-cel infusion, the geometric mean (coefficient of variation; CV%) for Cmax was 92,773 copies/µg DNA (156.7) and 860,815 copies/µg DNA×days (169.6) for AUC0–28d. The median Tmax was 14 days (range: 9–21 days). All responders (n=19) achieved measurable residual disease (MRD)-negative remission (i.e. less than 10–4 leukemic cells per local assessment). Seventeen of the 19 (89.5%) pts were still in ongoing remission at data cut-off. While in remission, 3/19 (15.8%) pts received SCT; 14 of the 16 pts (87.5%) who had not received SCT post obe-cel were in ongoing B-cell aplasia at data cut-off. Morphological relapse and emergence of MRD were observed in one pt each; both pts received further anti-leukemic therapy.Conclusions: Manufacture of obe-cel was successful for all pts.Obe-cel effectively expanded after a single infusion at a dose of 1.0×106/kg CAR T-cells. The safety profile of obe-cel in pediatric pts was consistent with that previously reported in adults, with low rates of high-grade CRS and ICANS. ORR was high at 95%; nearly 90% of responders had ongoing remission at data cut-off. While longer follow-up is needed, these preliminary findings support further development as obe-cel appears to be a promising treatment in pediatric pts with R/R B-ALL. Additional Phase Ib data will be presented and planning for the Phase II expansion trial is underway.