Chimeric antigen receptor (CAR) T-cell persistence at month 3 predicts clinical outcomes in adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) treated with obecabtagene autoleucel (obe-cel)

Abstract Background: Obe-cel is an autologous fast off-rate 4-1BB-ζ CD19-directed CAR T-cell therapy with demonstrated clinical efficacy in adult patients with R/R B-ALL from the Phase Ib/II FELIX study (NCT04404660; Roddie et al. NEJM 2024). Following treatment with obe-cel, 78.0% of patients achieved complete remission (CR) or CR with incomplete hematologic recovery (CRi); 24-month event-free survival (EFS) and overall survival (OS) probabilities were 43.0% and 46.0%, respectively. The identification of factors that could predict response and long-term survival outcomes can help clinical decision making. CAR T-cell persistence, as a time-dependent variable, was identified as an important predictive factor for EFS and OS following obe-cel infusion in multivariate analyses (Park et al. EHA 2025). Here, we report the impact of persistence status at Month 3 (M3) on survival outcomes in adult patients with R/R B-ALL who responded to obe-cel, and in patients with deep measurable residual disease (MRD)-negative remission who did not receive post obe-cel stem cell transplant (SCT). Methods: In FELIX, adult (≥18 years) patients with R/R B-ALL underwent lymphodepletion, followed by tumor burden-guided infusions of obe-cel to a total target dose of 410×106 CAR T-cells. Droplet digital polymerase chain reaction (ddPCR) was used to assess CAR transgene levels in peripheral blood samples collected from patients infused with at least one dose of obe-cel (N=127). Vector copy number per diploid genome was determined through duplex detection of the lentiviral vector Ψ region and the endogenous reference gene, RPP30. Samples with measurements above the lower limit of detection (LLoD; 11 copies/reaction) were identified as CAR T-cell positive; measurements below the LLoD indicated loss of CAR T-cell persistence. M3 landmark Kaplan-Meier analyses were conducted to evaluate EFS and OS by persistence status (ongoing vs loss of persistence) in patients who responded to obe-cel and were in ongoing remission beyond M3, and in patients who also had deep MRD-negative remission (defined as <10–6 leukemic cells) by next-generation sequencing (NGS) and had not undergone SCT post obe-cel. Results: As of 18 January 2025, the median study follow up was 32.8 months (range: 19.9–52.8). Of the 99 patients who achieved CR/CRi, 79 (79.8%) had ongoing remission beyond M3 post obe-cel infusion and comprised the subgroup of interest for the analyses reported herein. At M3 post infusion, 60/79 patients (75.9%) had ongoing CAR T-cell persistence, while 19/79 (24.1%) had lost persistence. Median EFS (95% confidence interval) was 44.6 months (18.9–not estimable [NE]) in patients with ongoing persistence at M3 post obe-cel vs 10.1 months (7.2–NE) in patients who had lost persistence. The 24-month EFS probability was 59.9% (46.0–71.3) vs 31.6% (12.9–52.2), and the 24-month OS probability was 69.2% (55.6–79.4) vs 52.6% (28.7–71.9), in patients with ongoing vs loss of persistence at M3, respectively. Among the 79 patients with ongoing remission at M3, 70 did not receive post obe-cel SCT. The median EFS and OS, and 24-month probabilities in these 70 patients, by persistence status at M3, aligned with those reported in the 79 patients with ongoing remission. Among the 70 patients without post obe-cel SCT, 54 had NGS calibration and 49/54 patients (90.7%) achieved deep MRD-negative remission by M3. In these 49 patients, median EFS was not reached vs 9.1 months (4.4–NE), 24-month EFS probability was 56.4% (38.7–70.7) vs 33.3% (7.8–62.3), and 24-month OS probability was 68.4% (50.9–80.7) vs 55.6% (20.4–80.5), in patients with (n=40) and those without persistence (n=9) at M3, respectively. Median OS was not reached for patients with or those without persistence at M3. Conclusions:In patients who remained in remission beyond M3, including those with deep MRD-negative remission and no post obe-cel SCT, ongoing CAR T-cell persistence at M3, measured by ddPCR, was associated with longer EFS and OS compared with loss of persistence. Persistence status at M3 may be a marker for predicting long-term outcomes following obe-cel treatment in patients with R/R B-ALL.