KTE-X19 anti-CD19 CAR T-cell therapy in adult relapsed/refractory acute lymphoblastic leukemia: ZUMA-3 phase 1 results

Abstract

ZUMA-3 is a phase 1/2 study evaluating KTE-X19, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in adult relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). We report the phase 1 results. After fludarabine-cyclophosphamide lymphodepletion, patients received a single infusion of KTE-X19 at 2 × 106, 1 × 106, or 0.5 × 106 cells per kg. The rate of dose-limiting toxicities (DLTs) within 28 days after KTE-X19 infusion was the primary end point. KTE-X19 was manufactured for 54 enrolled patients and administered to 45 (median age, 46 years; range, 18-77 years). No DLTs occurred in the DLT-evaluable cohort. Grade ≥3 cytokine release syndrome (CRS) and neurologic events (NEs) occurred in 31% and 38% of patients, respectively. To optimize the risk-benefit ratio, revised adverse event (AE) management for CRS and NEs (earlier steroid use for NEs and tocilizumab only for CRS) was evaluated at 1 × 106 cells per kg KTE-X19. In the 9 patients treated under revised AE management, 33% had grade 3 CRS and 11% had grade 3 NEs, with no grade 4 or 5 NEs. The overall complete remission rate correlated with CAR T-cell expansion and was 83% in patients treated with 1 × 106 cells per kg and 69% in all patients. Minimal residual disease was undetectable in all responding patients. At a median follow-up of 22.1 months (range, 7.1-36.1 months), the median duration of remission was 17.6 months (95% confidence interval [CI], 5.8-17.6 months) in patients treated with 1 × 106 cells per kg and 14.5 months (95% CI, 5.8-18.1 months) in all patients. KTE-X19 treatment provided a high response rate and tolerable safety in adults with R/R B-ALL. Phase 2 is ongoing at 1 × 106 cells per kg with revised AE management. This trial is registered at www.clinicaltrials.gov as #NCT02614066.

Graphical abstract

Figure 1

DOR, relapse-free survival (RFS), and OS by dose level. (A-B) Kaplan-Meier curves of DOR in patients achieving CR/CRi censored at SCT (A) or not censored at SCT (B). (C-D) Kaplan-Meier curves of RFS (C) and OS (D). Patients who were alive at the time of data cutoff were censored at their last date of contact. N/A, not applicable; NE, not estimable.

Figure 2

Peak CAR T-cell expansion and associations with response, MRD, and toxicity. (A) Expansion and persistence of CAR T cells depicted as medians and IQRs. (B) Peak CAR T-cell levels by dose level, including in original vs revised AE management (1 × 10⁶ cells per kg dose level). (C-F) Association between peak CAR T-cell expansion and ORR (C), MRD (D), grade ≥3 NEs (E), and grade ≥3 CRS (F). The horizontal line within each box represents the median, the lower and upper borders of each box represent the 25th and the 75th percentiles, respectively, and the error bars represent the 95% CI.

Figure 3

Cytokine and inflammatory marker levels over time. Serum biomarker levels by dose over the first 28 days after KTE-X19 infusion. BL, baseline; Rα, receptor α; RA, receptor antagonist.