Three-year results from phase I of ZUMA-4: KTE-X19 in pediatric relapsed/refractory acute lymphoblastic leukemia

Abstract

Here we present the 3-year results of ZUMA-4, a phase I/II multicenter study evaluating the safety and efficacy of KTEX19, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in pediatric/adolescent patients with relapsed/refractory B-cell acute lymphoblastic leukemia. Phase I explored two dose levels and formulations. The primary endpoint was the incidence of dose-limiting toxicities. Thirty-one patients were enrolled; KTE-X19 was administered to 24 patients (median age 13.5 years, range 3-20; median follow-up 36.1 months). No dose-limiting toxicities were observed. All treated patients had grade ≥3 adverse events, commonly hypotension (50%) and anemia (42%). Grade 3 cytokine release syndrome rates were 33% in all treated patients, 75% in patients given the dose of 2×106 CAR T cells/kg, 27% in patients given the dose of 1×106 cells/kg in the 68 mL formulation, and 22% in patients given the dose of 1×106 cells/kg in the 40 mL formulation; the percentages of patients experiencing grade ≥3 neurologic events were 21%, 25%, 27%, and 11% respectively. Overall complete remission rates (including complete remission with incomplete hematologic recovery) were 67% in all treated patients, 75% in patients given 2×106 CAR T cells/kg, 64% in patients given 1×106 cells/kg in the 68 mL formulation, and 67% in patients given 1×106 cells/kg in the 40 mL formulation. Overall minimal residual diseasenegativity rates were 100% among responders; 88% of responders underwent subsequent allogeneic stem-cell transplantation. In the 1×106 (40 mL) group (recommended phase II dose), the median duration of remission censored at allogeneic stem-cell transplantation and median overall survival were not reached. Pediatric/adolescent patients with relapsed/refractory B-cell acute lymphoblastic leukemia achieved high minimal residual disease-negative remission rates with a manageable safety profile after a single dose of KTE-X19. Phase II of the study is ongoing at the dose of 1×106 CAR T cells/kg in the 40 mL formulation. ClinicalTrials.gov: NCT02625480.

Figure 1.

Flow diagram of patients in the ZUMA-4 study. ^*Central nervous system lesion (lesion right middle cranial fossa). ^†In-eligible due to an adverse event (pericardial effusion). ^‡Death due to transverse myelitis.

Figure 2.

Duration of remission, relapse-free survival, and overall survival by dose level. (A) Kaplan-Meier curve of duration of remission. Patients who did not meet the criteria for relapse or who received subsequent anticancer therapy (including allogeneic stem-cell transplantation) and who remained alive were censored at the last evaluable disease assessment. (B) Kaplan-Meier curve of relapse-free survival. Patients who did not meet the criteria for relapse or who received subsequent anticancer therapy (including allogeneic stem-cell transplantation) and who remained alive were censored at the last evaluable assessment. (C) Kaplan-Meier curve of overall survival. Patients who had not died by the analysis data cutoff date were censored at their last contact date. DOR: duration of remission; mo: months; NE: not estimable; NR: not reached; OS: overall survival; RFS: relapse-free survival; 95% CI: 95% confidence interval.

Figure 3.

Peak chimeric antigen receptor gene copies/mg DNA and associations with response, minimal residual disease, and toxicity. (A) Expansion and persistence of chimeric antigen receptor (CAR) gene copies/mg DNA depicted as medians and interquartile ranges. (B) Peak CAR gene copies/mg DNA by dose level, including the two product formulations for the 1×10⁶ cells/kg dose level. (C-F) Association between peak CAR gene copies/mg DNA and overall remission rate (C), minimal residual disease (D), grade ≥3 neurologic events (E), and grade ≥3 cytokine release syndrome (F). Peak was defined as maximum CAR gene copies/mg of DNA in blood measured after infusion. Patients who were negative for minimal residual disease (MRD) included 16 responders (complete remission [CR] + CR with incomplete hematologic recovery [CRi]) and two non-CR+CRi patients, one with CR with partial hematologic recovery and one with blast-free hypoplastic/aplastic bone marrow. MRD assessment was not available for three patients. BL: baseline; CAR: chimeric antigen receptor; CRS: cytokine release syndrome; D: day; Mo: month; MRD: minimal residual disease; NE: neurologic events; Wk: week.

Figure 4.

Levels of cytokines and inflammatory markers over time. Levels of key serum biomarkers depicted as medians and interquartile ranges by dose cohort over the first 4 weeks following KTE-X19 infusion. BL: baseline; ICAM: intercellular adhesion molecule 1; IFN-γ: interferon gamma; IL: interleukin; TNF-α: tumor necrosis factor alpha.