Treatment with KTE-X19, which is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, provided high rates of durable response together with a manageable safety profile in adult patients with relapsed and/or refractory B-cell acute lymphoblastic leukaemia (R/R B-ALL). The findings from the pivotal phase II, multicentre, single arm ZUMA-3 study were presented at the 2021 ASCO Annual Meeting (4-8 June) and simultaneously published in the Lancet.

Lead author Bijal D. Shah of the Moffitt Cancer Centre in Tampa, FL, USA and an international research team evaluated KTE-X19 in adults with R/R B-ALL. From 1 October 2018 to 9 October 2019, ZUMA-3 recruited 71 adult patients with R/R B-ALL, ECOG performance status 0–1, and more than 5% bone marrow (BM) blasts by local evaluation; the median BM blasts at screening was 65% (range, 5–100). All of the patients underwent leukapheresis and KTE-X19 was successfully manufactured for 65 (92%) patients.

Fifty-five (77%) patients were treated with a single infusion of KTE-X19 after conditioning chemotherapy; the dose was 1×106 CAR T-cells per kilogram in patients with body weight less than 100 kilograms whereas those having body weight over 100 kilograms received a fixed dose of 1×10⁸ CAR T-cells. The patients’ median age was 40 (interquartile range [IQR] 2.8-5.2) years; of these, 8 (15%) patients were aged 65 years or older. Twenty-six (47%) patients had received 3 or more prior therapies; 45%, 22%, and 42% of patients had received blinatumomab, inotuzumab, or ozogamicin, respectively, and 42% had previously received allogeneic stem cell transplant (allo-SCT). Eighteen (33%) patients had primary refractory disease, 24 (44%) had relapsed or refractory disease post allo-SCT, and 43 (78%) had relapsed or refractory disease to two or more lines of systemic therapy.

The primary endpoint was the overall complete remission (CR) rate, defined as CR plus CR with incomplete haematologic recovery (CRi) by central review, and key secondary endpoints included duration of remission (DoR), relapse-free survival (RFS), overall survival (OS), the measurable residual disease (MRD) negativity rate by flow cytometry, and safety.

CAR T-cell therapy provided high rates of durable response in adult patients that were consistent across subgroups

With median follow-up of 16.4 (range, 13.8–19.6) months, the primary endpoint was met; 39 (55%) patients achieved CR or CRi recovery by central assessment (95% confidence interval [CI] 57–82, p < 0.0001). Of these patients, 31 (56%) had CR and 8 (15%) had CRi. Among the 39 patients with CR or CRi, the median time to first response was 1.1 months (IQR 1.0–1.9).

These responses were ongoing in 31% of responding patients for a median DoR of 14.6 months (95% CI 9.6–not estimable [NE]); patients with CRi demonstrated median DoR of 8.7 months (95% CI 1.0-12.8), and the median DoR in the 39 responding patients overall was 12.8 months (95% CI 8.7-NE).

All treated patients demonstrated median RFS of 11.6 months (95% CI 2.7–15.5) and median OS of 18.2 months (15.9–NE). Among responders, the median RFS and OS were 14.2 months (95% CI 11.6–NE) and not reached (95% CI 16.2–NE), respectively.

The CR and CRi recovery rates were largely consistent across most subgroups, including patients aged 65 years or older, those with one previous line of therapy, and among those previously receiving blinatumomab, inotuzumab, ozogamicin, or allo-SCT.

The secondary efficacy endpoint of MRD negativity rate was also met with 42 (76%) of all treated patients showing MRD negativity; the MRD negativity rate was 97% in patients achieving CR/CRi.

The most commonly reported Grade ≥3 adverse events (AEs) were anaemia in 49% of patients and pyrexia in 36% of patients. Grade ≥3 infections occurred in 14 (25%) patients and two Grade 5 KTE-X19-related events of brain herniation and septic shock occurred.

No deaths due to cytokine release syndrome (CRS) were reported; Ggrade ≥3 CRS occurred in 13 (24%) patients and Grade ≥3 neurological events occurred in 14 (25%) patients.


The ZUMA-3 investigators commented that their findings demonstrated a rapid manufacturing time, and high rates of complete remission or complete remission with incomplete haematological recovery. Furthermore, KTE-X19 provided median overall survival of more than 1.5 years overall and was not yet reached in responding patients. Survival was improved in heavily pre-treated adult patients and high disease burden who also demonstrated safety.

It was noted that in most instances cytokine release syndrome and neurological events occurred early, and were manageable.

According to the authors, the ZUMA-3 data suggest that KTE-X19 could confer long-term and clinically meaningful benefit to adults with R/R B-ALL.

Marcela V Maus of the Massachusetts General Hospital Cancer Center in Charlestown, MA, US wrote in an accompanied article published in The Lancet that longer-term data will be required to determine whether KTE-X19 will induce long-term durable responses frequently enough to consider it definitive therapy, but it seems to have a clear place in the management of R/R B-ALL in adults.

ZUMA-3 was sponsored by Kite, a Gilead Company.