Clinical trialPhase 2Leukaemia

KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study

The Lancet · 202171 patients were enrolled and underwent leukapheresis; 55 patients received KTE-X19 (treated population)

Shah BD, Ghobadi A, Oluwole OO, Logan AC, Boissel N, Cassaday RD, et al. The Lancet. 2021. 398:491-502

Study type: Clinical trial
Study name: ZUMA-3
Phase: Phase 2
Design: International, multicentre, single-arm, open-label study
Sample size: 71 patients were enrolled and underwent leukapheresis; 55 patients received KTE-X19 (treated population)
Source: The Lancet · 2021
Trial registration: NCT02614066

In plain words

In this study, the immune cells of adult patients with B-cell acute lymphoblastic leukaemia that had come back or had not responded to earlier treatments were collected and changed in the laboratory to recognise the cancer cells (a CAR T therapy called KTE-X19), and then given back to the patient. About 7 in 10 treated patients reached complete or near-complete remission. This treatment also had serious side effects, including severe immune and nervous system reactions, and it must be given at well-equipped centres with an experienced team.

Key results

Successfully manufactured for 65 patients (92%); administered to 55 patients (77%) of the 71 enrolled

Manufacture and administration of KTE-X19

39 patients (71%)

Complete remission or complete remission with incomplete haematological recovery (CR/CRi)

95% CI 57 to 82; P<0.0001; median follow-up 16.4 months (13.8 to 19.6)

31 patients (56%)

Complete remission (CR)

12.8 months

Median duration of remission

95% CI 8.7 to not estimable

11.6 months

Median relapse-free survival

2.7 to 15.5

18.2 months

Median overall survival

95% CI 15.9 to not estimable; not reached in responders

38 patients (97%)

MRD negativity in responders

10 patients (18%)

Consolidative allogeneic transplantation (allo-SCT) after KTE-X19

Drugs in this study:Cyclophosphamide (Endoxan)

Dose and schedule cards

Brexucabtagene autoleucel (CAR T-cell therapy; ZUMA-3)

Relapsed or refractory B-ALL in adultsCycle length: One-timeOn the page “Leukaemia” · Regimens and dosing in relapsed or refractory B-ALL

Relapsed or refractory B-ALL in adults

Drug	Dose	Route	Schedule
Lymphodepletion
Fludarabine	25 mg/m² over 30 minutes	IV	Days -4, -3 and -2 before infusion
Cyclophosphamide	900 mg/m² over 60 minutes	IV	Day -2 before infusion
One-time infusion
Brexucabtagene autoleucel	1 × 10⁶ CAR-positive viable T cells/kg (maximum 1 × 10⁸)	IV	Day 0

Cycle length: One-time
Duration: One-time

Give premedication 30 to 60 minutes before infusion: acetaminophen and diphenhydramine (or another H1 antihistamine).

On the page “Leukaemia” · Regimens and dosing in relapsed or refractory B-ALL

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1KTE-X19 (brexucabtagene autoleucel; single arm)

Leukapheresis to manufacture KTE-X19, followed by conditioning chemotherapy: fludarabine 25 mg/m² IV on days -4, -3 and -2 and cyclophosphamide 900 mg/m² IV on day -2; then a single infusion of KTE-X19 (autologous anti-CD19 CAR-T cells) at a dose of 1 × 10⁶ CAR-T cells per kg (label maximum: 1 × 10⁸ cells). Per the FDA label: premedication with paracetamol (acetaminophen) and diphenhydramine, and tocilizumab available.

Source of the regimen details: Full text of the paper in PMC (PMC11613962), Methods section, and the FDA label for brexucabtagene autoleucel (DailyMed)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Adults aged 18 years and older with relapsed or refractory B-precursor acute lymphoblastic leukaemia, ECOG performance status 0 to 1 and morphological disease in the bone marrow (more than 5% blasts). Patients were enrolled at 25 centres in the United States, Canada and Europe. Median age of treated patients was 40 years (IQR 28 to 52).

Endpoints

Primary endpoint: overall rate of complete remission (CR) or complete remission with incomplete haematological recovery (CRi) by central assessment.

Secondary endpoints: duration of remission, relapse-free survival, overall survival, MRD (minimal residual disease) negativity rate and rate of allogeneic stem-cell transplantation (allo-SCT). Efficacy and safety analyses were performed in the treated population (all patients who received one dose of KTE-X19).

Safety and side effects

The most common grade 3 or higher adverse events: anaemia (27 patients, 49%) and pyrexia (20 patients, 36%). Grade 3 or higher infections in 14 patients (25%). Two grade 5 events related to KTE-X19 occurred (brain herniation and septic shock). Grade 3 or higher cytokine release syndrome (CRS) was seen in 13 patients (24%) and grade 3 or higher neurological events in 14 patients (25%).

Clinical significance and place in guidelines

This single-arm phase 2 study showed that KTE-X19 produces a high rate of complete remission or complete remission with incomplete haematological recovery in adults with relapsed or refractory B-precursor acute lymphoblastic leukaemia, with manageable safety reported. The authors conclude that this treatment has the potential for long-term clinical benefit. The status of drug approvals and its place in treatment guidelines should be checked separately and cannot be inferred from the abstract.

Limitations

The study was single-arm and open-label without a control group, so direct comparison with other treatments is not possible. Only 55 of the 71 enrolled patients (77%) received KTE-X19, and analyses were performed in the treated population. Median follow-up was 16.4 months, and the long-term effect of treatment requires longer follow-up. The incidence of grade 3 or higher CRS and neurological events and two treatment-related deaths show that this treatment has considerable toxicity. The study was funded by Kite.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.