KTE-X19 Safe, Efficacious as Therapy for Pediatric B-Cell ALL in ZUMA-4

Results of the phase 1 portion of ZUMA-4 support continued investigation into the efficacy of KTE-X19 in pediatric patients with B-cell acute lymphoblastic leukemia.

Long-term efficacy assessment of chimeric antigen receptor (CAR) T-cell therapy with KTE-X19 (brexucabtagene autoleucel; Tecartus) demonstrated high rates of minimal residual disease (MRD) negativity and complete response (CR) in pediatric and adolescent patients with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL), according to data from the phase 1 portion of the ZUMA-4 trial (NCT02625480) presented in a poster at the 2021 European Hematologic Association (EHA) Congress.1

Objectives of the trial were to determine safety and efficacy of KTE-X19 in in patients 21 years of age or younger with relapsed/refractory B-cell ALL or non-Hodgkin lymphoma. The primary end point of phase 1 was the incidence of dose-limiting toxicities (DLTs) with key secondary end points of CR plus CR with incomplete hematologic recovery (CR/CRi) rate, relapse-free survival (RFS), pharmacokinetics/pharmacodynamics, duration of response (DOR), and overall survival (OS).

All patients were screened prior to leukapheresis and were allowed to receive bridging therapy at the discretion of the treating investigators, either treatment complete 7 or more days prior to 5 half-lives before condition chemotherapy. Treatment consisted of a conditioning regimen of fludarabine at 25 mg/m2 on days –4 to –2 plus cyclophosphamide at 900 mg/m2 on day –2 followed by KTE-X19 infusion at target doses of 1 × 106 or 2 × 106 CAR-positive T-cells.

At the data cut-off of September 9, 2020, the median follow-up was 36.1 months with 24 patients having received KTE-X19. The median time from leukapheresis to KTE-X19 production was 14.0 days for all patients; leukapheresis to infusion time averaged 27.0 days.

Patients treated at the 2 × 106 dose (n = 4) had a CR/CRi rate of 75%. In patients treated at the 1 × 106, 68 mL (n = 11) and the 1 × 106, 40 mL (n = 9) doses, rates of CR/CRi were 64% and 67%, respectively. The rate of CR/CRi in the entire patient cohort was 67%. One patient in the 1 × 106, 68 mL had a CR with partial hematologic recovery and 1 in the 1 × 106, 40 mL group had hypoplastic/aplastic bone marrow. One patient in each of the 1 × 106 dose groups had no response to treatment. Rates of MRD negativity in the 2 × 106; 1 × 106, 68 mL; and the 1 × 106, 40 mL dose groups were 75%, 73%, and 78%, respectively.

Across doses, patients with prior blinatumomab (Blincyto; n = 8) treatment experienced a CR/CRi rate of 38%. All patients treated with prior allogeneic stem cell transplant (alloSCT; n = 6) had a CR/CRi rate of 86%. There was a CR in 1 patient who received prior inotuzumab ozogamicin (Besponsa).

Patients achieving CR/CRi (n = 16) went on to receive alloSCT in 87.5% of cases, with a median time to transplant of 2.3 months (range, 1.4-24.9).

The median DOR in the 2 × 106 dose group was 4.1 months (95%, not evaluable [NE]-NE). In the 1 × 106, 68 mL and the 1 × 106, 40 mL dose groups, DOR was 10.7 months (95% CI, 7.2-14.2) and not reached (95% CI, NE-NE). DOR in 16 patients with a CR/CRi was 7.2 months (95% CI, 0.03-14.2).

Median RFS in the 1 × 106, 40 mL dose group was not reached. In the 2 × 106 and 1 × 106, 68 mL dose groups, median RFS was 5.2 months (95% CI, 0.03-5.2) and 9.1 months (95% CI, 0.03-17.8), respectively.

The median OS in the 2 × 106 dose group was 8.0 months (95%, 0.5-NE) and was not reached in either of the 1 × 106 dose groups. The rate of OS at 24 months in the 1 × 106, 40 mL dose group was 87.5% (95% CI, 38.7-98.1).

The investigators reported that “58% of treated patients (n = 14/24) were still alive and in continued follow-up as of the data cutoff.”

Peak CAR T-cell expansion were similar between doses but was greatest in the patients receiving KTE-X19 at 2 × 106 CAR-positive T cells. Patients with CR/CRi and those achieving MRD negativity tends to show the greatest expansion after infusion.

In terms of safety, no DLTs were observed in the 3 patients evaluable for DLT. Serious adverse effects (AEs) occurred in 71% of patients and 8 patients (33%) died on study. Deaths were attributed to disease progression in 6 participants and AEs other than grade 5 B-cell ALL in 2. The 2 grade 5 events were disseminated mucormycotic and Escherichia sepsis.

Notably, there were no reports of grade 4 or 5 cytokine release syndrome (CRS). In all patients, any CRS occurred in 88% and grade 3 CRS was seen in 33%. Three out of 4 patients treated at the 2 × 106 dose had grade 3 CRS, with incidence rates below 30% seen in the 1 × 106 dose groups. The median time to onset in the entire group was 5 days (range, 1-14) and was 2 days (range, 1-4) in the 2 × 106 dose group. All events of CRS were resolved.

Neurologic events occurred in 67% of patients overall, with only 1 grade 4 event of brain edema reported in the 1 × 106, 68 mL group. Grade 3 neurologic events occurred in 17% of patients overall and in 25% of those in the 2 × 106 dose group. Two of the 16 neurologic events did not resolve by the time of death, 1 each from progressive disease and an AE unrelated to KTE-X19.

Patients with B-cell ALL were eligible for therapy with KTE-X19 if they have 5% or more bone marrow blasts; had relapsed or refractory, Philadelphia chromosome–negative disease; adequate organ function; and a Lansky or Karnofsky performance status of 80% or greater. Prior treatment with blinatumomab required patients to have leukemic blasts with CD19 expression of 90% or more.

The phase 2 portion of the trial is currently enrolling patients with relapsed/refractory B-cell ALL with expanded inclusion criteria. KTE-X19 is currently approved to treat adult patients with relapsed/refractory mantle cell lymphoma,2 with numerous clinical trials ongoing in other treatment settings.


1. Wayne AS, Huynh V, Hijiya N, et al. ZUMA-4 phase 1 long-term results: kte-x19 chimeric antigen receptor tcell therapy in pediatric/adolescent patients with relapsed/refractory B-cell acute lymphoblastic leukemia. Presented at: 2021 European Society of Hematology Congress; June 9-17, 2021. Virtual. Accessed June 11, 2021. https://bit.ly/3gti2bi

2. FDA approves brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma. FDA. July 24, 2020. Accessed June 11, 2021. https://bit.ly/3gHlK1d