Two-year follow-up of KTE-X19 in adult patients with R/R B-ALL: ZUMA-3 trial

The overall prognosis in adult patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) is dismal, with reported median overall survival (OS) of <8 months with standard therapies. Brexucabtagene autoleucel (KTE-X19) became the first chimeric antigen receptor (CAR) T-cell therapy to be approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with acute lymphoblastic leukemia (ALL) in 2021. KTE-X19 has also been approved in the US to treat adults with R/R B-ALL and adults with R/R mantle cell lymphoma based on the results of the ZUMA-3 trial (NCT02614066). The ALL Hub previously reported an interview with Bijal Shah on the safety and efficacy of KTE-X19 in adult patients with R/R B-ALL.

KTE-X19 showed significant efficacy and a tolerable safety profile in heavily pretreated adults with R/R B-ALL during phase II of the ZUMA-3 trial. During the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, Bijal Shah presented the updated outcomes with 2-year follow-up in treated phase II patients, and a larger pooled analysis of treated phase I and II patients who received a dose of KTE-X19 in ZUMA-3 trial. Below, we summarize the key findings.

Study design

This is an ongoing, phase II part of the ZUMA-3 trial in patients aged ≥18 years with R/R B-ALL and bone marrow (BM) blasts >5%, who may have received prior blinatumomab and/or prior allogenic hematopoietic stem cell transplantation (allo-HSCT). All patients received colony-stimulating prophylaxis of an intrathecal regimen along with bridging therapy, particularly for those with >25% BM blasts or >1000 blasts/µL of peripheral blood at screening. Patients received conditioning chemotherapy followed by the pivotal dose of KTE-X19 (Figure 1).

Figure 1. Study design*

CSF, colony stimulating factor; KTE-X19, brexucabtagene autoleucel.
*Adapted from Shah.^1
†25 mg/m² intravenous.
^‡All patients received CSF prophylaxis consisting of an intrathecal regimen according to institutional or national guidelines.
^§recommended for all patients particularly those with >25% marrow blasts or >1000 blasts/µL of peripheral blood at screening.
^‖900 mg/m² intravenous.
^¶1 × 10⁶ anti-CD19 CAR T-cells/kg.

The primary endpoint was the overall complete remission (CR) rate (CR + complete remission with incomplete hematologic recovery [CRi]). Secondary endpoints included duration of response, relapse-free survival, subsequent allo-HSCT, overall survival (OS), safety, and CAR T-cell levels in the blood.

Post hoc subgroup analysis was performed based on:

• Age (18–25, 18–39, 40–59, ≥60 years).
• Baseline BM blasts percentage (0–5%, > 5–25%, > 25–50%, > 50–75%, >75–100%) following bridging therapy and prior to KTE-X19 infusion.

Results

Baseline characteristics

A total of 55 and 78 patients treated in phase II and pooled phase I and II, respectively, were included. The baseline characteristics were largely similar among the subgroups by age or baseline BM blasts. The median follow-up was 26.8 months (range, 20.7–32.6 months) for treated phase II patients and 29.7 (range, 20.7–58.3 months) for pooled phase I and II treated patients with a median number of two prior therapies.

Response rates and OS

At the data cut-off of July 2021, the median duration of remission was ≥20 months in treated phase II patients and the CR/CRi rate was 71%, with 56% and 15% of patients achieving CR and CRi, respectively. Of the 39 patients who achieved CR/CRi, 26% of patients received subsequent allo-HSCT and 36% relapsed (Figure 2). The subsequent allo-HSCT rate following KTE-X19 was 20%. Median duration of response and OS in patients with subsequent allo-HSCT was not reached.

Figure 2. Consort diagram of treated phase II patients*

Allo-HSCT, allogenic hematopoietic stem cell transplantation; CR, complete remission; CRi, complete remission with incomplete hematologic recovery.
*Adapted from Shah.¹