ZUMA-8: A Phase 1 Study of KTE-X19, an Anti-CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy, in Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia

Background Despite recent advances in treatments for patients with chronic lymphocytic leukemia (CLL), such as Bruton's tyrosine kinase (BTK) inhibitors and a Bcl-2 inhibitor, the disease remains generally incurable (Todorovic Z et al. Curr Oncol. 2022). Brexucabtagene autoleucel (brexu-cel; KTE-X19) is a CD19-directed genetically modified autologous T-cell (CAR T-cell) immunotherapy approved for use in patients with relapsed/refractory (R/R) mantle cell lymphoma and in patients with R/R B-cell precursor acute lymphoblastic leukemia; however, no CAR T-cell therapies are currently approved in CLL. The multicohort, multicenter Phase 1 ZUMA-8 (NCT03624036) trial is the first to evaluate the safety and tolerability of KTE-X19 in patients with R/R CLL. Methods In ZUMA-8, patients had R/R CLL after treatment with ≥2 prior lines of therapy (including a BTK inhibitor). Leukapheresis was performed within ~5 days after confirmed eligibility. Optional bridging therapy (continuation of preceding targeted therapy, anti-CD20 antibody, and/or high-dose corticosteroids) before conditioning therapy (CC) was allowed. Patients received 3 days of CC (fludarabine 30 mg/m2/day and cyclophosphamide 500 mg/m2/day) before KTE-X19 infusion. Patients in Cohorts 1 and 2 were administered 1 × 106 and 2 × 106 anti-CD19 CAR T cells/kg, respectively. Patients in Cohort 3 (patients who had low tumor burden, defined as ≤1% malignant cells in peripheral blood or absolute lymphocyte count [ALC] <5,000 cells/µL [patients with small lymphocytic lymphoma were also allowed]) and Cohort 4 (patients with any degree of tumor burden who were treated with the BTK inhibitor ibrutinib [alone or in combination] as the last line of therapy up to 30 hours prior to leukapheresis) received a target dose of 1 × 106 anti-CD19 CAR T cells/kg. Patients were hospitalized for observation ≥7 days after infusion. The primary endpoint was the incidence of dose-limiting toxicities (DLTs). Secondary endpoints were incidence of adverse events (AEs), objective response rate per investigator review according to the International Workshop on Chronic Lymphocytic Leukemia 2018 criteria, and CAR T-cell expansion. Results A total of 15 patients received KTE-X19 therapy across Cohort 1 (n=6), Cohort 2 (n=3), Cohort 3 (n=3, all with CLL), and Cohort 4 (n=3). At the data cutoff date of May 2, 2022, the median follow-up duration was 30.3 months (range, 15.5-40.4 months; Table). The median age was 63.0 years (range, 52-79 years), 10 patients (67%) were male, 8 patients (53%) had an Eastern Cooperative Oncology Group performance status of 1, 4 patients (27%) had a 17p deletion, and 7 patients (47%) presented with a complex karyotype (defined as ≥3 clonal chromosomal abnormalities). Patients were heavily pretreated; 12 patients (80%) received >3 prior lines of therapy, and 13 of 15 patients received bridging therapy. DLTs were observed in 1 patient in Cohort 3 (Grade 3-4 hypocalcemia, hyponatremia, hypotension, and cytokine release syndrome [CRS] events that met prespecified criteria for DLTs). Grade ≥3 AEs and Grade ≥3 serious AEs were reported in all patients (100%) and 5 patients (33%), respectively. Grade ≥3 treatment-related AEs were reported in 9 patients (60%). In addition to Grade 4 CRS reported in 1 patient (7%), Grade ≥3 neurologic events were reported in 3 patients (20%). Excluding disease progression, there were no Grade 5 AEs. As of the data cutoff date, objective responses were observed in 7 of 15 patients, including 2 patients with complete responses (CR; Figure). Two of 3 patients with low tumor burden (Cohort 3) achieved CR and 1 patient achieved a partial response. Appreciable CAR T-cell expansion occurred in 4 of 15 patients overall and in 3 of 3 patients with a low tumor burden. Peak CAR T-cell expansion (range, 0-679.38 cells/µL; n=14) had an apparent weak inverse correlation with baseline ALC (range, 0.72-122.95 × 109/L; n=15). Additional translational data will be presented. Conclusions KTE-X19 therapy did not have any new safety signals in patients with R/R CLL. Peak CAR T-cell expansion and objective responses in heavily pretreated patients with low tumor burden appeared to be improved compared with other cohorts. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal