It’s early days, but preliminary data show that a chimeric antigen receptor T-cell therapy (CAR T) product was associated with high rates of minimal residual disease (MRD) negativity, and complete or near-complete responses in children and adolescents with relapsed or refractory B-lineage acute lymphoblastic leukemia (B-ALL).
Among 24 patients aged 3-20 years with relapsed or refractory B-ALL treated with the CAR T construct brexucabtagene autoleucel (KTE-X19; Tecartus), 16 had either a complete response or CR with incomplete recovery of blood counts (CRi), for a combined CR/CRi rate of 67%, reported Alan S. Wayne, MD, from Children’s Hospital Los Angeles and the University of Southern California Norris Comprehensive Cancer Center, also in Los Angeles.
“Optimized KTE-X19 formulation of 40 mL and revised toxicity management were associated with an improved risk/benefit profile,” he said in audio narration accompanying a poster presented during the annual meeting of the American Society of Pediatric Hematology/Oncology.
Although overall survival for children and adolescents receiving first-line therapy for B-ALL is associated with remission rates of 80% or more, the prognosis is poor following relapse, despite the availability of newer therapies such as blinatumomab (Blincyto) and inotuzumab (Besponsa), with a 1-year overall survival rate of approximately 36%, he said.
To see whether they could improve on these odds, Dr. Wayne and colleagues conducted the phase 1 Zuma-4 trial, a single-arm, open-label study in children and adolescents with relapsed/refractory B-ALL.
He reported long-term follow-up results from the study.
Zuma-4 details
A total of 24 patients, median age 14 (range 3 to 20) years, received the CAR T product. Four patients received the starting dose of 2 x 106 CAR T per kg (these patients were enrolled per protocol for evaluation of dose-limiting toxicities).
Following the initial dosing and evaluation of safety, 11 patients were treated with a dose of 1 x 106 cells per kg with a total volume of 68 mL, and 9 received 1 x 106 per kg at a volume of 40 mL (the dose being used in current phase 2 trials).
The median follow-up at the time of data cutoff in September 2020 was 36.1 months.
The combined CR/CRi rate was 75% for patients treated at the starting dose, 64% for patients treated at the 1 x 106 68-mL dose, and 67% for those who received the 48-mL dose.
The respective median durations of response were 4.14 months, 10.68 months, and not reached.
All patients who had an objective response had undetectable MRD assessed by flow cytometry with a sensitivity of .01%.
The therapy served as a bridge to allogeneic transplant in 16 patients, including 2 in the initial dose group, 8 in the 68-mL group, and 6 in the 40-mL group.
Median overall survival was not reached in either of the two 1 x 106–dose groups, but was 8 months in the 2 x 106 group.
There were no dose-limiting toxicities seen, and the adverse event profile was consistent with that seen with the use of CAR T therapy for other malignancies.
Patients treated at either the 68-mL or 40-mL 1 x 106–dose levels received tocilizumab only for neurologic events occurring in context with the cytokine release syndrome (CRS), and were started on steroids for grade 2 or greater neurologic events.
Rates of grade 3 or greater neurologic events were 25% in the initial-dose group, 27% in the 68-mL group, and 11% in the 40-mL group. Respective rates of grade 3 or greater CRS were 75%, 27%, and 22%.
Four patients died on study, all from causes deemed unrelated to CAR T therapy: two from progressive disease, one from disseminated mucormycosis, and one from Escherichia sepsis.
Investigators are currently enrolling pediatric patients with relapsed/refractory B-ALL or non-Hodgkin lymphoma, including patients with MRD-positive disease and early relapse after first-line therapy, in phase 2 of the Zuma-4 study.