CAR-T therapy induces high, durable response in R/R B-cell ALL

A single infusion of brexucabtagene autoleucel (previously KTE-X19) induced high and durable response in heavily pretreated adults with relapsed or refractory (R/R) B-precursor acute lymphoblastic leukaemia (B-ALL), with a manageable safety profile, according to the pivotal ZUMA-3 trial presented at ASCO 2021.  

“The management of ALL in adults remains a therapeutic challenge, complicated by high rates of relapse and poor outcomes once relapse emerges, [which presents] a substantial unmet need,” said lead author Dr Bijal Shah from the Moffit Cancer Center in Tampa, Florida, US.

“Approximately 40–50 percent of adults with B-ALL experience a relapse after initial treatment, with an overall poor prognosis,” he explained. “The 1-year overall survival [OS] rate for patients with R/R B-ALL is just 26 percent after first salvage, and decreases with subsequent lines of therapy.”

During a median follow-up of 16.4 months, the primary endpoint of complete remission (CR) or CR with incomplete haematologic recovery (CRi) occurred in 70.9 percent of the patients— including a true CR rate of 56.4 percent. [ASCO 2021, abstract 7002; Lancet 2021;doi:10.1016/S0140-6736(21)01222-8]

The remission lasted for a median duration of 12.8 months. After brexucabtagene autoleucel therapy, 10 patients (18 percent) underwent allogeneic stem-cell transplantation (allo-SCT) consolidation.

“Despite most patients having high disease burden and heavy pretreatment, including novel agents, allo-SCT, or both, the rate of overall CR/CRi was largely consistent across these patient subgroups,” reported Shah and co-authors.

In addition, minimal residual disease (MRD) negativity was achieved in 42 patients (76 percent), with a median time to CR/CRi of 1.1 month. In particular, the rate of MRD negativity was even higher in responders, at 97 percent.  

The median OS in the overall population was 18.2 months, while this was not reached yet among responders.

For relapse-free survival, the median was 11.6 months in the overall population and 14.2 months in responders.

The multinational, single-arm, open-label, phase II study involved 71 adults with R/R B-ALL. Of these, 55 patients (median age 40 years, 60 percent male) eventually received treatment with a single infusion of brexucabtagene autoleucel (1 × 10⁶ CAR-T* cells per kg bodyweight), after leukapheresis and conditioning chemotherapy.

Brexucabtagene autoleucel is an autologous anti-CD19 CAR-T therapy which has been FDA-approved for R/R mantle cell lymphoma. The current pivotal trial aims to assess the drug in the R/R B-ALL setting.

According to the researchers, participants of ZUMA-3 are the largest, adult-only patient population for R/R B-ALL trial to date.

“The safety profile of KTE-X19 was manageable, with most instances of cytokine release syndrome [CRS] and neurological events occurring early, and no deaths due to CRS,” the researchers reported.

Anaemia (49 percent) and pyrexia (36 percent) were the most common grade ≥3 adverse events (AEs). Grade ≥3 infections occurred in 14 patients (25 percent), grade ≥3 CRS in 13 patients (24 percent), and grade ≥3 neurological events in 14 patients (25 percent). There were two grade 5 events that were considered related to the CAR-T therapy, involving brain herniation and septic shock.

“[Our findings] suggest that brexucabtagene autoleucel could confer long-term and clinically meaningful benefit to adults with R/R B-ALL,” said Shah and co-authors. “The rapid manufacturing time supports the feasibility of providing this novel therapy to adult patients with rapidly progressive disease.”

CAR-T: Chimeric antigen receptor T cell