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SAN DIEGO -- An investigational CAR T-cell therapy induced responses in nearly every single patient with childhood B-cell acute lymphoblastic leukemia (B-ALL), a researcher reported here.

In a cohort of more than 300 patients with relapsed or refractory disease, 99.1% treated with the CD19/CD22-directed product bicistronic achieved a complete remission or complete remission with incomplete count recovery, according to Hua Zhang, MD, PhD, of developer SPH Biotherapeutics in Shanghai.

At 1 year, event-free survival (EFS) and overall survival (OS) rates reached 75.5% and 93.5%, respectively. Cytokine release syndrome (CRS) developed in all patients, including grade 3/4 events in nearly half.

"Bicistronic CD19/CD22-targeted CAR T-cell therapy is a safe and effective regimen which achieved durable remission in children with relapsed or refractory B-ALL, including those with isolated and combined extramedullary relapse," Zhang said at a press briefing ahead of the American Society of Hematology meeting. "We found the severity of CRS is not related to the study dose range of infused cells, whereas it was highly correlated with disease burden and CAR-T viability."

Further study data showed that a small subset (n=38) who went on to receive consolidative allogeneic stem cell transplant had improved EFS but not OS at 1 year:

• EFS: 89.7% vs 76.8%
• OS: 95.8% vs 95.2%

The dual approach with bicistronic aimed to improve upon prior work, said Zhang. A reported last year that tested two CD19 and CD22 agents combined in childhood B-ALL had shown good results, but the CAR T cells had differing expansion dynamics and often an imbalance in persistence. That approach also proved cumbersome and costly, according to Zhang, leading researchers to develop a product that targeted both receptors at once.

Rachel Rau, MD, of the University of Washington and Seattle Children's Hospital, called the early data "promising" and said that dual CD19/CD22-targeting could fill a gap for patients who still need CAR T-cell therapy following standard upfront treatment.

"CD19 CAR T-cell therapy has been around for some time and has really changed the way we think about the management of patients who have relapsed disease from their B-ALL," said Rau, who was not involved in the study.

At the press briefing, she presented practice-changing data showing that patients with newly diagnosed childhood B-ALL lived significantly longer without disease recurrence when they received the bispecific T-cell engager blinatumomab (Blincyto) in addition to standard chemotherapy.

"Even though blinatumomab is likely to reduce the number of relapses in the upfront setting, there will still be patients who relapse, and one of the major gaps of blinatumomab is that we have not yet addressed the isolated central nervous system relapses," she told 番茄社区app. "Blinatumomab does not have great activity in the central nervous system, but CAR T-cell therapy does."

The investigator-initiated study presented by Zhang included 343 pediatric patients with relapsed or refractory B-ALL. Following 7 days for CAR-T manufacturing and preparation, patients underwent a single infusion of bicistronic with or without consolidative allogeneic stem cell transplant. Exclusion criteria included CD19-negative relapses, relapses after a prior anti-CD19 CAR-T agent or blinatumomab, and the presence of certain germline mutations such as TP53 and ETV6.

The study included two disease cohorts: 51 patients with isolated extramedullary relapse and 292 with refractory or combined hematologic relapse. The main endpoints were EFS, OS, and safety.

Complete remission or complete remission with incomplete count recovery was achieved in 202 of the 203 patients with isolated bone marrow relapse (one patient died before evaluation), in all 72 patients with bone marrow plus central nervous system relapse, and in all 17 patients who had bone marrow plus testis relapse.

As for safety, grade 3/4 CRS developed in 45.7%, which was associated with worse EFS at 1 year (70% vs 81% in patients with grade 0-2 CRS, P=0.0191). In addition, there were two CRS-related deaths. Immune effector cell-associated neurotoxicity syndrome was observed in 16%, though most cases were resolved quickly without intervention, said Zhang.

A phase I trial has now been launched to further test bicistronic.

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