A novel bicistronic CD19/CD22-directed CAR T-cell therapy (B019) has demonstrated high remission rates, durable responses, and a favorable safety profile among children with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL), including those with isolated or combined extramedullary disease. These findings were presented during the 2024 American Society of Hematology (ASH) Annual Meeting & Exposition.¹

Results from the investigator-initiated, early-phase trial (ChiCTR2000032211) showed a 1-year event-free survival rate of 75.5% and an overall survival rate of 93.5%. Among patients who underwent bridging bone marrow transplantation, the 1-year event-free survival rate was 89.7%, compared with 76.8% for those who did not. However, authors of the study emphasized that overall survival rates were comparable between the two patient groups.

“The promising efficacy and safety profile of this therapy represent a critical step forward in improving outcomes for pediatric patients with relapsed or refractory B-cell ALL, particularly those with complex disease presentations,” said presenting author Hua Zhang, MD, PhD, Vice President and Chief Scientific Officer at SPH Biotherapeutics (Hong Kong), Limited, during a virtual press briefing.

As Dr. Zhang reported, B-cell ALL remains a challenging disease in the relapsed or refractory setting, particularly for pediatric patients. Although prior studies demonstrated that CD19- and CD22-directed CAR T-cell therapy achieves high remission rates, durability of responses has been limited for patients with significant disease burden or extramedullary involvement.

The novel bicistronic CAR T-cell therapy was designed to target both CD19 and CD22 simultaneously. The goal is to enhance event-free survival, overall survival, and safety outcomes regardless of prior exposure to allogeneic hematopoietic cell transplantation.

Study Design

The single-arm, one-center trial enrolled 343 children (up to age 18) with relapsed or refractory B-cell ALL. Patients underwent debulking and lymphodepletion during a 7-day period while the CAR T cells were manufactured. The regimen was administered at doses ranging from 1 × 10⁶/kg to 10 × 10⁶/kg. Patients were stratified into two main cohorts:

• Isolated extramedullary disease (n = 51): This cohort included patients with isolated central nervous system (CNS) or testicular relapse.
• Refractory or combined hematologic relapse (n = 292): This cohort included patients who had bone marrow relapse with or without extramedullary involvement.

Patients underwent regular follow-up, including CAR T-cell expansion monitoring, cytokine production assessment, and bone marrow biopsies at defined intervals.

Efficacy and Safety

At a median follow-up of 13.9 months, the therapy demonstrated efficacy. Complete remission rates reached 99%, with measurable residual disease (MRD) negativity achieved in all evaluable patients. The 1-year event-free survival rate was 75.5%, and the overall survival rate was 93.5%.

As Dr. Zhang reported, patients who underwent bridging allogeneic hematopoietic cell transplantation achieved higher event-free survival rates (89.7%) than did those who did not (76.8%). However, as previously mentioned, overall survival rates were comparable between the two groups.

All patients with isolated extramedullary relapse achieved complete responses, whereas in the refractory/combined hematologic relapse cohort, one patient with isolated bone marrow relapse failed to achieve remission, dying prior to evaluation, according to Dr. Zhang.

Cytokine-release syndrome was the most common toxicity observed, with severity influencing patient outcomes. Grade 1 or 2 cytokine-release syndrome, reported in 172 patients, was associated with a 1-year event-free survival rate of 80.9%; grade 3 or 4 cytokine-release syndrome, observed in 145 patients, resulted in a lower 1-year event-free survival rate of 69.9%.

The severity of cytokine-release syndrome was not found to be associated with the dose of infused cells, but it did seem to correlate with disease burden and CAR T-cell viability, said Dr. Zhang. Other toxicities, including neurotoxicity, were infrequent and manageable. No unexpected safety signals were observed during the study.

Based on these findings, a phase I trial has been initiated to refine the dosing and evaluate long-term outcomes in a smaller cohort of patients. Investigators aim to enroll 12 to 18 participants in this next phase.

Expert Point of View

During a virtual press briefing at the 2024 ASH Annual Meeting & Exposition, Rachel E. Rau, MD, Associate Professor of Pediatrics at Seattle Children’s Hospital and the University of Washington, provided valuable context on the evolving role of CAR T-cell therapy in treating relapsed or refractory B-cell ALL.

“CD19 CAR T-cell therapy has been around for some time and has really changed the way we think about managing patients with relapsed B-cell ALL,” said Dr. Rau, who noted, however, that despite its transformative impact, CAR T-cell therapies still face challenges. “In intent-to-treat analyses of these CAR T products, there’s typically only about a 50% response rate. The field has continued to seek ways to improve upon the existing CAR T options available to our patients, and those efforts are still greatly warranted because there’s still going to be demand.”

Dr. Rau emphasized the need for ongoing innovation in CAR T-cell therapy to address gaps left by other treatments, such as the monoclonal antibody blinatumomab. “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 isolated central nervous system relapses. Blinatumomab does not have great activity in the central nervous system, but CAR T-cell therapy does,” she explained.

What Next?

Looking ahead, Dr. Rau highlighted the potential of novel bicistronic CAR T-cell therapies targeting CD19 and CD22 to address unmet needs.

“The promising results from the CD22 and CD19 CAR therapies suggest this approach could fill a critical gap for patients who still require CAR T-cell therapy, particularly as it builds on and improves upon the current options available,” she concluded.

DISCLOSURE: This trial was funded by SPH Biotherapeutics (Hong Kong) Limited, maker of bicistronic CD19/CD22 CAR T-cell therapy. Dr. Zhang is Vice President and Chief Scientific Officer at SPH Biotherapeutics (Hong Kong), Limited. Dr. Rau reported financial relationships with Jazz Pharmaceuticals, AbbVie, and Servier Pharmaceuticals.

REFERENCE

1. Wan X, Li W, Cai J, et al: Safety and efficacy of bicistronic CD19/CD22 CAR T cell therapy in childhood B cell acute lymphoblastic leukemia. 2024 ASH Annual Meeting & Exposition. Abstract 681. Presented December 8, 2024.