CART19 Yields Promising Efficacy in CNS-Relapsed B-ALL

For pediatric patients with B-cell acute lymphoblastic leukemia who have 1 or more central nervous system (CNS) relapses, CART19 appeared to be effective and less toxic, according to results from a phase 2 trial (NCT04276870) presented at the 2025 American Society of Hematology (ASH) Annual Meeting and Exhibition.¹

Among 42 evaluable patients with a median follow-up of 12 months, the 1-year event-free survival (EFS) rate was 90% (95% CI, 81%-100%), and at 2 years, it was 85% (95% CI, 72%-99%). The 1-year overall survival (OS) rate was 100%, and at 2 years, it was 90% (95% CI, 78%-100%). In 14 patients with more than 4 years of potential follow-up, the 4-year EFS was 71% (95% CI, 51%-99%), and the 4-year OS was 93% (95% CI, 80%-100%).

The best overall response rate was 100%, with 41 of 42 evaluable patients in remission at day 28. CNS relapse 2 occurred in 1 patient at day 28 but was cleared in month 2 without intervention.

“Although longer follow-up is needed, [the] 4-year EFS of 71% and OS of 93% in the 14 patients with potential of 4 years of follow-up is very promising and superior to the outcomes on the [phase 3 AALL1331 trial (NCT02101853)],” Amanda M. DiNofia, MD, MSCE, attending physician in the Cancer Center, member of the Center Childhood Cancer Research at Children's Hospital of Philadelphia, said during the presentation.

The basis of this study was that 4-year EFS for pediatric patients with isolated CNS was extremely poor, with results from the AALL1331 study showing a rate of 24%.² When the study added blinatumomab (Blincyto), outcomes were not improved. Additionally, for those with CNS relapse, the standard of care was cranial radiation, which may have significant neurological outcomes.

The phase 2 trial was a basket trial and included 4 different cohorts; this presentation focused on the CNS cohort. Eligibility criteria included being aged 29 years or younger with CNS relapse, having not received cranial radiation or hematopoietic stem cell transplant (HSCT) for the most recent relapse. The primary end point was 1-year EFS.

A total of 43 patients were enrolled in the CNS cohort and underwent lymphodepleting chemotherapy, pre-infusion disease assessment, 5x10⁶ CART19 cells/kg cell infusion, and day 28 tumor response, with follow-up on days 1, 3, 7, 10, 14, and 21. Throughout year 1, patients had monthly labs and exams with a quarterly disease evaluation. The long-term follow-up was 1 to 15 years.

The median age at infusion was 9 years, and 44% of patients were female. A total of 72% of patients were non-Hispanic White, with DiNofia noting that one patient did not report an ethnicity. At infusion, 91% of patients had experienced their first relapse. Additionally, 84% of patients had an isolated CNS relapse at referral. Prior blinatumomab use occurred in 23% of patients, and prior HSCT in 7%.

A total of 6 patients in the cohort experienced a relapse at the minimal residual disease level (n = 2), morphologic medullary (n = 2), isolated CNS2 (n = 1), and combined medullary and CNS (n = 1). Additionally, 10 patients in remission received alternate CAR T-cell therapy to improve resistance. Overall, 5 patients went to HSCT and were given total body irradiation, with 3 experiencing relapse and 2 having early B-cell recovery. DiNofia noted that the remaining 38 patients did not receive cranial radiation therapy.

At a median of 9 days, peripheral blood quantitative PCR peaked. There was a median of 31,620 copies/μg genomic DNA, and CART19 was detectable in cerebral spinal fluid at day 28 in 98% of the evaluable patients.

There was a cumulative incidence of B-cell recovery at 6 months, prior to manufacturing changes in 67% (95% CI, 35%-85%), and after manufacturing changes in 39% (95% CI, 19%-59%).

A total of 9% of patients had grade 3 immune effector cell-associated neurotoxicity syndrome (ICANS). This included focal cerebral edema (n = 1), seizure (n = 1), and encephalopathy (n = 2). There were no grade 4 ICANS or grade 5 toxicity. All toxicities were fully resolved.

References

1. DiNofia A, Myers R, Li Y, et al. CD19 CAR T cell therapy is an effective strategy for first CNS relapse in pediatric B ALL. Blood. 2025;146(suppl 1):648. doi.10.1182/blood-2025-648
2. Hogan LE, Brown PA, Ji L, et al. Children's Oncology Group AALL1331: phase iii trial of blinatumomab in children, adolescents, and young adults with low-risk B-cell ALL in first relapse. J Clin Oncol. 2023;41(25):4118-4129. doi:10.1200/JCO.22.02200