Tisagenlecleucel (tisa-cel) in pediatric and young adult patients with high-risk (HR) B-cell acute lymphoblastic leukemia (B-ALL) and minimal residual disease (MRD) at the end of frontline consolidation (EOC).

10000 Background: Persistent MRD portends a high risk of relapse in B-ALL. In the Children’s Oncology Group (COG) AALL0232 frontline trial for HR B-ALL, children and young adults with MRD ≥0.01% at the EOC had poor 5 y disease-free survival (DFS) of 39% (Borowitz, Blood , 2015). We report the primary analysis of a phase 2 trial, in collaboration with COG, of tisa-cel, a CD19-directed chimeric antigen receptor (CAR) T cell therapy, in this very high-risk (VHR) population. Methods: COG AALL1721/CASSIOPEIA (NCT03876769) is a global (34 sites in the US/Canada, 10 sites in EU/UK) phase 2 study of tisa-cel in patients (pts) aged 1-25 y with National Cancer Institute HR B-ALL and persistent MRD ≥0.01% by flow cytometry at EOC. A single dose of tisa-cel (0.2-5×10 6 CAR+ T cells/kg for pts ≤50 kg or 0.1-2.5×10 8 CAR+ T cells for pts >50 kg) was given after standard lymphodepleting chemotherapy. Reinfusion was available for pts with B-cell recovery within 6 mo and/or MRD ≥0.01% at any time. Primary endpoints were 4 y overall survival (OS) and 5 y DFS, defined as time from first infusion to morphologic relapse, secondary malignancy, or death, without censoring for new anticancer therapy, including stem cell transplant (SCT). Secondary endpoints included DFS with censoring, MRD negative rate (MRD <0.01%) at 3 mo, and safety. Results: The primary analysis included 121 infused pts; 1 pt was not infused due to adverse event. Median age was 14 y (range: 1-24 y), 67% were male, 6% had trisomy 21. As of August 20, 2025, median time from infusion to last follow-up was 38 mo. OS at 4 y was 85% (95% CI: 76-90%). DFS (95% CI) at 3 y and 5 y without censoring for new therapy was 71% (61-79%) and 64% (53-73%). DFS (95% CI) at 3 y and 5 y with censoring was 69% (55-79%) and 62% (46-74%). MRD negative rate at day 29 and 3 mo post infusion was 95% and 86%. Relapse occurred in 31 pts, of which 7 occurred after new therapy/SCT. 41 (34%) pts received a second infusion. 58 (48%) pts received new anticancer therapy/SCT without prior relapse. Median duration of B-cell aplasia was 5.6 mo. Probability (95% CI) of ongoing remission and B-cell aplasia at 3, 6, and 12 mo was 76% (67-83%), 47% (38-56%), and 31% (23-41%). Following first infusion, cytokine release syndrome (CRS) occurred in 37% (grade ≥3, 2%), immune effector cell–associated neurotoxicity syndrome (ICANS) in 3% (grade ≥3, 1%). There were 18 deaths, all post new therapy/SCT and/or relapse. Conclusions: Durable remissions, with very low rates of severe CRS/ICANS, were achieved with tisa-cel in a VHR population with persistent MRD in frontline therapy, who historically have low 5 y DFS. Nearly 50% of pts received new anticancer therapy, including SCT, without prior relapse. Longer follow-up is needed to confirm 5 y DFS. Clinical trial information: NCT03876769 .