TISAGENLECLEUCEL IN PEDIATRIC AND YOUNG ADULT PATIENTS WITH HIGH-RISK B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA AND MINIMAL RESIDUAL DISEASE AT THE END OF FRONTLINE CONSOLIDATION
Shannon Maude et al
Division of Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States of America
Background
- In patients with B-cell acute lymphoblastic leukemia (B-ALL), persistent minimal residual disease (MRD) is associated with a high risk of relapse.
- In the Children’s Oncology Group (COG) AALL0232 frontline trial, children and young adults with high-risk B-ALL and MRD ≥0.01% at the end of frontline consolidation (EOC) had a 5-year disease-free survival (DFS) of only 39% (Borowitz, Blood, 2015).
- The aim of this phase 2 trial, conducted in collaboration with the COG, was to evaluate the efficacy and safety of tisagenlecleucel, a CD19-directed chimeric antigen receptor (CAR) T cell therapy, in this very high-risk population.
Methods
- CASSIOPEIA/COGAALL1721 (NCT03876769) is a global (34 US/Canada sites, 10 EU/UK sites) phase 2 study of tisagenlecleucel in patients (1-25 years old) with National Cancer Institute high-risk B-ALL and persistent MRD ≥0.01% by flow cytometry at EOC. Patients received standard lymphodepleting chemotherapy followed by a single tisagenlecleucel dose (0.2-5×106 CAR+ T cells/kg for patients ≤50 kg or 0.1-2.5×108 CAR+ T cells for patients >50 kg).
- Patients with B-cell recovery within 6 months and/or MRD ≥0.01% at any time could receive a reinfusion. Primary endpoints were 4-year overall survival (OS) and 5-year 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 months, and safety.
Results
- The primary analysis included 121 infused patients; 1 patient was not infused due to an adverse event. Median age was 14 years (range: 1-24 years), 67% were male, 6% had trisomy 21. At data cut-off (August 20, 2025), median time from infusion to last follow-up was 38 months. Four-year OS was 85% (95% CI: 76-90%). DFS (95% CI) without censoring for new therapy was 71% (61-79%) at 3 years and 64% (53-73%) at 5 years. DFS (95% CI) with censoring was 69% (55-79%) at 3 years and 62% (46-74%) at 5 years. MRD negative rate post infusion was 95% at day 29 and 86% at 3 months.
- Relapse occurred in 31 patients, among which 7 relapsed after new therapy/SCT. A second infusion was given in 41 (34%) patients; 58 (48%) patients received new anticancer therapy/SCT without prior relapse. Median duration of B-cell aplasia was 5.6 months.
- Probability (95% CI) of ongoing remission and B-cell aplasia at 3, 6, and 12 months was 76% (67-83%), 47% (38-56%), and 31% (23-41%), respectively. Following first infusion, cytokine release syndrome (CRS) occurred in 37% (grade ≥3, 2%) and immune effector cell–associated neurotoxicity syndrome (ICANS) in 3% (grade ≥3, 1%). All 18 deaths occurred after relapse and/or new therapy/SCT.
Conclusion
- In a very high-risk population with persistent MRD in frontline therapy, who historically have low 5-year DFS, tisagenlecleucel produced durable remissions, with very low rates of severe CRS/ICANS.
- In this study, almost half of the patients received new anticancer therapy, including SCT, without experiencing prior relapses. Longer follow-up is needed to confirm 5-year DFS.