Background
Phase 2, multicenter, single-arm registration trial (ELIANA, NCT02435849). N=75 pediatric and young adult patients (age 3–25) with R/R BCP-ALL: ≥2 prior lines, prior allo-HSCT allowed, or early relapse after allo-HSCT. First global registration trial of a CAR-T cell therapy in pediatric/young adult ALL. Tisagenlecleucel (CTL019; Kymriah) is an autologous 4-1BBζ anti-CD19 CAR-T product. Published NEJM 2018; 3-year update JCO 2023.
Interventions and follow up
Regimen: Tisagenlecleucel (single IV infusion, 0.2–5.0 × 10⁶ CAR+ viable T cells/kg) after fludarabine/cyclophosphamide lymphodepletion in pediatric/young adult (≤25 yr) R/R B-ALL
Primary endpoint: Overall remission rate (CR + CRi) within 3 months
mFollow up: 38.8 months (3-year update)
Primary endpoint: Overall remission rate (CR + CRi) within 3 months
mFollow up: 38.8 months (3-year update)
Results
ORR within 3 months (primary): 81% (61/75; 95% CI 71–89%); CR 60% + CRi 21%
MRD-negative among responders: 100%
3-year EFS (all responders): 44%; mEFS 24 months
3-year OS: 63%; mOS not reached at 3 years
Ongoing remission without subsequent therapy (3-year update): 40% of responders
B-cell aplasia at 12 months (surrogate of CAR persistence): Maintained in ~60% among responders
MRD-negative among responders: 100%
3-year EFS (all responders): 44%; mEFS 24 months
3-year OS: 63%; mOS not reached at 3 years
Ongoing remission without subsequent therapy (3-year update): 40% of responders
B-cell aplasia at 12 months (surrogate of CAR persistence): Maintained in ~60% among responders
Adverse events
CRS: Grade 3–4 CRS 47% (managed with tocilizumab)
Neurologic (ICANS): Grade 3–4 13% (low vs adult CAR-T trials)
Hematologic/infectious: Prolonged B-cell aplasia and hypogammaglobulinemia requiring IVIG; opportunistic and bacterial infections common during B-cell aplasia
Second malignancy: Class-wide FDA boxed warning for secondary T-cell malignancy added to all CAR-T products in 2024
Neurologic (ICANS): Grade 3–4 13% (low vs adult CAR-T trials)
Hematologic/infectious: Prolonged B-cell aplasia and hypogammaglobulinemia requiring IVIG; opportunistic and bacterial infections common during B-cell aplasia
Second malignancy: Class-wide FDA boxed warning for secondary T-cell malignancy added to all CAR-T products in 2024
Conclusions
Tisagenlecleucel achieved 81% remission in pediatric/young adult R/R ALL with 100% MRD-negativity among responders. With 3-year EFS of 44% and mOS not reached, this represents the most durable remissions seen in heavily pretreated pediatric R/R ALL. A subset (~40%) maintained long-term remission without further therapy, suggesting curative potential.
Key Limitations
Single-arm design without randomized comparator. Manufacturing failures and rapid disease progression mean intent-to-treat outcomes are less favorable than treated-population results. High grade ≥3 CRS rate (47%) requires specialized infusion-center infrastructure. Relapse (including CD19-negative escape) remains the dominant cause of failure. Small sample size (N=75) limits subgroup analysis.
Clinical Context
ELIANA supported the landmark FDA approval (August 2017) of tisagenlecleucel — the first CAR-T cell therapy approved in any indication — for patients up to 25 years with R/R B-ALL; EMA approval followed in 2018. ASCO and ESMO guidance endorse CAR-T as standard of care for pediatric/young adult R/R B-ALL after ≥2 lines or post-transplant relapse.