Study of Efficacy and Safety of CTL019 in Pediatric ALL Patients

Rationale

Tisagenlecleucel (CTL019) is made from the patient's own T cells, collected by leukapheresis and engineered ex vivo to express a chimeric antigen receptor (CAR) that binds CD19 and activates the T cell when it meets a CD19-positive cell. CD19 is expressed on B-cell acute lymphoblastic leukemia (B-ALL) blasts and is restricted to the B-cell lineage, so CD19-directed T cells were expected to kill leukemia that had relapsed after or become refractory to chemotherapy or allogeneic stem cell transplant. A single intravenous infusion after lymphodepleting chemotherapy was expected to expand in vivo and persist, giving continued control of residual leukemia.

Results

In the CT.gov posted final results for the 79 infused main-cohort patients, tisagenlecleucel produced an overall remission rate (CR or CRi within 3 months, independent review) of 82.3% (65 of 79; 95% CI 72.1-90.0), rejecting the prespecified null of 20% or less (p<0.0001); 81.0% had MRD-negative CR/CRi. Remission was 96.0% (24 of 25) with baseline marrow blasts below 50% and 75.9% (41 of 54) at 50% or more. Median duration of remission was 46.8 months and median event-free survival 23.7 months; 33 of 79 died during follow-up. At the 5-year analysis (Grupp 2026, median follow-up 79.4 months), 5-year relapse-free survival among 70 responders was 47.3% and overall survival 55.0% of 79 (both censored at transplant or new therapy); 18 of 33 relapses were CD19-negative. In the primary analysis (Maude 2018, n=75), cytokine release syndrome (CRS) occurred in 77% and neurologic events in 40%, without cerebral edema. Posted serious adverse events: 63 of 79, CRS serious in 50 of 79 (non-serious in 37 of 79).

• In children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia, a single infusion of tisagenlecleucel (CTL019) produced an overall remission rate (CR or CRi within 3 months by independent review) of 82.3% (65 of 79 infused; 95% CI 72.1-90.0) in the ELIANA final analysis, above the prespecified null of 20% (p<0.0001). (Laetsch 2022)
• In the ELIANA primary analysis of tisagenlecleucel (CTL019) in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (n=75, median follow-up 13.1 months), 81% achieved CR or CRi within 3 months, all responders were MRD-negative by flow cytometry, and event-free and overall survival at 12 months were 50% (95% CI 35-64) and 76% (95% CI 63-86). (Maude 2018)
• In children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia treated with tisagenlecleucel (CTL019) in ELIANA, remission within 3 months was 96.0% (24 of 25) in patients with baseline bone marrow blasts below 50% and 75.9% (41 of 54) in patients with 50% or more. (Registry results)
• After a single infusion of tisagenlecleucel (CTL019) in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ELIANA, median follow-up 38.8 months), event-free survival at 3 years was 44% (95% CI 31-57) and overall survival 63% (95% CI 51-73) among 79 infused patients, with median event-free survival of 24 months. (Laetsch 2022)
• At 5 years after tisagenlecleucel (CTL019) in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ELIANA, median follow-up 79.4 months), relapse-free survival among 70 responders was 47.3% (95% CI 33.3-60.1) when censoring at stem cell transplant or other new therapy and 51.0% (95% CI 37.6-62.8) without censoring at transplant; overall survival of all 79 infused patients was 55.0% and 62.4% under the same two censoring rules. (Grupp 2026)
• Among children and young adults with B-cell acute lymphoblastic leukemia who relapsed after remission on tisagenlecleucel (CTL019) in ELIANA, 18 of 33 relapses (55%) were CD19-negative and 8 (24%) CD19-positive at 5-year follow-up. (Grupp 2026)
• In a post hoc analysis of ELIANA responders with B-cell acute lymphoblastic leukemia, 5-year relapse-free survival after tisagenlecleucel (CTL019) was 71.1% above versus 41.9% at or below the median dose of 3.0x10^6 cells/kg in patients 50 kg or less (46 patients), and 72.9% versus 11.4% above versus at or below the median dose of 1.0x10^8 cells in patients over 50 kg (20 patients). (Grupp 2026)
• In children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia responding to tisagenlecleucel (CTL019) in ELIANA, median time to B-cell recovery was 35.3 months; median duration of remission was 12.1 months in the 10 responders whose B cells recovered within 6 months of infusion, and 28 months in 50 responders with sustained B-cell aplasia (median follow-up 38.8 months). (Laetsch 2022)
• In the ELIANA primary analysis of tisagenlecleucel (CTL019) in 75 children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia, cytokine release syndrome occurred in 77% (48% of these received tocilizumab), neurologic events in 40% with no cerebral edema, and grade 3 or 4 adverse events suspected to be related to tisagenlecleucel in 73%. (Maude 2018)
• In the ELIANA final posted results for tisagenlecleucel (CTL019) in 79 children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia, serious adverse events occurred in 63 of 79 patients, including cytokine release syndrome reported as serious in 50 of 79 (non-serious in 37 of 79); hypogammaglobulinemia was reported as a non-serious event in 32 of 79, and 33 of 79 patients died during up to 60 months of follow-up. (Registry results)
• After tisagenlecleucel (CTL019) in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ELIANA, median follow-up 38.8 months), grade 3 or 4 adverse events occurred in 83.5% of patients within 8 weeks of infusion, 49% from 8 weeks to 1 year, and 29% beyond 1 year (49 patients followed), when infections (20.4%) were the most frequent grade 3 or 4 events. (Laetsch 2022)
• In children and young adults aged 8 to 23 years with relapsed or refractory B-cell acute lymphoblastic leukemia treated with tisagenlecleucel (CTL019) in ELIANA, the PedsQL total quality-of-life score improved from baseline by a mean of 13.3 points (95% CI 8.9-17.6) at month 3, and 30 of 37 patients reached the minimal clinically important difference. (Laetsch 2019)

Design implications

A single infusion of autologous CD19 CAR T cells can be definitive therapy in multiply relapsed pediatric B-ALL: about half of responders stayed in remission at 5 years without consolidative transplant, so a CAR-T program need not be designed only as a bridge to transplant. Loss of CD19 caused most relapses (18 of 33), so single-antigen CARs are limited by antigen escape; dual-antigen targeting or CD19 monitoring at relapse are the next steps. Response fell with high marrow blast burden (75.9% vs 96.0%), which supports treating at lower disease burden. In a post hoc analysis, doses above the median gave longer relapse-free survival, so dosing at the upper end of the range deserves testing. B-cell recovery within 6 months marked early relapse, so B-cell aplasia is a usable pharmacodynamic readout of CAR persistence, at the cost of hypogammaglobulinemia. CRS is the dominant acute toxicity and needs a management protocol (tocilizumab) built into any CD19 CAR-T trial.

Limitations

Single-arm, open-label phase 2 with no concurrent control; remission was tested against a historical null of 20%. 18 of 98 enrolled patients were never infused, and efficacy covers infused patients only. Long-term survival estimates depend on censoring for transplant and new therapy. The dose-response analysis is post hoc in small subgroups. Cohorts 1 (1 patient) and 2 (none) stopped for poor recruitment.