Background: CTL019 is an investigational therapy derived from autologous T-cells expressing a CD19-specific chimeric antigen receptor (CAR). A single center, phase I/IIa trial of CTL019 showed complete and durable remissions in pediatric/young adult patients (pts) with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) (Maude et al NEJM 2014); these results have yet to be reproduced in a multicenter setting. Here, we report results from a 6-month interim analysis of the first multicenter phase II trial of an engineered cell therapy in leukemia.

Methods: 9 US sites participated in this single-arm phase II study in pediatric/young adult pts with R/R B-ALL. Leukapheresis products were shipped for centralized manufacturing according to the University of Pennsylvania (Penn) process in an academic-industry collaboration. T cells were transduced with a lentiviral vector encoding a CAR composed of anti-CD19 scFv, CD3ζ and 4-1BB domains. Following lymphodepletion with fludarabine and cyclophosphamide, a single dose of CTL019 cells was administered (target dose 2.0-5.0×106 cells/kg for ≤50 kg and 1.0-2.5×108 cells for >50 kg). The primary endpoint was overall remission rate (ORR = CR + CRi [CRi, complete remission with incomplete blood count recovery] maintained at 2 evaluations ≥28 days apart) as determined by an Independent Review Committee. Secondary objectives included minimal residual disease (MRD), relapse-free survival (RFS), overall survival (OS) and safety. All analyses were performed on infused patient set.

Results: 29/35 pts enrolled (82.9%) were infused with CTL019; 6 withdrew prior to infusion (2 manufacturing failures [1 lack of growth, 1 contamination]; 4 deaths [median, 48 days from enrollment; 2 progressive disease, 1 multi-organ failure, 1 pneumonia]). Mean bone marrow involvement at enrollment was 68.2% (SD, 27.3%; Table 1). 2 pts did not receive lymphodepleting chemotherapy due to leukopenia. Collection, manufacturing and infusion were feasible in a multicenter setting with a median time from enrollment to infusion of 37 days. Target cell dose was met in 24/33 (72.7%) manufactured products. ORR in all infused pts was 69.0% (20/29 pts; 98.95% CI 43.6, 88.1). Of the 5 pts who received CTL019 below the target dose, 2 achieved CR/CRi. Of note, deep remission with no evidence of MRD (<0.01%) was achieved in 18/29 pts (62.1%; 95% CI 42.3, 79.3) within 6 months. Median RFS and median survival have not yet been reached. Median duration of follow-up was 6.4 months (range 0.4-14.0). CR/CRi was not achieved in 9 pts: 2 pts died before Day 28 (1 ALL; 1 embolic stroke not attributed to CTL019 at Day 25 after infusion), 6 did not respond and 1 pt achieved CRi at Day 28 but relapsed 17 days later. Of the 20 pts who achieved a CR/CRi, 8 pts relapsed 1.7-7.6 months after onset of remission; 2 were CD19 negative. RFS and OS at 6 months (Figures 1, 2) were 66.4% and 75.7%, respectively. Serious adverse events occurred in 79.3% of pts within 8 weeks of infusion. Overall 10 deaths occurred at 0.4-8.8 months (9 ALL; 1 embolic stroke); no deaths attributable to CTL019. The most common adverse event was cytokine release syndrome (CRS), which was graded on the Penn scale and managed according to a standardized algorithm. All 26 (89.7%) cases of CRS were reversible; 11 pts (37.9%) had grade 3 or 4 CRS, of which 7 (26.9%) required systemic anti-cytokine therapy, 9 (34.6%) required high dose vasopressors for hypotension, 6 (23.1%) required mechanical ventilation, 4 (15.4%) underwent dialysis. Reversible neuropsychiatric events occurred in 9 (31%) pts (1 grade 3; no grade 4), including seizures in 2 pts but no cases of cerebral edema.

Conclusions: In this first multicenter trial of CAR-modified T cell therapy, CTL019 therapy was feasible and efficacious, showing a high ORR with durable remissions in pediatric/young adult pts with R/R B-ALL. Despite the high rate of toxicity with CTL019 in the R/R setting, the rate of grade 3 or 4 CRS was comparable to the single center study, and standardized management of CRS was successful in a multicenter trial with no deaths attributable to CRS. In this highly refractory population, a vast majority of eligible pts can be successfully infused in a timely fashion and outcomes appear reproducible in a multicenter setting despite a more heterogeneous population than the single center study. The trial is continuing under Novartis manufacturing.


Maude:Novartis: Consultancy. Pulsipher:Medac: Other: Travel support for a study group; Chimerix: Consultancy, Other: Advisory Board ; Jazz Pharmaceutical: Consultancy, Other: Advisory Board; Novartis: Consultancy, Other: Advisory Board, Steering Committee for Phase II Study. Grupp:Pfizer: Consultancy; Novartis: Consultancy, Research Funding. Davies:Novartis: Honoraria. Verneris:Bimogen: Other: Advisory Board. Schlis:Novartis: Honoraria. Driscoll:Novartis: Consultancy. June:Immune Design: Consultancy, Equity Ownership; Pfizer: Honoraria; Celldex: Consultancy, Equity Ownership; Novartis: Honoraria, Patents & Royalties, Research Funding; Johnson & Johnson: Honoraria; Novartis: Honoraria, Patents & Royalties, Research Funding; Tmunity Therapeutics: Equity Ownership. Levine:GE Healthcare Bio-Sciences: Consultancy; Novartis: Patents & Royalties, Research Funding. Wood:Novartis Pharmaceuticals: Employment, Other: Stock. Yi:Novartis: Employment.

Author notes


Asterisk with author names denotes non-ASH members.

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