Sustained remissions with CD19-specific chimeric antigen receptor (CAR)-modified T cells in children with relapsed/refractory ALL.

3011 Background: Targeted immunotherapy with chimeric antigen receptor (CAR)-modified T cells can produce potent anti-tumor responses. We previously reported complete remissions (CR) and prolonged persistence in children and adults with relapsed/refractory (r/r) acute lymphoblastic leukemia (ALL) treated with CD19-specific CART cells (CTL019). We now report on outcomes and longer follow-up of 59 children with r/r ALL. Methods: T cells collected from the patient were transduced with a lentiviral vector encoding a CAR composed of anti-CD19 scFv, CD3z, and 4-1BB domains, activated/expanded ex vivo with anti-CD3/CD28 beads, and then infused at a dose of 107 to 108cells/kg with a transduction efficiency of 2.3-45%. 54/59 patients received lymphodepleting chemotherapy the week prior to cell infusion. Results: Of 59 patients aged 20mo-24y with CD19+ ALL, 44 had detectable disease prior to CTL019 cell infusion, while 15 were MRD-. 39 were treated for relapse after prior stem cell transplant (SCT). 15 patients had CNS disease within a year of infusion. At assessment 1 month after infusion, 55/59 (93%) were in CR. MRD < 0.01% by flow cytometry was achieved in 52 patients. CTL019 cells were detected in the CSF and no CNS relapses have been seen. With median follow-up 12 mo (1-43 mo), 34 patients had ongoing CR, with only 6 receiving subsequent therapy (5 SCT, 1 donor lymphocyte infusion), RFS was 76% (95% CI, 65-89%) at 6 mo and 55% at 12 mo (95% CI, 42-73%), and OS was 79% (95% CI, 69-91%) at 12 mo. 20 patients subsequently relapsed, 13 with CD19- disease. CTL019 persistence was accompanied by B cell aplasia, which continued up to last assessment (1-39 mo) in 24/34 patients with ongoing CR. Cytokine release syndrome (CRS) was seen in 88% of patients. Severe CRS requiring hemodynamic or respiratory support occurred in 27%, was associated with high disease burden, and was reversed with the anti-IL6R agent tocilizumab. We could predict development of severe CRS through regression modeling using IFNγ, sgp130, and sIL1RA measured in the first 72h (sens 86%, spec 89%, AUC 0.93). Conclusions: Single-agent CTL019 immunotherapy can induce durable responses with control of CNS disease in patients with r/r ALL. Clinical trial information: NCT01626495.