Efficacy and safety of CD19-targeted 19-28Z CAR modified T cells in adult patients with relapsed or refractory B-ALL

Background: Adult patients with relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL) have dismal prognosis. We previously reported high anti-tumor activity of autologous T cells genetically modified to express 19-28z chimeric antigen receptor (CAR) targeting CD19 in adult patients with ALL. Aims: Herein, we report the long-term outcome of our phase I clinical trial in adults with R/R ALL (NCT01044069). Methods: Adult patients with R/R B-ALL underwent leukapheresis, and T cells were transduced with a gammaretroviral vector encoding a CAR construct composed of anti-CD19 scFv linked to CD28 and CD3ζ signaling domains (19- 28z). All patients received conditioning chemotherapy followed by 1-3x106 19- 28z CAR T cells/kg. Results: 33 patients have been treated, and 32 patients are evaluable for response. The median age was 54 years (range, 22-74). 12 patients (36%) had Ph+ ALL, 11 patients (33%) had prior allogeneic stem cell transplant (allo- SCT), and 14 patients (42%) had ≥3 prior lines of therapy. At the time of CAR T cell infusion, 16 had morphologic disease (>5% blasts in BM) and the remaining 16 patients had minimal residual disease (MRD). 13/16 patients with morphologic disease (81%) and 16/16 patients with MRD (100%) were in complete remission (CR) after 19-28z CAR T cell infusion, yielding an overall CR rate of 91% (29/32). Of the 28 MRD evaluable patients, MRD negative CR rate was 82%. 11 patients underwent allo-SCT following the CAR T cells. As of 1/25/15, the median follow-up was 5.1 months (range, 1.0-37.6+), with 14 patients having ≥6 months of follow-up. 6-month overall survival (OS) rate of all patients was 58% (95% CI.: 36-74). Among the patients who achieved CR, OS rate at 6 months for patients who had allo-SCT vs no allo-SCT following CAR T cells was 70% (95% CI.: 33-89) vs 61% (95% CI.: 29-82; p=0.30). Severe cytokine release syndrome (sCRS) requiring vasopressors or mechanical ventilation for hypoxia was observed in 7 patients, effectively managed with IL-6R inhibitor and/or corticosteroids. Summary and Conclusions: 19-28z CAR T cells can induce a high CR rate of 91% in adult patients with R/R ALL. The risk of sCRS correlates with disease burden and can be effectively managed. These findings strongly support the use of 19-28z CAR T cells in adults with R/R ALL and warrants investigation in a phase 2 trial.