Chimeric Antigen Receptor CTL019 lentivirally transduced T cells show prolonged persistence and durable antitumor activity in ALL (NEJM 2013 & 2014). We report here on outcomes and longer follow up of 59 children and young adults with r/r ALL. One day prior to CTL019 infusion 44/59 patients had detectable ALL, while 15 were MRD(-). A median of 4.3x106 CTL019 cells/kg (1–17.4x106/kg) were infused. 55 patients (93%) achieved a CR. Four did not respond. MRD measured by clinical flow cytometry was <0.01% at D28 in 50 responding patients and positive at 0.024%-1.1% in 5 patients, with 2 patients becoming negative by 3 mo with no further therapy. With median follow up of 12 mo (2–43 mo), 34 patients have ongoing CR, with only 6 receiving subsequent SCT. Relapse Free Survival is 76% at 6 mo (95%CI 65–89%) and 55% at 12 mo (95%CI 42–73%), and Overall Survival is 79% at 12 mo (95%CI 69–91%). CTL019 was detected by qPCR in the CSF of 46/47 patients, 4 patients with CNS2a ALL experienced a CR in CSF, and there have been no CNS recurrences. All but 7 (88%) patients developed grade 1–4 cytokine release syndrome (CRS) at peak T cell expansion. Treatment for CRS was required for hemodynamic or respiratory instability in 28% of patients and was reversed in all cases with IL6 blockade (tocilizumab). Grade 4 CRS was associated with pre-infusion high disease burden. Using regression modeling, we could accurately predict which patients would develop severe CRS using 3 analytes measured within 72h post-infusion: IFNg, sgp130, and IL1RA. 11 patients received a repeat infusion of murine CTL019, which in some cases prolonged B cell aplasia. Retreatment with a humanized scFv CD19-directed CAR T product can induce remission of ALL refractory to prior CD19-directed murine CAR T cell therapy, suggesting immune-mediated rejection as an important mechanism of resistance in patients with rapid CAR cell loss and loss of B cell aplasia. CTL019 cells can undergo robust in vivo expansion and can persist for >3y in patients with r/r ALL detected by flow cytometry and/or qPCR, allowing for the possibility of longterm disease control without subsequent therapy such as SCT. This approach also has promise as salvage therapy for patients who relapse after allo SCT with a low risk of GVHD. CTL019 therapy has received Breakthrough Therapy designation from the FDA in pediatric and adult ALL, and phase 2 multicenter and global registration trials are well underway.
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