Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia

BACKGROUND: In a single-center phase 1-2a study, the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). METHODS: We conducted a phase 2, single-cohort, 25-center, global study of tisagenlecleucel in pediatric and young adult patients with CD19+ relapsed or refractory B-cell ALL. The primary end point was the overall remission rate (the rate of complete remission or complete remission with incomplete hematologic recovery) within 3 months. RESULTS: For this planned analysis, 75 patients received an infusion of tisagenlecleucel and could be evaluated for efficacy. The overall remission rate within 3 months was 81%, with all patients who had a response to treatment found to be negative for minimal residual disease, as assessed by means of flow cytometry. The rates of event-free survival and overall survival were 73% (95% confidence interval [CI], 60 to 82) and 90% (95% CI, 81 to 95), respectively, at 6 months and 50% (95% CI, 35 to 64) and 76% (95% CI, 63 to 86) at 12 months. The median duration of remission was not reached. Persistence of tisagenlecleucel in the blood was observed for as long as 20 months. Grade 3 or 4 adverse events that were suspected to be related to tisagenlecleucel occurred in 73% of patients. The cytokine release syndrome occurred in 77% of patients, 48% of whom received tocilizumab. Neurologic events occurred in 40% of patients and were managed with supportive care, and no cerebral edema was reported. CONCLUSIONS: In this global study of CAR T-cell therapy, a single infusion of tisagenlecleucel provided durable remission with long-term persistence in pediatric and young adult patients with relapsed or refractory B-cell ALL, with transient high-grade toxic effects. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02435849.

Relative nutritional quality of C 3 and C 4 grasses for a graminivorous lepidopteran, Paratrytone melane (Hesperiidae)

We tested the hypothesis that C 4 grasses are inferior to C 3 grasses as host plants for herbivorous insects by measuring the relative performance of larvae of a graminivorous lepidopteran, Paratrytone melane (Hesperiidae), fed C 3 and C 4 grasses. Relative growth rates and final weights were higher in larvae fed a C 3 grass in Experiment I. However, in two additional experiments, relative growth rates and final weights were not significantly different in larvae fed C 3 and C 4 grasses. We examined two factors which are believed to cause C 4 grasses to be of lower nutritional value than C 3 grasses: foliar nutrient levels and nutrient digestibility. In general, foliar nutrient levels were higher in C 3 grasses. In Experiment I, protein and soluble carbohydrates were digested from a C 3 and a C 4 grass with equivalent efficiencies. Therefore, differences in larval performance are best explained by higher nutrient levels in the C 3 grass in this experiment. In Experiment II, soluble carbohydrates were digested with similar efficiencies from C 3 and C 4 grasses but protein was digested with greater efficiency from the C 3 grasses. We conclude (1) that the bundle sheath anatomy of C 4 grasses is not a barrier to soluble carbohydrate digestion and does not have a nutritionally significant effect on protein digestion and (2) that P. melane may consume C 4 grasses at compensatory rates.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47798/1/442_2004_Article_BF00317268.pd