@article{b925960928f24c16b3da6091cc9a4758,
title = "Clinical Pharmacology of Tisagenlecleucel in B-cell Acute Lymphoblastic Leukemia",
abstract = "Purpose: Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR19) T-cell therapy approved for the treatment of children and young adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL). Patients and Methods: We evaluated the cellular kinetics of tisagenlecleucel, the effect of patient factors, humoral immunogenicity, and manufacturing attributes on its kinetics, and exposure-response analysis for efficacy, safety and pharmacodynamic endpoints in 79 patients across two studies in pediatric B-ALL (ELIANA and ENSIGN). Results: Using quantitative polymerase chain reaction to quantify levels of tisagenlecleucel transgene, responders (N ¼ 62) had 2-fold higher tisagenlecleucel expansion in peripheral blood than nonresponders (N ¼ 8; 74% and 104% higher geometric mean Cmax and AUC0-28d, respectively) with persistence measurable beyond 2 years in responding patients. Cmax increased with occurrence and severity of cytokine release syndrome (CRS). Tisagenlecleucel continued to expand and persist following tocilizumab, used to manage CRS. Patients with B-cell recovery within 6 months had earlier loss of the transgene compared with patients with sustained clinical response. Clinical responses were seen across the entire dose range evaluated (patients 50 kg: 0.2 to 5.0 106/kg; patients >50 kg: 0.1 to 2.5 108 CAR-positive viable T cells) with no relationship between dose and safety. Neither preexisting nor treatment-induced antimurine CAR19 antibodies affected the persistence or clinical response. Conclusions: Response to tisagenlecleucel was associated with increased expansion across a wide dose range. These results highlight the importance of cellular kinetics in understanding determinants of response to chimeric antigen receptor T-cell therapy.",
author = "Mueller, {Karen Thudium} and Edward Waldron and Grupp, {Stephan A.} and Levine, {John E.} and Laetsch, {Theodore W} and Pulsipher, {Michael A.} and Boyer, {Michael W.} and August, {Keith J.} and Jason Hamilton and Rakesh Awasthi and Stein, {Andrew M.} and Denise Sickert and Abhijit Chakraborty and Levine, {Bruce L.} and June, {Carl H.} and Lori Tomassian and Shah, {Sweta S.} and Mimi Leung and Tetiana Taran and Wood, {Patricia A.} and Maude, {Shannon L.}",
note = "Funding Information: Data collected from patients enrolled in the studies ELIANA (ref. 5; N = 50) and ENSIGN (ref. 7; N = 29) were pooled for this analysis as these multicenter studies enrolled identical patient populations and had similar study designs. Pooling the data allowed for a more robust analysis with an appropriate number of patients to evaluate clinical pharmacology endpoints. The global, multicenter ELIANA study was sponsored and designed by Novartis Pharmaceuticals Corporation and supported by Novartis manufacturing process. The US multicenter ENSIGN trial was codeveloped by Novartis and the University of Pennsylvania and was supported by the University of Pennsylvania manufacturing processes (5, 7). Comparability studies were performed between manufacturing sites as part of the technology transfer from the University of Pennsylvania to Novartis. The pivotal, single-arm, open-label, phase II ELIANA study was conducted at 25 sites and aims to determine the efficacy and safety of tisagenlecleucel in pediatric and young adult patients with r/r B-ALL ages between 3 years at the time of screening and 21 years at the time of initial diagnosis (5). The patients from the phase II ENSIGN study were treated at nine sites (7). For both studies, patients were required to have active bone marrow disease (≥5% blasts) at enrollment and no prior anti-CD19 therapy (5, 7). The protocol-specified dose ranges studied were 0.2 to 5.0 ⨯ 106 CAR19-positive viable T cells per kg body weight in patients who weighed ≤ 50 kg and 0.1 to 2.5 ⨯ 108 CAR19-positive viable T cells in patients who weighed > 50 kg, administered as a single infusion of 10 to 20 mL per minute. Funding Information: K.T. Mueller has ownership interests (including patents) at Novartis Pharmaceuticals Corporation. S.A. Grupp is a consultant/advisory board member for and reports receiving commercial research grants from Novartis. J.E. Levine is a consultant/advisory board member for Novartis. T.W. Laetsch is a consultant/advisory board member for Bayer, Eli Lilly, Loxo Oncology and Novartis. M.A. Pulsipher reports receiving speakers bureau honoraria from and is a consultant/advisory board member for Novartis. K. August reports receiving speakers bureau honoraria from Novartis Pharmaceuticals. J. Hamilton has ownership interests (including patents) at Novartis. R. Awasthi has ownership interests (including patents) at Celgene. A. Chakraborty has ownership interests (including patents) at Novartis. B.L. Levine is a consultant/advisory board member for Avectas, Brammer Bio, CRC Oncology/Cure Genetics, Incysus, and Novartis, and reports receiving commercial research grants from Novartis and Tmunity. C.H. June has ownership interests (including patents) at and reports receiving commercial research grants from Novartis. S.Shah has ownership interests (including patents) at Novartis Pharmaceuticals. M. Leung is an employee of Novartis. T. Taran has ownership interests (including patents) in Novartis. S.L. Maude has ownership interests (including patents) in Novartis. No potential conflicts of interest were disclosed by the other authors. Publisher Copyright: {\textcopyright} 2018 American Association for Cancer Research.",
year = "2018",
month = dec,
day = "15",
doi = "10.1158/1078-0432.CCR-18-0758",
language = "English (US)",
volume = "24",
pages = "6175--6184",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "24",
}