Clinical Pharmacology of Tisagenlecleucel in B-cell Acute Lymphoblastic Leukemia

Karen Thudium Mueller, Edward Waldron, Stephan A. Grupp, John E. Levine, Theodore W Laetsch, Michael A. Pulsipher, Michael W. Boyer, Keith J. August, Jason Hamilton, Rakesh Awasthi, Andrew M. Stein, Denise Sickert, Abhijit Chakraborty, Bruce L. Levine, Carl H. June, Lori Tomassian, Sweta S. Shah, Mimi Leung, Tetiana Taran, Patricia A. WoodShannon L. Maude

Research output: Contribution to journalArticlepeer-review

121 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)6175-6184
Number of pages10
JournalClinical Cancer Research
Issue number24
StatePublished - Dec 15 2018

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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