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 journalArticle

25 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)6175-6184
Number of pages10
JournalClinical Cancer Research
Volume24
Issue number24
DOIs
StatePublished - Dec 15 2018

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Clinical Pharmacology
Precursor Cell Lymphoblastic Leukemia-Lymphoma
B-Lymphocytes
Antigen Receptors
Cell- and Tissue-Based Therapy
Transgenes
CD19 Antigens
Cytokines
T-Lymphocytes
Safety
Young Adult
Pediatrics
Polymerase Chain Reaction
Antibodies
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Mueller, K. T., Waldron, E., Grupp, S. A., Levine, J. E., Laetsch, T. W., Pulsipher, M. A., ... Maude, S. L. (2018). Clinical Pharmacology of Tisagenlecleucel in B-cell Acute Lymphoblastic Leukemia. Clinical Cancer Research, 24(24), 6175-6184. https://doi.org/10.1158/1078-0432.CCR-18-0758

Clinical Pharmacology of Tisagenlecleucel in B-cell Acute Lymphoblastic Leukemia. / Mueller, Karen Thudium; Waldron, Edward; Grupp, Stephan A.; Levine, John E.; Laetsch, Theodore W; Pulsipher, Michael A.; Boyer, Michael W.; August, Keith J.; Hamilton, Jason; Awasthi, Rakesh; Stein, Andrew M.; Sickert, Denise; Chakraborty, Abhijit; Levine, Bruce L.; June, Carl H.; Tomassian, Lori; Shah, Sweta S.; Leung, Mimi; Taran, Tetiana; Wood, Patricia A.; Maude, Shannon L.

In: Clinical Cancer Research, Vol. 24, No. 24, 15.12.2018, p. 6175-6184.

Research output: Contribution to journalArticle

Mueller, KT, Waldron, E, Grupp, SA, Levine, JE, Laetsch, TW, Pulsipher, MA, Boyer, MW, August, KJ, Hamilton, J, Awasthi, R, Stein, AM, Sickert, D, Chakraborty, A, Levine, BL, June, CH, Tomassian, L, Shah, SS, Leung, M, Taran, T, Wood, PA & Maude, SL 2018, 'Clinical Pharmacology of Tisagenlecleucel in B-cell Acute Lymphoblastic Leukemia', Clinical Cancer Research, vol. 24, no. 24, pp. 6175-6184. https://doi.org/10.1158/1078-0432.CCR-18-0758
Mueller, Karen Thudium ; Waldron, Edward ; Grupp, Stephan A. ; Levine, John E. ; Laetsch, Theodore W ; Pulsipher, Michael A. ; Boyer, Michael W. ; August, Keith J. ; Hamilton, Jason ; Awasthi, Rakesh ; Stein, Andrew M. ; Sickert, Denise ; Chakraborty, Abhijit ; Levine, Bruce L. ; June, Carl H. ; Tomassian, Lori ; Shah, Sweta S. ; Leung, Mimi ; Taran, Tetiana ; Wood, Patricia A. ; Maude, Shannon L. / Clinical Pharmacology of Tisagenlecleucel in B-cell Acute Lymphoblastic Leukemia. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 24. pp. 6175-6184.
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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.",
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T1 - Clinical Pharmacology of Tisagenlecleucel in B-cell Acute Lymphoblastic Leukemia

AU - Mueller, Karen Thudium

AU - Waldron, Edward

AU - Grupp, Stephan A.

AU - Levine, John E.

AU - Laetsch, Theodore W

AU - Pulsipher, Michael A.

AU - Boyer, Michael W.

AU - August, Keith J.

AU - Hamilton, Jason

AU - Awasthi, Rakesh

AU - Stein, Andrew M.

AU - Sickert, Denise

AU - Chakraborty, Abhijit

AU - Levine, Bruce L.

AU - June, Carl H.

AU - Tomassian, Lori

AU - Shah, Sweta S.

AU - Leung, Mimi

AU - Taran, Tetiana

AU - Wood, Patricia A.

AU - Maude, Shannon L.

PY - 2018/12/15

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N2 - 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.

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