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 language | English (US) |
|---|---|
| Pages (from-to) | 6175-6184 |
| Number of pages | 10 |
| Journal | Clinical Cancer Research |
| Volume | 24 |
| Issue number | 24 |
| DOIs | |
| State | Published - Dec 15 2018 |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
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 journal › Article
}
TY - JOUR
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
Y1 - 2018/12/15
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85058453793&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85058453793&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-18-0758
DO - 10.1158/1078-0432.CCR-18-0758
M3 - Article
C2 - 30190371
AN - SCOPUS:85058453793
VL - 24
SP - 6175
EP - 6184
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 24
ER -