Clinical Pharmacology of Tisagenlecleucel in B-cell Acute Lymphoblastic Leukemia

被引：182

作者：

Mueller, Karen Thudium ^{[1
]}

Waldron, Edward ^{[2
]}

Grupp, Stephan A. ^{[3
,4
,5
]}

Levine, John E. ^{[6
,7
]}

Laetsch, Theodore W. ^{[8
,9
]}

Pulsipher, Michael A. ^{[10
]}

Boyer, Michael W. ^{[11
]}

August, Keith J. ^{[12
]}

Hamilton, Jason ^{[13
]}

Awasthi, Rakesh ^{[1
]}

Stein, Andrew M. ^{[14
]}

Sickert, Denise ^{[15
]}

Chakraborty, Abhijit ^{[2
]}

Levine, Bruce L. ^{[16
]}

June, Carl H. ^{[16
]}

Tomassian, Lori ^{[2
]}

Shah, Sweta S. ^{[2
]}

Leung, Mimi ^{[2
]}

Taran, Tetiana ^{[2
]}

Wood, Patricia A. ^{[2
]}

Maude, Shannon L. ^{[3
,4
,5
]}

机构：

[1] Novartis Inst BioMed Res, One Hlth Plaza, E Hanover, NJ 07936 USA

[2] Novartis Pharmaceut, E Hanover, NJ USA

[3] Univ Penn, Perelman Sch Med, Dept Pediat, Philadelphia, PA 19104 USA

[4] Childrens Hosp Philadelphia, Ctr Childhood Canc Res, Div Oncol, Philadelphia, PA 19104 USA

[5] Childrens Hosp Philadelphia, Canc Immunotherapy Program, Philadelphia, PA 19104 USA

[6] Univ Michigan, Ann Arbor, MI 48109 USA

[7] Icahn Sch Med Mt Sinai, New York, NY 10029 USA

[8] Univ Texas Southwestern Med Ctr Dallas, Dept Pediat, Dallas, TX USA

[9] Childrens Hlth, Pauline Allen Gill Ctr Canc & Blood Disorders, Dallas, TX USA

[10] USC Keck Sch Med, Childrens Hosp Los Angeles, Div Hematol Oncol Blood & Marrow Transplant, Los Angeles, CA USA

[11] Univ Utah, Salt Lake City, UT USA

[12] Childrens Mercy Kansas City, Kansas City, MO USA

[13] Legend Biotech, Piscataway, NJ USA

[14] Novartis Inst BioMed Res, Cambridge, MA USA

[15] Novartis Pharma AG, Basel, Switzerland

[16] Univ Penn, Perelman Sch Med, Ctr Cellular Immunotherapies, Philadelphia, PA 19104 USA

来源：

CLINICAL CANCER RESEARCH | 2018年 / 24卷 / 24期

关键词：

PEDIATRIC-PATIENTS; T-CELLS; CLOFARABINE;

D O I：

10.1158/1078-0432.CCR-18-0758

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 = 62) had approximate to 2-fold higher tisagenlecleucel expansion in peripheral blood than nonresponders (N = 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 x 10(6)/kg; patients >50 kg: 0.1 to 2.5 x 10(8) 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. (C) 2018 AACR.

引用

页码：6175 / 6184

页数：10

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