Universität zu Köln

Awasthi, Rakesh, Pacaud, Lida, Waldron, Edward, Tam, Constantine S., Jager, Ulrich, Borchmann, Peter, Jaglowski, Samantha ORCID: 0000-0002-4335-2554, Foley, Stephen Ronan, van Besien, Koen ORCID: 0000-0002-8164-6211, Wagner-Johnston, Nina D., Kersten, Marie Jose, Schuster, Stephen J., Salles, Gilles, Maziarz, Richard T., Anak, Ozlem, del Corral, Christopher, Chu, Jufen, Gershgorin, Irina, Pruteanu-Malinici, Iulian, Chakraborty, Abhijit, Mueller, Karen Thudium and Waller, Edmund K. (2020). Tisagenlecleucel cellular kinetics, dose, and immunogenicity in relation to clinical factors in relapsed/refractory DLBCL. Blood Adv., 4 (3). S. 560 - 573. WASHINGTON: AMER SOC HEMATOLOGY. ISSN 2473-9537

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Abstract

The anti-CD19 chimeric antigen receptor (CAR)-T cell therapy tisagenlecleucel was evaluated in the global, phase 2 JULIET study in adult patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). We correlated tisagenlecleucel cellular kinetics with clinical/product parameters in 111 patients treated in JULIET. Tisagenlecleucel persistence in responders and nonresponders, respectively, was demonstrated for 554 and 400 days maximum by flow cytometry and for 693 and 374 days maximum by quantitative polymerase chain reaction (qPCR). No relationships were identified between cellular kinetics (qPCR) and product characteristics, intrinsic/extrinsic factors, dose, or immunogenicity. Most patients with 3-month response had detectable transgene at time of response and continued persistence for >= 6 months. Expansion (maximal expansion of transgene/CAR-positive T-cell levels in vivo postinfusion [C-max]) was potentially associated with response duration but this did not reach statistical significance (hazard ratio for a twofold increase in C-max, 0.79; 95% confidence interval, 0.61-1.01). Tisagenlecleucel expansion was associated with cytokine-release syndrome (CRS) severity and tocilizumab use; no relationships were observed with neurologic events. Transgene levels were associated with B-cell levels. Dose was associated with CRS severity, but this was not statistically significant after adjusting for baseline tumor burden. In contrast to the results from B-cell precursor acute lymphoblastic leukemia (B-ALL) and chronic lymphocytic leukemia, similar exposure was observed in DLBCL in this study regardless of response and expansion was lower in DLBCL than B-ALL, likely from differences in cancer location and/or T-cell intrinsic factors. Relationships between expansion and CRS severity, and lack of relationships between dose and exposure, were similar between DLBCL and B-ALL. Tisagenlecleucel cellular kinetics in adult relapsed/refractory DLBCL improve current understanding of in vivo expansion and its relationships with safety/efficacy endpoints.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Awasthi, Rakesh UNSPECIFIED UNSPECIFIED UNSPECIFIED Pacaud, Lida UNSPECIFIED UNSPECIFIED UNSPECIFIED Waldron, Edward UNSPECIFIED UNSPECIFIED UNSPECIFIED Tam, Constantine S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Jager, Ulrich UNSPECIFIED UNSPECIFIED UNSPECIFIED Borchmann, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Jaglowski, Samantha UNSPECIFIED orcid.org/0000-0002-4335-2554 UNSPECIFIED Foley, Stephen Ronan UNSPECIFIED UNSPECIFIED UNSPECIFIED van Besien, Koen UNSPECIFIED orcid.org/0000-0002-8164-6211 UNSPECIFIED Wagner-Johnston, Nina D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kersten, Marie Jose UNSPECIFIED UNSPECIFIED UNSPECIFIED Schuster, Stephen J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Salles, Gilles UNSPECIFIED UNSPECIFIED UNSPECIFIED Maziarz, Richard T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Anak, Ozlem UNSPECIFIED UNSPECIFIED UNSPECIFIED del Corral, Christopher UNSPECIFIED UNSPECIFIED UNSPECIFIED Chu, Jufen UNSPECIFIED UNSPECIFIED UNSPECIFIED Gershgorin, Irina UNSPECIFIED UNSPECIFIED UNSPECIFIED Pruteanu-Malinici, Iulian UNSPECIFIED UNSPECIFIED UNSPECIFIED Chakraborty, Abhijit UNSPECIFIED UNSPECIFIED UNSPECIFIED Mueller, Karen Thudium UNSPECIFIED UNSPECIFIED UNSPECIFIED Waller, Edmund K. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-345036
DOI:	10.1182/bloodadvances.2019000525
Journal or Publication Title:	Blood Adv.
Volume:	4
Number:	3
Page Range:	S. 560 - 573
Date:	2020
Publisher:	AMER SOC HEMATOLOGY
Place of Publication:	WASHINGTON
ISSN:	2473-9537
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language B-CELL; T-CELLS; THERAPY; CTL019 Multiple languages Hematology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/34503