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242 Impact of Tisagenlecleucel Chimeric Antigen Receptor (CAR)-T Cell Therapy Product Attributes on Clinical Outcomes in Adults with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (r/r DLBCL)

Program: Oral and Poster Abstracts
Type: Oral
Session: 626. Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)—Results from Prospective Clinical Trials: Results from CAR T-Cell Trials
Hematology Disease Topics & Pathways:
Diseases, Therapies, Clinically relevant
Saturday, December 7, 2019: 2:15 PM
Hall E2, Level 2 (Orange County Convention Center)

Veronika Bachanova, MD, PhD1, Constantine S. Tam, MBBS, MD2*, Peter Borchmann3, Ulrich Jaeger, MD4, Joseph P. McGuirk, DO5, Harald Holte, MD, PhD6, Edmund K. Waller, PhD, MD7, Samantha Jaglowski, MD, MPH8, Michael R. Bishop, MD9, Charalambos Andreadis, MD, MSCE10*, Stephen Ronan Foley, MD, FRCPC11, Jason R. Westin, MD12, Isabelle Fleury, MD13*, P Joy Ho, MBBS(Syd) DPhil(Oxon) FRACP FRCPA FFSc(RCPA)14*, Stephan Mielke, MD15, Takanori Teshima, MD16, Gilles A. Salles, MD, PhD17, Stephen J Schuster, MD18, Richard T. Maziarz, MD19, Koen Van Besien, MD, PhD20, Koji Izutsu, MD, PhD21*, Marie Jose Kersten, MD, PhD22, John M. Magenau, MD23*, Nina D. Wagner-Johnston, MD24,25, Koji Kato, MD, PhD26, Paolo Corradini, MD27, Jufen Chu, PhD28*, Irina Gershgorin, PhD28*, Therese Choquette, PhD28*, Lida Bubuteishvili Pacaud, MD28* and Margit Jeschke, PhD29*

1Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN
2Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
3Department I of Internal Medicine and Center of Integrated Oncology Aachen, Bonn, Cologne, Düsseldorf, German Hodgkin Study Group, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Koln, Germany
4Clinical Division of Hematology and Hemostaseology, Department of Medicine I, Vienna General Hospital - Medical University of Vienna, Vienna, AA, Austria
5Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS
6Norwegian Cancer Genomics Consortium, Oslo, Norway
7Winship Cancer Institute, Emory University, Atlanta, GA
8The Ohio State University, Columbus, OH
9Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL
10Department of Medicine, University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA
11Hamilton Health Sciences, Hamilton, ON, CAN
12Department of Lymphoma and Myeloma, MD Anderson, Houston, TX
13Maisonneuve-Rosemont Hospital and University of Montreal, Montreal, Canada
14Department of Haematology, Institute of Haematology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia
15University of Würzburg, Center of Allogeneic Stem Cell Transplantation, Department of Internal Medicine II, Würzburg University Medical Center, Würzburg, Germany
16Department of Hematology, Hokkaido University Hospital, Sapporo Hokkaido, Japan
17Lyon-Sud University Hospital Complex, Pierre-Bénite, France
18Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
19Center for Hematologic Malignancies, Oregon Health & Science University, Portland, OR
20Division of Hematology and Oncology, Weill Cornell Medical College, New York, NY
21Department of Hematology, Toranomon Hospital, National Cancer Center Hospital, Tokyo, Japan
22Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
23Blood and Marrow Transplant Program, University of Michigan, Ann Arbor, MI
24Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Hospital, Baltimore, MD
25Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD
26Department of Hematology and Oncology, Kyushu University Hospital, Fukuoka, Japan
27Fondazione IRCCS Istituto Nazionale dei Tumori, University of Milan, Milan, Italy
28Novartis Pharmaceuticals Corporation, East Hanover, NJ
29Novartis Pharma AG, Basel, Switzerland

Background: In the phase 2 JULIET trial, tisagenlecleucel, an anti-CD19 CAR-T cell therapy, demonstrated durable responses and manageable safety in adult patients (pts) with r/r DLBCL. Here, we examine the impact of key product cellular attributes of tisagenlecleucel on clinical outcomes.

Methods: JULIET is a single-arm, global, phase 2 trial of tisagenlecleucel in adult pts with r/r DLBCL. Samples from 115 tisagenlecleucel individual products were examined at the end of manufacturing at the batch release testing for various product attributes (Table). Additional detailed immunophenotyping for 66 attributes was conducted on previously frozen product samples via flow cytometry (FC). For each cell population of CAR+ T cells, the percentage and absolute number of the subpopulation were analyzed. Univariate and multivariate analyses were performed to evaluate effects of product attributes and CAR+ T-cell phenotypes on efficacy (Month 3 response [M3R], duration of response [DOR], progression-free survival [PFS], overall survival [OS]) and safety (cytokine release syndrome [CRS] and neurological events [NE], grade 0-2 [low] vs 3-4 [severe]). Several exploratory approaches, including machine learning methods (eg, elastic net and random forest), were pursued in conjunction with logistic regression to identify a set of variables associated with clinical outcomes. We included clinically relevant characteristics evaluated at baseline per protocol (LDH, CRP, and tumor volume) with the product attributes in multivariate modeling. Logistic regression was used to model M3R, CRS, and NE. Cox regression was used to model DOR, PFS, and OS.

Results: As of December 11, 2018, 115 pts were infused and evaluable. The median T-cell transduction efficiency by FC was 28% (range, 5.3-63.2%); no relationship of these attributes with efficacy (M3R, DOR, PFS, or OS) or safety (severe CRS or NE) was observed. The percentage of viable cells had no impact on efficacy or safety outcomes; this was anticipated since tisagenlecleucel dose is formulated based on the number of viable CAR+ T cells.

Tisagenlecleucel demonstrated in vitro functional activity upon CD19-specific stimulation, as evidenced by IFNγ release, with a wide range among different batches (range, 23.7-938 fg/CAR+ cell). Durable responses were observed across the entire range of IFNγ release; high IFNγ release was not associated with severe CRS or NE.

The median ratio of CAR+ CD4+ to CD8+ cells was 3.70 (range, 0.26-65.3); no relationship with clinical outcomes was observed (Figure).

CAR+ T cells showed variability in T-cell phenotypes, with central memory (CM) cells as the predominant subpopulation of both CD4+ and CD8+ CAR+ T cells (Figure). The majority of CAR+ T cells were highly activated (co-expressing HLA-DR and CD38), as measured by FC. Relative and absolute number of less mature T cells (naive and CM T cells) in the product did not correlate with efficacy.

There was no significant correlation between cell populations and efficacy on multivariate analyses. For CRS, the total number of certain CD4+ T cells expressing activation markers (HLA-DR+, CD25+, or HLA-DR+CD38+) and CM cells showed trends of correlation with more severe CRS, but none of these were significant after p-value adjustment; in a multivariate regression model adjusted for LDH and other clinically relevant factors, HLA-DR+ CD38+CD4+ T cells showed a correlation with severe CRS. Correlation analyses did not reveal product attributes significantly related to severe NE.

Conclusions: In JULIET, tisagenlecleucel CAR-T cell product attributes had no significant impact on efficacy or NE; the total number of activated CD4+ cells infused positively correlated with higher-grade CRS. There is great variability in the product attributes, especially with respect to T-cell phenotypes, though this variability appears to play a minor role on efficacy. Additional analyses with larger data sets are required to confirm these findings. ClinicalTrials.gov Identifier: NCT02445248.

Disclosures: Bachanova: Novartis: Research Funding; Gamida Cell: Research Funding; GT Biopharma: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Incyte: Research Funding. Tam: Janssen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; BeiGene: Honoraria; Novartis: Honoraria; Roche: Honoraria; Pharmacyclics LLC, an AbbVie company: Honoraria. Jaeger: Novartis, Roche, Sandoz: Consultancy; AbbVie, Celgene, Gilead, Novartis, Roche, Takeda Millennium: Research Funding; Amgen, AbbVie, Celgene, Eisai, Gilead, Janssen, Novartis, Roche, Takeda Millennium, MSD, BMS, Sanofi: Honoraria; Celgene, Roche, Janssen, Gilead, Novartis, MSD, AbbVie, Sanofi: Membership on an entity's Board of Directors or advisory committees. McGuirk: Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ArticulateScience LLC: Other: Assistance with manuscript preparation; Pluristem Ltd: Research Funding; Gamida Cell: Research Funding; Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bellicum Pharmaceuticals: Research Funding; Astellas: Research Funding; Fresenius Biotech: Research Funding; Novartis: Research Funding. Holte: Novartis: Honoraria, Other: Advisory board. Waller: Amgen: Consultancy; Kalytera: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Other: Travel expenses, Research Funding; Cerus Corporation: Other: Stock, Patents & Royalties; Chimerix: Other: Stock; Cambium Oncology: Patents & Royalties: Patents, royalties or other intellectual property . Jaglowski: Juno: Consultancy, Other: advisory board; Kite: Consultancy, Other: advisory board, Research Funding; Novartis: Consultancy, Other: advisory board, Research Funding; Unum Therapeutics Inc.: Research Funding. Bishop: CRISPR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Andreadis: Celgene: Research Funding; Novartis: Research Funding; Jazz Pharmaceuticals: Consultancy; Roche: Equity Ownership; Pharmacyclics: Research Funding; Merck: Research Funding; Gilead: Consultancy; Kite: Consultancy; Genentech: Consultancy, Employment; Juno: Research Funding. Foley: Celgene: Speakers Bureau; Amgen: Speakers Bureau; Janssen: Speakers Bureau. Westin: Unum: Research Funding; Genentech: Other: Advisory Board, Research Funding; Novartis: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Kite: Other: Advisory Board, Research Funding; 47 Inc: Research Funding; Curis: Other: Advisory Board, Research Funding; MorphoSys: Other: Advisory Board; Celgene: Other: Advisory Board, Research Funding. Fleury: Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; AstraZeneca: Consultancy. Ho: Janssen: Other: Trial Investigator meeting travel costs; Celgene: Other: Trial Investigator meeting travel costs; La Jolla: Other: Trial Investigator meeting travel costs; Novartis: Other: Trial Investigator meeting travel costs. Mielke: Miltenyi: Consultancy, Honoraria, Other: Travel and speakers fee (via institution), Speakers Bureau; DGHO: Other: Travel support; Jazz Pharma: Honoraria, Other: Travel support, Speakers Bureau; EBMT/EHA: Other: Travel support; Celgene: Honoraria, Other: Travel support (via institution), Speakers Bureau; ISCT: Other: Travel support; Bellicum: Consultancy, Honoraria, Other: Travel (via institution); GILEAD: Consultancy, Honoraria, Other: travel (via institution), Speakers Bureau; Kiadis Pharma: Consultancy, Honoraria, Other: Travel support (via institution), Speakers Bureau; IACH: Other: Travel support. Teshima: Novartis: Honoraria, Research Funding. Salles: Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Amgen: Honoraria, Other: Educational events; BMS: Honoraria; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Epizyme: Consultancy, Honoraria. Schuster: Novartis: Honoraria, Patents & Royalties: Combination CAR-T and PD-1 Inhibitors, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Acerta: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Nordic Nanovector: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Loxo Oncology: Consultancy, Honoraria. Maziarz: Kite: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Incyte: Consultancy, Honoraria; Celgene/Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Van Besien: Miltenyi Biotec: Research Funding. Izutsu: Eisai, Chugai, Zenyaku: Honoraria; Chugai, Celgene, Daiichi Sankyo, Astra Zeneca, Eisai, Symbio, Ono, Bayer, Solasia, Zenyaku, Incyte, Novartis, Sanofi, HUYA Bioscience, MSD, Astellas Amgen, Abbvie, ARIAD, Takeda, Pfizer: Research Funding; Eisai, Symbio, Chugai, Zenyaku: Research Funding; Kyowa Kirin, Eisai, Takeda, MSD, Chugai, Nihon Medi-physics, Janssen, Ono, Abbvie, Dainihon Sumitomo, Bayer, Astra Zeneca, HUYA Japan, Novartis, Bristol-Byers Squibb, Mundi, Otsuka, Daiichi Sankyo, Astellas, Asahi Kasei: Honoraria; Celgene: Consultancy. Kersten: Celgene: Consultancy, Research Funding; Kite: Consultancy, Other: Travel grants, honorarium, or advisory boards; Janssen/Cilag: Other: Travel grants, honorarium, or advisory boards; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Other: Travel grants, honorarium, or advisory boards; Gilead: Other: Travel grants, honorarium, or advisory boards; Amgen: Other: Travel grants, honorarium, or advisory boards; Roche: Other: Travel grants, honorarium, or advisory boards; Celgene: Other: Travel grants, honorarium, or advisory boards; Roche: Consultancy, Research Funding, Travel grants, honorarium, or advisory boards; MSD: Other: Travel grants, honorarium, or advisory boards; Bristol Myers Squibb: Other: Travel grants, honorarium, or advisory boards. Wagner-Johnston: ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Corradini: Celgene: Honoraria, Other: Travel Costs; Jazz Pharmaceutics: Honoraria; KiowaKirin: Honoraria; Kite: Honoraria; Novartis: Honoraria, Other: Travel Costs; Roche: Honoraria; Sanofi: Honoraria; Servier: Honoraria; Takeda: Honoraria, Other: Travel Costs; BMS: Other: Travel Costs; AbbVie: Consultancy, Honoraria, Other: Travel Costs; Amgen: Honoraria; Janssen: Honoraria, Other: Travel Costs; Gilead: Honoraria, Other: Travel Costs; Daiichi Sankyo: Honoraria. Chu: Novartis: Employment. Gershgorin: Novartis: Employment. Choquette: Novartis: Employment. Bubuteishvili Pacaud: Novartis: Employment. Jeschke: Novartis: Employment.

*signifies non-member of ASH