Clinical Outcomes of Patients with High-Risk Relapsed/Refractory Follicular Lymphoma Treated with Tisagenlecleucel: Phase 2 ELARA 4-Year Update

Background: Treatment strategies for patients (pts) with relapsed/refractory follicular lymphoma (r/r FL) require consideration of prior therapies and pt-related factors to identify those who are likely to benefit from available treatment options. Tisagenlecleucel is a CAR-T cell therapy approved in the United States and Europe for adults with r/r FL after ≥2 lines of prior therapy. The primary analysis of the phase 2 ELARA trial reported high response rates and a favorable safety profile in pts with high-risk r/r FL. Here we report 4-year follow-up of efficacy, safety, and pharmacokinetics findings.

Methods: Eligible pts with r/r FL (grades 1-3A) previously treated with ≥2 lines of systemic therapy (including an anti-CD20 monoclonal antibody and alkylating agent) received a single tisagenlecleucel infusion (0.6-6×10⁸ CAR+ viable T cells). Bridging therapy was permitted. Baseline clinical characteristics and circulating blood naive T cells were correlated with progression-free survival (PFS) and overall survival (OS). Cellular kinetics were determined by measurement of transgene levels by quantitative polymerase chain reaction. Minimal residual disease (MRD) levels were determined via clonoSEQ® Next Generation Sequencing assay performed at Adaptive Biotechnologies (Seattle, WA, USA): pre-infusion tissue samples were used for the clonotype identification; MRD tracking was performed in post-infusion plasma (ctDNA) samples.

Results: As of March 27, 2024, 97 pts were infused. Ninety-four pts were evaluable for efficacy with a median follow-up of 53 months (range: 46-62). At baseline, among efficacy-evaluable pts, key pt subgroups at high-risk were identified; 72.3% of pts had FL that was refractory to ≥2 prior regimens, 66.0% had bulky disease (>7 cm or 3 lesions >3 cm), 64.9% had progression of disease within 2 years of frontline systemic therapy (POD24), 60.6% had high Follicular Lymphoma International Prognostic Index (FLIPI; ≥3), and 21.3% had high tumor burden (total metabolic tumor volume >510 mL). Median PFS was 53.3 months (95% CI: 18.2-NE) by independent review committee (IRC) among all pts; 48-mo PFS was 50.2% in all pts and 66.1% in pts with a best overall response of complete response. Among identified pt subgroups at high risk, 48-mo PFS by IRC was 45.5% (POD24), 45.5% (high FLIPI), 45.2% (bulky disease), 52.8% (double refractory), and 23.2% (high tumor burden). Median OS was not reached; 48-mo OS was 79.3% in efficacy-evaluable pts. Among identified pt subgroups at high risk, 48-mo OS was 80.8% (POD24), 73.2% (high FLIPI), 73.0% (bulky disease), 83.7% (double refractory), and 65.5% (high tumor burden). MRD data were available on 32/97 pts (33.0%); 28/32 pts (87.5%) achieved MRD negativity at any time point. MRD-negative status was achieved in 82.8% (24/29) of evaluable pts at day 28, 77.8% (14/18) at month 3, 72.7% (16/22) at month 6, and 82.4% (14/17) at month 12, respectively. CAR transgene persistence (T_last; time to last quantifiable transgene level) was observed for up to 1680 days; median T_last was 210 days (range: 13-1680). No new safety signals have been reported since the last data cut. Second primary malignancies (defined as any new cancer occurring post infusion regardless of tisagenlecleucel relationship) were reported in 6 (6.2%) pts and included basal cell carcinoma (n=2), squamous cell carcinoma (n=2), acute myeloid leukemia (n=1), bladder transitional cell carcinoma (n=1), Bowen's disease (n=1), malignant melanoma (n=1), metastatic squamous cell carcinoma (n=1), and myelodysplastic syndrome (n=1). As of the data cutoff, 19 pts have died during the study: 8 due to progressive disease, 10 due to AEs (1 pt each; acute myeloid leukemia, bladder transitional cell carcinoma, cardiac arrest, CRS, encephalitis, gastrointestinal hemorrhage, infection, metastatic squamous cell carcinoma, pneumonia, sepsis), and 1 from euthanasia.

Conclusions: Updated long-term follow-up from the ELARA trial continues to demonstrate robust durable responses >4 years post infusion, alongside a favorable safety profile. Correlative analyses suggest that most baseline high-risk disease characteristics (double-refractory disease, bulky disease, POD24, and high FLIPI) are not associated with inferior efficacy following tisagenlecleucel infusion in pts with r/r FL. Furthermore, high frequencies of MRD-negative status were achieved in a subset of evaluable pts.

Thieblemont:ADC Therapeutics: Honoraria; AstraZeneca: Honoraria; Incyte: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; Novartis: Consultancy, Honoraria; Cellectis: Honoraria; Janssen: Consultancy, Honoraria; Bayer: Honoraria; Roche: Honoraria, Research Funding; BeiGene: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb/Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Kite/Gilead: Consultancy, Honoraria, Research Funding; University of Paris: Current Employment, Ended employment in the past 24 months; Regeneron: Consultancy, Honoraria. Dreyling:AbbVie, Bayer, BMS/Celgene, Gilead/Kite, Janssen, Lilly, F. Hoffmann-La Roche Ltd.: Research Funding; AstraZeneca, Beigene, Gilead/Kite, Janssen, Lilly, Novartis, F. Hoffmann-La Roche Ltd.: Honoraria; AbbVie, AstraZeneca, Beigene, BMS/Celgene, Gilead/Kite, Janssen, Lilly/Loxo, Novartis, F. Hoffmann-La Roche Ltd.: Membership on an entity's Board of Directors or advisory committees. Dickinson:Kite: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Adicet Bio: Consultancy, Honoraria; Genmab: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau. Martínez-Lopez:Amgen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Kite: Consultancy, Honoraria; Incity: Research Funding. Ghosh:Novartis: Research Funding; Cargo: Consultancy; Kite/Gilead: Research Funding; BMS: Consultancy; Cabaletta Bio: Consultancy, Research Funding. Popplewell:Hoffmann-La Roche: Honoraria; Pfizer: Honoraria; Seattle Genetics: Consultancy, Honoraria; Novartis: Consultancy. Chavez:Merck: Research Funding; AstraZeneca: Consultancy; Lilly: Honoraria, Speakers Bureau; Janssen: Honoraria; Abbvie: Consultancy; GenMab: Consultancy, Research Funding; Cellectis: Consultancy; Allogene: Consultancy; BeiGene: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy; Novartis: Consultancy; Kite, a Gilead Company: Consultancy. Bachy:Amgen: Research Funding; AbbVie, Roche, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria; Novartis: Honoraria, Other: Personal Fees; Bristol Myers Squibb: Honoraria, Other: Personal Fees, Research Funding; Janssen: Consultancy, Honoraria; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Other: Personal Fees; Kite, a Gilead Company: Consultancy, Honoraria, Other: Personal Fees. Harigae:Sumitomo Corporation: Research Funding; Kyowa Kirin: Research Funding; AbbVie Inc.: Honoraria; Novartis International AG: Honoraria; CHUGAI PHARMACEUTICAL CO.,LTD.: Honoraria, Research Funding; Sanofi: Honoraria. Kersten:Miltenyi Biotec: Consultancy, Honoraria; Kite, a Gilead company: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Roche: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria, Research Funding. Andreadis:Novartis: Research Funding; Astra Zeneca: Consultancy; Gilead/Kite: Consultancy; Merck: Research Funding; Genmab: Research Funding; Abbvie: Consultancy; Roche: Research Funding; BMS: Consultancy; Seattle Genetics: Consultancy. Riedell:Genmab: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria; Tessa Therapeutics: Research Funding; Cargo Therapeutics: Research Funding; Calibr: Research Funding; CRISPR Therapeutics: Research Funding; Xencor: Research Funding; Fate Therapeutics: Research Funding; Cellectis: Research Funding; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; CVS Caremark: Consultancy; NektarTherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sana Biotechnology: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Research Funding; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Intellia Therapeutics: Membership on an entity's Board of Directors or advisory committees. Ho:Novartis: Other: Research support on medical writing. Pérez-Simón:Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; J&J: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Chen:Elsevier: Consultancy; ADC Therapeutics: Consultancy; Kite: Research Funding; Fate Therapeutics: Research Funding; BMS: Research Funding; Novartis: Research Funding. Nastoupil:Caribou Biosciences: Honoraria, Research Funding; Denovo Biopharma: Honoraria; Daiichi Sankyo: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; BMS: Honoraria, Research Funding; AbbVie: Honoraria; ADC Therapeutics: Honoraria; Genmab: Honoraria, Research Funding; Gilead Sciences/Kite Pharma: Honoraria, Research Funding; Incyte Corporation: Honoraria; Janssen: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Regeneron: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Abbvie, BMS, Caribou Biosciences, Genentech, Genmab, Gilead/Kite, Janssen, Incyte, Ipsen, Merck, Novartis, Regeneron, Takeda: Consultancy; BMS, Caribou Biosciences, Daiichi Sankyo, Genentech, Genmab, Gilead/Kite, Janssen, Incyte, Ipsen, Merck, Novartis, Takeda: Research Funding; Abbvie, BMS, Caribou Biosciences, Daiichi Sankyo, Genentech, Genmab, Gilead/Kite, Janssen, Incyte, Ipsen, Novartis, Takeda: Honoraria. von Tresckow:AbbVie, AstraZeneca, Gilead Kite, Janssen-Cilag, Lilly, Merck Sharp & Dohme, Pierre Fabre, Roche, Takeda, and Novartis: Other: Travel and congress support ; Esteve (Inst), Merck Sharp & Dohme (Inst), Novartis (Inst), and Takeda (Inst): Research Funding; AbbVie, AstraZeneca, BMS/Celgene, Gilead Kite, Incyte, Janssen-Cilag, Lilly, Merck Sharp & Dohme, Novartis, Roche and Takeda: Honoraria; Allogene, Amgen, BMS/Celgene, Cerus, Gilead Kite, Incyte, IQVIA, Janssen-Cilag, Lilly, Merck Sharp & Dohme, Miltenyi, Novartis, Noscendo, Pentixapharm, Pfizer, Pierre Fabre, Qualworld, Regeneron, Roche, Sobi and Takeda: Consultancy. Teshima:Meiji Seika Pharma: Consultancy, Honoraria; Chugai: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria, Research Funding; Sumitomo Pharma: Research Funding; Gilead: Honoraria; Janssen: Honoraria; Eisai: Research Funding; Shionogi: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; LUCA Science: Research Funding; Symbio: Honoraria; Daiichi Sankyo: Honoraria, Research Funding; Nippon Shinyaku: Consultancy, Honoraria; Genmab: Honoraria; Abbvie: Honoraria; Asahi Kasei Pharma: Honoraria, Research Funding; Roche Diagnostics: Consultancy; Novartis: Honoraria; Astellas: Honoraria, Research Funding; AstraZeneca: Honoraria; Pfizer: Honoraria; Pharma Essentia Japan: Research Funding; Bristol-Myers Squibb: Honoraria; Nippon Kayaku: Honoraria, Research Funding; JCR Pharma: Honoraria, Research Funding; Fuji Pharma: Honoraria, Research Funding; Sanofi: Honoraria; MSD: Honoraria. Patten:AstraZeneca: Honoraria, Research Funding; AbbVie: Honoraria, Other: Travel, accommodations, expenses, Research Funding; BeiGene: Honoraria, Other: Travel, accommodations, expenses, Research Funding; Janssen: Honoraria, Other: Travel, accommodations, expenses, Research Funding; Novartis: Research Funding. McGuirk:NEKTAR therapeutics: Consultancy; Sana technologies: Consultancy; Caribou bio: Consultancy; CRISPR therapeutics: Consultancy; Autolus: Consultancy; Envision: Consultancy; Allo Vir: Consultancy; Novartis: Consultancy; Kite: Consultancy; BMS: Consultancy; Legend biotech: Consultancy. Viardot:AbbVie, Amgen, Kite, Roche, Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; AbbVie, BMS, Kite, Novartis, Roche, Sobi: Honoraria. Zinzani:Secura Bio, Sandoz, ADC Therapeutics: Consultancy; Celltrion, Gilead, Janssen-Cilag, BMS, Servier, MSD, AstraZeneca, Takeda, Roche, EUSA Pharma, Kyowa Kirin, Novartis, Incyte, Beigene: Consultancy, Speakers Bureau. Zia:Novartis: Current Employment, Current equity holder in publicly-traded company. Awasthi:Novartis: Current Employment, Current equity holder in publicly-traded company. Germano:Novartis: Current Employment, Current equity holder in publicly-traded company. Ramos:Novartis: Current Employment, Current equity holder in publicly-traded company. Hsu:Novartis: Current Employment, Current equity holder in publicly-traded company. Fowler:Novartis: Consultancy; Bayer: Consultancy; TG Therapeutics: Consultancy; Roche/Genentech: Consultancy, Research Funding; BostonGene: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company; CelGene: Consultancy; Verastem: Consultancy.