Real-World Outcomes for Patients with Relapsed or Refractory (R/R) Aggressive B-Cell Non-Hodgkin's Lymphoma (aBNHL) Treated with Commercial Tisagenlecleucel: Subgroup Analyses from the Center for International Blood and Marrow Transplant Research (CIBMTR) Registry

Background: Tisagenlecleucel is an autologous CD19-directed T-cell immunotherapy that provides high rates of durable response, with a manageable safety profile, in adult patients with R/R diffuse large B-cell lymphoma (DLBCL). An overall response rate (ORR) of 53% and progression-free survival (PFS) rate of 33% at 24 months were observed in the pivotal Phase II trial, JULIET (NCT02445248) [Schuster et al. Lancet Oncol 2021; Jaeger et al. Blood 2020]. CIBMTR registry data revealed similar efficacy and a more favorable safety profile for patients with aBNHL treated with tisagenlecleucel in the commercial setting [Landsburg et al.Blood 2021]. The analyses presented here feature a larger cohort with longer follow-up, with outcomes analyzed by pre-infusion clinicopathologic and treatment characteristics.

Methods: This non-interventional prospective study used data from the CIBMTR registry and included adult patients with R/R aBNHL in the USA, Canada, and Israel who received commercial tisagenlecleucel after August 30, 2017. Patients were stratified by eligibility for JULIET based on characteristics reported in the registry, such as disease histology, ECOG performance status (PS), comorbidities (recorded as pulmonary, cardiac, renal, or hepatic), and disease status at infusion. Outcomes were assessed in subgroups by reason for JULIET ineligibility, and by lactate dehydrogenase (LDH) level and lymphodepleting chemotherapy (LDC) regimen. LDH was taken as the last known value prior to LDC, or prior to infusion for patients who did not receive LDC. The safety and efficacy sets comprised patients who completed Day 100 safety and efficacy forms, respectively, including those who died prior to Day 100. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded per ASTCT criteria.

Results: As of May 4, 2022, data were collected from 1159 patients who received commercial tisagenlecleucel; the median manufacturing turnaround time was 26 days (IQR 24-30). Median age was 67.1 years, 61.2% were male, and 80% had DLBCL. There were 361 JULIET-eligible patients, 641 JULIET-ineligible patients, and 157 patients whose eligibility status could not be defined due to missing data.

In the efficacy set (N=968), over a median follow-up of 23.2 months (range: 3.1-46.4), the ORR was 59.5% (Table 1). Month 24 outcomes were 28.4% for PFS, 52.6% for duration of response, and 43.6% for overall survival (OS). Patients with normal versus elevated LDH had improved efficacy outcomes (Table 2), while type of LDC regimen did not appear to impact efficacy (Table 2).

Considering individual reasons for JULIET ineligibility, patients in morphologic complete response (CR) at infusion had higher ORR (87.3%) and 24-month PFS (46.3%) and OS (66.1%) than JULIET-eligible patients (Table 1). In patients with ECOG PS ≥2, as well as those with comorbidities (including pulmonary, cardiac, and hepatic disease), PFS was comparable with the JULIET-eligible population (Table 1).

In the safety set (N=990), grade ≥3 CRS and ICANS occurred in 6.0% and 7.4% of patients, respectively. Compared with JULIET-eligible patients, rates of CRS and ICANS were lower for patients in morphologic CR at infusion, and higher among those with ECOG PS ≥2. Rates of grade ≥3 CRS were similar between patients with comorbidities and the JULIET-eligible population (Table 1).

Conclusions: These analyses using data reported to the CIBMTR, with 1159 patients and >20 months' median follow-up, confirm that real-world outcomes with tisagenlecleucel are broadly similar to those observed in JULIET. Among all patients, normal LDH pre-infusion, but not LDC regimen received, was associated with significantly improved efficacy outcomes. Patients with comorbidities that would have rendered them ineligible for JULIET had similar efficacy outcomes to JULIET-eligible patients. Additionally, efficacy outcomes were similar in patients ineligible for JULIET due to ECOG PS ≥2, albeit with higher rates of grade ≥3 CRS and ICANS. A significantly higher response rate and trend towards improved survival outcomes were observed among patients in morphologic CR before infusion. These data suggest that tisagenlecleucel is appropriate therapy for several subsets of patients who would have been ineligible for JULIET.

Landsburg:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Calithera: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; Curis, Inc: Research Funding; Triphase: Research Funding. Frigault:Novartis: Consultancy, Research Funding; Arcellx: Research Funding; BMS: Consultancy; Iovance: Consultancy; JnJ/Legend: Consultancy; Kite/Gilead: Consultancy, Research Funding; Cytoagents: Consultancy. Foley:BMS: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Hill:Novartis: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Research Funding; BMS: Consultancy, Honoraria, Research Funding. Jacobson:Lonza: Consultancy, Honoraria, Other: Travel Support; ImmPACT Bio: Consultancy, Honoraria; Clinical Care Options: Speakers Bureau; Axis: Speakers Bureau; Precision BioSciences: Consultancy, Honoraria, Other: Travel Support; Daiichi Sankyo: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Humanigen: Consultancy, Honoraria, Other: Travel Support; Pfizer: Other: Travel Support, Research Funding; BMS/Celgene: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Ispen: Consultancy, Honoraria; Nkarta: Consultancy, Honoraria; Instil Bio: Consultancy, Honoraria; bluebird bio: Consultancy, Honoraria; Celgene: Other: Travel Support; Novartis: Consultancy, Honoraria, Other: Travel Support; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding. Jaglowski:Novartis: Research Funding; Kite: Consultancy, Research Funding; Gamida: Consultancy; CRISPR Therapeutics: Consultancy. Locke:A2: Consultancy; BMS: Research Funding; Imedex: Other: Education or editorial activity; Society for Immunotherapy of Cancer: Other: Education or editorial activity; Daiichi Sankyo: Consultancy; CERo Therapeutics: Research Funding; Sana: Consultancy; Takeda: Consultancy;), National Cancer Institute: Research Funding; BioPharm Communications: Other: Education or editorial activity; Clinical Care Options Oncology: Other: Education or editorial activity; CAREducation: Other: Education or editorial activity; ASH: Other: Education or editorial activity; Leukemia and Lymphoma Society: Research Funding; Aptitude Health: Other: Education or editorial activity; Celgene: Consultancy; Other: Patents & Royalties: patents, royalties, other intellectual property from several patents held by the institution in my name (unlicensed) in the field of cellular immunotherapy.; Wugen: Consultancy; Umoja: Consultancy; Novartis: Consultancy, Research Funding; Legend Biotech: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Janssen: Consultancy; Iovance: Consultancy; GammaDelta Therapeutics: Consultancy; Emerging Therapy Solutions Gerson Lehrman Group: Consultancy; EcoR1: Consultancy; Cowen: Consultancy; Calibr: Consultancy; Cellular Biomedicine Group: Consultancy; Bristol Myers Squibb/Celgene: Consultancy; Bluebird Bio: Consultancy, Research Funding; Allogene: Consultancy, Research Funding; Amgen: Consultancy. Ram:BMS: Honoraria; Takeda: Honoraria; Novartis Pharmaceuticals: Honoraria; Gilead: Honoraria. Riedell:BeiGene: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees; Sana Biotechnology: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Intellia Therapeutics: Membership on an entity's Board of Directors or advisory committees; Nektar Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Research Funding; Calibr: Research Funding; Tessa Therapeutics: Research Funding; Fate Therapeutics: Research Funding; Xencor: Research Funding. Shah:Beyond Spring: Research Funding; Amgen: Research Funding; Janssen: Research Funding. Tiwari:Novartis Healthcare Private Limited: Current Employment. Lim:Novartis Pharmaceuticals Corporation: Current Employment. Majdan:Novartis: Current Employment. Masood:Novartis: Current Employment, Current holder of stock options in a privately-held company. Pasquini:Kite: Research Funding; Novartis: Research Funding; Janssen: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding. Turtle:Kite Pharma, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Century Therapeutics: Membership on an entity's Board of Directors or advisory committees; Arsenal Bio: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Myeloid Therapeutics: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; T-CURX: Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics, a BMS Company: Patents & Royalties, Research Funding; Nektar Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Bioscience: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Eureka Therapeutics: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Caribou Bioscience: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Decheng Capital: Consultancy, Membership on an entity's Board of Directors or advisory committees; Expert Connect: Consultancy; Allogene: Membership on an entity's Board of Directors or advisory committees; Prescient Therapeutics: Membership on an entity's Board of Directors or advisory committees.