Real-World Efficacy and Safety Outcomes for Patients with Relapsed or Refractory (R/R) Aggressive B-Cell Non-Hodgkin's Lymphoma (aBNHL) Treated with Commercial Tisagenlecleucel: Update from the Center for International Blood and Marrow Transplant Research (CIBMTR) Registry
Authors: Landsburg Daniel J , Frigault Matthew J. , Hu Zhen-Huan , Jaglowski Samantha , Locke Frederick L. , Ho Christine , Perales Miguel-Angel , Jacobson Caron , Hill Brian T. , Foley Stephen Ronan , Riedell Peter A. , Tiwari Ranjan , Masood Aisha , Lim Stephen , Majdan Marta , Pasquini Marcelo C , Turtle Cameron J. 
Published: November 2021

Abstract
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 (OR) rate of 53% and progression-free survival (PFS) rate of ~35% at 12 months were observed in the pivotal Phase II trial, JULIET (NCT02445248) [Jaeger et al. Blood 2020; Schuster et al. NEJM 2019]. Early data from the CIBMTR registry indicate similar efficacy and a more favorable safety profile in the commercial setting [Pasquini et al. Blood Adv 2020]. Outcomes are reported here for a larger group of patients with aBNHL who received commercial tisagenlecleucel with longer follow-up, including those considered ineligible for JULIET.
Methods: This non-interventional prospective study used data from the CIBMTR registry and included adult patients with R/R aBNHL in the USA and Canada. Patients who received commercial tisagenlecleucel after August 30, 2017 were included, stratified by eligibility for JULIET based on patient characteristics reported in the registry (eg disease histology, treatment history, ECOG performance status, organ function). The safety and efficacy sets included those with completed Day 100 safety and efficacy forms, respectively, with ≥6 months' follow-up. Patients who died or discontinued prior to data cut-off were also included. Center-reported efficacy outcomes included OR rate, complete response (CR) rate, partial response (PR) rate, PFS, duration of response (DOR) and overall survival (OS). Adverse events of interest, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), were reported using the ASTCT grading criteria.
Results: As of October 30, 2020, data were collected from 405 patients who received commercial tisagenlecleucel ≥6 months prior to data cut-off, with 365 patients included in the safety set and 362 in the efficacy set. In the full cohort, DLBCL was the histologic subtype in 79.5% of patients. Median time from receipt of leukapheresis product at the manufacturing site to shipment was 27 days (interquartile range: 25-33). At infusion, median age was 66 years, with 54.3% of patients aged ≥65 years. Patients had received a median of 3 (range: 0-11) prior lines of therapy and 34.3% had primary refractory disease. ECOG performance status at screening was &lt;2 in 80.2% of patients. Based on the above criteria, 263 patients (64.9%) were considered JULIET-ineligible.
In the efficacy set (median follow-up 15.8 months), the OR rate was 59.4% (95% CI 54.1-64.5), and 39.5% achieved a CR. Six patients with a 100-day best overall response of PR converted to CR. The 12-month PFS rate was 33.5% (95% CI 27.9-39.3), 12-month OS rate was 60.3% (95% CI 53.7-66.2) and median DOR was not reached. Overall, efficacy outcomes in the JULIET-ineligible subgroup reflected those of the wider study population (Table 1).
In the safety set, any-grade CRS within 100 days of infusion was observed in 47.7% (n=174) patients, with Grade ≥3 CRS in 4.9% (n=18). Median time to CRS onset from infusion was 4 days (range: 1-15) and median duration was 5 days (95% CI 5-6). Any-grade ICANS within 100 days of infusion was observed in 17.0% (n=62) patients, with Grade ≥3 in 6.0% (n=22). Median time to onset from infusion was 7 days (range: 1-33) and median duration was 9 days (95% CI 6-12). The safety profile of tisagenlecleucel in the JULIET-ineligible subgroup reflected that of the wider study population (Table 1).
Conclusions: Updated registry data confirm that aBNHL patients receiving commercial tisagenlecleucel experience similar efficacy outcomes and more favorable safety outcomes than those enrolled in JULIET, even though approximately two-thirds of patients did not appear to meet JULIET eligibility criteria. The CIBMTR registry remains an important source of safety and efficacy outcomes for a large population of aBNHL patients treated with commercial tisagenlecleucel. Updated data will be presented at the meeting.
Figure 1 Figure 1.

Disclosures
Landsburg: Curis: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; ADCT: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Triphase: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: DSMB member; Morphosys: Membership on an entity's Board of Directors or advisory committees. Frigault: BMS: Consultancy; Editas: Consultancy; Takeda: Consultancy; Iovance: Consultancy; Arcellx: Consultancy; Kite: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Hu: Kite/Gilead: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Jaglowski: Takeda: Consultancy; Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; CRISPR Therapeutics: Consultancy; Novartis: Consultancy, Research Funding. Locke: Legend Biotech: Consultancy, Other; GammaDelta Therapeutics: Consultancy, Other: Scientific Advisory Role; Kite, a Gilead Company: Consultancy, Other: Scientific Advisory Role, Research Funding; Wugen: Consultancy, Other; Umoja: Consultancy, Other; Novartis: Consultancy, Other, Research Funding; Janssen: Consultancy, Other: Scientific Advisory Role; Cowen: Consultancy; EcoR1: Consultancy; Emerging Therapy Solutions: Consultancy; Gerson Lehrman Group: Consultancy; Calibr: Consultancy, Other: Scientific Advisory Role; Cellular Biomedicine Group: Consultancy, Other: Scientific Advisory Role; BMS/Celgene: Consultancy, Other: Scientific Advisory Role; Iovance Biotherapeutics: Consultancy, Other: Scientific Advisory Role; Takeda: Consultancy, Other; Bluebird Bio: Consultancy, Other: Scientific Advisory Role; Amgen: Consultancy, Other: Scientific Advisory Role; Allogene Therapeutics: Consultancy, Other: Scientific Advisory Role, Research Funding; Moffitt Cancer Center: Patents & Royalties: field of cellular immunotherapy. Perales: Nektar Therapeutics: Honoraria, Other; MorphoSys: Honoraria; Miltenyi Biotec: Honoraria, Other; Merck: Honoraria; Medigene: Honoraria; Kite/Gilead: Honoraria, Other; Karyopharm: Honoraria; Incyte: Honoraria, Other; Equilium: Honoraria; Cidara: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; NexImmune: Honoraria; Novartis: Honoraria, Other; Omeros: Honoraria; Sellas Life Sciences: Honoraria; Servier: Honoraria; Takeda: Honoraria. Jacobson: Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support; Lonza: Consultancy, Honoraria, Other: Travel support; Nkarta: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; Precision Biosciences: Consultancy, Honoraria, Other: Travel support; AbbVie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel support; Humanigen: Consultancy, Honoraria, Other: Travel support; Axis: Speakers Bureau; Clinical Care Options: Speakers Bureau. Hill: Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; AstraZenica: Consultancy, Honoraria; Gentenech: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Incyte/Morphysis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celgene (BMS): Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Foley: Novartis: Honoraria; Gilead: Honoraria; BMS: Honoraria. Riedell: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Calibr: Research Funding; Xencor: Research Funding; Tessa Therapeutics: Research Funding; MorphoSys: Research Funding; Kite/Gilead: Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Consultancy. Tiwari: Novartis Healthcare private limited: Current Employment. Masood: Novartis: Current Employment, Current holder of stock options in a privately-held company. Lim: Novartis Pharmaceuticals Corporation: Current Employment. Majdan: Novartis: Current Employment. Pasquini: Kite Pharma: Research Funding; Novartis: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; GlaxoSmithKline: Research Funding. Turtle: Myeloid Therapeutics: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; T-CURX: Other: Scientific Advisory Board; Century Therapeutics: Consultancy, Other: Scientific Advisory Board; Arsenal Bio: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Eureka Therapeutics: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Caribou Biosciences: Consultancy, Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Precision Biosciences: Current holder of stock options in a privately-held company, Other: Scientific Advisory Board; Nektar Therapeutics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Juno Therapeutics/BMS: Patents & Royalties: Right to receive royalties from Fred Hutch for patents licensed to Juno Therapeutics, Research Funding; Asher Bio: Consultancy; Amgen: Consultancy; PACT Pharma: Consultancy; TCR2 Therapeutics: Research Funding; Allogene: Consultancy.