A Characterization of Bridging Therapies Leading up to Commercial CAR T-Cell Therapy
Authors: Dwivedy Nasta Sunita , Hughes Mitchell E. , Namoglu Esin C. , Landsburg Daniel J. , Chong Elise A. , Barta Stefan K. , Frey Noelle V. , Gerson James N. , Maity Amit , Plastaras John , Porter David L. , Ruella Marco , Svoboda Jakub , Ballard Hatcher J. , Schuster Stephen J. 
Published: November 2019

Introduction: Implementation of cellular therapy has transformed the treatment paradigm for diffuse large B-cell lymphoma with sustained responses observed in JULIET and ZUMA-1. Bridging therapies were permitted on the JULIET trial but were excluded on ZUMA-1 (Schuster, NEJM, 2019; Locke, Lancet, 2018). CAR T-cell therapy (CAR-T) is indicated after 2 lines of therapy; however, in the standard of care setting (SOC), the choice and timing of prior salvage therapies can vary widely. We sought to characterize common therapies received immediately prior to CAR-T administration at our institution.
Patients and Methods: We conducted a retrospective study of all adult patients who had a successful product manufactured for commercial CAR-T with tisagenlecleucel (tisa-cel) or axicabtagene ciloleucel (axi-cel) therapy at the University of Pennsylvania between 10/2017 and 7/2019. Demographics, therapy prior to CAR-T including bridging therapies, and status of disease by physician report in a binary assessment of progression prior to CAR-T were collected. Bridging therapy was defined as therapy given after T-cell apheresis but prior to CAR-T infusion, not including lymphodepleting chemotherapy (LD). Therapies were combined into groups for analysis: small molecule targeted agents +/-radiation, immunotherapy+/-radiation, chemoimmunotherapy +/-radiation, and radiation alone.
Results: We identified 64 patients with non-Hodgkin lymphoma for this analysis. Prior to eligibility evaluation for CAR-T, all patients received at least 2 lines of prior therapy; with 25% receiving prior autologous stem cell transplant and one patient receiving prior allogeneic stem cell transplant. Eleven patients (17%) received prior bendamustine and/or purine analogue therapy. At the time of leukapheresis, median ECOG performance status was 1 (Range 0-3). Of the 64 patients, 49 patients (77%) proceeded to cellular therapy, 9 patients (14%) died prior to CAR-T infusion and 6 patients (9%) are awaiting infusion and were not included in the analysis of bridging therapy. The median time from the last therapy prior to CAR-T infusion, including bridging therapy, was 28 days (range 0-406 days). Of those who received CAR-T, 39% received axi-cel and 61% received tisa-cel. At the time of data cutoff, 22 of 49 patients had progressive disease post CAR-T infusion. Of these patients, 10 patients (45%) entered CAR-T with progressive disease and 4 patients (18%) had stable disease. In patients not having progression post CAR-T therapy (27 of 49 patients), 4 patients (15%) had PD entering LD and CAR-T infusion.
Of the patients who successfully received CAR-T, 34 of 49 pts required bridging therapy (69%). Bridging therapy was initiated by the treating physician for reducing tumor burden or palliation of lymphoma symptoms while awaiting CAR-T infusion. Therapies most commonly received were combination chemoimmunotherapy (21%), obinutuzumab (15%), radiation (15%), ibrutinib (15%), systemic therapy + radiation therapy (12), lenalidomide (6%), cyclophosphamide (3%), and rituximab/lenalidomide (3%). For patients receiving targeted agents, one of 8 patients (13%) had progressive disease (PD) at the time of CAR-T infusion. Two of 9 patients (22%) receiving immunotherapy had PD at the time of CAR-T infusion. In the chemoimmunotherapy group, 3 of 12 patients (25%) had PD at the time of CAR-T infusion. Five patients received only radiation as bridging and 1 had PD at time of CAR-T infusion.
Conclusion: Our single-institution experience with CAR-T noted that most patients required bridging therapy prior to CAR-T infusion but no single bridging therapy was identified as preferable. Rapid disease progression through bridging entering into CAR-T therapy may predict for a lack of response. Further analysis is ongoing for other factors. Of note, systemic therapy was tailored to patients by treating physician with a trend toward more targeted therapy, with radiation providing site specific disease control. Further study is warranted to determine optimal bridging as well as the utility of response assessment immediately prior to the time of T-cell reinfusion.

Disclosures
Dwivedy Nasta: Merck: Consultancy, Other: data safety monitorin; Roche: Research Funding; Rafael: Research Funding; Millenium/takeda: Research Funding; Debiopharm: Research Funding; Aileron: Research Funding; ATARA: Research Funding; Pharmacyclics: Research Funding; Celgene: Honoraria; 47 (Forty Seven): Research Funding. Hughes:Genzyme: Membership on an entity's Board of Directors or advisory committees; Acerta Pharna/HOPA: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees. Landsburg:Seattle Genetics: Speakers Bureau; Seattle Genetics: Speakers Bureau; Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Triphase: Research Funding; Triphase: Research Funding. Chong:Novartis: Consultancy; Merck: Research Funding; Tessa: Consultancy. Barta:Celgene: Research Funding; Bayer: Consultancy, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Mundipharma: Honoraria; Seattle Genetics: Honoraria, Research Funding; Takeda: Research Funding; Mundipharma: Honoraria. Frey:Novartis: Research Funding. Gerson:Abbvie: Consultancy; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy. Porter:Immunovative: Membership on an entity's Board of Directors or advisory committees; Glenmark Pharm: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Wiley and Sons: Honoraria; Genentech: Employment; American Board of Internal Medicine: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees. Ruella:AbClon: Membership on an entity's Board of Directors or advisory committees; Nanostring: Consultancy, Speakers Bureau; Novartis: Patents & Royalties: CART for cancer. Svoboda:AstraZeneca: Consultancy; Celgene: Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding; Kyowa: Consultancy; Merck: Research Funding; BMS: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding. Schuster:Novartis: Other: a patent (with royalties paid to Novartis) on combination therapies of CAR and PD-1 inhibitors.; Nordic Nanovector, Pfizer, AstraZeneca, Loxo Oncology, Acerta, and Celgene: Honoraria; Novartis, Celgene, Genentech, Merck, Pharmacyclics, Acerta, and Gilead: Other: Grants, Research Funding; Novartis, Nordic Nanovector, and Pfizer: Membership on an entity's Board of Directors or advisory committees.