Association of Bridging Therapy Utilization with Clinical Outcomes in Patients Receiving Chimeric Antigen Receptor (CAR) T-Cell Therapy
Authors: Johnson P. Connor , Jacobson Caron , Yi Alisha , El-Jawahri Areej , Frigault Matthew J. 
Published: November 2021

Abstract
Background: CAR T-cell therapy has altered the landscape of treatment options for patients with hematologic malignancies. Because CAR T-cell therapy involves manufacturing an autologous cellular product over a period of weeks, patients can receive bridging therapy while awaiting CAR T-cells. Currently there is no standard of care for use of bridging therapy. Moreover, data are lacking regarding the impact of bridging therapy use on clinical outcomes.
Methods: We conducted a retrospective analysis of 236 patients who received CAR-T cell therapy at two tertiary care centers from 2/2016-12/2019. We abstracted clinical outcomes from review of the Electronic Health Record (EHR) including 1) overall response rate (ORR); 2) complete response (CR) rate; 3) progression-free survival (PFS); 4) overall survival (OS); 5) health care utilization (length of stay [LOS], intensive care unit [ICU] admission during admission for CAR T-cell therapy, and hospital readmission within 3 months of CAR T-cell infusion); and 6) rates of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) [all grades and grade 3+]. We assessed the association of bridging therapy use with ORR, CR rate, rates of ICU admission and hospital readmission, and rates of CRS (any grade) and ICANS (any grade and grade 3+) using the chi square test. We assessed the association of bridging therapy use with LOS using the Wilcoxon-Mann-Whitney test given the distribution of LOS and with grade 3+ CRS using Fisher's Exact Test given the sample size of this outcome. To assess the association of bridging therapy use with PFS and OS, we used Cox multivariable regression analyses adjusting for age, sex, marital status, Charlson comorbidity index, lymphoma diagnosis, number of prior therapies, history of autologous stem cell transplant, time from relapse to CAR T-cell therapy, vein to vein time, Eastern Cooperative Oncology Group performance status (closest to day 0), LDH (&gt; 500 vs &lt;=500), CRP, ferritin, and platelet count (&lt; 100 vs &gt;=100) prior to CAR T-cell infusion, CAR T-cell product, total dose of steroids received (days 0-31), and receipt of tocilizumab.
Results: Patients had a median age of 62.8 years (range: 19-82) and the majority were male (145/236, 61.4%). The most common diagnosis was de novo diffuse large B cell lymphoma (DLBCL) (101/236, 42.8%) and most patients received axicabtagene ciloleucel (axi-cel) (192/236, 81.4%). All patients received lymphodepletion with cyclophosphamide and fludarabine. Overall, 39.4% (93/236) received bridging therapy. Regimens utilized for bridging therapy included systemic chemotherapy (48/236, 20.3%), corticosteroids (25/236, 10.6%), radiation (10/236, 4.2%), and other systemic therapies (10/236, 4.2%). Among the entire cohort, ORR and CR rate were 85.2% (201/236) and 64.8% (153/236), respectively, and bridging therapy use was not associated with ORR (80.0% with bridging therapy vs. 88.8% without bridging therapy; χ 2=3.81; p=0.051) or CR rate (63.4% with bridging therapy vs. 65.7% without bridging therapy; χ 2=0.13; p=0.718). In univariate Cox regression analyses, bridging therapy was associated with worse PFS (HR=1.47; p=0.049) and worse OS (HR=1.85; p=0.006). In multivariable Cox regression models adjusting for covariates (Tables 1 and 2), bridging therapy use was not associated with PFS (HR=1.43; p=0.163) but was associated with worse OS (HR=2.23; p=0.006). Bridging therapy use was not associated with LOS (p=0.451), ICU admission (χ 2=0.22; p=0.638), hospital readmission (χ 2=0.95; p=0.329), CRS (all grades: χ 2=0.46; p=0.500; grades 3+: p=0.574), or ICANS (all grades: χ 2=0.13; p=0.719; grades 3+: χ 2=0.23; p=0.632).
Conclusions: We identified that bridging therapy use is not associated with differences in response rates, PFS, health care utilization, or rates of CRS or ICANS but is associated with worse OS in patients receiving CAR T-cell therapy. These findings underscore the need for novel bridging therapy regimens to optimize outcomes in this patient population.
Figure 1 Figure 1.

Disclosures
Jacobson: Celgene: Consultancy, Honoraria, Other: Travel support; Axis: Speakers Bureau; Humanigen: Consultancy, Honoraria, Other: Travel support; Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support; AbbVie: Consultancy, Honoraria; Nkarta: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; Lonza: Consultancy, Honoraria, Other: Travel support; Precision Biosciences: Consultancy, Honoraria, Other: Travel support; Clinical Care Options: Speakers Bureau. Frigault: Novartis: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Arcellx: Consultancy; Iovance: Consultancy; Takeda: Consultancy; Editas: Consultancy; BMS: Consultancy.