Clinical Factors Associated with Failure to Manufacture Commercial CAR-T Cell Products Among LBCL Patients

Background Chimeric antigen receptor T-cell (CAR-T) therapy has demonstrated impressive responses for relapsed/refractory (RR) large B-cell lymphoma (LBCL) patients (pts). In the pivotal Zuma-1 (Neelapu NEJM 2017), Transform (Abramson Lancet 2020) and Juliet (Schuster NEJM 2019) studies, less than 1% of eligible pts experienced manufacturing failure. However, factors associated with CART manufacturing failure have not been examined outside of clinical trials. We aimed to find pt- and disease-specific variables associated with failure to manufacture a commercial CART product for LBCL pts. Methods Pts with RR LBCL who underwent apheresis for a CAR-T product between 12/2017 and 2/2023 were included. The study was approved by the Institutional Review Board. Manufacture failure (MF) defined as failure to produce an infusible product that either met commercial specifications or enrollment on an expanded access protocol (EAP) while manufacture group (MG) defined as product meeting FDA specification on any apheresis or out-of-specification products infused on EAP. Baseline characteristics and clinical data were collected at time of apheresis. The Chi-square test or Fisher's exact test used for comparison of two categorical variables. Statistical software SAS 9.4 (SAS, Cary, NC) and S-Plus 8.2 (TIBCO Software Inc., Palo Alto, CA) were used. Results 283 pts were included. Baseline characteristics are shown in Table 1. All 15 (4.3%) patients who experienced a CART MF (Axicabtagene ciloleucel: 11/261 (4.2%), Tisagenlecleucel 3/31 (9.3%), Lisocabtagene maraleucel 1/52 (1.9%)), died without receiving a CAR T product. Seven (46.7%) pts died of disease progression, 2 (13.3%) organ failure, 1 (6.7%) infection. For 5 pts (33.3%) cause of death was unspecified. Comparison of clinical variables demonstrated in Table 2. Factors associated with MF, compared to MG, were: LDH (289.5, 638, P=0.002), CRP (14.12, 144.8,P=0.0026), ferritin (726,15980, P=0.0175), ALC (0.61,0.27, P=0.0311), AMC (0.52,0.26, P=0.0117), HGB (10.3, 8,7, P=0.0034), and PLT (139, 57, P=0.0064). Pts in MF group were more likely to have a poor ECOG PS ≥ 2 compared to MG (73.3% vs 18.7% p=<.0001). Conclusions Factors at apheresis predictive of manufacturing failure include poor PS, elevated LDH, CRP, ferritin and reduced ALC, AMC, HGB and PLT counts. Further studies are needed to better prospectively identify factors contributing to MF and stratify pts who may benefit from alternative treatment strategies.