Lymphodepletion with Fludarabine/Cyclophosphamide Shows Higher Complete Response Rates Compared to Bendamustine Prior to CAR-T Therapy
Authors: McKiever Mary , Pereiras Maribel , Lee Geeny , Donato Michele L. 
Published: December 2024

Background
Lymphodepletion (LD) prior to chimeric antigen receptor T-cell (CAR-T) infusion establishes a more favorable environment for CAR T-cell expansion and survival. The standard LD regimen consists of fludarabine (Flu) and cyclophosphamide (Cy). However, with the recent shortage of Flu, the preferred LD regimen was no longer a feasible option. Many cancer centers opted to postpone CAR-T therapies or utilize alternative LD regimens. Bendamustine (Benda) is a potential alternative LD regimen. Due to the limited number of studies assessing the impact of Benda for LD, gaps remain on its efficacy and safety. This study aimed to investigate the impact of Benda as an alternative LD regimen compared to standard LD with Flu/Cy on CAR-T therapy outcomes.
Methods
This was a single-center retrospective cohort study comparing outcomes between LD with Flu/Cy and Benda prior to infusion of commercially available CAR-T products (tisagenlecleucel, brexucabtagene autoleucel, axicabtagene ciloleucel, lisocabtagene maraleucel, ciltacabtagene autoleucel, idecabtagene vicleucel). Patients were excluded from analysis if they were a part of an investigational study, received out of specification CAR-T products, or received Benda for renal impairment. Cohort 1 included patients who received Flu/Cy LD from January 1, 2021 to April 30, 2022. Cohort 2 included patients who received Benda LD from May 1, 2022 to August 31, 2023. The primary outcome was complete response (CR) at 90 days after CAR-T cell infusion. Additional outcomes included CR at 30 days, Cytokine Release Syndrome (CRS), Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), cytopenias, and infections.
Results
There were 170 patients screened and 20 patients met exclusion criteria. Based on FDA approval time of ciltacabtagene autoleucel the effect of LD regimen could not be assessed and these patients were removed from the current analysis. A total of 128 patients were analyzed with 54 and 74 patients having received Flu/Cy and Benda, respectively.
Baseline characteristics between Flu/Cy and Benda were similar. There was no difference in median age (Flu/Cy 68 years vs Benda 69 years; p= 0.54). A majority of patients were male (Flu/Cy 57.4% vs Benda 55.4%; p= 0.54) and had an ECOG score of 1 (Flu/Cy 70.3% vs Benda 59.5%; p= 0.28). The most common indication was Diffuse large B-cell lymphoma (Flu/Cy 44.4% vs Benda 47.3%; p= 0.89).
At 90 days, 50 patients in the Flu/Cy cohort and 67 patients in the Benda cohort were able to be assessed for CR. CR at 90 days after CAR-T infusion was significantly higher with Flu/Cy compared to Benda (72% vs 41.8%; p=0.0022). CR at any time point (75% vs 43.1%; p=0.0008) and CR at 30 days (66.6% vs 30.8%; p=0.004) were higher with Flu/Cy compared to Benda. Subgroup analysis demonstrated a higher CR rate with Flu/Cy for Axicabtagene ciloleucel (85.7% vs 45.5%; p=0.0041). CR rates were similar for other products, however this may be limited due to their sample size. A difference was observed for CD19-targeting products with CR at 90 days higher with Flu/Cy compared to Benda (80.6% vs 50%; p=0.0052).
Occurrence of CRS was higher with Flu/Cy compared to Benda (83.3% vs 59.5%; p=0.0069). No differences were observed between grades of CRS with no patients in either cohort experiencing grade 4. Occurrence of ICANS was higher with Flu/Cy compared to Benda (31.5% vs 13.5%; p=0.025). No differences were observed between grades of ICANS. There was no difference in CRS or ICANS between Flu/Cy and Benda LD prior to Idecabtagene vicleucel. Occurrence of neutropenia was higher with Flu/Cy compared to Benda (100% vs 60.8%; &lt;0.0001). No significant difference in thrombocytopenia or infections were observed.
Conclusion
When compared to Benda, Flu/Cy demonstrated higher rates of CR at 90 days while also having higher rates of adverse events, including CRS and ICANS. Additional larger, prospective studies are needed to fully assess Benda's potential as an alternative LD regimen, especially in light of recent small retrospective studies indicating inferiority with Benda.