Bendamustine Is an Effective Alternative to Fludarabine-Based Lymphodepletion in LBCL
In the wake of fludarabine shortages, lemphodepletion with bendamustine was found to be an effective alternative compared for patients with large B-cell lymphoma being treated with a CD19-directed CAR T-cell therapy.
Alaa Ali, MD
Lymphodepletion with bendamustine brought about similar efficacy findings with fewer adverse events (AEs) compared with fludarabine/cyclophosphamide for patients with large B-cell lymphoma (LBCL) being treated with a CD19-directed CAR T-cell therapy, according findings from 5256 patients enrolled in a real-world study presented at the 66th American Society of Hematology (ASH) Annual Meeting, held December 7-10, 2024, in San Diego, California.
In the study, patients received either axicabtagene ciloleucel (axi-cel; Yescarta), tisagenlecleucel (tisa-cel; Kymriah), or lisocabtagene maraleucel (liso-cel; Breyanzi). The objective response rate (ORR) was higher with the fludarabine-based therapy; however, complete response (CR) rates were not significantly different between the groups. Findings were also similar for progression-free survival (PFS) and overall survival (OS). Common AEs associated with CAR T-cell therapies were less common, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and prolonged cytopenias.
"Bendamustine may be a viable lymphodepletion option for patients at high risk of toxicity; however, longer follow-up is needed to confirm its impact on survival outcomes," lead investigator Alaa Ali, MD, from the Lombardi Comprehensive Cancer Center, Georgetown University, said during a presentation of the results. "There are efficacy trade-offs, as bendamustine shows a lower ORR but maintains similar PFS and OS compared with fludarabine-based lymphodepletion in diffuse large B-cell lymphoma treated with CD19 CAR T cells."
The study was commenced in 2017 and ran through 2023; however, limited data on alternative lymphodepletion regimens were available until 2022, when a nationwide shortage of fludarabine. An additional subset analysis was added seeking to add data on bendamustine with enrollment taking place in 2021-2023.
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Across the main analysis, most patients received a fludarabine/cyclophosphamide regimen (n = 4809) compared with bendamustine (n = 447). The median age of patients was similar in each group. There were differences seen in KPS, with 19.9% having a KPS of less than 80 in the fludarabine-containing group compared with 26.2% of those in the bendamustine arm. Moreover, more patients in the bendamustine arm had a complete response at the time of infusion compared with fludarabine (10.3% vs 4.8%). Additionally, more patients in the fludarabine arm had received 3 or more prior therapies (62.9% vs 51.0%). Those in the bendamustine arm were more likely to have an elevated LDH prior to infusion (33.6% vs 21.2%).
The ORR in those treated with fludarabine lymphodepletion was 55.5% at 100 days compared with 44.5% with bendamustine (P <.01). At day 180, the ORR was 61.2% with fludarabine-based therapy compared with 50.8% for bendamustine (P <.01). The 12-month PFS rate was 45.4% with fludarabine and 39.1% with bendamustine, which was not statistically significant (P = .03). The 12-month OS rate was 62.2% with fludarabine and 61.0% with bendamustine, which was also not statistically significantly different (P = .655).
Outside of the lymphodepletion therapy, other factors were seen to be correlated with PFS and OS, namely KPS, disease status, bridging therapy, and type of treatment received. These factors, including age, were also associated with response rates.
Overall, the risk of experiencing CRS was halved by bendamustine vs fludarabine (odds ratio [OR], 0.45; 95% CI, 0.3-0.6). Additionally, the odds of developing ICANS was also half with bendamustine lymphodepletion vs fludarabine (OR, 0.43; 95% CI, 0.4-0.5). Prolonged cytopenias were also cut in half with bendamustine vs fludarabine (OR, 0.48; 95% CI, 0.4-0.6). Other factors were found to be associated with risk, with axi-cel found to be more likely to cause CRS, ICANS, and prolonged cytopenias compared with the other agents. Liso-cel was also found to cause fewer of these AEs.
"Bendamustine is associated with fewer severe cases of CRS, ICANS, and prolonged cytopenias, offering a potentially safer alternative for select patients," said Ali.
In general, the subset analysis conducted between 2021 and 2023 did contain a higher proportion of bendamustine treated patients, with 364 in the fludarabine group and 2571 in the bendamustine arm; however, the findings from this group were similar with the main analysis. The ORR with bendamustine remained inferior whereas CRS, ICANS, and cytopenias were less. The OS and PFS were not different.
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