ICML 2025 | Selecting between bendamustine and FluCy for lymphodepletion prior to axi-cel treatment in R/R LBCL

Absolutely. So at ICML Lugano 2025, we’re presenting a study that is actually a follow-up work on a presentation that we shared at ASH 2024. That earlier study was the first large real-world analysis comparing Bendamustine to the more traditional Fludarabine cyclophosphamide, or FluCy as a lymphodepleting chemotherapy regimen prior to CD19 targeting CAR T-cell therapy in relapsed/refractory large B cell lymphoma. And we used data from the CIBMTR registry and looked at over 5,200 patients treated with Axi-cel, Tisa-cel, and Liso-cel between 2017 and 2023. And what we found in that study was interesting. 

So while Bendamustine was associated with lower overall response rate, it actually showed a better safety profile and importantly, did not compromise progression-free or overall survival. Now, in this follow-up study, we’re drilling down specifically on Axi-cel. And so we looked at patients treated with commercial Axi-cel between January 2022 and July 2023 and compared outcomes based on whether they got Bendamustine or FluCy for lymphodepletion. We applied propensity score weighting as well as multivariate analysis to adjust for baseline differences and isolate the impact of lymphodepletion. And we ended up with over 650 Axi-cel patients of whom about 20% received Bendamustine, and again, Bendamustine showed a clear reduction in toxicity. We saw lower rates of CRS and ICANS overall, including fewer cases of grade 3 or higher neurotoxicity. Thrombocytopenia was also less frequent and we also saw less frequent use of tocilizumab and steroids in the Bendamustine group compared to the fludarabine-cyclophosphamide group, which again indicates that the toxicity with Bendamustine was generally milder. Now, in terms of efficacy, there was definitely a trade-off. The CR rate and progression-free survival were modestly lower with Bendamustine, but overall survival was comparable between the two groups. 

So how does this compare to other regimens? So I think fludarabine-cyclophosphamide is still the standard, and it’s backed by the strongest efficacy data. That said, during the fludarabine shortage in 2022 and 2023, a lot of centers switched to Bendamustine. And this study really helps contextualize that real-world experience. So compared to fludarabine-based regimens, Bendamustine appears to offer a better safety profile but at a modest cost to efficacy. All other regimens or combinations have not been studied as robustly. So in my opinion, Bendamustine stands out as the most well-studied and practical alternative when fludarabine is not available or when you are prioritizing less toxicity. 

And I can go in a little more detail with that. So there were some notable differences between the two groups. So after adjusting with propensity score weighting and multivariate modeling, we found that Bendamustine was associated with less toxicity overall. For example, any grade CRS was lower with Bendamustine compared to fludarabine-cyclophosphamide, 76% versus 86%. Any grade ICANS was also lower in the Bendamustine group, 31% versus 49%, and grade 3 or higher ICANS was also lower in the Bendamustine group 12% versus 25%. So these differences were statistically significant for any grade CRS, any grade ICANS and grade 3 or higher neurotoxicity. Now we also saw less frequent use of tocilizumab and steroids which again is consistent with milder toxicity profile with Bendamustine. Another interesting observation was that the toxicity appeared to occur a bit later with Bendamustine. For example, the median time to CRS onset was five days with Bendamustine compared to four days with fludarabine-cyclophosphamide. And the median time to ICANS onset was also longer with Bendamustine, eight days versus six days. So these findings in general support the conclusion that Bendamustine may offer a more favorable safety profile. 

So based on what we’ve seen so far with these studies comparing Bendamustine and fludarabine-cyclophosphamide, I think Bendamustine may not replace FluCy across the board, but it’s definitely a viable alternative in select patients. It’s especially helpful during drug shortages or in patients where toxicity is a big concern, like those who are older or have cardiac, pulmonary, or renal comorbidities. It may also facilitate the outpatient administration of CAR T-cell therapies, which is a big deal in terms of access, quality of life, and economic and financial burden. Now, of course, there’s a balance to strike here, and you’re giving up a bit in terms of CR and progression-free survival, so patient selection really matters. This is not a one-size-fits-all kind of approach, but rather another tool in our toolbox to help us individualize care for those patients. And we hope that this work can help guide clinicians and decision-making during drug shortages or for patients who are high risk and maybe even spark more attention to lymphodepletion as a modifiable integral part or component of CAR T-cell therapy, something that deserves more focus, both for reducing toxicity and potentially perhaps even improving efficacy. I think this study also underscores the critical role of registry data in generating real-world evidence, especially in areas where prospective or randomized trials are lacking or simply not feasible due to logistical or ethical constraints. And those large-scale registries like the CIBMTR allows us to answer important clinical questions using real world patients.

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