RWD Reveal Efficacy Trade-Offs Between Two CAR T-Cell Lymphodepletion Agents for Advanced DLBCL

Among patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) treated with CD19 chimeric antigen receptor (CAR) T-cell therapy, bendamustine as a lymphodepleting agent resulted in a lower objective response rate (ORR) but demonstrated similar progression-free and overall survival (OS) outcomes versus fludarabine lymphodepletion.

Results come from a presentation of real-world findings at the 66th American Society of Hematology (ASH) Annual Meeting by Alaa Ali, MD, MSc, of Medstar Health and Georgetown University School of Medicine.

The endpoints explored in the study were ORR, progression-free survival (PFS), OS, and safety. The study also explored factors that affect treatment outcomes by lymphodepleting regimens. Patients were stratified by age and risk factors including hematopoietic stem cell transplantation (HSCT)–specific comorbidity, Karnofsky performance score (KPS), disease status, bridging therapy, and CAR T-cell product received.

Of all patients assessed, 4,809 (92.4%) received fludarabine and 447 (8.5%) received bendamustine. Patients in the fludarabine group had a median age of 64.3 years (range, 18.0–91.2 years), and those in the bendamustine group had a median age of 65.3 years (range, 20.4–86.4 years). A KPS of lower than 80 was seen in 19.9% of the fludarabine group and 26.2% of the bendamustine group. Most patients in each group had an HSCT-CI score of 3+ and refractory disease.

Of the patients given fludarabine, 65.0% presented with elevated lactate dehydrogenase before infusion, as did 55.5% of those given bendamustine. In terms of prior treatment, 62.9% of the fludarabine group had three or more prior lines of therapy, as did 51.0% of the bendamustine group. Axicabtagene ciloleucel (axi-cel) was the most common bridging therapy and was received by 70.0% of the fludarabine group and 52.1% of the bendamustine group. Other patients received either tisagenlecleucel (tisa-cel) or lisocabtagene maraleucel (liso-cel).

At a median follow-up of 23.8 months (range, 0.5–66.9 months) in the fludarabine group and 9.8 months (range, 1.0–51.1 months) in the bendamustine group, the ORR at day 100 was 55.5% and 44.5% (P=.01), respectively. At day 180, the ORR was 61.2% and 50.8% (P =.01). The difference in ORR at both time points was deemed statistically significant.

“The multivariant analysis showed inferior response rate in the bendamustine group compared to the fludarabine group, with a hazard ratio of 0.7. Additionally, patients at the age of 65 or younger had lower rates of response, while higher rates of response were observed with axi-cel and liso-cel compared with tisa-cel,” explained Ali during his presentation.

Fludarabine-based lymphodepletion also performed better in terms of complete responses (CR), with a CR rate at day 100 of 39.6% versus 31.3% among patients treated with a bendamustine-based lymphodepletion (P<.01). At day 180, the CR rate was 45.1% and 37.4%, respectively (P <.01). The results were statistically significant.

Ali explained the CR results, stating, “the multivariant analysis showed a trend toward lower rates of complete response in the bendamustine group, but that difference does not reach a statistical significance. Patients at the age of 65 or younger, and those with lower performance status had lower rates of complete response, while higher rates of complete response were observed with axi-cel cell and liso-cel compared with tisa-cel.”

The probability of PFS and OS benefit at six months and 12 months was evaluated in the study. The PFS was significantly higher in the fludarabine group than in the bendamustine group (P=.030). Longer follow-up is needed to confirm the PFS findings due to a shorter duration of follow-up in the bendamustine group versus the fludarabine group. There was no significant difference between the two lymphodepletion groups in terms of OS (P=.655).

The multivariate analysis for PFS and OS showed that clinical characteristics, disease status, and use of bridging therapy were all associated with longer survival. Furthermore, use of axi-cel and liso-cel as bridging therapy extended PFS and OS compared with tis-cel.

Safety results show higher rates of cytokine release syndrome (CRS; 774% vs 61.1%) and severe CRS (7.7% vs 4.5%) with fludarabine versus bendamustine. The incidence of immune effector cell–associated neurotoxicity syndrome (ICANS) (44.2% vs 23%), severe ICANS (16.7% vs 8.3%), and prolonged cytopenia (20.5% vs 11.6) were also respectively higher with fludarabine-based versus bendamustine-based lymphodepleting chemotherapy. Ali et al concluded that bendamustine is a safer alternative to fludarabine for lymphodepletion.

Overall, the analysis shows that fludarabine-based lymphodepletion is more effective than bendamustine-based lymphodepletion, but more follow-up is needed to confirm the findings. Furthermore, bendamustine should be considered for patients who are at high risk of toxicity.

Reference

Ali A, Ahmed N, Kim S, et al. World comparison of efficacy and safety of fludarabine-versus bendamustine-based lymphodepleting chemotherapy for cd19 chimeric antigen receptor (CAR) T-cell therapy in relapse/refractory (r/r) large B-cell lymphoma (LBCL). Abstract #71. Presented at the 66th American Society of Hematology Annual Meeting & Exposition; December 7-10, 2024; San Diego, California.