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Bendamustine treatment before apheresis is known to reduce survival in large B-cell lymphoma (LBCL) patients receiving chimeric antigen receptor (CAR) T-cell therapy. Bendamustine has been shown to have a deleterious effect on CAR T-cell production due to a prolonged lymphotoxic effect. The of a combination of rituximab, polatuzumab, and bendamustine for relapsed/refractory LBCL has increased the number of potential patients exposed to bendamustine before CAR T-cell therapy.

advise avoiding bendamustine in CAR T-cell candidates, but additional questions regarding the optimal washout period before apheresis and the impact of cumulative bendamustine dose on CAR T-cell outcomes have remained unanswered.

Pere Barba, MD, PhD, of University Hospital Vall d'Hebron in Barcelona, Spain, and colleagues set out to comprehensively address the impact of bendamustine exposure before leukapheresis for CAR T-cell therapy in a standard-of-care cohort of patients with relapsed/refractory LBCL. The study was published in the .

The authors were not available for comment, and the answers here are from the text of the report.

What does the study add to the literature?

In this multicenter study, we identified that a recent exposure to bendamustine before apheresis has an independent deleterious effect on CAR T-cell efficacy. The study included CAR T-cell recipients from seven European sites. Safety, efficacy, and CAR T-cell expansion kinetics were analyzed according to pre-apheresis bendamustine exposure. Additional studies on the impact of the washout period and bendamustine dose were performed.

Patients who received CAR T-cell therapy and were recently exposed to bendamustine before apheresis had a shorter progression-free survival (PFS) and overall survival (OS) in comparison with the bendamustine-naive group.

The risk of cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome was similar between the two groups of patients. Hematologic toxicity and severe infections were more common in bendamustine-exposed patients.

The study included 439 patients with relapsed/refractory LBCL infused with CD19-targeted commercial CAR T cells; 80 patients had received bendamustine before apheresis. Exposed patients had significantly lower CD3-positive cells and platelets at apheresis. These patients had a lower overall response rate (ORR; 53% vs 72%), a shorter PFS (3.1 vs 6.2 months), and OS (10.3 vs 23.5 months) in comparison with the bendamustine-naive group. Following adjustment methods for baseline variables, these differences were mitigated.

Focusing on the impact of bendamustine washout before apheresis, the 42 patients with recent (less than 9 months) exposure displayed a lower ORR (40% vs 72%), shorter PFS (1.3 vs 6.2 months), and OS (4.6 vs 23.5 months) in comparison with bendamustine-naive patients.

These differences remained significant after inverse probability treatment weighting (IPTW) and propensity score matching (PSM) analysis. Conversely, the cumulative dose of bendamustine before apheresis did not affect CAR-T efficacy outcomes.

Are the findings consistent with other studies?

In our study, 9 months was the optimal washout before apheresis, similar to other published data analyzing the and in . Patients who received bendamustine within 9 months of apheresis had a shorter PFS and OS in comparison with bendamustine-naive patients.

Interestingly, the 12-month cutoff yielded similar results, signaling for a continuous treatment failure risk after exposure to this alkylating agent. However, the design of this study precludes establishing a definitive cutoff beyond which patients should not be considered for CAR T-cell manufacturing. Noteworthy, the total dose of bendamustine did not have an impact on survival outcomes.

Taken together, these results suggest that the deleterious effect of this agent on CAR T-cell efficacy would rely more on the recent exposure rather than on the dose. Our clinical observation is consistent with , reporting similar recovery kinetics irrespective of the number of cycles, suggesting that a low dose of this agent is sufficient to generate T-cell dysfunction.

What are the limitations of the study?

The main limitations of the study derived from its retrospective nature, which did not allow a perfect balance across all patient and disease characteristics between groups. The initial differences observed between bendamustine-exposed and bendamustine-naive patients were mitigated with the IPTW and PSM analyses; only patients with a recent exposure retained the shorter survival after the adjustment methods.

We did not collect data on all patients who underwent apheresis with the intention to manufacture a commercial CAR T-cell product, precluding an analysis of manufacturing failure risk in bendamustine-exposed patients. Also, circulating CAR T-cell data were assessed locally at each infusing site, without centralized review. However, to overcome this limitation and reduce potential interhospital variability, we analyzed the expansion results in a two-step process.

What is the bottom-line message to practicing oncologists?

On the basis of our results, bendamustine should be avoided before apheresis in potential CAR T-cell candidates. In patients already exposed to bendamustine, the decision to move forward with leukapheresis for CAR T-cell therapy should take into account the washout period from last bendamustine dose, other available treatment options, and their potential impact on T-cell fitness.

Read the study here.