A retrospective multicentre study has revealed that prior bendamustine treatment significantly increases the risk of manufacturing failures in chimeric antigen receptor (CAR) T-cell therapy for patients with large B-cell lymphoma (LBCL).
The research, which examined 981 LBCL patients approved for CAR T-cell therapy, found that 38 patients (3.87%) experienced manufacturing failures (MF) – situations where the manufacturing process failed to yield a product or resulted in one that was out-of-specification (OOS).
Manufacturing Failures and Patient Outcomes
Among the 38 patients with manufacturing failures, 11 received delayed infusion with an in-specification product following 21 remanufacturing attempts. Thirteen patients received an out-of-specification product, while 14 patients did not receive any infusion. The study included 38 LBCL controls without manufacturing failures for comparison, of whom 29 received infusion.
Dr. Benjamin Derman, hematologist at the University of Chicago Medicine, who was not involved in the study, commented: "These findings provide valuable real-world data on CAR T-cell manufacturing challenges that weren't fully captured in the pivotal trials."
Bendamustine Identified as Key Risk Factor
Prior bendamustine treatment emerged as the only baseline variable significantly associated with manufacturing failure risk. This association was particularly strong when bendamustine therapy occurred within six months prior to CAR T-cell manufacturing, affecting 23.7% of the manufacturing failure group compared to 0% in the control group (P = 0.0029).
"The clear association with recent bendamustine exposure provides important guidance for clinicians planning treatment sequences for patients who may be candidates for CAR T-cell therapy in the future," said Dr. Derman.
Comparable Survival Outcomes
Encouragingly, overall survival (OS) and progression-free survival (PFS) were not significantly different between patients who received out-of-specification products and those who received standard products.
The one-year overall survival rates were:
- 52.8% for OOS-infused patients
- 46.8% for delayed-infused patients
- 68.4% for controls-infused patients
Similarly, one-year progression-free survival rates were:
- 46.2% for OOS-infused patients
- 24.2% for delayed-infused patients
- 41.4% for controls-infused patients
Statistical analysis showed no significant differences in PFS between groups (PFS HR OOS-infused vs controls-infused 1.41, P = 0.40; delayed-infused vs controls-infused 1.64, P = 0.25; and OOS-infused vs delayed-infused 0.86, P = 0.76).
Safety Profile Remains Consistent
The study also found that cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and cytopenias were not significantly different between the cohorts, suggesting that out-of-specification products maintain a similar safety profile to standard products.
Manufacturing Failure Rates in Context
The 3.87% manufacturing failure rate observed in this real-world study falls within the range reported in pivotal clinical trials, where manufacturing failures have been reported in 4-10% of anti-CD19 CAR T-cell products. By comparison, anti-BCMA CAR T-cell products used in multiple myeloma have shown lower failure rates of 0-1% in clinical trials.
Implications for Clinical Practice
The findings suggest that clinicians should carefully consider the timing of bendamustine therapy in patients who may be candidates for CAR T-cell therapy in the future. Additionally, the study provides reassurance that out-of-specification products can still provide clinical benefit.
"Outcomes for OOS-infused LBCL patients following manufacturing failure are encouraging," the researchers noted. "Remanufacturing led to infusion of a product in-specification in around 50% and may be an option for patients where a suitable OOS product is not available."
Future Directions
As CAR T-cell therapy continues to evolve, manufacturing processes are likely to improve, potentially reducing failure rates. The researchers suggest that further studies are needed to optimize manufacturing protocols, particularly for patients with prior bendamustine exposure.
The study highlights the importance of continued refinement in CAR T-cell manufacturing processes and provides valuable insights for clinicians managing patients with relapsed/refractory large B-cell lymphoma.
