Be Cautious to Adopt a Second CAR T-Cell Infusion after Failure of CD19/CD22 Cocktail CAR T-Cell Therapy in Relapsed/Refractory B-NHL

Objective: Chimeric antigen receptor (CAR) T-cell infusion (CTI) has emerged as a breakthrough therapy for relapsed/refractory B-cell non-Hodgkin's lymphoma (R/R B-NHL) patients. Nevertheless, there are still a significant number of patients suffering treatment failure (failed to respond or eventually relapsed after a partial or complete response, PR/CR) post the first time CTI (CTI1). The issue how to salvage this group of patients should be urgently addressed. Our study aimed to provide clues for exploring the potentially effective salvage strategies and finally improving the prognosis of them by analyzing the efficacy and safety especially between the second time CTI (CTI2) and other different therapies (non-CTI2).

Methods: Herein,a retrospective analysis was performed on total 61 patients after failure of CD19/22 cocktail CTI1 (ChiCTR-OPN-16008526) between January 2017 and May 2022 in our hospital. Among them, 27 of 61 patients with a prior determination of no antigen loss received CTI2 for compassionate use. The other 34 patients were administrated as non-CTI2 therapies. The clinical characteristics, efficacy, safety, survival analysis and outcome-related risk factors were all evaluated.

Results: The CTI2 group achieved a higher overall response rate (ORR) at 30 days assessment (8/27 vs. 2/34, P=0.017). Nevertheless, the non-CTI2 group showed a better event-free survival (EFS) (P=0.007) (Figure1, left panel) and overall survival (OS) (P=0.048) (Figure1, middle panel) than the CTI2 group with a median follow-up of 6.7 months (range, 3-45.5) and 4.7 months (range, 1.1-53). Further analysis on copies of CAR transgene in peripheral blood at 90 days detection revealed that the better CAR T cells expansion was related to a better response in CTI2 group (P=0.012)(data not shown). Additionally, neither of the CTI2 and non-CTI2 was the independent risk factor of survival (HR: 1.665, 95%CI: 0.883-3.141, P=0.115). Either of Ann Arbor stage (HR: 1.970,9 5%CI: 1.944-3.997, P=0.029) or bulky disease (HR: 2.879, 95%CI: 1.321-6.276, P=0.008) at disease onset was the related independent risk factor instead. As shown in Figure1 right panel, the best responses to different salvage therapies suggested that the regimen (Polatuzumab vedotin,-pola, Bendamustine, Rituximab, pola+BR) was likely to be a potentially optimal non-CTI2 salvage therapy, even without statistically significant differences due to the limitation of the sample size. The adverse effects of CTI2 were generally similar to those of non-CTI2. Remarkably the infection-related mortality rate was significantly higher (59% vs. 21%, P=0.025) in CTI2 group.

Conclusion: Our study provides novel insights and clues that clinicians should be cautious to adopt a CTI2 after failure of the CD19/22 cocktail CTI1 in R/R B-NHL. It is noteworthy that the choice of pola+BR regimen probably has an advantage in salvage strategies. Large-scale prospective studies are warranted in the future.

No relevant conflicts of interest to declare.