Real-world analysis of axicabtagene ciloleucel (axi-cel) as consolidation therapy following first-line treatment in B-cell lymphoma with high-risk factors

Abstract

Abstract Background: Approximately 60% of patients with large B-cell lymphoma (LBCL) achieve cure with standard first-line (1L) therapies, such as R-CHOP or DA-EPOCH-R. However, 10% of patients remain refractory to 1L treatment, and 30% of responders experienced relapse within two years. Axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy, is approved for the treatment of patients with relapsed/refractory LBCL. Furthermore, ZUMA-12, a multicenter phase 2 study investigating axi-cel as part of 1L treatment of high-risk LBCL patients, demonstrated high and durable response rates. With a median follow-up of 40.9 months, axi-cel achieved an objective response rate (ORR) of 92%, complete response (CR) rate of 86%, with responses ongoing in 73% of response-evaluable patients. This study aims to explore the efficacy and safety of CAR-T as consolidation in 1L treatment responders with high risk of relapse. Methods: This real-world case series study enrolled patients with B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), who received axi-cel as consolidation therapy after achieving CR or partial response (PR) to 1L treatment. Efficacy endpoints included complete metabolic response (CMR), 18-month overall survival (OS) rate, and progression-free survival (PFS) rate. Safety endpoints comprised the incidence of adverse events (AEs) including cytokine release syndrome (CRS), leukopenia, thrombocytopenia, and abnormal liver function. Additionally, this study explored the impact of post-infusion maintenance therapy on CAR-T cell expansion. Results: A total of 5 patients were enrolled in this study, with a median age of 66 years and a male-to-female ratio of 3:2. The lymphoma subtypes included 2 cases of non germinal center B-cell-like DLBCL (DLBCL-non-GCB), 2 cases of germinal center B-cell-like DLBCL (DLBCL-GCB), and 1 case of MCL. DLBCL patients had at least one of the following high-risk factors: International Prognostic Index (IPI) score≥4 /age-adjusted IPI (aaIPI) ≥2, double expression, or Ki-67 >90%. High-risk features in the MCL patient included advanced age and Ki-67 >30%. All 4 DLBCL patients received R-CHOP or R-CHOP-like regimens as 1L therapy, while the MCL patient received bendamustine and rituximab (BR) as 1L therapy. Leukapheresis was performed prior to initiation of 1L chemotherapy in the MCL patient and 2 DLBCL patients, while the remaining two underwent leukapheresis after 3 and 4 cycles of chemotherapy, respectively. Before lymphodepletion, 2 patients had achieved CR and 3 achieved PR, and the median time from leukapheresis to infusion was 95 days. With a median follow-up of 21 months since infusion, the best CMR rate was 100 %, and all patients achieved CMR within one month after infusion. The 18-month OS and PFS rates were both 100%. The median peak CAR-T cell counts were 74.65 cells/μL, and the median CAR-T cell counts at 30 days post-infusion were 7.26 cells/μL. Following infusion, 3 patients received IL-2 monotherapy (n=1) or PD-1 inhibitor combined with IL-2 (n=2). At 6 months post-infusion, CAR-T cells were detectable in the peripheral blood of all 3 treated patients, whereas only one of the 2 patients who did not receive PD-1 inhibitor or IL-2 had detectable CAR-T cells. CRS of any grade occurred in 100% of patients (including 1 case of capillary leak syndrome), with no grade ≥3 CRS and no incidence of immune effector cell-associated neurotoxicity syndrome (ICANS). The median time from CAR-T cell infusion to the onset of CRS was 4 days, and the median time from CRS onset to resolution was 3 days. After infusion, the incidence rates of grade ≥3 leukopenia, grade ≥3 thrombocytopenia, and liver dysfunction were 60%, 20%, and 60%, respectively. Conclusions: Consolidation therapy with CAR-T following 1L treatment demonstrated encouraging rates of CMR, PFS, and OS in B-cell lymphoma patients with high risk of relapse. Administration of PD-1 inhibitors and/or IL-2 post-infusion may support sustained expansion and persistence of CAR-T cells. The safety profile was manageable: all CRS were mild, and no ICANS were observed, providing a valuable insight for CAR-T consolidation following 1L treatment. However, the small sample size of this study warrants validation in a larger cohort study.