Real-World Axicabtagene Ciloleucel Shows Consistent Efficacy, Safety in R/R LBCL

A retrospective analysis of real-world data confirmed the efficacy of axi-cel in relapsed/refractory large B-cell lymphoma, with outcomes comparable to the ZUMA-7 trial.

Results shared at the 2025 EHA Congress showed that axicabtagene ciloleucel (axi-cel; Yescarta) demonstrated consistent outcomes in real-world patients with relapsed/refractory large B-cell lymphoma (LBCL), largely aligning with results from the phase 3 ZUMA-7 trial (NCT03391466), regardless of patient comorbidities, age, and performance status.1

Among 454 evaluable patients in the real-world study, the overall response (ORR) was 79%, including a complete response (CR) rate of 64% and partial response (PR) rate of 15%. Conversely, the ORR was 83% in ZUMA-7, including a CR rate of 65%.1,2 The 1-year duration of response (DOR) rate was 66% (95% CI, 61%-71%) in the real-world setting vs 60% in ZUMA-7, Dasom (Caroline) Lee, MD, a fellow in the Division of Hematology at Stanford University in Palo Alto, California, stated in a presentation of the data. Time to response (TTR) and time to CR (TTCR) at 3 months were 60% (95% CI, 56%-65%) and 45% (95% CI, 40%-49%), respectively; at 6 months, these rose to 79% (95% CI, 75%-82%) and 61% (95% CI, 56%-65%).1 Landmark CR rates at 3 and 6 months post-infusion were 45% (95% CI, 40%-50%) and 61% (95% CI, 56%-66%), respectively.

At a median follow-up of 12.4 months, 1-year event-free survival (EFS) and overall survival (OS) rates were 54% (95% CI, 49%-59%) and 74% (95% CI, 69%-78%), respectively. These rates were comparable to EFS (49%) and OS (75%) rates in ZUMA-7, Lee noted.1 The cumulative incidence of relapse or progressive disease at 1 year was 41% (95% CI, 36%-45%).

“This is the largest national study investigating the safety and effectiveness of axi-cel in the second-line setting,” Lee explained in the presentation. “At a median follow-up of 12 months, outcomes were consistent with the ZUMA-7 trial, [despite the fact that] nearly half of the patients [in this analysis] did not meet the eligibility criteria for ZUMA-7.”

Multivariable logistic and Cox regression analyses were also performed to identify patient-level predictors of safety and efficacy. Univariate analysis of subgroup covariance on the effectiveness outcomes showed that the presence of cardiac comorbidities and a KPS of 70 or less was associated with shorter OS. In patients with (n = 48) vs without (n = 413) cardiac comorbidities, the 1-year OS rates were 55% (95% CI, 38-69) and 76% (95% CI, 71%-80%) Among those with a KPS of 70 or less (n = 89), the OS rate was 61% (95% CI, 50%-71%); conversely, the OS rates for those with a KPS of 80 (n = 149) and 90 to 100 (n = 189) were 67% (95% CI, 59%-74%) and 83% (95% CI, 76%-88%).

Multivariable logistics and Cox regression analysis were also performed and similarly found that patients with cardiac comorbidity had shorter OS (HR, 1.70; 95% CI, 1.03-2.80). Shorter OS was also observed in patients aged 65 or higher (HR, 1.58; 95% CI, 1.10-2.27) and 75 years or older (HR, 1.70; 95% CI, 1.02-2.81) compared with those 65 years of age or younger. No significant associations were found between hepatic, pulmonary, or infection comorbidities and the effectiveness of axi-cel.

“We used multivariable logistic and Cox regression statistics to identify which patient-related factors were associated with safety and effectiveness and found no association between age and response rates or EFS, although [patients] aged 65 or higher had increased risk of…immune effector cell–associated neurotoxicity syndrome [ICANS] and shorter OS,” Lee added.

Study Design and Baseline Characteristics

This retrospective study collected patient-level observational data from the CIMBTR registry. From this national database, the study population comprised adult patients with LBCL who received commercial second-line axi-cel between April 2022 and July 2023 across 89 U.S. centers.

Efficacy outcomes of interest encompassed ORR, CR rate, DOR, EFS, and OS. Key safety outcomes, including cytokine release syndrome (CRS), ICANS, prolonged cytopenias, second primary malignancies, causes of death, and non-relapse mortality, were also assessed.

The baseline characteristics of 461 patients included in the study show that overall disease characteristics, including LDH levels and refractory disease, were consistent with those in the ZUMA-7 trial, Lee continued. In the real-world study, key subgroups were defined by age, performance status, and comorbidities. Notably, 46% of patients were aged 65 years or older, compared with 28% in ZUMA-7. Most patients had an ECOG performance status (PS) of 0 or 1 (97%). Karnofsky Performance Status (KPS) scores were distributed as follows: 44% had scores of 90 to 100, 35% had scores of 80, and 21% had scores of 70 or less.

Clinically significant comorbidities were present in 71% of patients. Hepatic comorbidities (9%) included mild chronic hepatitis or moderate/severe liver cirrhosis. Cardiac comorbidities (10%) comprised coronary artery disease, congestive heart failure, myocardial infarction, and/or an ejection fraction of 50% or less. Other clinically significant comorbidities included arrhythmia (9%), moderate/severe pulmonary disease (20%), infection (4%), and moderate/severe renal disease (1%).

Given the short follow-up period, descriptive statistics were used to summarize baseline characteristics, clinical outcomes, and key subgroups, according to Lee. Notably, KPS and arrhythmia were excluded from multivariable logistic and Cox regression analyses due to high collinearity with other variables, and patients with an ECOG PS of 2 or greater or renal disease were excluded due to small sample sizes.

Safety Outcomes and Analyses

The incidence of any-grade CRS was 88% in the real-world study compared with 92% in ZUMA-7, while grade 3 or higher CRS occurred in 5% vs 6%, respectively.1,2 Any-grade ICANS occurred in 48% vs 60%, and grade 3 or greater ICANS occurred in 23% vs 21%, respectively. The onset and duration of CRS and ICANS were comparable between studies. Real-world CRS and ICANS events resolved in 98% and 91% of patients, respectively.1 Most patients received tocilizumab (Actemra; 70%), corticosteroids (68%), or anakinra (Kineret; 16%) as treatment for CRS and/or ICANS.

Prolonged neutropenia and thrombocytopenia within 30 days post-infusion were assessed; however, comparison with ZUMA-7 was limited due to the trial’s differing assessment timeline of 30 days or beyond.1,2 In the real-world study, 6% of patients experienced prolonged neutropenia, defined as failure to recover absolute neutrophil count of 500/mm³ or greater with 3 consecutive normal laboratory values, and 11% had prolonged thrombocytopenia, defined as failure to recover platelet count of 20,000/mm³ or greater.1 At 12-month median follow-up, 3% developed second primary malignancies, with no T-cell malignancies reported.

Death occurred in 27% of patients. Among patients who died during follow-up, the most common causes of death were primary disease (20%), followed by infection (2%), organ failure (2%), malignancy (1%), and neurotoxicity (1%). The cumulative incidence of non-relapse mortality at 1 year was 5% (95% CI, 3%-7%).

Univariate analysis showed that age at infusion was associated with the risk of developing any-grade ICANS. In patients aged 65 years or older at infusion, the incidence of any-grade ICANS was 58% (95% CI, 51%-65%); conversely, 39% of patients younger than 65 years had ICANS (95% CI, 33%-45%). No other covariates showed significant associations.

Multivariable logistic and Cox regression analyses confirmed that an age of 65 years or older was associated with higher risk of both any-grade ICANS (odds ratio [OR], 2.25; 95% CI, 1.51-3.36) and grade 3 or higher ICANS (OR, 1.69; 95% CI, 1.07-2.67). Additionally, infection-related comorbidities were linked to an increased risk of prolonged neutropenia (HR, 4.38; 95% CI, 1.13-17.00). No other comorbid conditions were significantly associated with safety outcomes.

“Further multicenter, real-world studies are needed to validate this association,” Lee concluded. “Such efforts are crucial, as risk stratification in patients receiving second-line axi-cel enables personalized approaches to improve safety and effectiveness in this [patient] population.”

References

1. Lee D, Kambhampati S, Bobillo M, et al. Real-world effectiveness and safety outcomes among key subgroups of second-line (1L) axicabtagene ciloleucel (axi-cel) for patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Presented at: European Hematology Association Congress; June 12-15, 2025; Milan, Italy. Abstract S237.
2. Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. 2022;386(7):640-654. doi:10.1056/NEJMoa2116133