Axi-Cel Plus Rituximab Yield Efficacy, Safety in Refractory Large B-Cell Lymphoma

Findings from the ZUMA-14 trial (NCT04002401) show that the combination therapy of axicabtagene ciloleucel (axi-cel; Yescarta) and rituximab (Rituxan) yielded efficacious results and favorable safety outcomes in patients with refractory large B-cell lymphoma (LBCL).¹

The combination therapy demonstrated high rates of deep and durable responses. The primary end point of the study, complete response (CR) rate, was 73% (n = 19/26). The overall response rate (ORR) was 88% (n = 23/26). At the data cut off, 46% of patients had an ongoing response. The median duration of response (DOR) was 26.0 months. The 24-month DOR rate was 54.5%. The median progression-free survival (PFS) was 23.6 months, and the 24-month PFS rate was 48.2%. The median overall survival (OS) was not reached. The OS rate was 72.9% at 24 months and 52.2% at 36 months. Seven participants (27%) converted from a partial response (PR) to a CR. All such conversions occurred 100 days or more after the axi-cel infusion.

Safety and Tolerability

The combination of axi-cel and rituximab was well-tolerated with no new safety signals identified. The safety profile was manageable and compared favorably to historical data from axi-cel monotherapy trials like ZUMA-1 (NCT02348216).²

All 26 patients (100%) experienced a treatment-emergent adverse event (AE), with 92% experiencing a grade ≥3 event. Two grade 5 AEs (acute myeloid leukemia) occurred.

Of the total patients, 96% had cytokine release syndrome (CRS). All AEs were low-grade, with 54% being grade 1 and 42% being grade 2. No AEs of grade ≥3 CRS were reported.

Additionally, 62% of patients experienced neurologic events. The majority of AEs were low-grade, with 15% of patients experiencing a grade ≥3 AE. The most common symptoms were confusional state and tremor.

B-cell aplasia was more pronounced through month 12 compared with ZUMA-1, as expected with the addition of rituximab. Despite prolonged aplasia, the rate of infections through month 12 was lower in ZUMA-14 (21.4%) than in the ZUMA-1 cohort 1 (42.9%). The incidence of grade ≥3 infections was 23%.

Study Overview and Rationale

The ZUMA-14 trial was an open-label, multicenter, single-arm phase 2 study designed to assess the preliminary safety and efficacy of combining axi-cel, a CD19-directed chimeric antigen receptor (CAR) T-cell therapy, with rituximab in adults with refractory LBCL.¹

Resistance to axi-cel can occur through antigen escape, where lymphoma cells lose the CD19 protein. CD19-negative relapse occurs in approximately 30% of responding patients. However, biopsies show that these relapsed tumor cells often retain expression of the CD20 antigen. The study hypothesized that a dual-targeting approach, using axi-cel for CD19 and rituximab for CD20, could minimize antigen-negative relapse and improve outcomes.

Participants received standard lymphodepleting chemotherapy followed by a single infusion of axi-cel. Rituximab was administered 5 days before axi-cel, on day 21 after, and then every 28 days for a total of 6 doses.

The primary end point was the investigator-assessed CR rate. Secondary end points included ORR, DOR, PFS, OS, and safety.

Patient Demographics

The study enrolled 27 patients, with 26 receiving the axi-cel infusion and at least 1 dose of rituximab, forming the modified intention-to-treat (mITT) and safety populations. The data cut-off was March 28, 2023, with a median follow-up of 25.1 months.

The median age of patients was 62.5 years (range, 38–82). Over half of patients (54%) had an ECOG performance score of 1. Of the total patients, 21 (81%) had disease stage III or IV. Most patients had a median of 2 prior therapies (73%).

Pharmacological Insights

Exploratory analyses provided insights into the biological activity of the combination therapy and identified potential biomarkers of response.

The expansion and persistence of axi-cel CAR T-cells were consistent with observations from the ZUMA-1 trial, indicating that rituximab did not negatively impact CAR T-cell kinetics.

Higher peak CAR T-cell levels (when normalized to tumor burden) and higher rituximab exposure were positively associated with achieving a CR and having an ongoing response.

Minimal residual disease (MRD), measured by circulating tumor DNA, was highly predictive of outcomes. MRD negativity on day 28 was strongly associated with achieving a CR. MRD positivity on day 28 had a positive predictive value of 87.5% for subsequent relapse or nonresponse. At month 5, this value was 100%.

Analysis of baseline tumor biopsies from 13 patients revealed that patients with an ongoing response had significant enrichment of gene signatures related to cytotoxicity and natural killer (NK) cell activity. Genes associated with NK cells (CD27, GZMA) were upregulated, suggesting a potential role for NK-cell–driven activity in enhancing treatment efficacy.

Analysis of the preinfusion axi-cel products showed that patients who achieved a CR had significantly higher frequencies of naive and central memory CAR T cells. In contrast, those who did not achieve a CR had higher frequencies of effector memory CAR T cells.

Future Directions

The combination of axi-cel and rituximab is a feasible, safe, and highly effective regimen for patients with refractory LBCL, producing deep and durable responses.

“Overall, results from ZUMA-14 support the continued optimization of dual CD19/CD20-targeting approaches, including bicistronic CD19/CD20-directed CAR constructs, for [patients] with chemorefractory aggressive [L]BCL,” concluded Strati P et al, authors of the study.

REFERENCES

1.Strati P, Leslie L, Shiraz P, et al. Axicabtagene ciloleucel in combination with rituximab for refractory large B cell lymphoma: the phase 2, single-arm ZUMA-14 trial. Nat Cancer (2026). doi: 10.1038/s43018-025-01102-1

2.Study evaluating the safety and efficacy of KTE-C19 in adult participants with refractory aggressive non-Hodgkin lymphoma (ZUMA-1). ClinicalTrials.gov. Updated June 4, 2024. Accessed January 13, 2026. https://clinicaltrials.gov/study/NCT02348216