Frontline Axi-Cel Elicits 74% CR Rate in High-Risk Large B-Cell Lymphoma

March 15, 2021
Kristi Rosa
Kristi Rosa

Managing Editor, OncLive®
Kristi Rosa joined MJH Life Sciences in 2016 and has since held several positions within the company. She helped launch the rapidly growing infectious disease news resource Contagion, strengthened the Rare Disease Report, of HCPLive, and now serves as the main digital news writer for OncLive. Prior to working at the company, she served as lead copywriter and marketing coordinator at The Strand Theater. Email:

Axicabtagene ciloleucel elicited a high objective response rate of 85%, with a complete response rate of 74% when used as a first-line therapy in patients with high-risk large B-cell lymphoma.

Axicabtagene ciloleucel (axi-cel; Yescarta) elicited a high objective response rate (ORR) of 85%, with a complete response (CR) rate of 74% when used as a first-line therapy in patients with high-risk large B-cell lymphoma (LBCL), according to updated data from the phase 2 ZUMA-12 trial (NCT03761056) presented during the Virtual 47th Annual Meeting of the EBMT.1

Additionally, the partial response rate was 11% with the product, while 15% of patients experienced stable disease (SD). Notably, at a median follow-up of 9.3 months, 70% of the 27 response-evaluable patients were found to have an ongoing response to treatment.

“ZUMA-12 is the first study evaluating CAR T-cell therapy as first-line therapy in [patients with] high-risk LBCL, defined by both histology and/or International Prognostic Index and dynamic risk assessment with PET scan,” Catherine Thieblemont, MD, PhD, head of the Hemato-Oncology Department at Hôpital Saint-Louis, said during a presentation of the data. “Axi-cel may be safety administered and demonstrates substantial clinical benefit in patients with an unmet medical need.”

Patients who have high-risk LBCL are known to have poor outcomes, including lower response rates and poorer OS.2 Notably, patients who experience early disease recurrence following frontline treatment with rituximab (Rituxan)-based chemoimmunotherapy are at an increased risk of death.3,4

In October 2017, the FDA approved axi-cel for use in adult patients with LBCL after 2 or more previous therapies, including those with diffuse large B-cell lymphoma (DLBCL). The product was also indicated for patients with primary mediastinal LBCL, high-grade B-cell lymphoma, and DLBCL transformed from follicular lymphoma. The regulatory decision was based on data from the phase 2 ZUMA-1 trial (NCT02348216), where the CAR T-cell product elicited an ORR of 82% with a CR rate of 54%.5 At a median follow-up of 51.1 months, the median overall survival (OS) was 25.8 months.6

The multicenter, open-label, single-arm ZUMA-12 trial enrolled patients with high-risk LBCL defined as high-grade BCL with MYC and BCL2 and/or BCL6 translocations or LBCL with an International Prognostic Index (IPI) score of 3 or higher any time prior to enrollment. Participants were treated with 2 cycles of an anti-CD20 monoclonal antibody plus an anthracycline-containing regimen. To be eligible for enrollment, patients had to be 18 years of age or older and have an ECOG performance status of either 0 or 1.

Patients underwent leukapheresis followed by potential nonchemotherapy bridging therapy, which was then followed by conditioning chemotherapy plus axi-cel infusion. The conditioning regimen comprised intravenous (IV) fludarabine at 30 mg/m2 plus IV cyclophosphamide at 500 mg/m2 on days -5, -4, and -3. Axi-cel was administered via a single IV infusion of 2 x 106 CAR T cells/kg on day 0.

The primary end point of the trial was CR per investigator assessment and Lugano classification, while key secondary end points comprised ORR, duration of response (DOR), event-free survival, progression-free survival (PFS), OS, safety, as well as CAR T cells in the blood and cytokine levels in serum.

A total of 37 patients were enrolled to the trial; 32 of these patients received conditioning chemotherapy and 32 were given the CAR T-cell product. Five patients did not receive axi-cel. The data cutoff was August 25, 2020, and the median follow-up time in the efficacy-evaluable patients was 9.3 months (range, 0.9-18), while the median follow-up time in the safety-evaluable patients (n = 32) was 9.5 months (range, 0.9-18).

Of the 32 patients who received axi-cel, the median age was 61 years, 72% were male, 88% had stage III/IV disease, and 66% had an ECOG performance status of 1. All patients had received at least 1 previous line of systemic treatment. Moreover, 72% of patients had an IPI score of 3 or higher at baseline.

Additional results from the trial presented during the meeting showed that the median time to initial objective response with axi-cel was 1.0 months (range, 0.9-3.1), while the median time to CR was also 1.0 months (range, 0.9-6.4). Fifteen percent of patients converted from a PR to a CR, while 4% converted from SD to a CR.

Notably, the median DOR, PFS, and OS had not yet been reached at a median follow-up of 9.3 months.

Moreover, a higher frequency of CCR7+CD45RA+ T cells in the pre-infusion product was linked with greater expansion of CAR T cells in the ZUMA-12 trial vs the ZUMA-1 trial, which could indicate improved T-cell fitness in frontline treatment, according to Thieblemont.

The median tumor burden was noted to be lower in ZUMA-12 vs cohort 1 of ZUMA-1, at 2091 mm2 vs 3684 mm2, respectively. Moreover, the median time to peak levels of CAR T cells in the blood was 8 days in the ZUMA-12 trial. Pharmacokinetic profiles proved to be comparable in patients with double- or triple-hit lymphoma and DLBCL with an IPI score of 3 or higher.

Regarding safety, any-grade treatment-emergent toxicities were reported in all patients who received axi-cel; 22% of these effects were grade 3, 56% were grade 4, and 3% were grade 5 in severity. The most frequently reported grade 3 or higher toxicities included encephalopathy (16%), increased alanine aminotransferase (9%), and decreased neutrophil count (9%). One grade 5 effect was reported, and this was noted to be due to COVID-19.

Any-grade cytokine release syndrome (CRS) was reported in all 32 patients evaluated for safety; this was grade 3 in 9% of patients. The most common any-grade symptoms of CRS included pyrexia (100%), chills (25%), and hypotension (25%). Fifty-three percent of patients received tocilizumab (Actemra) to manage the CRS, while 25% were given steroids. The median time to onset of CRS was 4 days, and the median duration of events was 6 days. All patients had their CRS resolve. Notably, no grade 4 or 5 CRS effects were observed.

Sixty-nine percent of patients experienced any-grade neurologic toxicity; in 25% of these patients, the effect was grade 3 in severity. The most frequently any-grade symptoms of these neurologic effects included encephalopathy (31%) and a confusional state (28%). Six percent of patients had grade 4 neurologic toxicities, but no grade 5 effects were reported. Thirty-four percent of patients received steroids to manage these toxicities. Here, the median time to onset was 9 days, while the median duration of events was 6 days. Ninety-one percent of patients had resolved events. The 2 unresolved events were grade 1 tremor and grade 1 memory impairment.

The median peak serum analytes linked with grade 3 or higher neurologic effects or CRS in ZUMA-12 proved to be consistent with previous data yielded from ZUMA-1, concluded Thieblemont.


  1. Neelapu SS, Dickinson M, Munoz J, et al. Interim analysis of ZUMA-12: a phase 2 study of axicabtagene ciloleucel (axi-cel) as first-line therapy in patients with high-risk large B-cell lymphoma. Presented at: Virtual 47th Annual Meeting of the EBMT; March 13-16, 2021; Virtual. Accessed March 15, 2021.
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  4. Casasnovas R-O, Ysebart L, Thieblemont, et al. FDG-PET-driven consolidation strategy in diffuse large B-cell lymphoma: final results of a randomized phase 2 study. Blood. 2017;130(11):1315-1326. doi:10.1182/blood-2017-02-766691
  5. Yescarta (axicabtagene ciloleucel) Prescribing Information. Santa Monica, CA: Kite Pharma, Inc. 2020.
  6. Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 2019;20(1):31-42. doi:10.1016/S1470-2045(18)30864-7