Real-World Evidence With Axicabtagene Ciloleucel CAR T Treatment Similar to ZUMA-1 Trial Findings


A multicenter retrospective study that evaluated the efficacy and safety of chimeric antigen receptor (CAR) T-cell treatment, axicabtagene ciloleucel (axi-cel; Yescarta), in a real-world setting found a similar response as well as toxicity compared with the ZUMA-1 clinical trial.

A multicenter retrospective study that evaluated the efficacy and safety of chimeric antigen receptor (CAR) T-cell treatment, axicabtagene ciloleucel (axi-cel; Yescarta), in a real-world setting found a similar response as well as toxicity compared with the ZUMA-1 clinical trial. Predictors of response included low day 0 C-reactive protein (CRP) and high absolute lymphocyte count at leukapheresis. The results were presented at the 60th American Society of Hematology Annual Meeting & Exposition, being held December 1-4, in San Diego, California.

Approved in fall 2017, long-term results with the treatment were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) earlier this year. Per the results presented at ASCO, the best objective response rate (ORR) was 82% at 8.7 months, which was maintained by the long-term 15.4 months follow-up time. The complete response (CR) rate was 58% at the long-term follow-up.

Caron A. Jacobson, MD, instructor in medicine, Department of Medical Oncology, Dana-Farber Cancer Institute, first author of the study, said that in the real-world setting, where eligibility criteria and patient management factors may be very distinct from a clinical trial setting, bridging therapy may be needed between leukapheresis and treatment with the CAR T product.

Their study objective, therefore, was to examine patient and disease characteristics and biomarkers of response or toxicity following axi-cel treatment in a real-world setting, which in this case were 6 US academic medical centers that used commercial axi-cel.

Among the 104 patients with lymphoma that were a part of this retrospective study (median age was 63.8 years; range, 21-80), 94 (90%) had an European Cooperative Oncology Group (ECOG) performance status 0-1, and 48 (46%) had a pre-lymphodepletion International Prognostic Index (IPI) ≥3. Twenty-eight (27%) patients had a prior autologous transplant and 3 (3%) had received a prior allogenic stem cell transplant. Forty two patients (40%) had bulky disease (tumor bulk >5 cm) and 42 (40%) received bridging therapy following leukapheresis.

At a median follow-up of 5.6 months, 13 patients had their T-cells collected but they did not receive CAR T-cell infusion: 6 patients had progressive disease (PD), 2 patients had infection, 3 patients had technical issues with cell production, 1 patient had complete response to bridging therapy, and 1 patient was diagnosed with another malignancy.

The best ORR when evaluated in 95 patients was observed in 67 (71%) patients. CR was observed in 42 (44%) patients and partial response (PR) in 25 (26%) patients. Among 51 patients with a 6-month follow-up, ORR was observed in 22 (43%).

Half of the patients who had an initial PR and who were not being followed went on to have a CR, Jacobson said. The median duration of response was 4.9 months.

According to Jacobson, univariate analysis showed that ECOG performance status (P = .009), tumor bulk (P = .016), baseline CRP (P = .029), and prior ibrutinib treatment (P = .002) had a significant association with lack of response to treatment with axi-cel.


A majority (96%) of the treated patients experienced cytokine-release syndrome (CRS)—a flare-up that is characterized by low/high fever, low blood pressure, and can sometimes also lead to capillary leak syndrome, according to Stephen Schuster, MD, of the Perelman School of Medicine.

In 17 (16%) patients, CRS was grade 3 or higher; 2 patients (2%) died from CRS. While median time to onset was 1 day (range, 0-14), symptoms associated with the flare-up lasted a median of 6 days (range, 1-27). Fifty-eight (76%) patients experienced neurotoxicity following treatment with axi-cel, 29 (39%) of whom had grade 3 or higher neurotoxicity. There was 1 fatality associated with this toxic effect. Neurotoxic effects had a median onset time of 5 days (range, 0-34) and lasted for a median of 8 days (range, 1-52 days). Patients received tocilizumab (n = 70) and steroids (n = 66) to counter the toxicity, and 30% of patients required a stay in an intensive care unit.

Six patients died following disease progression and 5 died from toxicity.

Univariate analysis that the researchers conducted for toxicity, mainly grade 3 or higher CRS or neurotoxicity, found no association with PS, tumor bulk, IPI, prior treatment, bridging therapy, or eligibility for ZUMA-1.

Cytogenetic and immunohistochemistry staining found that 3 patients with programmed death (PD) ligand-1-positive tumors were refractory to CAR T-cell therapy. Based on the staining results, a positive response could be associated with increased expression of PD1, 41BB, ICOS, and Ki67, as well as CC3 indicating apoptosis, when CAR T cell levels peaked by day 7. Subsequently, CAR T cells reduced by day 14.

Jacobson said that the deviation from observations in the ZUMA-1 trial may be due to the inclusion of sicker patients with a poorer performance status, and/or different histologies in this patient population. While rates of CRS and neurotoxicity were similar to ZUMA-1, toxicity was not associated with tumor bulk or response, rather with higher peak inflammatory markers and absolute lymphocyte count, indicative of peak CAR T cell levels.

“Unique combination approaches are necessary for specific patients/tumors,” she added, adding that their trial results support the use of axi-cel outside of strict clinical trial criteria, although the outcomes may be slightly inferior.


Jacobson CA, Hunter B, Armand P, et al. Aggressive lymphoma (diffuse large B-cell and other aggressive B-cell Non-Hodgkin lymphomas)—results from retrospective/observational studies: outcomes with CD19 CAR T therapy and checkpoint blockade in the real-world setting. In: Proceedings from the American Society of Hematology; December 1-3, 2018; San Diego, CA. Abstract 92.

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