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. 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.