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Durable responses to axicabtagene ciloleucel CAR T-cell therapy in patients with refractory non-Hodgkin lymphoma

In the ZUMA-1 study, CD19 targeting CAR T-cell therapy with axicabtagene ciloleucel (axi-cel) demonstrated long-term efficacy in patients with refractory non-Hodgkin lymphoma (NHL). One year after a single infusion with axi-cel, 42% of patients in the study remained in remission and 40% of patients exhibited no evidence of cancer. The results presented at ASH 2017 also provide insights into the mechanisms underlying resistance to CD19 CAR T-cell therapy.

Patients with refractory NHL experience poor outcomes to currently available therapies. ZUMA-1 is a phase I/II study evaluating CAR T-cell therapy with axi-cel in a total of 108 patients with refractory diffuse large B cell lymphoma, transformed follicular lymphoma, or primary mediastinal large B cell lymphoma. Refractory disease was defined as progressive disease, or stable disease as best response to the last line of therapy, or relapse within 12 months after an autologous stem cell transplantation (ASCT). In order to be eligible for the study, patients had to be previously treated with an anti-CD20 antibody- and an anthracycline-containing regimen. Patients in the study received a conditioning regimen consisting of cyclophosphamide (500 mg/m2) plus fludarabine (30 mg/m2) for 3 days after which they received axi-cel at a dose of 2 ×106 CAR+ cells/kg. The primary endpoint of the study was the objective response rate (ORR) per 2007 International Working Group criteria, with the duration of response (DoR), overall survival (OS) and the incidence of adverse events (AEs) as key secondary objectives. In addition to this, exploratory biomarker analyses were conducted in an attempt to shed more light on the mechanisms of resistance to anti-CD19 CAR T-cell treatment.

The median age of patients in the study was 58 years (25% 65 years or older) and 68% was male. In 57% of patients an ECOG performance status of 1 was reported, 83% had disease stage III/IV and 44% had an IPI score of 3-4. Seventy percent of patients received 3 prior lines of therapy and 74% of patients were refractory to their second, or later line of therapy (best response of progressive disease to prior therapy in 65%). Finally, 23% of patients had disease relapse after an ASCT.

During ASH 2017 the results were presented of the pooled data form the phase I and II part of the ZUMA-1 study, including a total of 108 patients. After a median follow-up of 15.4 months, the ORR was 82% with a complete response (CR) in 58%. In 42% of patients the response (PR or CR) was on-going at the time of the analysis. Of the 60 patients with either a PR (N=35) or stable disease (N=25) at the first tumour assessment (1 month post–axi-cel), 23 subsequently achieved a CR up to 15 months post-infusion without additional therapy (11 from PR and 12 from SD). The median time to conversion from PR to CR was 64 days. Overall, the median duration of response was 11.1 months. Among patients with a CR, this median was not yet reached after 15 months, while this was 1.9 months for patients in a PR. In three patients who were enrolled in the phase I part of the study (N=7), the CR was still on-going after 24 months of follow-up. With a median follow-up of 15.4 months, 42% of patients remained free of progression and 56% of patients were still alive (6, 12 and 18 month PFS rates: 49%, 44% and 41%; 6, 12 and 18 month OS rates: 78%, 59% and 52%).

Grade 3-5 AEs were reported in 97% of patients with serious grade 3-5 AEs in 46%. Ten patients experienced a serious AE six months after the primary analysis, including infections in eight patients. All serious AEs had resolved at the time of data cut-off of 15,4 months. Cytokine release syndrome (CRS) of grade 3 or more was seen in 12% of the patients and in 31% grade 3-5 neurologic AEs (NE) were seen. In total, 4 AE related deaths were seen in the study (2 axi-cel related, 2 unrelated). Since the primary analysis with at least 6 months of follow-up, there were no new axi-cel–related CRS, NE, or grade 5 AEs.

The presentation also provided clues as to why some patients relapse or do not respond to CAR T-cell therapy. After analysing tumour tissue from before and after treatment in patients who relapsed, the researchers found that in a third of patients the CD19 protein was no longer present on cancer cells. Secondly, more than two-thirds of tumours showed expression of PD-L1, likely helping the cancer cells to survive by inhibiting the function of the infused T cells. Follow-up studies are now underway to identify possible approaches to overcoming these problems.

In summary, the ZUMA-1 study, demonstrated that axi-cel provides significant, durable clinical benefit with manageable AEs in patients with no curative treatment options. With the existing therapeutic options, the median survival for patients with this disease is only 6 months. In this study, 59% of patients are still alive over a year after treatment. A randomized trial to compare the efficacy of this therapy with second-line standard of care, which includes autologous stem cell transplantation for relapse after first-line therapy, is planned in patients with aggressive B-cell NHL.


Neelapu S, Locke F, Bartlett N, et al. Long-Term Follow-up ZUMA-1: A Pivotal Trial of Axicabtagene Ciloleucel (Axi-Cel; KTE-C19) in Patients with Refractory Aggressive Non-Hodgkin Lymphoma (NHL). Presented at ASH 2017; Abstract #578.

Speaker Sattva Neelapu


Professor Sattva S. Neelapu, MD, PhD, The University of Texas MD Anderson Cancer Center, Houston, TX, USA


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