On 28 December 2017, Sattva S. Neelapu of the M.D. Anderson Cancer Center in Houston, Texas and colleagues published in The New England Journal of Medicine, interim results from a phase II study (sponsored by Kite, now a Gilead company, and the Leukemia and Lymphoma Society Therapy Acceleration Program) in patients with refractory large B-Cell lymphoma (LBCL). In this multicenter clinical trial, the safety and efficacy of axicabtagene ciloleucel (axi-cel) was evaluated in patients with diffuse LBCL, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma (FL) who had refractory disease despite undergoing recommended prior therapy (NCT02348216).
The purpose of this study was to determine if this autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is a safe and effective treatment regimen for these lymphoma-type patients who have received a conditioning regimen of low-dose cyclophosphamide and fludarabine. The primary endpoint was objective response rate (ORR), with secondary endpoints of overall survival (OS), safety, and biomarker assessments.
- Axi-cel was associated with durable response in refractory LBCL
- Higher CAR T-cell levels in blood were associated with response
- A total of N = 111 patients with DLBCL, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma with refractory disease despite undergoing recommended prior therapy
- Patients received a target dose of 2 x 106 anti-CD19 CAR T-cells/kilogram body weight after receiving low-dose cyclophosphamide and fludarabine
- Primary endpoint was ORR
- Secondary endpoints included OS, safety, and biomarker assessments
- National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.03 was used to grade symptoms of cytokine release syndrome and neurologic events, along with other adverse events
- ORR = 82%, and complete response (CR) rate was 54%
- 40% continuing to have a CR
- Median time to response = 1.0 month
- Median duration of response (DOR) = 8.1 months
- Median overall survival was not reached, 18-month OS rate = 52%
- Median duration of progression-free survival (PFS) = 5.8 months
- Most common adverse events of grade 3 or higher during treatment were neutropenia (78%), anemia (43%), and thrombocytopenia (38%)
- Grade 3 or higher cytokine release syndrome (CRS) and neurologic events occurred in 13% and 28% of the patients, respectively
- Most common symptoms of CRS > grade 3 were pyrexia (11%), hypoxia (9%), and hypotension (9%)
- 44 patient deaths were reported:
- disease progression (n=37)
- cytokine release syndrome related to treatment (n=2)
- pulmonary embolism unrelated to treatment (n=1)
- Other causes after disease progression unrelated to treatment (n=4)
In this multicenter study, patients with refractory large B-cell lymphoma who received axi-cel therapy experienced deep and durable responses, with a safety profile that included myelosuppression, the cytokine release syndrome, and neurologic events. It’s important to note that in order to achieve these results, a feasible and reliable CAR T-cell manufacturing protocol and process must be in place. This was clearly demonstrated as axi-cel was manufactured for 110 patients (99%) and administered to 101 of them (91%). What’s more, 82% of the 101 treated patients with refractory LBCL had an objective response, and 54% had a complete response. The authors noted that there may be a limitation with CD19 detection due to the fact that response rates were similar in both CD19-negative and –positive disease. Additionally, they mentioned that an analysis of molecular and cytogenetic characteristics could have been included in the study in order to determine the influence of CAR T-cell therapy outcomes on disease biology.
In consideration of these among many factors and the results of this study, axi-cel was shown to be an effective therapeutic option in adult patients with relapsed or refractory large B-cell lymphoma after at least two prior systemic therapies.