ZUMA-12: Axicabtagene ciloleucel for high-risk large B cell lymphoma

Prof Sattva Neelapu - MD Anderson Cancer Center, Houston, USA

At ASH this year we are presenting the interim analysis of the ZUMA-12 study which is a phase II multicentre study evaluating axi-cel as part of first line therapy for patients with high risk large B-cell lymphoma. Axi-cel was previously approved for relapsed refractory large B-cell lymphoma after two or more lines of therapy; in this study we evaluated axi-cel as part of first line therapy in patients with high-risk large B-cell lymphoma which is defined as patients with a diagnosis of double-hit or triple-hit lymphoma or large B-cell lymphoma with an IPI score of 3 or greater. In addition, they had to have a dynamic risk assessment, as well, after two cycles of standard frontline chemotherapy such as R-CHOP or R-EPOCH; a PET scan should be FDG positive with a dual score of 4 or 5 to be eligible for the study.

We enrolled a total of 32 patients as of the data cut-off who received cyclophosphamide and fludarabine conditioning chemotherapy followed by a single infusion of axi-cel at a dose of two million CAR positive cells per kilogram bodyweight. The median follow-up on the study was a little over nine months and this was a planned interim analysis. The best overall response rate on the study was 85% and the complete response rate was 74%. As of the data cut-off, 70% of the responses are ongoing.

The therapy itself was quite well tolerated, almost all the patients developed cytokine release syndrome but these were mostly grade 1 and grade 2 with 9% of the patients having grade 3 or higher CRS. Neurological toxicity of grade 3 or higher was observed in 25% of the patients but these were all reversible and there were no grade 5 adverse events due to CRS or neurological toxicity.

We also found that the axi-cel product had a higher frequency of [?] naïve and younger phenotype of CAR T-cells that were CCR7 positive and CD45RA positive compared to new axi-cel products used in the ZUMA-1 study evaluating this product in third line and beyond. This was associated with a greater expansion of the CAR T-cells in these patients compared to the ZUMA-1 study.

So, in summary, in the ZUMA-12 study where we evaluated axi-cel as part of first-line therapy, axi-cel was found to be safe and it demonstrated substantial clinical benefit in patients with an unmet medical need. The high overall response rate of 85% and CR rate was 74% with 70% of the patients had ongoing response after a median follow up of 9.3 months. The higher frequency of the naïve phenotype of the CAR T-cells in the B infusion product was associated with a greater expansion of CAR T-cells, suggesting improved T-cell fitness in first line treatment.

What does the future look like for this research?

This is the first study evaluating CAR T-cell therapy in first line therapy. While this is an interim analysis and further follow-up is necessary, these early results indicate that CAR T-cell therapy can be highly effective, even in very high risk large B-cell lymphoma. If long-term durability of these responses is confirmed and this efficacy could be demonstrated in a much larger study, this could potentially change how we manage patients with large B-cell lymphoma at initial diagnosis in the future.