The ZUMA-5 is a single arm phase II multicentre study where we evaluated axicabtagene ciloleucel, which is an anti-CD19 autologous CAR T-cell therapy product, in patients with relapsed/refractory indolent non-Hodgkin lymphoma. To be eligible these patients had to have either follicular lymphoma grades 1-3a or marginal zone lymphoma either nodal or extranodal disease. So historically patients with relapsed/refractory indolent lymphomas have been treated with multiple lines of chemotherapy. These patients have progressively decreasing duration of response with each successive line of therapy. Most patients eventually stop responding. In this context this therapy was evaluated in patients relapsing or refractory after two or more lines of systemic therapy for follicular lymphoma and marginal zone lymphoma. Rituximab monotherapy was not considered as a line of therapy for eligibility.

The patients initially underwent leukapheresis and once the product had been generated they received conditioning therapy with cyclophosphamide and fludarabine for three days and after two days of rest received a single infusion of axi-cel at a dose of two million CAR [??] cells per kilogram body weight. The first tumour assessment was done at day 30 and the primary endpoint for the study was overall response rate.

What were the key findings?

We enrolled and treated a total of 149 patients, 124 of them were follicular lymphoma and 25 were marginal zone lymphoma. Of those all patients were evaluable for safety but in this two-year update that we are presenting at ASH 2021 the efficacy evaluable patients included 110 patients including 86 with follicular lymphoma and 24 with marginal zone lymphoma.

We previously reported the primary analysis at ASH 2020 where at least 80 patients with follicular lymphoma have had at least one month of follow-up. Now in this follow-up analysis, 86 follicular lymphoma patients have had at least 24 months of follow-up. The median follow-up now is 31 months for follicular lymphoma and 24 months for marginal zone lymphoma.

We observed an overall response rate of 94% in follicular lymphoma and 79% had complete remission. In the marginal zone lymphoma cohort the overall response rate was 83% and the complete response rate was 63%. At a median follow-up of 31 months in follicular lymphoma 57% of these responses were ongoing and the median duration of response and progression free survival is approximately 40 months for these patients and the median overall survival has not been reached.

For marginal zone lymphoma about 50% of the patients are in ongoing remission after a median follow-up of 24 months.

Were there any adverse events?

The patients, the most common adverse event related to CAR T-cell therapy that has been observed is cytokine release syndrome and neurological toxicity. While most patients have cytokine release syndrome these were primarily grade 1 and grade 2. Grade 3 or higher CRS was observed in less than 10% of the patients and grade 3 [??] was observed in about 19% of the patients. In fact, patients with follicular lymphoma appeared to have much lower toxicity compared to the marginal zone lymphoma cohort as well as large B-cell lymphoma patients who were previously treated with the same product.

In addition we also observed evidence of B-cell aplasia early on after CAR T-cell therapy, however, the majority of these patients eventually recovered their normal B-cells, suggesting that long-term persistence of the CAR T-cells may not be needed to maintain durability of responses in these patients.

What are the next steps?

Based on this pivotal single arm phase II study axi-cel was approved in the US for treatment of patients with relapsed or refractory follicular lymphoma after two or more lines of systemic therapy. Follow-up is ongoing in patients with marginal zone lymphoma. In addition, we are actively in discussions to evaluate axi-cel in earlier lines of therapy. Of course we would like to continue to follow these patients long-term to see if a proportion of these patients are potentially cured with this therapy or not. At least in large B-cell lymphoma it appears that axi-cel is potentially curative for approximately 40% of the patients where we have seen long-term durability of responses. It remains to be seen with longer follow-up whether cure is possible in patients with follicular lymphoma as well.