ASH20: Zuma-5 Analysis Shows Potential For CAR T-cell Treatment in Indolent Lymphomas

By Mary Ellen Schneider

The anti-CD19 chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel achieved a complete response rate of more than 75% among patients with relapsed/refractory indolent non-Hodgkin lymphomas, according to findings presented at the annual meeting of the American Society of Hematology.

The findings come from a primary analysis of the phase 2 Zuma-5 trial, which evaluated axicabtagene ciloleucel (axi-cel) in 124 patients with follicular lymphoma and 22 patients with marginal zone lymphoma (Abstract 700).

“Advanced-stage indolent B-cell non-Hodgkin lymphomas are largely incurable with conventional therapies,” said Caron Jacobson, MD, of Dana-Farber Cancer Institute in Boston, who presented the Zuma-5 results. “Many patients experience multiple relapses over the course of their illness, with shortening remission duration with subsequent lines of therapy. In particular, available third-line therapies rarely lead to complete responses and response duration is, on average, just about 1 year.”

Axi-cel is already approved in the United States and the European Union for the treatment of relapsed/refractory aggressive B-cell non-Hodgkin lymphoma after at least two lines of systemic therapy. Those approvals were based on results from the pivotal Zuma-1 study of axi-cel in relapsed large B-cell lymphomas, which demonstrated an objective response rate of 82% and a complete response rate of 58% for the CAR T-cell therapy, Dr. Jacobson said.

Zuma-5 evaluated patients with relapsed/refractory disease indolent non-Hodgkin lymphoma after at least two lines of therapy. “This was a heavily pretreated and high-risk population,” she said. “The majority had stage IV disease, high tumor bulk, and had progressed within 24 months of their first chemo-immunotherapy regimen.”

Patients underwent leukapheresis followed by conditioning therapy with cyclophosphamide and fludarabine, followed by a single infusion of axi-cel at 2 x 106 CAR T cells/kg.

At a median follow-up of 17.5 months, the objective response rate was 92% among 104 efficacy-evaluable patients. Overall, the complete response rate was 76%.

Among patients with follicular lymphoma, the objective response rate was 94%, with a complete response rate of 80%. Among marginal zone lymphoma patients, the objective response rate was 85% and the complete response rate was 60%.

“Although it appears that the response rate is lower in marginal zone lymphoma, this is largely due to the fact that 15% of patients were found to not have measurable disease by central radiology review, even though the treating investigators felt that they had had measurable disease and were eligible for the study,” Dr. Jacobson explained.

At the data cutoff, 62% of treated patients had ongoing responses to therapy. Among responding follicular lymphoma patients, nearly 80% maintained their response past 12 months. With a median follow-up of 17.5 months, median duration of response had not been reached. “Patients who achieved a complete response were much more likely to maintain their response, compared with those whose best response was a partial response,” Dr. Jacobson said.

The follow-up for the marginal zone lymphoma patients is more limited, Dr. Jacobson said, making the duration of response data immature.

Grade 3 or higher adverse events occurred in 86% of patients, with most events relating to cytopenias. Grade 3 or higher cytokine release syndrome occurred in 7% of patients and grade 3 or higher neurologic events occurred in 19% of patients. Most cases of cytokine release syndrome and neurologic events of any grade resolved. Grade 5 adverse events occurred in three patients, but only one event — multisystem organ failure related to cytokine release syndrome — was deemed to be related to axi-cel treatment.

“The safety profile was manageable and reversible and appeared to be at least similar to that of axi-cel in aggressive lymphomas,” Dr. Jacobson said. “Of note though, patients with follicular lymphoma appear to have lower rates of any-grade [cytokine release syndrome] and any- and high-grade neurologic toxicity, compared with marginal zone lymphoma.”

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