Axicabtagene Ciloleucel Induces Durable Responses in Indolent Non-Hodgkin Lymphoma

A total of 80% of patients with relapsed or refractory indolent non-Hodgkin lymphoma (NHL) achieved a complete response (CR) to axicabtagene ciloleucel (Yescarta), and those responses have proved durable, according to the interim results of the phase 2 ZUMA-5 study, said Caron A. Jacobson, MD, Medical Director, Immune Effector Cell Therapy Program, Dana-Farber Cancer Institute, Boston, MA, at the ASCO 2020 virtual annual meeting.

Among the first 80 patients with follicular lymphoma who were evaluable for efficacy and had at least 9 months of follow-up, the objective response rate (ORR) was 95%, and 80% of the patients have durable responses at a median follow-up of 15.3 months.

“The median overall survival has not been reached, and 94% of patients remain alive at 12 months of follow-up,” said Dr Jacobson. “Given the long natural history of these diseases, safety is of paramount importance. The safety profile was manageable and reversible, and appeared to be similar to that of [axicabtagene ciloleucel] in aggressive lymphomas.”

Advanced-stage indolent NHL is largely incurable with conventional therapies, with many patients having multiple relapses over the natural history of their disease, and remission shortening with subsequent therapies, she said. Axicabtagene ciloleucel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy with a CD28 costimulatory domain that is approved for the treatment of relapsed or refractory aggressive B-cell NHL in adults who have received ≥2 lines of treatment.

ZUMA-5 Study

ZUMA-5 is a multicenter, single-arm study that evaluated axicabtagene ciloleucel in patients with relapsed or refractory indolent NHL (grade 1-3a follicular lymphoma or nodal or extranodal marginal-zone lymphoma [MZL]) after ≥2 previous lines of therapy. A total of 148 patients had leukapheresis and received lymphodepleting chemotherapy, and 140 patients (124 with follicular lymphoma and 16 with MZL) received treatment with axicabtagene ciloleucel infusion at 2 × 106 CAR T-cells/kg.

The efficacy analysis included 96 patients, which included 80 patients with follicular lymphoma who had ≥9 months of follow-up and the 16 patients with MZL who had ≥1 months of follow-up. All 140 patients were evaluable for safety, with a median follow-up of 12.8 months.

The baseline characteristics showed that 70% of patients received ≥3 previous therapies (median therapies, 3). More than 50% of the patients had stage IV disease, and 49% had a high tumor bulk. Approximately 66% of the patients progressed less than 2 years after receiving the initial anti-CD20 monoclonal antibody-containing therapy, and 73% of the patients had disease that was refractory to the last treatment received. Approximately 25% of the patients had previous autologous stem-cell transplant.

By independent review, the ORR was 93% with a CR of 80%. For the cohort with follicular lymphoma, the ORR was 95% with a CR of 81%. The MZL cohort had an ORR of 81% and a CR rate of 75%. “Although it appears that the response rate is lower in the MZL cohort, this is largely due to the fact that 19% of patients were found to not have measurable disease by central radiology review prior to CAR T-cell infusion,” said Dr Jacobson.

Durable Treatment Responses

Among the patients with follicular lymphoma, 13% with an initial partial response at 1 month subsequently converted to a CR.

The estimated duration of response in the overall study population was 20.8 months, and 68% of patients with follicular lymphoma had an ongoing response. Of the patients with follicular lymphoma, 80% maintained their response past 12 months. The median duration of response in the patients with MZL was 10.6 months. The median progression-free survival was 23.5 months in all patients.

Grade ≥3 adverse events were common, the majority of which were related to cytopenias, said Dr Jacobson. There were 2 grade 5 adverse events in patients with follicular lymphoma, including 1 patient with multiorgan failure in the context of cytokine release syndrome (CRS) and 1 patient with an aortic dissection that was not related to treatment with axicabtagene ciloleucel. Overall, 79% of patients had any-grade CRS, and 8% of patients had grade ≥3 CRS. The CRS was managed with tocilizumab (Actemra) in 47% of patients and with corticosteroids in 17%.

The incidence of any-grade neurotoxicity was 58%, with grade 3 or 4 neurotoxicity observed in 17% of the patients. The most common manifestations of neurotoxicity were tremor (51%) and confusion (41%). Approximately 34% of patients received corticosteroids for the treatment of neurotoxicity.

The patients with follicular lymphoma had lower rates of high-grade CRS and neurotoxicity than patients with MZL.

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