In the phase II ZUMA-5 trial, the cellular immunotherapy axicabtagene ciloleucel led to responses in 92% of patients with indolent non-Hodgkin lymphoma (NHL), researchers reported at the 2020 American Society of Hematology (ASH) Annual Meeting & Exposition.1
Axicabtagene ciloleucel has improved the outlook for patients with large B-cell lymphomas. Although indolent B-cell lymphomas generally progress less rapdily and are associated with longer survival, better treatments are also needed for the many patients who relapse. Approved treatments for heavily pretreated patients with follicular lymphoma yield complete response rates of up to 14%, with median durations of response not exceeding 1 year or so. Axicabtagene ciloleucel may potentially improve upon these outcomes.
“In ZUMA-5, axicabtagene ciloleucel had considerable and durable clinical benefit in patients with indolent lymphoma, with high response rates and complete response rates,” said Caron A. Jacobson, MD, MMSc, of Dana-Farber Cancer Institute, Boston. Responses were consistent among patients with high-risk features, and, at a median follow-up of 17.5 months, the responses were ongoing for 64% of patients with follicular lymphoma.
Caron A. Jacobson, MD, MMSc
The safety profile was manageable, and, at least in the follicular subset, it appeared more favorable than what has been reported for this agent in large B-cell lymphoma. The activity also seemed more robust than has been seen in large B-cell lymphoma.2
“We were very impressed with the magnitude of the responses and also the durability,” said Dr. Jacobson. “This treatment has meaningfully affected high-risk patients with these diseases. I was also struck early on by how favorable the safety profile was compared with what we’ve been seeing in the fast-growing lymphomas such as large B-cell lymphoma.”
Axicabtagene ciloleucel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for adults with relapsed or refractory large B-cell lymphoma previously treated with at least two regimens. ZUMA-5 tested this approach in patients with relapsed indolent NHL after two or more previous lines of therapy.
Researchers administered axicabtagene ciloleucel to 146 patients, including 124 with follicular lymphoma and 22 with marginal zone lymphoma. After conditioning, patients received axicabtagene ciloleucel at 2 × 106 CAR-positive cells/kg. The primary endpoint was objective response rate.
Axicabtagene ciloleucel was successfully manufactured for all patients and was delivered to the study site a median of 17 days after leukapheresis. The efficacy analysis was performed on 104 patients, including 84 with follicular lymphoma who had at least 12 months of follow-up and 20 with marginal zone lymphoma. The safety analysis included all 146 patients.
Objective Response Rate of 92%
As of March 12, 2020, the median follow-up was 17.5 months for efficacy and 15.1 months for safety. Overall, 92% of participants responded to axicabtagene ciloleucel, and 76% achieved a complete response. By tumor type, responses were seen in 94% of patients with follicular lymphoma and 85% of patients with mantle zone lymphoma, with 80% and 60%, respectively, being complete responses, Dr. Jacobson reported.
The median time to first response was 1 month. Among the 25 patients with follicular lymphoma who initially had a partial response, 13 (52%) subsequently converted to a complete response after a median of 2.2 months. By independent radiology review, responses were consistent among key subgroups, she added.
In a press briefing, Dr. Jacobson was asked to speculate on the higher response rates seen in follicular vs large B-cell lymphomas. “It’s probably a combination of two things. The disease biology itself may make patients more or less susceptible to immunologic killing. Also, we know that fludarabine and cyclophosphamide [for conditioning] are good drugs for follicular lymphoma, and we’ll need to tease out the chemotherapy effect vs the CAR T-cell effect. This would apply to early responses. Durable remissions would assuredly be related to the CAR T cells and not from a single cycle of chemotherapy.”
Duration of Response
At a median follow-up of 17.5 months, the estimated median duration of response was not reached for all patients, and 64% of those with follicular lymphoma had an ongoing response at data cutoff. The 12-month duration of response was 71.7%.
Among patients with follicular lymphoma, the median duration of response was not reached for complete responders; at 12 months, 78% were still responding. In contrast, the majority of partial responders relapsed by 3 months, with only 13.6% still responding at 12 months. In patients with marginal zone lymphoma, the median duration of response was 10.6 for complete responders and 8.1 months for partial responders.
Median progression-free survival and overall survival were not reached. At 12 months, 73.7% of all patients were progression-free, and 92.9% were alive. Although overall survival was nearly identical between the two subtypes, progression-free survival was higher in the follicular subset (77.5%) than in the marginal zone subset (45.1%).
Response rates were slightly higher, and rates of adverse events were slightly lower among patients with follicular lymphoma compared with those who had marginal zone lymphoma. These trends should become better understood after data become available for more patients with marginal zone lymphoma, predicted Dr. Jacobson.
Adverse events grade ≥ 3 were experienced by 86% of patients, most commonly cytopenias (70%) and infections (16%). Cytokine-release syndrome grade ≥ 3 occurred in 7%, and grade ≥ 3 neurologic events occurred in 19%. Three patients died; one was related to axicabtagene ciloleucel, which was from multisystem organ failure in the context of cytokine-release syndrome on day 7.
Grade 4 neurologic events were reported for three patients. Six patients had neurologic events of lesser severity, including memory impairment, attention disturbance, intermittent paresthesia, tremor, and facial paresthesia.
“Patients with marginal zone lymphoma did have slightly worse toxicity and elevations in inflammatory markers,” Dr. Jacobson observed. Since this is similar to what is seen in aggressive lymphomas, she speculated that “the disease itself is probably what dictates the toxicity.”
“Based on the safety profile we observed, we plan to evaluate the potential for outpatient treatment with axicabtagene ciloleucel in indolent lymphoma,” she added.
CAR T-Cell Expansion
The median time to peak anti-CD19 CAR T-cell expansion after axicabtagene ciloleucel infusion was 9 days. This trended higher in patients with marginal zone lymphoma. In patients with follicular lymphoma, peak CAR T-cell levels were numerically greater among patients with ongoing responses at 12 months. Peak levels were also associated with grade ≥ 3 cytokine-release syndrome and neurologic events. Similar associations between CAR T-cell expansion and outcomes were observed in patients with marginal zone lymphoma.
DISCLOSURE: Dr. Jacobson has been a consultant for Kite/Gilead, Novartis, BMS/Celgene, Nkarta, Lonza, Precision Biosciences, AbbVie, and Bluebird Bio; and has received research funding from Pfizer and Kite.
1. Jacobson C, Chavez JC, Sehgal AR, et al: Primary analysis of ZUMA-5: A phase 2 study of axicabtagene ciloleucel in patients with relapsed/refractory indolent non-Hodgkin lymphoma. 2020 ASH Annual Meeting & Exposition. Abstract 700. Presented December 7, 2020.
2. Neelapu SS, Locke FL, Bartlett NL, et al: Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med 377:2531-2544, 2017.
James Essell, MD, Medical Director of the Blood Cancer Center, The Jewish Hospital-Mercy Health Cincinnati Cancer and Cellular Therapy Center, and Chair of Cellular Therapy, observed that axicabtagene ciloleucel compares favorably with other CAR T-cell products being evaluated for indolent...