Conference Correspondent

Preliminary Results of Prophylactic Tocilizumab After Axicabtagene Ciloleucel (axi-cel; KTE-C19) Treatment for Patients with Relapsed/Refractory, Aggressive NHL

Conference Correspondent - ASH 2017 - CLL

ZUMA-1 is a pivotal, multicenter trial of axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, for the treatment of patients with refractory, aggressive non-Hodgkin lymphoma (NHL).1 The objective response rate (ORR) was 82% with a 54% rate of complete response (CR), and 44% of responses were ongoing at the time of the primary analysis.2 Grade ≥3 cytokine release syndrome (CRS) and neurologic events (NEs) occurred in 13% and 28% of patients, respectively.

At ASH 2017, the authors presented the results of a safety management study (SMS) that was added to ZUMA-1 to further characterize mechanisms underlying CRS and NEs associated with CAR T-cell therapy. The SMS was also designed to evaluate the impact of prophylactic use of tocilizumab and levetiracetam on the rates of these adverse events (AEs).3

In the SMS, patients with relapsed or refractory transplant-ineligible NHL received low-dose conditioning of 500 mg/m2 of cyclophosphamide and 30 mg/m2 of fludarabine for 3 days, followed by axi-cel at a target dose of 2 × 106 CAR T-cells/kg. Patients also received prophylactic treatment with 750 mg of levetiracetam twice daily on day 0, and 8 mg/kg of tocilizumab on day 2 after axi-cel infusion. A total of 34 patients were included in the SMS analysis (59% had stage III-IV disease, 74% were refractory to ≥second-line therapy, and 24% relapsed ≤12 months after autologous stem-cell transplant).

Most patients in the SMS experienced at least 1 grade ≥3 AE. The most common grade ≥3 AEs were neutropenia/decreased neutrophil count (74%), anemia (50%), thrombocytopenia/decreased platelet count (50%), leukopenia/decreased white blood cell count (32%), febrile neutropenia (29%), encephalopathy (26%), and hypotension (24%). One patient experienced grade 4 CRS, while grade 3 and 4 NEs occurred in 1 patient each. There was 1 death due to AEs: a patient died of cerebral edema.

Among the 34 patients in the SMS, the preliminary ORR was 62%, including a CR rate of 44%. Follow-up duration, however, is currently limited.

The authors concluded that tocilizumab use on day 2 may reduce the incidence of severe CRS but not the incidence of severe NEs in patients treated with CAR T-cell therapy. These data provide evidence that the underlying pathophysiology of NE differs from that of CRS, which may help to further improve the benefit‒risk profile for CAR T-cell therapy.

References
1. Locke FL, et al. Mol Ther. 2017;25:285-295.
2. Locke FL, et al. AACR 2017. Abstract 9986.
3. Locke FL, et al. ASH 2017. Abstract 1547.

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