ZUMA-2: brexu-cel CAR-T for mantle cell lymphoma that has failed BTK inhibitors
In mantle cell lymphoma that had stopped responding to BTK inhibitors, a single CAR-T infusion produced responses in 93% of patients and complete remissions in two-thirds.
ZUMA-2 was a single-arm phase 2 study of KTE-X19 (brexucabtagene autoleucel), a CD19 CAR-T manufactured with removal of circulating tumour cells, in relapsed or refractory mantle cell lymphoma after up to five prior lines including a BTK inhibitor. Of 74 patients enrolled, 68 received the product. In the primary efficacy analysis of the first 60 treated patients the overall response rate was 93% and complete response 67%; estimated 12-month PFS was 61% and OS 83%. Grade 3 or higher CRS occurred in 15% and neurological events in 31%. It led to FDA approval in 2020, the first CAR-T for mantle cell lymphoma.
- 74 enrolled, 68 treated; all had prior BTK inhibitor; 60 in primary efficacy analysis.
- Overall response 93%; complete response 67%.
- Estimated 12-month PFS 61%; 12-month OS 83%.
- Grade 3 or higher CRS 15%; grade 3 or higher neurological events 31%.
- Responses seen in high-risk features including TP53 mutation and blastoid morphology.
ZUMA-2 gave patients with BTK-inhibitor-refractory mantle cell lymphoma, who previously had a median survival under a year, a therapy with durable remissions in a substantial fraction. Brexu-cel is now standard after BTK inhibitor failure and CAR-T is being tested earlier in the disease. Neurotoxicity rates are higher than in other lymphoma CAR-T trials.
- Single-arm; no randomised comparison.
- High rates of neurological toxicity, and a treatment-related death rate that requires experienced centres.
- Later real-world data showed lower complete response rates than the trial.
- Long-term durability is limited by late relapses in roughly half of responders.