One-Year Follow-up of ZUMA-2, the Multicenter, Registrational Study of KTE-X19 in Patients with Relapsed/Refractory Mantle Cell Lymphoma

Background: KTE-X19, an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy, is currently being evaluated in patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) who received 1 – 5 prior therapies (including a Bruton tyrosine kinase inhibitor) in the Phase 2, registrational, multicenter ZUMA-2 study. With a median follow-up of 12.3 months, we previously reported an objective response rate (ORR) of 93% (67% complete response [CR] rate) with KTE-X19 treatment in the 60 efficacy-evaluable patients in ZUMA-2 (Wang et al. N Engl J Med. 2020;382:1331). Here, we present an updated analysis of efficacy, safety, and pharmacology for all patients with a minimum follow-up of 1 year.

Methods: Eligible patients with R/R MCL underwent leukapheresis and conditioning chemotherapy followed by a single infusion of KTE-X19 (2 × 10⁶ CAR T cells/kg; Wang et al. N Engl J Med. 2020;382:1331). The primary endpoint was ORR (CR + partial response) as assessed by an Independent Review Committee according to the Lugano Classification (Cheson et al. J Clin Oncol. 2014;32:3059). Efficacy data are reported for the 60 treated patients with ≥ 1 year of follow-up; safety data are presented for all 68 treated patients.

Results: As of December 31, 2019, the median follow-up was 17.5 months (range, 12.3 – 37.6). The ORR was 92% (95% CI, 81.6 – 97.2), with a CR rate of 67% (95% CI, 53.3 – 78.3). Of all efficacy-evaluable patients, 48% had ongoing responses at the data cutoff. Medians were not reached for duration of response, progression-free survival (PFS), or overall survival; 15-month estimates were 58.6% (95% CI, 42.5 – 71.7), 59.2% (95% CI, 44.6 – 71.2), or 76.0% (95% CI, 62.8 – 85.1), respectively. In patients who achieved a CR, the median PFS was not reached (15-month rate, 75.1% [95% CI, 56.8 – 86.5]); in those who achieved a partial response, the median PFS was 3.1 months (95% CI, 2.3 – 5.2). Median PFS was 1.1 months (95% CI, 0.9 – 3.0) in nonresponding patients. The first 28 patients treated had a median follow-up of 32.3 months (range, 30.6 – 37.6); 39.3% of these patients remain in remission with no further therapy.

Common grade ≥ 3 adverse events were neutropenia (85%), thrombocytopenia (53%), anemia (53%), and infections (34%). Grade ≥ 3 cytopenias were reported in 60% of patients ≥ 30 days post-infusion. Grade ≥ 3 cytokine release syndrome (CRS; per Lee et al. [Blood. 2014;124:188]) occurred in 15% of patients; 59% received tocilizumab for management of CRS. Grade ≥ 3 neurologic events (NEs) were reported in 31% of patients, and 38% received steroids for NE management. All CRS events and most NEs (37/43) resolved, as previously reported. There were no Grade 5 CRS events or NEs, and no new Grade 5 events occurred with additional follow-up. As previously reported, there were 2 cases of Grade 2 cytomegalovirus infection, 1 case each of Grade ≥ 3 hypogammaglobulinemia and Grade ≥ 3 tumor lysis syndrome, and no cases of Epstein–Barr virus-associated lymphoproliferation, replication-competent retrovirus, hemophagocytic lymphohistiocytosis, or KTE-X19–related secondary cancers.

Median peak CAR T cell levels and median area under the curve (Days 0 – 28) were 98.9 cells/µL (range, 0.2 – 2565.8) and 1394.9 cells/µL (range, 3.8 – 27,700) in patients with ongoing responses at 12 months, 202.6 cells/µL (range, 1.6 – 2589.5) and 2312.3 cells/µL (range, 19.0 – 27,200) in patients who were relapsed at 12 months, and 0.4 cells/µL (range, 0.2 – 95.9) and 5.5 cells/µL (range, 1.8 – 1089.1) in nonresponders. Of the 57 efficacy-evaluable patients with data available, 84% had B cells detectable by flow cytometry at baseline. Of those in ongoing responses at 12 months, 10 of 26 patients (38%) with evaluable samples had B cells detectable at 3 months, and 10 of 18 (56%) had detectable B cells at 12 months; gene-marked CAR T cells were no longer detectable at 12 months in 5 of 28 evaluable patients (17%).

Conclusions: The ZUMA-2 study continues to demonstrate substantial and durable clinical benefit of KTE-X19 therapy with manageable safety in patients with R/R MCL. Within this patient population, which lacks curative treatment options, most patients achieved durable CR, and no new safety signals were reported. Although early CAR T cell expansion was higher in patients who achieved an objective response, those who later relapsed showed elevated CAR T cell levels pointing to alternate mechanisms of secondary treatment failure in MCL.