Three-Year Follow-Up of KTE-X19 in Patients With Relapsed/Refractory Mantle Cell Lymphoma, Including High-Risk Subgroups, in the ZUMA-2 Study

Abstract

PURPOSE Brexucabtagene autoleucel (KTE-X19) autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is approved for the treatment of relapsed/refractory mantle cell lymphoma (MCL). Outcomes after a 3-year follow-up in the pivotal ZUMA-2 study of KTE-X19 in relapsed/refractory MCL are reported, including for subgroups by prior therapy (bendamustine and type of Bruton tyrosine kinase inhibitor [BTKi]) or high-risk characteristics. METHODS Patients with relapsed/refractory MCL (one to five prior therapies, including prior BTKi exposure) received a single infusion of KTE-X19 (2 × 106 CAR T cells/kg). RESULTS After a median follow-up of 35.6 months, the objective response rate among all 68 treated patients was 91% (95% CI, 81.8 to 96.7) with 68% complete responses (95% CI, 55.2 to 78.5); medians for duration of response, progression-free survival, and overall survival were 28.2 months (95% CI, 13.5 to 47.1), 25.8 months (95% CI, 9.6 to 47.6), and 46.6 months (95% CI, 24.9 to not estimable), respectively. Post hoc analyses showed that objective response rates and ongoing response rates were consistent among prespecified subgroups by prior BTKi exposure or high-risk characteristics. In an exploratory analysis, patients with prior bendamustine benefited from KTE-X19, but showed a trend toward attenuated T-cell functionality, with more impact of bendamustine given within 6 versus 12 months of leukapheresis. Late-onset toxicities were infrequent; only 3% of treatment-emergent adverse events of interest in ZUMA-2 occurred during this longer follow-up period. Translational assessments revealed associations with long-term benefits of KTE-X19 including high-peak CAR T-cell expansion in responders and the predictive value of minimal residual disease for relapse. CONCLUSION These data, representing the longest follow-up of CAR T-cell therapy in patients with MCL to date, suggest that KTE-X19 induced durable long-term responses with manageable safety in patients with relapsed/refractory MCL and may also benefit those with high-risk characteristics.

Addendum to British Society for Haematology Guideline for the management of mantle cell lymphoma, 2018 (Br. J. Haematol. 2018; 182: 46–62): Risk assessment of potential CAR T candidates receiving a covalent Bruton tyrosine kinase inhibitor for relapsed/refractory disease

“…Tecartus, an autologous CD19‐targeting CAR T‐cell therapy, has been granted conditional marketing authorisation by the European Medicines Agency (EMA) for relapsed or refractory MCL after two lines of therapy, including a BTKi. The ZUMA‐2 study reported impressive initial responses (overall response 93%, complete response 67%) with 37% of evaluable patients in ongoing response at a median follow‐up of 35.6 months 3,4 . Overall initial responses in high‐risk disease such as pleomorphic/blastoid morphology, TP53 mutations or Ki‐67 proliferation index ≥50% appeared comparable but small numbers preclude valid conclusions.…”

“…The ZUMA-2 study reported impressive initial responses (overall response 93%, complete response 67%) with 37% of evaluable patients in ongoing response at a median follow-up of 35.6 months. 3,4 Overall initial responses in high-risk disease such as pleomorphic/blastoid morphology, TP53 mutations or Ki-67 proliferation index ≥50% appeared comparable but small numbers preclude valid conclusions. Significant adverse events of grade 3 or higher included cytokine release syndrome (15%), neurological events (31%) and infection (32%).…”

CAR T-Based Therapies in Lymphoma: A Review of Current Practice and Perspectives

“…Two recent multicenter trials have shown clear clinical benefits from brexucabtagene autoleucel (brexu-cel) and liso-cel in r/r MCL. ZUMA-2 enrolled 74 patients with heavily pretreated r/r MCL, the vast majority failing or relapsing after BTKi [ 54 ]. The impressive ORR of 85% and CR of 59% seen in the intention-to-treat analysis led to FDA approval of brexu-cel for this indication ( Table 1 and Table 2 ).…”

Current and Future Perspectives for Chimeric Antigen Receptor T Cells Development in Poland

“…The difference is in the manufacturing process which in case brexucabtagene autoleucel involves the removal of CD19-expressing cells from the population of CAR-T cells [ 22 ]. In a three-year follow-up study ORR for patients with MCL was found to be 91%, while CRR was 68% [ 27 ].…”