HAEMATOLOGICAL CANCER

KTE-X19 active in MCL

The survival outcomes of patients with relapsed and/or refractory mantle-cell lymphoma (MCL) after receiving BTK inhibitors are poor; therefore, new treatment options are needed for these patients. Chimeric antigen receptor (CAR) T cell therapies targeting CD19 have demonstrated efficacy in several subtypes of B cell lymphomas, although limited results in patients with MCL have been reported. Now data from the ZUMA-2 trial reveal promising activity of the anti-CD19 CAR T cell product KTE-X19 against MCL.

In ZUMA-2, KTE-X19 was successfully manufactured for 71 of 74 patients with relapsed and/or refractory MCL. A high content of leukaemic blasts in peripheral blood has been proposed as the cause of failed manufacturing of CAR T cells because it results in proportionally low numbers of non-exhausted T cells in the starting cell population. During the manufacturing of KTE-X19, circulating CD19+ malignant cells were removed in order to address this issue by reducing the potential activation and exhaustion of anti-CD19 CAR T cells in the ex vivo portion of the process.

KTE-X19 was administered to 68 patients. Among 60 patients with at least 7 months of follow-up monitoring, the objective response rate (ORR) was 93%, with a complete response (CR) rate of 67%. ORRs were consistent across patient subgroups, including those with high-risk disease. At a median of 12.3 months, 57% of the 60 patients and 78% of those with a CR had an ongoing response. Of note, all these patients received a single infusion of KTE-X19.

Exploratory analyses of minimal residual disease revealed that 24 of 29 patients (83%) and 15 of 19 patients (79%) had no detectable residual disease at 4 weeks and 6 months, respectively. The 12-month progression-free survival and overall survival estimates were 61% and 83%, respectively.

Grade ≥3 adverse events (AEs) occurred in 99% of 68 patients, the most common of which were cytopenias (94%) and infections (32%). Grade 1–2 and ≥3 cytokine-release syndrome (CRS) occurred in 76% and 15% of patients, respectively. Two infectious AEs were fatal. All CRS events resolved with treatment within a median of 11 days. Grade 1–2 and ≥3 neurological AEs occurred in 32% and 31% of patients. These events resolved with treatment in 37 of 43 patients (86%) at a median of 12 days. No deaths resulted from CRS or neurological AEs.

In conclusion, the results of ZUMA-2 indicate that patients with relapsed and/or refractory MCL can derive clinical benefit from CAR T cells, although at the expense of a high risk of toxicities. The majority of AEs reported in this trial were manageable. Moreover, the toxicity profile of KTE-X19 was deemed similar to that of the CAR T cell products used to treat patients with other B cell lymphomas. Longer follow-up results will help to determine the durability of these responses; in addition, the results of other trials of CAR T cell products in patients with MCL are eagerly awaited.

References

Original article

  1. Wang, M. et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N. Engl. J. Med. 383, 1331–1342 (2020)

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Correspondence to Diana Romero.

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Romero, D. KTE-X19 active in MCL. Nat Rev Clin Oncol 17, 336 (2020). https://doi.org/10.1038/s41571-020-0373-3

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