In a phase II trial reported in The New England Journal of Medicine, Michael Wang, MD, and colleagues found that the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy KTE-X19 produced a high response rate in patients with relapsed or refractory mantle cell lymphoma who had received previous Bruton’s tyrosine kinase (BTK) inhibitor therapy.
Michael Wang, MD
As stated by the authors, treatment was associated with severe toxicity similar to that observed in prior studies of anti-CD19 CAR T-cell therapies in aggressive B-cell lymphoma.
Study Details
The ZUMA-2 study, conducted at sites in the United States and Europe, enrolled 74 patients who had received up to five prior lines of therapy that included anthracycline- or bendamustine-containing chemotherapy, an anti-CD20 monoclonal antibody, and BTK inhibitor treatment with ibrutinib or acalabrutinib. Patients underwent leukapheresis and optional bridging therapy (37% of patients) followed by conditioning chemotherapy and a single infusion of KTE-X19 at 2×106 CAR T cells/kg. The primary endpoint was percentage of patients with objective response on independent radiologic review using the Lugano classification. The primary efficacy analysis was conducted after 60 patients had been treated and followed for 7 months.
Responses
KEY POINTS
- In the primary efficacy analysis, objective response was observed in 56 (93%) of 60 patients, with complete response in 40 (67%).
- Among the 68 patients who received treatment, grade ≥ 3 cytopenias occurred in 94%, including neutropenia in 85%, thrombocytopenia in 51%, and anemia in 50%; 26% had cytopenias at > 90 days after KTE-X19 administration.
Among the 74 enrolled patients, KTE-X19 was manufactured for 71 patients; 68 received treatment. In the primary efficacy analysis, objective response was observed in 56 (93%) of 60 patients, with complete response in 40 (67%). The median time to initial response was 1.0 month. Median duration of response was not reached (95% confidence interval = 8.6 months–not estimable). At a median follow-up of 12.3 months (range = 7.0–32.3 months), 57% of the patients in the primary efficacy analysis and 78% of those with complete response were in remission. At 12 months, estimated progression-free and overall survival rates were 61% and 83%. Median progression-free and overall survival had not been reached at time of analysis. In intention-to-treat analysis among all enrolled patients, response was observed in 85%, with complete response in 59%.
Toxicity
Among the 68 patients who received treatment, grade ≥ 3 cytopenias occurred in 94%, including neutropenia in 85%, thrombocytopenia in 51%, and anemia in 50%; 26% had cytopenias at > 90 days after KTE-X19 administration. Additional grade ≥ 3 toxicities included infections in 32% of patients (pneumonia in nine patients), cytokine release syndrome in 15% (no fatal cases), and neurologic events in 31% (no fatal cases). Serious adverse events occurred in 68% of patients. Adverse events led to death in two patients, consisting of organizing pneumonia related to conditioning chemotherapy in one patient and staphylococcal bacteremia related to conditioning chemotherapy and KTE-X19 therapy in the other.
The investigators concluded, “KTE-X19 induced durable remissions in a majority of patients with relapsed or refractory mantle cell lymphoma. The therapy led to serious and life-threatening toxic effects that were consistent with those reported with other CAR T-cell therapies.”
Disclosure: The study was funded by Kite, a Gilead company. For full disclosures of the study authors, visit nejm.org.
