KTE-X19 CAR T-Cell Therapy in Relapsed or Refractory Mantle-Cell Lymphoma

Abstract

Background: Patients with relapsed or refractory mantle-cell lymphoma who have disease progression during or after the receipt of Bruton's tyrosine kinase (BTK) inhibitor therapy have a poor prognosis. KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, may have benefit in patients with relapsed or refractory mantle-cell lymphoma.

Methods: In a multicenter, phase 2 trial, we evaluated KTE-X19 in patients with relapsed or refractory mantle-cell lymphoma. Patients had disease that had relapsed or was refractory after the receipt of up to five previous therapies; all patients had to have received BTK inhibitor therapy previously. Patients underwent leukapheresis and optional bridging therapy, followed by conditioning chemotherapy and a single infusion of KTE-X19 at a dose of 2×10⁶ CAR T cells per kilogram of body weight. The primary end point was the percentage of patients with an objective response (complete or partial response) as assessed by an independent radiologic review committee according to the Lugano classification. Per the protocol, the primary efficacy analysis was to be conducted after 60 patients had been treated and followed for 7 months.

Results: A total of 74 patients were enrolled. KTE-X19 was manufactured for 71 patients and administered to 68. The primary efficacy analysis showed that 93% (95% confidence interval [CI], 84 to 98) of the 60 patients in the primary efficacy analysis had an objective response; 67% (95% CI, 53 to 78) had a complete response. In an intention-to-treat analysis involving all 74 patients, 85% had an objective response; 59% had a complete response. At a median follow-up of 12.3 months (range, 7.0 to 32.3), 57% of the 60 patients in the primary efficacy analysis were in remission. At 12 months, the estimated progression-free survival and overall survival were 61% and 83%, respectively. Common adverse events of grade 3 or higher were cytopenias (in 94% of the patients) and infections (in 32%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 15% and 31% of patients, respectively; none were fatal. Two grade 5 infectious adverse events occurred.

Conclusions: 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. (Funded by Kite, a Gilead company; ZUMA-2 ClinicalTrials.gov number, NCT02601313.).

Figure 1.. Objective Response, Duration of Response, Progression-free Survival, and Overall Survival.

Panel A shows the numbers and percentages of patients who had an objective response (complete response or partial response) among the 60 patients who had been treated with KTE-X19 and were included in the primary efficacy analysis. Panel B shows the Kaplan–Meier estimate of the duration of response, as assessed on the basis of review by the independent radiologic review committee, among the 56 patients in the primary efficacy analysis who had a response. Tick marks indicate censored data. Kaplan–Meier estimates of progression-free survival and overall survival among the 60 patients who were included in the primary efficacy analysis are shown in Panels C and D, respectively. NE denotes could not be estimated. CR complete response, ORR objective response rate, PD progressive disease, PR partial response, SD stable disease.

Figure 2.. Subgroup Analysis of Objective Response.

Shown is the analysis of objective response according to key baseline and clinical covariates. The Clopper–Pearson method was used to calculate the 95% confidence interval (not adjusted for multiplicity). Ki-67 is a marker of cellular proliferation, as detected by immunohistochemical testing. Tumor burden was assessed as the sum of the product diameters. The Simplified Mantle Cell Lymphoma International Prognostic Index (MIPI) is used in patients with mantle-cell lymphoma to assess risk on the basis of age, Eastern Cooperative Oncology Group performance-status score, lactate dehydrogenase (LDH) level, and white-cell count. BTK denotes Bruton’s tyrosine kinase, MCL mantle-cell lymphoma, SCT stem-cell transplantation, and ULN upper limit of the normal range.