Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma

Abstract

Background: In a phase 1 trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, showed efficacy in patients with refractory large B-cell lymphoma after the failure of conventional therapy.

Methods: In this multicenter, phase 2 trial, we enrolled 111 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma who had refractory disease despite undergoing recommended prior therapy. Patients received a target dose of 2×10⁶ anti-CD19 CAR T cells per kilogram of body weight after receiving a conditioning regimen of low-dose cyclophosphamide and fludarabine. The primary end point was the rate of objective response (calculated as the combined rates of complete response and partial response). Secondary end points included overall survival, safety, and biomarker assessments.

Results: Among the 111 patients who were enrolled, axi-cel was successfully manufactured for 110 (99%) and administered to 101 (91%). The objective response rate was 82%, and the complete response rate was 54%.With a median follow-up of 15.4 months, 42% of the patients continued to have a response, with 40% continuing to have a complete response. The overall rate of survival at 18 months was 52%. The most common adverse events of grade 3 or higher during treatment were neutropenia (in 78% of the patients), anemia (in 43%), and thrombocytopenia (in 38%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 13% and 28% of the patients, respectively. Three of the patients died during treatment. Higher CAR T-cell levels in blood were associated with response.

Conclusions: In this multicenter study, patients with refractory large B-cell lymphoma who received CAR T-cell therapy with axi-cel had high levels of durable response, with a safety profile that included myelosuppression, the cytokine release syndrome, and neurologic events. (Funded by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program; ZUMA-1 ClinicalTrials.gov number, NCT02348216 .).

Figure 1. Objective Response Rate among the 101 Treated Patients

Panel A shows the objective response rate (ORR; calculated as complete response [CR] plus partial response [PR]) among the patients who received axi-cabtagene ciloleucel (axi-cel), an anti-CD19 chimeric antigen receptor T-cell therapy, as well as the response among the patients with stable disease (SD), disease progression (PD), and those who could not be evaluated (NE). The patients in the modified intention-to-treat population were evaluated according to the two main disease cohorts: diffuse large B-cell lymphoma (DLBCL) and either primary mediastinal large B-cell lymphoma (PMBCL) or transformed follicular lymphoma (TLF). The numbers in parentheses indicate the number of patients who had the specified response. On independent central review, the objective response rate was 71%, including a complete response rate of 51% and a partial response rate of 20%. Panel B shows the subgroup analysis of the objective response rate for key baseline and clinical covariates. Scores on the International Prognostic Index (IPI) include low risk (0 or 1 point), low-intermediate risk (2 points), high-intermediate risk (3 points), and high risk (4 or 5 points). The 95% confidence interval (CI) was calculated with the use of the Clopper–Pearson method. ASCT denotes autologous stem-cell transplantation.

Figure 2. Kaplan–Meier Estimates of the Duration of Response, Progression-free Survival, and Overall Survival

Panel A shows the duration of response, according to investigator assessment, in the 89 study patients who had an objective response, including those with a complete response and those with a partial response. Patients who had a complete response had a longer duration of response than those with an objective or partial response. According to independent central review, the median duration of response was 8.1 months (range, 3.5 to could not be estimated [NE]). Panel B shows the rate of progression-free survival, and Panel C the rate of overall survival in the 108 patients who were treated in the phase 1 and phase 2 studies. Tick marks indicate the time of data censoring at the last follow-up. NR denotes not reached.

Figure 3. CAR T-Cell Expansion and Correlations with Response and Adverse Events

Serial blood samples were analyzed for chimeric antigen receptor (CAR) T-cell levels and serum biomarkers in all 101 patients who were treated with axi-cel, as described previously.21 Panel A shows CAR T-cell expansion and persistence with median values and interquartile ranges (Q1 and Q3). Panel B shows the association between CAR T-cell expansion, which was measured as peak levels of CAR cells per microliter of blood, and the objective response rate, neurologic events, and the cytokine release syndrome. The peak factor change is shown for patients with a response as compared with those without a response, for those with neurologic events of grade 3 or higher, and for those with the cytokine release syndrome of grade 3 or higher. P values were calculated by means of the Wilcoxon rank-sum test. Panel C shows serum biomarkers (interleukin-2, granulocyte–macrophage colony-stimulating factor [GM-CSF], and ferritin) that were associated only with neurologic events and not with the cytokine release syndrome. The peak value is defined as the maximum level of the cytokine after baseline. The peak factor is the value in patients with neurologic events of grade 3 or higher versus those with events of grade 0 to 2. Adjusted P values were calculated with the use of Holm’s procedure after multiple testing by means of the Wilcoxon rank-sum test. In Panels B and C, the horizontal line within each box represents the median, and the lower and upper borders of each box represent the 25th and the 75th percentiles, respectively, and the I bars represent the minimum and maximum range.