CD19 Directed Chimeric Antigen Receptor T Cell Therapy in Acute Lymphoblastic Leukemia: A Systematic Review and Meta-Analysis

Abstract

Introduction Chimeric antigen receptor (CAR) T-cells targeting CD19 have led to complete response (CR) rates of 70-90% in children and adults with refractory/relapsed B-cell acute lymphoblastic leukemia (ALL), which led to their FDA approval in 2017. However, different constructs have been used and the response rates vary among different studies. Toxicities in the form of cytokine release syndrome (CRS) and neurotoxicity remain a challenge. We conducted a systematic review and meta-analysis of all published and presented trials of anti-CD19 CAR T-cells in relapsed/refractory ALL. Objectives 1) To determine the efficacy of anti-CD19 CAR T-cells in ALL. 2) To describe the toxicities of anti-CD19 CAR T-cells in ALL. 3) To examine differences in efficacy and toxicity by age groups and construct type. Methods We searched MEDLINE and EMBASE and included studies that reported raw data on the outcomes of adults and children that were treated with anti-CD19 CAR T-cells for ALL. The random effects model was used to derive estimates of complete response (CR) and progression-free survival (PFS) at 1 year and toxicities. Secondary outcome was minimal residual disease (MRD) at 1 year. We planned subgroup analysis based on age (adults vs. children) and construct type. Results Of 1,139 potentially relevant references, 18 noncomparative trials were included with a total of 573 patients (309 adults and 264 children). Pooled CR was comparable between adults [84% (95 CI 80-86%)] and children [83% (95 CI 79-88%)], but varied by construct [86% (95 CI 82-90%) for 41BB co-stimulated CART cells vs 74% (95 CI 68-81%) for CD28 co-stimulated CART cells vs 86% (95 CI 80-91%) for fourth generation CART cells]. Pooled 1-year PFS was comparable for adults and children [53% (95 CI 31-74%) vs 56% (95 CI 50-65%)]. CRS rates were comparable among adults and children [76% (95 CI 71-81%) vs 72% (95% CI 68-77%)]. CRS was lower in CD28 compared to other constructs [47% (95 CI 41-53%) in CD28 vs 86% (95 CI 82-91%) in 41BB vs 76% (95 CI 69-83%) in fourth generation]. Neurotoxicity occurred more commonly in adults [44% (95 CI 35-54%) vs 17% (95 CI 12-22%)] and in those treated with 41BB compared to those treated with CD28 [34% (95 CI 27-40%) vs 14% (95% CI 9-20%)]. Pooled MRD negativity at 1 year was 77% (95 CI 71-82%) in adults and 82% (95 CI 77-87%) in children. CD28 construct led to lower MRD negativity [62% (95 CI 54-70%) vs 85% (95 CI 81-89%) in 41BB vs 81% (95 CI 69-93%) in fourth generation]. These data are summarized in Figure 1. Conclusions Pooled 1-year CR was 84%, pooled 1-year PFS was 57% and the efficacy of CAR T-cell therapy was comparable between adults and children. Analysis by construct type revealed differences in the efficacy and toxicity between different constructs with CD28 leading to lower efficacy and toxicity. This is the first study to systemically analyze the outcomes of anti-CD19 CAR T-cell therapy in ALL.