Efficacy of CAR-T cell therapy in chronic lymphocytic leukemia: A meta-analysis

Abstract INTRODUCTION: Chronic Lymphocytic Leukemia (CLL) is the most common type of leukemia in the adult population in western countries with an average age of diagnosis of 69. Although the use of CAR-T cell therapy has revolutionized the treatment of several B-cell malignancies, their clinical development for CLL has faced hurdles due to inferior response rates and short response duration compared to other B-cell malignancies. Given these challenges, this meta-analysis aims to comprehensively evaluate the efficacy of CAR-T cell therapies in CLL and generate more robust evidence to inform and support their clinical application METHODS: A systematic literature search was conducted to identify clinical trials investigating CAR-T cell therapies for CLL. We screened 408 records from PubMed and ASH 2024 abstracts, of which 6 studies (4 clinical trials and 2 ASH abstracts) were included in the final analysis. Using random-effect models, primary outcomes for overall response rate (ORR), complete response (CR) and minimal residual disease (MRD) negativity were reported as pooled proportions with 95% confidence intervals. Applying the median of medians method, pooled estimates for the median duration of response (DOR), median progression-free survival (PFS), and median overall survival (OS) were also reported with 95% confidence intervals. RESULTS: A total of 262 patients across 6 studies were included in the analysis. ORRs were reported in a population of 192 patients across 6 studies. The pooled ORR was 0.608 [95% CI; 0.493; 0.716]. There was moderate heterogeneity between the studies (I2 = 51.8%, Cochran's Q = 10.37 (p-value = 0.0654)). Turtle et al expressed the highest ORR (0.708) of all the 6 studies. The pooled CR reported in 168 patients across 5 studies was 0.288 [95% CI; 0.101; 0.519] with high heterogeneity (I2 = 86.7%, Cochran's Q = 30.08 (p-value < 0.0001)). MRD negativity was reported in 120 patients across 4 studies. The pooled MRD negativity was 0.708 [95% CI; 0.583; 0.820] with lower heterogeneity (I2 = 39.1%, Cochran's Q = 4.93 (p-value = 0.1773)). The pooled estimate for median DOR was 18.9 months [95% CI; 6.4; 18.9], while median PFS and OS were 11.9 months [95% CI; 8.9, 24.6] and 43.2 months [95% CI; 14.4, 43.2]. CONCLUSION: CAR-T cell therapy demonstrates moderate efficacy in treating CLL, with an ORR of 60.8% and CR of 28.8%. Although the MRD negativity rates look promising (70.8%), response durability remains a challenge, as reflected by modest PFS and OS. This highlights the need for continued development and long-term assessment of CAR-T therapy to fully establish its role in CLL management. LIMITATIONS: This study primarily includes phase 1 and 2 trials, which may not accurately reflect real world efficacy. Additionally, since efficacy endpoints in these trials are often secondary objectives, there is a higher risk of bias. The small sample sizes further limit the statistical power of the analysis.