Clinical Outcomes of Patients with Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia Receiving Autologous Chimeric Antigen Receptor T-Cell Therapy: A Meta-Analysis of 1,154 Patients Included in Clinical Trials

Introduction: Chimeric antigen receptor (CAR) T-cell therapy has improved the outcome of patients (pts) with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (ALL). Several CAR T-cell constructs are being studied in this setting and 2 of them have already been approved. However, most of the data come from single-arm phase 1/2 clinical trials with a limited number of pts. In the absence of randomized trials, other comparative approaches are warranted to understand the differential benefits of these products and to identify risk factors associated with disease outcomes. Therefore, we conducted a meta-analysis to assess safety and efficacy of ALL pts treated with CAR T-cell therapy in clinical trials.

Methods: A systematic review was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement. PubMed database was used to identify potential eligible published studies. We included trials with R/R B-cell ALL pts receiving a single autologous CAR T-cell product. The co-primary endpoint was i) overall response rate (ORR) including pts in morphological complete remission with (CR) or without (CRi) hematological recovery and ii) percentage of MRD negativity (MRD-neg). MRD-neg was considered following each trial definition. Random-effect models using the DerSimonian-Laird method were used to provide pooled results.

Results:

Among the initial 87 trials identified with the pre-established search criteria, 30 trials involving 1,154 pts met the eligibility criteria and were included in the analysis. Overall, 22 trials targeted CD19 (CD19-CAR), 5 targeted CD22 (CD22-CAR) and 3 targeted both CD19/CD22 (CD19/22-CAR). The most common costimulatory domain (CD) was 4-1BB (67%), followed by CD28 (20%). Most trials included both pediatric and adult pts (60%) and 32% had received a previous allogeneic stem cell transplantation.

The pooled ORR and MRD-neg response across the 30 trials were 81% (95%CI 77-86) and 73% (95%CI 67–78), respectively. Pts receiving CD19-CAR or CD19/22-CAR showed a higher percentage of MRD-neg responses compared with those treated with CD22-CAR (74% and 85% vs 60%, respectively). Similarly, trials including CAR-T naïve pts reported higher MRD-neg responses than those including pts with prior CAR T-cell treatment (75% vs 61%). Regarding patient age and type of CD, the percentage of MRD-neg responses was higher in trials including pediatric pts only compared with those including adults or both (82% vs. 71% vs. 72%), and in products using 4-1BB as CD compared to CD28 (74% vs. 58%).

To limit heterogeneity, we then focused on trials that exclusively used CD19-CAR (n=22). Again, trials that included only CAR-T naive pts reported higher ORR and MRD-neg CR compared to those that included CAR-T exposed pts (83%/75% vs. 74%/46%). Similarly, trials using 4-1BB as the CD showed better outcomes compared to those using CD28 (83%/77% vs. 79%/58%).

In trials with overall survival (OS) results (n=20, 67% of the trials), median OS was not reached in 5 trials and ranged from 7.2 to 23.7 months in the other 15 trials, with a median OS of 14.6 months (IQR, 12.9 - 17.18). Relapse-free survival (RFS) or event-free survival (EFS) was detailed in 18 trials. The median RFS/EFS ranged from 2.53 to 15.2 months, with a median of 6.1 months (IQR, 4.23 - 11.24).

In terms of safety, all-grade and grade ≥3 CRS occurred in 85% (95% CI 78-90) and 15% (95% CI 10-22) of pts, respectively. The prevalence of all-grade CRS was similar between CD19-CAR and CD22-CAR (85% vs. 87%), but grade ≥3 CRS was more frequent with CD19-CAR (20% vs. 7%, respectively). A similar prevalence of all grade and grade ≥3 CRS was observed with 4-1BB and CD28 products. Regarding ICANS, the estimates were 25% (95% CI 18-34) for all grades and 9% (95% CI 6-15) for grades ≥3. Pts receiving CD19-CAR had a higher prevalence of grade ≥ 3 ICANS compared with those receiving CD22-CAR (14% vs 3%). Additionally, pts treated with CAR T-cells using CD28 as CD had a higher prevalence of grade ≥3 ICANS than those using 4-1BB (17% vs 9%, respectively).

Conclusions: This pooled analysis of 1,154 pts with R/R ALL treated with CAR T-cells confirms the encouraging efficacy and manageable toxicity profile of this therapy. Products using 4-1BB as CD showed better efficacy and safety outcomes than those using CD28. Additionally, CD22-CAR demonstrated a better toxicity profile but lower efficacy compared to CD19-CAR.