Novel risk stratification of ph-like ALL cohort receiving CD19-directed CAR-T therapy

Abstract

Abstract Background: Preliminary studies, including ours, have demonstrated that CAR-T (CAR19) therapy confers suboptimal therapeutic efficacy in high-risk B-cell acute lymphoblastic leukemia (B-ALL), particularly in cases with IKZF1 deletion (IKZF1DEL) and Ph-like phenotype (2023 EHA oral presentation, 2024 Hemasphere). Yet such findings in the Ph-like ALL cohort lack validation in large cohorts. Here we seek to explore the efficacy of CAR19 therapy in high-risk Ph-like ALL. Method: This multicenter, retrospective cohort study included 75 patients with Ph-like ALL in five centers of China from 2017 to 2023. We collected and analyzed the data of clinical characteristics. The event-free survival (EFS) and overall survival (OS) were investigated. Result: A total of 75 patients with Ph-like ALL receiving CAR19 therapy were enrolled. Patients were aged from 6 to 64 years, with the median follow-up time of 445 days (95%CI: 330-559). This cohort was grouped as ABL-class fusions (11/75, 14.6%; ABL1, ABL2, CSF1R, PDGFRB), CRLF2 positive (16/75, 21.3%; rearrangement or high-expression), EPOR or JAK2 rearrangement (8/75, 10.6%), JAK-STAT pathway mutations (16/75, 21.3%; IL7R, SH2B3, JAK1, JAK3, FLT3), Ras pathway mutations only (24/75, 32%; KRAS, NRAS, PTPN11, NF1). Consistent with our previous study, patients with IKZF1 deletion (24/75, 32%) conferred inferior outcome compared with those without (51/75, 68%), with 1y-EFS 14.1% vs. 71.5%, (P=0.002), and 1y-OS 55.7% vs. 80.8% (P=0.22), respectively. Furthermore, within the IKZF1WT group, CAR19 therapy showed different efficacy among various Ph-like subgroups. Synthesized the above findings, patients were further divided into three groups following the survival difference: Standard Risk (SR, IKZF1WTwith ABL1-class fusion or CRLF2 positive, n=18); Medium Risk (MR, IKZF1WT with JAK-STAT pathway mutation or Ras pathway mutation, n=28), and High Risk (HR, IKZF1WT with EPOR or JAK2 rearrangement and IKZF1DEL, n=29). Results demonstrated that HR group showed significantly worse outcomes compared to the other two groups (1y-EFS 79.6% in SR, 73.2% in MR, 12.7% in HR, respectively, P=0.02; 1y-OS 100% in SR, 73.6% in MR, 54.6% in HR, respectively, P=0.018). Conclusion: This study isolated the highest-risk subgroup of Ph-like ALL for CAR19 therapy, which serves as a valuable prognostic feature in Ph-like ALL.