Pre-transplant MRD negativity and TP53 mutation status determine survival after CAR-T therapy bridged to allo-HSCT for refractory/relapse B-ALL.

Abstract

6556 Background: The feasibility and outcomes of bridging relapsed/refractory (R/R) B-lineage acute lymphoblastic leukemia (B-ALL) patients to allogeneic hematopoietic stem cell transplantation (allo-HSCT) following CAR-T therapy require further investigation. This study evaluated long-term outcomes and prognostic factors in this setting. Methods: We conducted a retrospective analysis of 300 consecutive R/R B-lineage leukemia patients (295 B-ALL, 98.3%) who underwent allo-HSCT after CAR-T therapy. Somatic mutation screening via next-generation sequencing was performed on 179 patients. Univariate Cox regression analyzed factors associated with transplant outcomes. A contemporaneous cohort of 36 transplanted patients without prior CAR-T served as a comparator. Results: Median age at transplant was 14 years (range, 1-68). Prior to HSCT, 220 (73.3%), 75 (25.0%), and 5 (1.7%) patients received CD19-, CD22-, and Mix-CAR-T, respectively; 265 (88.3%) achieved complete remission (CR), and 39 (13.0%) were minimal residual disease (MRD)-positive. The 3-year disease-free survival (DFS), overall survival (OS), cumulative incidence of relapse (CIR), and non-relapse mortality (NRM) for the CAR-T bridging cohort were 64.0% (95%CI, 58.6-69.8%), 74.5% (95%CI, 69.5-79.9%), 28.4% (95%CI, 23.6-34.1%), and 7.6% (95%CI, 5.04-11.3%), respectively. Outcomes did not differ significantly from the non-CAR-T cohort (OS, p=0.54; DFS, p=0.24). Failure to achieve CR pre-HSCT (HR=3.31, p<0.0001) and MRD-positivity (HR=3.69, p<0.0001) were risk factors for relapse, while chronic graft-versus-host disease was protective (HR=0.35, p=0.0002). Pre-HSCT MRD-positivity, fungal infection, and viral cystitis increased NRM risk. TP53 (15.1%), KMT2D (14.5%), NRAS (14.0%), KRAS (13.4%), and ABL1 (9.5%) were the most frequently mutated genes. TP53 mutation was a significant risk factor for inferior DFS (HR=3.37, p<0.0001) and OS (HR=3.56, p<0.0001). GNAS and KDM6A mutations predicted higher CIR, while ETV6 mutation was associated with increased NRM. Conclusions: Bridging to allo-HSCT after CAR-T therapy is a feasible and effective strategy for R/R B-ALL, providing substantial long-term survival. Achieving pre-transplant CR and MRD-negative status is critical for outcome. Somatic mutations, particularly TP53, hold significant prognostic value, aiding in risk stratification and treatment optimization for these patients.